Lung Cancer

Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC). Many patients are unable to undergo a biopsy safely because of poor pulmonary function or underlying emphysema and are then empirically treated with radiotherapy if they meet criteria. In these patients, local control can be achieved with SABR with minimal toxicity.¹ Considering that median overall survival (OS) among patients with untreated stage I NSCLC has been reported to be as low as 9 months, early treatment with SABR could lead to increased survival of 29 to 60 months.^2-4

The RTOG 0236 trial showed a median OS of 48 months and the randomized phase III CHISEL trial showed a median OS of 60 months; however, these survival data were reported in patients who were able to safely undergo a biopsy and had confirmed NSCLC.^4,5 For patients without a diagnosis confirmed by biopsy and who are treated with empiric SABR, patient factors that influence radiation toxicity and OS are not well defined.

It is not clear if empiric radiation benefits survival or if treatment causes decline in lung function, considering that underlying chronic lung disease precludes these patients from biopsy. The purpose of this study was to evaluate the factors associated with radiation toxicity with empiric SABR and to evaluate OS in this population without a biopsy-confirmed diagnosis.

Methods

This was a single center retrospective review of patients treated at the radiation oncology department at the Kansas City Veterans Affairs Medical Center from August 2014 to February 2019. Data were collected on 69 patients with pulmonary nodules identified by chest computed tomography (CT) and/or positron emission tomography (PET)-CT that were highly suspicious for primary NSCLC.

These patients were presented at a multidisciplinary meeting that involved pulmonologists, oncologists, radiation oncologists, and thoracic surgeons. Patients were deemed to be poor candidates for biopsy because of severe underlying emphysema, which would put them at high risk for pneumothorax with a percutaneous needle biopsy, or were unable to tolerate general anesthesia for navigational bronchoscopy or surgical biopsy because of poor lung function. These patients were diagnosed with presumed stage I NSCLC using the criteria: minimum of 2 sequential CT scans with enlarging nodule; absence of metastases on PET-CT; the single nodule had to be fluorodeoxyglucose avid with a minimum standardized uptake value of 2.5, and absence of clinical history or physical examination consistent with small cell lung cancer or infection.

After a consensus was reached that patients met these criteria, individuals were referred for empiric SABR. Follow-up visits were at 1 month, 3 months, and every 6 months. Variables analyzed included: patient demographics, pre- and posttreatment pulmonary function tests (PFT) when available, pre-treatment oxygen use, tumor size and location (peripheral, central, or ultra-central), radiation doses, and grade of toxicity as defined by Human and Health Services Common Terminology Criteria for Adverse Events version 5.0 (dyspnea and cough both counted as pulmonary toxicity): acute ≤ 90 days and late > 90 days (Table 1).

Results

The median follow-up was 18 months (range, 1 to 54). The median age was 71 years (range, 59 to 95) (Table 2). Most patients (97.1%) were male. The majority of patients (79.4%) had a 0 or 1 for the Eastern Cooperative Oncology group performance status, indicating fully active or restricted in physically strenuous activity but ambulatory and able to perform light work. All patients were either current or former smokers with an average pack-year history of 69.4. Only 11.6% of patients had operable disease, but received empiric SABR because they declined surgery. Four patients did not have pretreatment spirometry available and 37 did not have pretreatment diffusing capacity for carbon monoxide (DLCO) data.

Most patients had a pretreatment forced expiratory volume during the first seconds (FEV₁) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).

Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).

Discussion

SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.⁶ Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.⁷ Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.¹ These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).³ Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).⁸ With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.⁴

Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.⁹ They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.^10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV₁ (5.8%) and DLCO (6%) at 2 years.¹²

Limitations

Our study is limited by caveats of a retrospective study and its small sample size, but is in line with the reported literature (ranging from 33 to 88 patients).^1,7,8 Another limitation is that data on pretreatment DLCO was missing in 37 patients and the lack of statistical robustness in terms of the smaller inoperable cohort, which limits the analyses of these factors in regards to anticipated morbidity from SABR. Also, given this is data collected from the US Department of Veterans Affairs, only 3% of our sample was female.

Conclusions

Empiric SABR for patients with presumed early-stage NSCLC appears to be safe and might positively impact OS. Development of any acute toxicity grade ≥ 2 was significantly associated with dependence on supplemental oxygen before treatment, central tumor location, and development of new oxygen requirement. No association was found in patients with poor pulmonary function before treatment because we could not find a FEV₁ or DLCO cutoff that could preclude patients from empiric SABR. Considering the poor survival of untreated early-stage NSCLC, coupled with the efficacy and safety of empiric SABR for those with presumed disease, definitive SABR should be offered selectively within this patient population.

Acknowledgments

Drs. Park, Whiting and Castillo contributed to data collection. Drs. Park, Govindan and Castillo contributed to the statistical analysis and writing the first draft and final manuscript. Drs. Park, Govindan, Huang, and Reddy contributed to the discussion section.

Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC). Many patients are unable to undergo a biopsy safely because of poor pulmonary function or underlying emphysema and are then empirically treated with radiotherapy if they meet criteria. In these patients, local control can be achieved with SABR with minimal toxicity.¹ Considering that median overall survival (OS) among patients with untreated stage I NSCLC has been reported to be as low as 9 months, early treatment with SABR could lead to increased survival of 29 to 60 months.^2-4

The RTOG 0236 trial showed a median OS of 48 months and the randomized phase III CHISEL trial showed a median OS of 60 months; however, these survival data were reported in patients who were able to safely undergo a biopsy and had confirmed NSCLC.^4,5 For patients without a diagnosis confirmed by biopsy and who are treated with empiric SABR, patient factors that influence radiation toxicity and OS are not well defined.

It is not clear if empiric radiation benefits survival or if treatment causes decline in lung function, considering that underlying chronic lung disease precludes these patients from biopsy. The purpose of this study was to evaluate the factors associated with radiation toxicity with empiric SABR and to evaluate OS in this population without a biopsy-confirmed diagnosis.

Methods

This was a single center retrospective review of patients treated at the radiation oncology department at the Kansas City Veterans Affairs Medical Center from August 2014 to February 2019. Data were collected on 69 patients with pulmonary nodules identified by chest computed tomography (CT) and/or positron emission tomography (PET)-CT that were highly suspicious for primary NSCLC.

These patients were presented at a multidisciplinary meeting that involved pulmonologists, oncologists, radiation oncologists, and thoracic surgeons. Patients were deemed to be poor candidates for biopsy because of severe underlying emphysema, which would put them at high risk for pneumothorax with a percutaneous needle biopsy, or were unable to tolerate general anesthesia for navigational bronchoscopy or surgical biopsy because of poor lung function. These patients were diagnosed with presumed stage I NSCLC using the criteria: minimum of 2 sequential CT scans with enlarging nodule; absence of metastases on PET-CT; the single nodule had to be fluorodeoxyglucose avid with a minimum standardized uptake value of 2.5, and absence of clinical history or physical examination consistent with small cell lung cancer or infection.

After a consensus was reached that patients met these criteria, individuals were referred for empiric SABR. Follow-up visits were at 1 month, 3 months, and every 6 months. Variables analyzed included: patient demographics, pre- and posttreatment pulmonary function tests (PFT) when available, pre-treatment oxygen use, tumor size and location (peripheral, central, or ultra-central), radiation doses, and grade of toxicity as defined by Human and Health Services Common Terminology Criteria for Adverse Events version 5.0 (dyspnea and cough both counted as pulmonary toxicity): acute ≤ 90 days and late > 90 days (Table 1).

Results

The median follow-up was 18 months (range, 1 to 54). The median age was 71 years (range, 59 to 95) (Table 2). Most patients (97.1%) were male. The majority of patients (79.4%) had a 0 or 1 for the Eastern Cooperative Oncology group performance status, indicating fully active or restricted in physically strenuous activity but ambulatory and able to perform light work. All patients were either current or former smokers with an average pack-year history of 69.4. Only 11.6% of patients had operable disease, but received empiric SABR because they declined surgery. Four patients did not have pretreatment spirometry available and 37 did not have pretreatment diffusing capacity for carbon monoxide (DLCO) data.

Most patients had a pretreatment forced expiratory volume during the first seconds (FEV₁) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).

Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).

Discussion

SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.⁶ Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.⁷ Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.¹ These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).³ Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).⁸ With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.⁴

Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.⁹ They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.^10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV₁ (5.8%) and DLCO (6%) at 2 years.¹²

Limitations

Our study is limited by caveats of a retrospective study and its small sample size, but is in line with the reported literature (ranging from 33 to 88 patients).^1,7,8 Another limitation is that data on pretreatment DLCO was missing in 37 patients and the lack of statistical robustness in terms of the smaller inoperable cohort, which limits the analyses of these factors in regards to anticipated morbidity from SABR. Also, given this is data collected from the US Department of Veterans Affairs, only 3% of our sample was female.

Conclusions

Empiric SABR for patients with presumed early-stage NSCLC appears to be safe and might positively impact OS. Development of any acute toxicity grade ≥ 2 was significantly associated with dependence on supplemental oxygen before treatment, central tumor location, and development of new oxygen requirement. No association was found in patients with poor pulmonary function before treatment because we could not find a FEV₁ or DLCO cutoff that could preclude patients from empiric SABR. Considering the poor survival of untreated early-stage NSCLC, coupled with the efficacy and safety of empiric SABR for those with presumed disease, definitive SABR should be offered selectively within this patient population.

Acknowledgments

Drs. Park, Whiting and Castillo contributed to data collection. Drs. Park, Govindan and Castillo contributed to the statistical analysis and writing the first draft and final manuscript. Drs. Park, Govindan, Huang, and Reddy contributed to the discussion section.

Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage non-small cell lung cancer (NSCLC). Many patients are unable to undergo a biopsy safely because of poor pulmonary function or underlying emphysema and are then empirically treated with radiotherapy if they meet criteria. In these patients, local control can be achieved with SABR with minimal toxicity.¹ Considering that median overall survival (OS) among patients with untreated stage I NSCLC has been reported to be as low as 9 months, early treatment with SABR could lead to increased survival of 29 to 60 months.^2-4

The RTOG 0236 trial showed a median OS of 48 months and the randomized phase III CHISEL trial showed a median OS of 60 months; however, these survival data were reported in patients who were able to safely undergo a biopsy and had confirmed NSCLC.^4,5 For patients without a diagnosis confirmed by biopsy and who are treated with empiric SABR, patient factors that influence radiation toxicity and OS are not well defined.

It is not clear if empiric radiation benefits survival or if treatment causes decline in lung function, considering that underlying chronic lung disease precludes these patients from biopsy. The purpose of this study was to evaluate the factors associated with radiation toxicity with empiric SABR and to evaluate OS in this population without a biopsy-confirmed diagnosis.

Methods

This was a single center retrospective review of patients treated at the radiation oncology department at the Kansas City Veterans Affairs Medical Center from August 2014 to February 2019. Data were collected on 69 patients with pulmonary nodules identified by chest computed tomography (CT) and/or positron emission tomography (PET)-CT that were highly suspicious for primary NSCLC.

These patients were presented at a multidisciplinary meeting that involved pulmonologists, oncologists, radiation oncologists, and thoracic surgeons. Patients were deemed to be poor candidates for biopsy because of severe underlying emphysema, which would put them at high risk for pneumothorax with a percutaneous needle biopsy, or were unable to tolerate general anesthesia for navigational bronchoscopy or surgical biopsy because of poor lung function. These patients were diagnosed with presumed stage I NSCLC using the criteria: minimum of 2 sequential CT scans with enlarging nodule; absence of metastases on PET-CT; the single nodule had to be fluorodeoxyglucose avid with a minimum standardized uptake value of 2.5, and absence of clinical history or physical examination consistent with small cell lung cancer or infection.

After a consensus was reached that patients met these criteria, individuals were referred for empiric SABR. Follow-up visits were at 1 month, 3 months, and every 6 months. Variables analyzed included: patient demographics, pre- and posttreatment pulmonary function tests (PFT) when available, pre-treatment oxygen use, tumor size and location (peripheral, central, or ultra-central), radiation doses, and grade of toxicity as defined by Human and Health Services Common Terminology Criteria for Adverse Events version 5.0 (dyspnea and cough both counted as pulmonary toxicity): acute ≤ 90 days and late > 90 days (Table 1).

Results

The median follow-up was 18 months (range, 1 to 54). The median age was 71 years (range, 59 to 95) (Table 2). Most patients (97.1%) were male. The majority of patients (79.4%) had a 0 or 1 for the Eastern Cooperative Oncology group performance status, indicating fully active or restricted in physically strenuous activity but ambulatory and able to perform light work. All patients were either current or former smokers with an average pack-year history of 69.4. Only 11.6% of patients had operable disease, but received empiric SABR because they declined surgery. Four patients did not have pretreatment spirometry available and 37 did not have pretreatment diffusing capacity for carbon monoxide (DLCO) data.

Most patients had a pretreatment forced expiratory volume during the first seconds (FEV₁) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).

Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).

Discussion

SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.⁶ Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.⁷ Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.¹ These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).³ Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).⁸ With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.⁴

Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.⁹ They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.^10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV₁ (5.8%) and DLCO (6%) at 2 years.¹²

Limitations

Our study is limited by caveats of a retrospective study and its small sample size, but is in line with the reported literature (ranging from 33 to 88 patients).^1,7,8 Another limitation is that data on pretreatment DLCO was missing in 37 patients and the lack of statistical robustness in terms of the smaller inoperable cohort, which limits the analyses of these factors in regards to anticipated morbidity from SABR. Also, given this is data collected from the US Department of Veterans Affairs, only 3% of our sample was female.

Conclusions

Empiric SABR for patients with presumed early-stage NSCLC appears to be safe and might positively impact OS. Development of any acute toxicity grade ≥ 2 was significantly associated with dependence on supplemental oxygen before treatment, central tumor location, and development of new oxygen requirement. No association was found in patients with poor pulmonary function before treatment because we could not find a FEV₁ or DLCO cutoff that could preclude patients from empiric SABR. Considering the poor survival of untreated early-stage NSCLC, coupled with the efficacy and safety of empiric SABR for those with presumed disease, definitive SABR should be offered selectively within this patient population.

Acknowledgments

Drs. Park, Whiting and Castillo contributed to data collection. Drs. Park, Govindan and Castillo contributed to the statistical analysis and writing the first draft and final manuscript. Drs. Park, Govindan, Huang, and Reddy contributed to the discussion section.

Sharing their personal experiences on social media can emphasize oncologists’ humanity and have substantive, beneficial effects on patient care, according to a presentation at the Collaboration for Outcomes using Social Media in Oncology (COSMO) inaugural meeting.

Mark A. Lewis, MD, explained to the COSMO meeting audience how storytelling on social media can educate and engage patients, advocates, and professional colleagues – advancing knowledge, dispelling misinformation, and promoting clinical research.

Dr. Lewis, an oncologist at Intermountain Healthcare in Salt Lake City, reflected on the bifid roles of oncologists as scientists engaged in life-long learning and humanists who can internalize and appreciate the unique character and circumstances of their patients.

Patients who have serious illnesses are necessarily aggregated by statistics. However, in an essay published in 2011, Dr. Lewis noted that “each individual patient partakes in a unique, irreproducible experiment where n = 1” (J Clin Oncol. 2011 Aug 1;29[22]:3103-4).

Dr. Lewis highlighted the duality of individual data points on a survival curve as descriptors of common disease trajectories and treatment effects. However, those data points also conceal important narratives regarding the most highly valued aspects of the doctor-patient relationship and the impact of cancer treatment on patients’ lives.

In referring to the futuristic essay “Ars Brevis,” Dr. Lewis contrasted the humanism of oncology specialists in the present day with the fictional image of data-regurgitating robots programmed to maximize the efficiency of each patient encounter (J Clin Oncol. 2013 May 10;31[14]:1792-4).

Dr. Lewis reminded attendees that to practice medicine without using both “head and heart” undermines the inherent nature of medical care.

Unfortunately, that perspective may not match the public perception of oncologists. Dr. Lewis described his experience of typing “oncologists are” into an Internet search engine and seeing the auto-complete function prompt words such as “criminals,” “evil,” “murderers,” and “confused.”

Obviously, it is hard to establish a trusting patient-doctor relationship if that is the prima facie perception of the oncology specialty.
 

Dispelling myths and creating community via social media

A primary goal of consultation with a newly-diagnosed cancer patient is for the patient to feel that the oncologist will be there to take care of them, regardless of what the future holds.

Dr. Lewis has found that social media can potentially extend that feeling to a global community of patients, caregivers, and others seeking information relevant to a cancer diagnosis. He believes that oncologists have an opportunity to dispel myths and fears by being attentive to the real-life concerns of patients.

Dr. Lewis took advantage of this opportunity when he underwent a Whipple procedure (pancreaticoduodenectomy) for a pancreatic neuroendocrine tumor. He and the hospital’s media services staff “live-tweeted” his surgery and recovery.

With those tweets, Dr. Lewis demystified each step of a major surgical procedure. From messages he received on social media, Dr. Lewis knows he made the decision to have a Whipple procedure more acceptable to other patients.

His personal medical experience notwithstanding, Dr. Lewis acknowledged that every patient’s circumstances are unique.

Oncologists cannot possibly empathize with every circumstance. However, when they show sensitivity to personal elements of the cancer experience, they shed light on the complicated role they play in patient care and can facilitate good decision-making among patients across the globe.
 

Social media for professional development and patient care

The publication of his 2011 essay was gratifying for Dr. Lewis, but the finite number of comments he received thereafter illustrated the rather limited audience that traditional academic publications have and the laborious process for subsequent interaction (J Clin Oncol. 2011 Aug 1;29[22]:3103-4).

First as an observer and later as a participant on social media, Dr. Lewis appreciated that teaching points and publications can be amplified by global distribution and the potential for informal bidirectional communication.

Social media platforms enable physicians to connect with a larger audience through participative communication, in which users develop, share, and react to content (N Engl J Med. 2009 Aug 13;361[7]:649-51).

Dr. Lewis reflected on how oncologists are challenged to sort through the thousands of oncology-focused publications annually. Through social media, one can see the studies on which the experts are commenting and appreciate the nuances that contextualize the results. Focused interactions with renowned doctors, at regular intervals, require little formality.

Online journal clubs enable the sharing of ideas, opinions, multimedia resources, and references across institutional and international borders (J Gen Intern Med. 2014 Oct;29[10]:1317-8).
 

Social media in oncology: Accomplishments and promise

The development of broadband Internet, wireless connectivity, and social media for peer-to-peer and general communication are among the major technological advances that have transformed medical communication.

As an organization, COSMO aims to describe, understand, and improve the use of social media to increase the penetration of evidence-based guidelines and research insights into clinical practice (Future Oncol. 2017 Jun;13[15]:1281-5).

At the inaugural COSMO meeting, areas of progress since COSMO’s inception in 2015 were highlighted, including:

• The involvement of cancer professionals and advocates in multiple distinctive platforms.
• The development of hashtag libraries to aggregate interest groups and topics.
• The refinement of strategies for engaging advocates with attention to inclusiveness.
• A steady trajectory of growth in tweeting at scientific conferences.

An overarching theme of the COSMO meeting was “authenticity,” a virtue that is easy to admire but requires conscious, consistent effort to achieve.

Disclosure of conflicts of interest and avoiding using social media simply as a recruitment tool for clinical trials are basic components of accurate self-representation.

In addition, Dr. Lewis advocated for sharing personal experiences in a component of social media posts so oncologists can show humanity as a feature of their professional online identity and inherent nature.

Dr. Lewis disclosed consultancy with Medscape/WebMD, which are owned by the same parent company as MDedge. He also disclosed relationships with Foundation Medicine, Natera, Exelixis, QED, HalioDX, and Ipsen.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Sharing their personal experiences on social media can emphasize oncologists’ humanity and have substantive, beneficial effects on patient care, according to a presentation at the Collaboration for Outcomes using Social Media in Oncology (COSMO) inaugural meeting.

Mark A. Lewis, MD, explained to the COSMO meeting audience how storytelling on social media can educate and engage patients, advocates, and professional colleagues – advancing knowledge, dispelling misinformation, and promoting clinical research.

Dr. Lewis, an oncologist at Intermountain Healthcare in Salt Lake City, reflected on the bifid roles of oncologists as scientists engaged in life-long learning and humanists who can internalize and appreciate the unique character and circumstances of their patients.

Patients who have serious illnesses are necessarily aggregated by statistics. However, in an essay published in 2011, Dr. Lewis noted that “each individual patient partakes in a unique, irreproducible experiment where n = 1” (J Clin Oncol. 2011 Aug 1;29[22]:3103-4).

Dr. Lewis highlighted the duality of individual data points on a survival curve as descriptors of common disease trajectories and treatment effects. However, those data points also conceal important narratives regarding the most highly valued aspects of the doctor-patient relationship and the impact of cancer treatment on patients’ lives.

In referring to the futuristic essay “Ars Brevis,” Dr. Lewis contrasted the humanism of oncology specialists in the present day with the fictional image of data-regurgitating robots programmed to maximize the efficiency of each patient encounter (J Clin Oncol. 2013 May 10;31[14]:1792-4).

Dr. Lewis reminded attendees that to practice medicine without using both “head and heart” undermines the inherent nature of medical care.

Unfortunately, that perspective may not match the public perception of oncologists. Dr. Lewis described his experience of typing “oncologists are” into an Internet search engine and seeing the auto-complete function prompt words such as “criminals,” “evil,” “murderers,” and “confused.”

Obviously, it is hard to establish a trusting patient-doctor relationship if that is the prima facie perception of the oncology specialty.
 

Dispelling myths and creating community via social media

A primary goal of consultation with a newly-diagnosed cancer patient is for the patient to feel that the oncologist will be there to take care of them, regardless of what the future holds.

Dr. Lewis has found that social media can potentially extend that feeling to a global community of patients, caregivers, and others seeking information relevant to a cancer diagnosis. He believes that oncologists have an opportunity to dispel myths and fears by being attentive to the real-life concerns of patients.

Dr. Lewis took advantage of this opportunity when he underwent a Whipple procedure (pancreaticoduodenectomy) for a pancreatic neuroendocrine tumor. He and the hospital’s media services staff “live-tweeted” his surgery and recovery.

With those tweets, Dr. Lewis demystified each step of a major surgical procedure. From messages he received on social media, Dr. Lewis knows he made the decision to have a Whipple procedure more acceptable to other patients.

His personal medical experience notwithstanding, Dr. Lewis acknowledged that every patient’s circumstances are unique.

Oncologists cannot possibly empathize with every circumstance. However, when they show sensitivity to personal elements of the cancer experience, they shed light on the complicated role they play in patient care and can facilitate good decision-making among patients across the globe.
 

Social media for professional development and patient care

The publication of his 2011 essay was gratifying for Dr. Lewis, but the finite number of comments he received thereafter illustrated the rather limited audience that traditional academic publications have and the laborious process for subsequent interaction (J Clin Oncol. 2011 Aug 1;29[22]:3103-4).

First as an observer and later as a participant on social media, Dr. Lewis appreciated that teaching points and publications can be amplified by global distribution and the potential for informal bidirectional communication.

Social media platforms enable physicians to connect with a larger audience through participative communication, in which users develop, share, and react to content (N Engl J Med. 2009 Aug 13;361[7]:649-51).

Dr. Lewis reflected on how oncologists are challenged to sort through the thousands of oncology-focused publications annually. Through social media, one can see the studies on which the experts are commenting and appreciate the nuances that contextualize the results. Focused interactions with renowned doctors, at regular intervals, require little formality.

Online journal clubs enable the sharing of ideas, opinions, multimedia resources, and references across institutional and international borders (J Gen Intern Med. 2014 Oct;29[10]:1317-8).
 

Social media in oncology: Accomplishments and promise

The development of broadband Internet, wireless connectivity, and social media for peer-to-peer and general communication are among the major technological advances that have transformed medical communication.

As an organization, COSMO aims to describe, understand, and improve the use of social media to increase the penetration of evidence-based guidelines and research insights into clinical practice (Future Oncol. 2017 Jun;13[15]:1281-5).

At the inaugural COSMO meeting, areas of progress since COSMO’s inception in 2015 were highlighted, including:

• The involvement of cancer professionals and advocates in multiple distinctive platforms.
• The development of hashtag libraries to aggregate interest groups and topics.
• The refinement of strategies for engaging advocates with attention to inclusiveness.
• A steady trajectory of growth in tweeting at scientific conferences.

An overarching theme of the COSMO meeting was “authenticity,” a virtue that is easy to admire but requires conscious, consistent effort to achieve.

Disclosure of conflicts of interest and avoiding using social media simply as a recruitment tool for clinical trials are basic components of accurate self-representation.

In addition, Dr. Lewis advocated for sharing personal experiences in a component of social media posts so oncologists can show humanity as a feature of their professional online identity and inherent nature.

Dr. Lewis disclosed consultancy with Medscape/WebMD, which are owned by the same parent company as MDedge. He also disclosed relationships with Foundation Medicine, Natera, Exelixis, QED, HalioDX, and Ipsen.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Sharing their personal experiences on social media can emphasize oncologists’ humanity and have substantive, beneficial effects on patient care, according to a presentation at the Collaboration for Outcomes using Social Media in Oncology (COSMO) inaugural meeting.

Mark A. Lewis, MD, explained to the COSMO meeting audience how storytelling on social media can educate and engage patients, advocates, and professional colleagues – advancing knowledge, dispelling misinformation, and promoting clinical research.

Dr. Lewis, an oncologist at Intermountain Healthcare in Salt Lake City, reflected on the bifid roles of oncologists as scientists engaged in life-long learning and humanists who can internalize and appreciate the unique character and circumstances of their patients.

Patients who have serious illnesses are necessarily aggregated by statistics. However, in an essay published in 2011, Dr. Lewis noted that “each individual patient partakes in a unique, irreproducible experiment where n = 1” (J Clin Oncol. 2011 Aug 1;29[22]:3103-4).

Dr. Lewis highlighted the duality of individual data points on a survival curve as descriptors of common disease trajectories and treatment effects. However, those data points also conceal important narratives regarding the most highly valued aspects of the doctor-patient relationship and the impact of cancer treatment on patients’ lives.

In referring to the futuristic essay “Ars Brevis,” Dr. Lewis contrasted the humanism of oncology specialists in the present day with the fictional image of data-regurgitating robots programmed to maximize the efficiency of each patient encounter (J Clin Oncol. 2013 May 10;31[14]:1792-4).

Dr. Lewis reminded attendees that to practice medicine without using both “head and heart” undermines the inherent nature of medical care.

Unfortunately, that perspective may not match the public perception of oncologists. Dr. Lewis described his experience of typing “oncologists are” into an Internet search engine and seeing the auto-complete function prompt words such as “criminals,” “evil,” “murderers,” and “confused.”

Obviously, it is hard to establish a trusting patient-doctor relationship if that is the prima facie perception of the oncology specialty.
 

Dispelling myths and creating community via social media

A primary goal of consultation with a newly-diagnosed cancer patient is for the patient to feel that the oncologist will be there to take care of them, regardless of what the future holds.

Dr. Lewis has found that social media can potentially extend that feeling to a global community of patients, caregivers, and others seeking information relevant to a cancer diagnosis. He believes that oncologists have an opportunity to dispel myths and fears by being attentive to the real-life concerns of patients.

Dr. Lewis took advantage of this opportunity when he underwent a Whipple procedure (pancreaticoduodenectomy) for a pancreatic neuroendocrine tumor. He and the hospital’s media services staff “live-tweeted” his surgery and recovery.

With those tweets, Dr. Lewis demystified each step of a major surgical procedure. From messages he received on social media, Dr. Lewis knows he made the decision to have a Whipple procedure more acceptable to other patients.

His personal medical experience notwithstanding, Dr. Lewis acknowledged that every patient’s circumstances are unique.

Oncologists cannot possibly empathize with every circumstance. However, when they show sensitivity to personal elements of the cancer experience, they shed light on the complicated role they play in patient care and can facilitate good decision-making among patients across the globe.
 

Social media for professional development and patient care

The publication of his 2011 essay was gratifying for Dr. Lewis, but the finite number of comments he received thereafter illustrated the rather limited audience that traditional academic publications have and the laborious process for subsequent interaction (J Clin Oncol. 2011 Aug 1;29[22]:3103-4).

First as an observer and later as a participant on social media, Dr. Lewis appreciated that teaching points and publications can be amplified by global distribution and the potential for informal bidirectional communication.

Social media platforms enable physicians to connect with a larger audience through participative communication, in which users develop, share, and react to content (N Engl J Med. 2009 Aug 13;361[7]:649-51).

Dr. Lewis reflected on how oncologists are challenged to sort through the thousands of oncology-focused publications annually. Through social media, one can see the studies on which the experts are commenting and appreciate the nuances that contextualize the results. Focused interactions with renowned doctors, at regular intervals, require little formality.

Online journal clubs enable the sharing of ideas, opinions, multimedia resources, and references across institutional and international borders (J Gen Intern Med. 2014 Oct;29[10]:1317-8).
 

Social media in oncology: Accomplishments and promise

The development of broadband Internet, wireless connectivity, and social media for peer-to-peer and general communication are among the major technological advances that have transformed medical communication.

As an organization, COSMO aims to describe, understand, and improve the use of social media to increase the penetration of evidence-based guidelines and research insights into clinical practice (Future Oncol. 2017 Jun;13[15]:1281-5).

At the inaugural COSMO meeting, areas of progress since COSMO’s inception in 2015 were highlighted, including:

• The involvement of cancer professionals and advocates in multiple distinctive platforms.
• The development of hashtag libraries to aggregate interest groups and topics.
• The refinement of strategies for engaging advocates with attention to inclusiveness.
• A steady trajectory of growth in tweeting at scientific conferences.

An overarching theme of the COSMO meeting was “authenticity,” a virtue that is easy to admire but requires conscious, consistent effort to achieve.

Disclosure of conflicts of interest and avoiding using social media simply as a recruitment tool for clinical trials are basic components of accurate self-representation.

In addition, Dr. Lewis advocated for sharing personal experiences in a component of social media posts so oncologists can show humanity as a feature of their professional online identity and inherent nature.

Dr. Lewis disclosed consultancy with Medscape/WebMD, which are owned by the same parent company as MDedge. He also disclosed relationships with Foundation Medicine, Natera, Exelixis, QED, HalioDX, and Ipsen.


Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Lung cancer is the leading cause of cancer mortality both in the US and worldwide.¹ Many patients diagnosed with lung cancer present with advanced disease with thoracic symptoms such as cough, hemoptysis, dyspnea, and chest pain.^2-4 Palliative radiotherapy is routinely used in patients with locally advanced and metastatic lung cancer with the goal of relieving these symptoms and improving quality of life. Guidelines published by the American Society for Radiation Oncology (ASTRO) in 2011, and updated in 2018, provide recommendations on palliation of lung cancer with external beam radiotherapy (EBRT) and clarify the roles of concurrent chemotherapy and endobronchial brachytherapy (EBB) for palliation.^5,6

After prostate cancer, lung cancer is the second most frequently diagnosed cancer in the Veterans Health Administration (VHA).⁷ The VHA consists of 172 medical centers and is the largest integrated health care system in the US. At the time of this study, 40 of these centers had onsite radiation facilities. The VHA Palliative Radiation Taskforce has conducted a series of surveys to evaluate use of palliative radiotherapy in the VHA, determine VHA practice concordance with ASTRO and American College of Radiology (ACR) guidelines, and direct educational efforts towards addressing gaps in knowledge. These efforts are directed at ensuring best practices throughout this large and heterogeneous healthcare system. In 2016 a survey was conducted to evaluate concordance of VHA radiation oncologist (RO) practice with the 2011 ASTRO guidelines on palliative thoracic radiotherapy for non-small cell lung cancer (NSCLC).

Methods

A survey instrument was generated by VHA National Palliative Radiotherapy Taskforce members. It was reviewed and approved for use by the VHA Patient Care Services office. In May of 2016, the online survey was sent to the 88 VHA ROs practicing at the 40 sites with onsite radiation facilities. The survey aimed to determine patterns of practice for palliation of thoracic symptoms secondary to lung cancer.

Demographic information obtained included years in practice, employment status, academic appointment, board certification, and familiarity with ASTRO lung cancer guidelines. Two clinical scenarios were presented to glean opinions on dose/fractionation schemes preferred, use of concurrent chemotherapy, and use of EBB and/or yttrium aluminum garnet (YAG) laser technology. Survey questions also assessed use of EBRT for palliation of hemoptysis, chest wall pain, and/or stridor as well as use of stereotactic body radiotherapy (SBRT) for palliation.

Survey results were assessed for concordance with published ASTRO guidelines. χ² tests were run to test for associations between demographic factors such as academic appointment, years of practice, full time vs part time employment, and familiarity with ASTRO palliative lung cancer guidelines, with use of EBRT for palliation, dose and fractionation preference, use of concurrent chemotherapy, and strategy for management of endobronchial lesions.

Results

Of the 88 physicians surveyed, 54 responded for a response rate of 61%. Respondents represented 37 of the 40 (93%) VHA radiation oncology departments (Table 1). Among respondents, most were board certified (96%), held academic appointments (91%), and were full-time employees (85%). Forty-four percent of respondents were in practice for > 20 years, 19% for 11 to 20 years, 20% for 6 to 10 years, and 17% for < 6 years. A majority reported familiarity with the ASTRO guidelines (64%), while just 11% reported no familiarity with the guidelines.

When asked about use of SBRT for palliation of hemoptysis, stridor, and/or chest pain, the majority (87%) preferred conventional EBRT. Of the 13% who reported use of SBRT, most (11%) performed it onsite, with 2% of respondents referring offsite to non-VHA centers for the service. When asked about use of EBB for palliation, only 2% reported use of that procedure at their facilities, while 26% reported referral to non-VHA facilities for EBB. The remaining 72% of respondents favor use of conventional EBRT.

Respondents were presented with a case of a male patient aged 70 years who smoked and had widely metastatic NSCLC, a life expectancy of about 3 months, and 10/10 chest wall pain from direct tumor invasion. All respondents recommended palliative radiotherapy. The preferred fractionation was 20 Gray (Gy) in 5 fractions, which was recommended by 69% of respondents. The remainder recommended 30 Gy in 10 fractions (22%) or a single fraction of 10 Gy (9%). No respondent recommended the longer fractionation options of 60 Gy in 30 fractions, 45 Gy in 15 fractions, or 40 Gy in 20 fractions. The majority (98%) did not recommend concurrent chemotherapy.

When the above case was modified for an endobronchial lesion requiring palliation with associated lung collapse, rather than chest wall invasion, 20 respondents (38%) reported they would refer for EBB, and 20 respondents reported they would refer for YAG laser. As > 1 answer could be selected for this question, there were 12 respondents who selected both EBB and YAG laser; 8 selected only EBB, and 8 selected only YAG laser. Many respondents added comments about treating with EBRT, which had not been presented as an answer choice. Nearly half of respondents (49%) were amenable to referral for the use of EBB or YAG laser for lung reexpansion prior to radiotherapy. Three respondents mentioned referral for an endobronchial stent prior to palliative radiotherapy to address this question.

Discussion

This survey was conducted to evaluate concordance of management of metastatic lung cancer in the VHA with ASTRO guidelines. The relationship between respondents’ familiarity with the guidelines and responses also was evaluated to determine the impact such guidelines have on decision-making. The ASTRO guidelines for palliative thoracic radiation make recommendations regarding 3 issues: (1) radiation doses and fractionations for palliation; (2) the role of EBB; and (3) the use of concurrent chemotherapy.^5,6

Radiation Dose and Fractionation for Palliation

A variety of dose/fractionation schemes are considered appropriate in the ASTRO guideline statement, including more prolonged courses such as 30 Gy/10 fractions as well as more hypofractionated regimens (ie, 20 Gy/5 fractions, 17 Gy/2 fractions, and a single fraction of 10 Gy). Higher dose regimens, such as 30 Gy/10 fractions, have been associated with prolonged survival, as well as increased toxicities such as radiation esophagitis.⁸ Therefore, the guidelines support use of 30 Gy/10 fractions for patients with good performance status while encouraging use of more hypofractionated regimens for patients with poor performance status. In considering more hypofractionated regimens, one must consider the possibility of adverse effects that can be associated with higher dose per fraction. For instance, 17 Gy/2 fractions has been associated with myelopathy; therefore it should be used with caution and careful treatment planning.⁹

For the survey case example (a male aged 70 years with a 3-month life expectancy who required palliation for chest wall pain), all respondents selected hypofractionated regimens; with no respondent selected the more prolonged fractionations of 60 Gy/30 fractions, 45 Gy/15 fractions, or 40 Gy/20 fractions. These more prolonged fractionations are not endorsed by the guidelines in general, and particularly not for a patient with poor life expectancy. All responses for this case selected by survey respondents are considered appropriate per the consensus guideline statement.

Role of Concurrent Chemotherapy

The ASTRO guidelines do not support use of concurrent chemotherapy for palliation of stage IV NSCLC.^5,6 The 2018 updated guidelines established a role for concurrent chemotherapy for patients with stage III NSCLC with good performance status and life expectancy of > 3 months. This updated recommendation is based on data from 2 randomized trials demonstrating improvement in overall survival with the addition of chemotherapy for patients with stage III NSCLC undergoing palliative radiotherapy.^10-12

These newer studies are in contrast to an older randomized study by Ball and colleagues that demonstrated greater toxicity from concurrent chemotherapy, with no improvement in outcomes such as palliation of symptoms, overall survival, or progression free survival.¹³ In contrast to the newer studies that included only patients with stage III NSCLC, about half of the patients in the Ball and colleagues study had known metastatic disease.^10-13 Of note, staging for metastatic disease was not carried out routinely, so it is possible that a greater proportion of patients had metastatic disease that would have been seen on imaging. In concordance with the guidelines, 98% of the survey respondents did not recommend concurrent chemotherapy for palliation of intrathoracic symptom; only 1 respondent recommended use of chemotherapy for palliation.

Role of Endobronchial Brachytherapy

EBB involves implantation of radioactive sources for treatment of endobronchial lesions causing obstructive symptoms.¹⁴ Given the lack of randomized data that demonstrate a benefit of EBB over EBRT, the ASTRO guidelines do not endorse routine use of EBB for initial palliative management.^15,16 The ASTRO guidelines reference a Cochrane Review of 13 trials that concluded that EBRT alone is superior to EBB alone for initial palliation of symptoms from endobronchial NSCLC.¹⁷

Of respondents surveyed, only 1 facility offered onsite EBB. The majority of respondents (72%) preferred the use of conventional EBRT techniques, while 26% refer to non-VHA centers for EBB. Lack of incorporation of EBB into routine VHA practice likely is a reflection of the unclear role of this technology based on the available literature and ASTRO guidelines. In the setting of a right lower lung collapse, more respondents (49%) would consider use of EBB or YAG laser technology for lung reexpansion prior to EBRT.

The ASTRO guidelines recommend that initial EBB in conjunction with EBRT be considered based on randomized data demonstrating significant improvement in lung reexpansion and in patient reported dyspnea with addition of EBB to EBRT over EBRT alone.¹⁸ However, the guidelines do not mandate the use of EBB in this situation. It is possible that targeted education regarding the role of EBB would improve knowledge of the potential benefit in the setting of lung collapse and increase the percentage of VHA ROs who would recommend this procedure.

Limitations

The study is limited by lack of generalizability of these findings to all ROs in the country. It is also possible that physician responses do not represent practice patterns with complete accuracy. The use of EBB varied among practitioners. Further study of this technology is necessary to clarify its role in the management of endobronchial obstructive symptoms and to determine whether efforts should be made to increase access to EBB within the VHA.

Conclusions

Most of the ROs who responded to our survey were cognizant and compliant with current ASTRO guidelines on management of lung cancer. Furthermore, familiarity with ASTRO guidelines and management choices were not associated with the respondents’ years in practice, academic appointment, full-time vs part-time status, or familiarity with ASTRO guidelines. This study is a nationwide survey of ROs in the VHA system that reflects the radiation-related care received by veterans with metastatic lung cancer. Responses were obtained from 93% of the 40 radiation oncology centers, so it is likely that the survey accurately represents the decision-making process at the majority of centers. It is possible that those who did not respond to the survey do not treat thoracic cases.

Lung cancer is the leading cause of cancer mortality both in the US and worldwide.¹ Many patients diagnosed with lung cancer present with advanced disease with thoracic symptoms such as cough, hemoptysis, dyspnea, and chest pain.^2-4 Palliative radiotherapy is routinely used in patients with locally advanced and metastatic lung cancer with the goal of relieving these symptoms and improving quality of life. Guidelines published by the American Society for Radiation Oncology (ASTRO) in 2011, and updated in 2018, provide recommendations on palliation of lung cancer with external beam radiotherapy (EBRT) and clarify the roles of concurrent chemotherapy and endobronchial brachytherapy (EBB) for palliation.^5,6

After prostate cancer, lung cancer is the second most frequently diagnosed cancer in the Veterans Health Administration (VHA).⁷ The VHA consists of 172 medical centers and is the largest integrated health care system in the US. At the time of this study, 40 of these centers had onsite radiation facilities. The VHA Palliative Radiation Taskforce has conducted a series of surveys to evaluate use of palliative radiotherapy in the VHA, determine VHA practice concordance with ASTRO and American College of Radiology (ACR) guidelines, and direct educational efforts towards addressing gaps in knowledge. These efforts are directed at ensuring best practices throughout this large and heterogeneous healthcare system. In 2016 a survey was conducted to evaluate concordance of VHA radiation oncologist (RO) practice with the 2011 ASTRO guidelines on palliative thoracic radiotherapy for non-small cell lung cancer (NSCLC).

Methods

A survey instrument was generated by VHA National Palliative Radiotherapy Taskforce members. It was reviewed and approved for use by the VHA Patient Care Services office. In May of 2016, the online survey was sent to the 88 VHA ROs practicing at the 40 sites with onsite radiation facilities. The survey aimed to determine patterns of practice for palliation of thoracic symptoms secondary to lung cancer.

Demographic information obtained included years in practice, employment status, academic appointment, board certification, and familiarity with ASTRO lung cancer guidelines. Two clinical scenarios were presented to glean opinions on dose/fractionation schemes preferred, use of concurrent chemotherapy, and use of EBB and/or yttrium aluminum garnet (YAG) laser technology. Survey questions also assessed use of EBRT for palliation of hemoptysis, chest wall pain, and/or stridor as well as use of stereotactic body radiotherapy (SBRT) for palliation.

Survey results were assessed for concordance with published ASTRO guidelines. χ² tests were run to test for associations between demographic factors such as academic appointment, years of practice, full time vs part time employment, and familiarity with ASTRO palliative lung cancer guidelines, with use of EBRT for palliation, dose and fractionation preference, use of concurrent chemotherapy, and strategy for management of endobronchial lesions.

Results

Of the 88 physicians surveyed, 54 responded for a response rate of 61%. Respondents represented 37 of the 40 (93%) VHA radiation oncology departments (Table 1). Among respondents, most were board certified (96%), held academic appointments (91%), and were full-time employees (85%). Forty-four percent of respondents were in practice for > 20 years, 19% for 11 to 20 years, 20% for 6 to 10 years, and 17% for < 6 years. A majority reported familiarity with the ASTRO guidelines (64%), while just 11% reported no familiarity with the guidelines.

When asked about use of SBRT for palliation of hemoptysis, stridor, and/or chest pain, the majority (87%) preferred conventional EBRT. Of the 13% who reported use of SBRT, most (11%) performed it onsite, with 2% of respondents referring offsite to non-VHA centers for the service. When asked about use of EBB for palliation, only 2% reported use of that procedure at their facilities, while 26% reported referral to non-VHA facilities for EBB. The remaining 72% of respondents favor use of conventional EBRT.

Respondents were presented with a case of a male patient aged 70 years who smoked and had widely metastatic NSCLC, a life expectancy of about 3 months, and 10/10 chest wall pain from direct tumor invasion. All respondents recommended palliative radiotherapy. The preferred fractionation was 20 Gray (Gy) in 5 fractions, which was recommended by 69% of respondents. The remainder recommended 30 Gy in 10 fractions (22%) or a single fraction of 10 Gy (9%). No respondent recommended the longer fractionation options of 60 Gy in 30 fractions, 45 Gy in 15 fractions, or 40 Gy in 20 fractions. The majority (98%) did not recommend concurrent chemotherapy.

When the above case was modified for an endobronchial lesion requiring palliation with associated lung collapse, rather than chest wall invasion, 20 respondents (38%) reported they would refer for EBB, and 20 respondents reported they would refer for YAG laser. As > 1 answer could be selected for this question, there were 12 respondents who selected both EBB and YAG laser; 8 selected only EBB, and 8 selected only YAG laser. Many respondents added comments about treating with EBRT, which had not been presented as an answer choice. Nearly half of respondents (49%) were amenable to referral for the use of EBB or YAG laser for lung reexpansion prior to radiotherapy. Three respondents mentioned referral for an endobronchial stent prior to palliative radiotherapy to address this question.

Discussion

This survey was conducted to evaluate concordance of management of metastatic lung cancer in the VHA with ASTRO guidelines. The relationship between respondents’ familiarity with the guidelines and responses also was evaluated to determine the impact such guidelines have on decision-making. The ASTRO guidelines for palliative thoracic radiation make recommendations regarding 3 issues: (1) radiation doses and fractionations for palliation; (2) the role of EBB; and (3) the use of concurrent chemotherapy.^5,6

Radiation Dose and Fractionation for Palliation

A variety of dose/fractionation schemes are considered appropriate in the ASTRO guideline statement, including more prolonged courses such as 30 Gy/10 fractions as well as more hypofractionated regimens (ie, 20 Gy/5 fractions, 17 Gy/2 fractions, and a single fraction of 10 Gy). Higher dose regimens, such as 30 Gy/10 fractions, have been associated with prolonged survival, as well as increased toxicities such as radiation esophagitis.⁸ Therefore, the guidelines support use of 30 Gy/10 fractions for patients with good performance status while encouraging use of more hypofractionated regimens for patients with poor performance status. In considering more hypofractionated regimens, one must consider the possibility of adverse effects that can be associated with higher dose per fraction. For instance, 17 Gy/2 fractions has been associated with myelopathy; therefore it should be used with caution and careful treatment planning.⁹

For the survey case example (a male aged 70 years with a 3-month life expectancy who required palliation for chest wall pain), all respondents selected hypofractionated regimens; with no respondent selected the more prolonged fractionations of 60 Gy/30 fractions, 45 Gy/15 fractions, or 40 Gy/20 fractions. These more prolonged fractionations are not endorsed by the guidelines in general, and particularly not for a patient with poor life expectancy. All responses for this case selected by survey respondents are considered appropriate per the consensus guideline statement.

Role of Concurrent Chemotherapy

The ASTRO guidelines do not support use of concurrent chemotherapy for palliation of stage IV NSCLC.^5,6 The 2018 updated guidelines established a role for concurrent chemotherapy for patients with stage III NSCLC with good performance status and life expectancy of > 3 months. This updated recommendation is based on data from 2 randomized trials demonstrating improvement in overall survival with the addition of chemotherapy for patients with stage III NSCLC undergoing palliative radiotherapy.^10-12

These newer studies are in contrast to an older randomized study by Ball and colleagues that demonstrated greater toxicity from concurrent chemotherapy, with no improvement in outcomes such as palliation of symptoms, overall survival, or progression free survival.¹³ In contrast to the newer studies that included only patients with stage III NSCLC, about half of the patients in the Ball and colleagues study had known metastatic disease.^10-13 Of note, staging for metastatic disease was not carried out routinely, so it is possible that a greater proportion of patients had metastatic disease that would have been seen on imaging. In concordance with the guidelines, 98% of the survey respondents did not recommend concurrent chemotherapy for palliation of intrathoracic symptom; only 1 respondent recommended use of chemotherapy for palliation.

Role of Endobronchial Brachytherapy

EBB involves implantation of radioactive sources for treatment of endobronchial lesions causing obstructive symptoms.¹⁴ Given the lack of randomized data that demonstrate a benefit of EBB over EBRT, the ASTRO guidelines do not endorse routine use of EBB for initial palliative management.^15,16 The ASTRO guidelines reference a Cochrane Review of 13 trials that concluded that EBRT alone is superior to EBB alone for initial palliation of symptoms from endobronchial NSCLC.¹⁷

Of respondents surveyed, only 1 facility offered onsite EBB. The majority of respondents (72%) preferred the use of conventional EBRT techniques, while 26% refer to non-VHA centers for EBB. Lack of incorporation of EBB into routine VHA practice likely is a reflection of the unclear role of this technology based on the available literature and ASTRO guidelines. In the setting of a right lower lung collapse, more respondents (49%) would consider use of EBB or YAG laser technology for lung reexpansion prior to EBRT.

The ASTRO guidelines recommend that initial EBB in conjunction with EBRT be considered based on randomized data demonstrating significant improvement in lung reexpansion and in patient reported dyspnea with addition of EBB to EBRT over EBRT alone.¹⁸ However, the guidelines do not mandate the use of EBB in this situation. It is possible that targeted education regarding the role of EBB would improve knowledge of the potential benefit in the setting of lung collapse and increase the percentage of VHA ROs who would recommend this procedure.

Limitations

The study is limited by lack of generalizability of these findings to all ROs in the country. It is also possible that physician responses do not represent practice patterns with complete accuracy. The use of EBB varied among practitioners. Further study of this technology is necessary to clarify its role in the management of endobronchial obstructive symptoms and to determine whether efforts should be made to increase access to EBB within the VHA.

Conclusions

Most of the ROs who responded to our survey were cognizant and compliant with current ASTRO guidelines on management of lung cancer. Furthermore, familiarity with ASTRO guidelines and management choices were not associated with the respondents’ years in practice, academic appointment, full-time vs part-time status, or familiarity with ASTRO guidelines. This study is a nationwide survey of ROs in the VHA system that reflects the radiation-related care received by veterans with metastatic lung cancer. Responses were obtained from 93% of the 40 radiation oncology centers, so it is likely that the survey accurately represents the decision-making process at the majority of centers. It is possible that those who did not respond to the survey do not treat thoracic cases.

Lung cancer is the leading cause of cancer mortality both in the US and worldwide.¹ Many patients diagnosed with lung cancer present with advanced disease with thoracic symptoms such as cough, hemoptysis, dyspnea, and chest pain.^2-4 Palliative radiotherapy is routinely used in patients with locally advanced and metastatic lung cancer with the goal of relieving these symptoms and improving quality of life. Guidelines published by the American Society for Radiation Oncology (ASTRO) in 2011, and updated in 2018, provide recommendations on palliation of lung cancer with external beam radiotherapy (EBRT) and clarify the roles of concurrent chemotherapy and endobronchial brachytherapy (EBB) for palliation.^5,6

After prostate cancer, lung cancer is the second most frequently diagnosed cancer in the Veterans Health Administration (VHA).⁷ The VHA consists of 172 medical centers and is the largest integrated health care system in the US. At the time of this study, 40 of these centers had onsite radiation facilities. The VHA Palliative Radiation Taskforce has conducted a series of surveys to evaluate use of palliative radiotherapy in the VHA, determine VHA practice concordance with ASTRO and American College of Radiology (ACR) guidelines, and direct educational efforts towards addressing gaps in knowledge. These efforts are directed at ensuring best practices throughout this large and heterogeneous healthcare system. In 2016 a survey was conducted to evaluate concordance of VHA radiation oncologist (RO) practice with the 2011 ASTRO guidelines on palliative thoracic radiotherapy for non-small cell lung cancer (NSCLC).

Methods

A survey instrument was generated by VHA National Palliative Radiotherapy Taskforce members. It was reviewed and approved for use by the VHA Patient Care Services office. In May of 2016, the online survey was sent to the 88 VHA ROs practicing at the 40 sites with onsite radiation facilities. The survey aimed to determine patterns of practice for palliation of thoracic symptoms secondary to lung cancer.

Demographic information obtained included years in practice, employment status, academic appointment, board certification, and familiarity with ASTRO lung cancer guidelines. Two clinical scenarios were presented to glean opinions on dose/fractionation schemes preferred, use of concurrent chemotherapy, and use of EBB and/or yttrium aluminum garnet (YAG) laser technology. Survey questions also assessed use of EBRT for palliation of hemoptysis, chest wall pain, and/or stridor as well as use of stereotactic body radiotherapy (SBRT) for palliation.

Survey results were assessed for concordance with published ASTRO guidelines. χ² tests were run to test for associations between demographic factors such as academic appointment, years of practice, full time vs part time employment, and familiarity with ASTRO palliative lung cancer guidelines, with use of EBRT for palliation, dose and fractionation preference, use of concurrent chemotherapy, and strategy for management of endobronchial lesions.

Results

Of the 88 physicians surveyed, 54 responded for a response rate of 61%. Respondents represented 37 of the 40 (93%) VHA radiation oncology departments (Table 1). Among respondents, most were board certified (96%), held academic appointments (91%), and were full-time employees (85%). Forty-four percent of respondents were in practice for > 20 years, 19% for 11 to 20 years, 20% for 6 to 10 years, and 17% for < 6 years. A majority reported familiarity with the ASTRO guidelines (64%), while just 11% reported no familiarity with the guidelines.

When asked about use of SBRT for palliation of hemoptysis, stridor, and/or chest pain, the majority (87%) preferred conventional EBRT. Of the 13% who reported use of SBRT, most (11%) performed it onsite, with 2% of respondents referring offsite to non-VHA centers for the service. When asked about use of EBB for palliation, only 2% reported use of that procedure at their facilities, while 26% reported referral to non-VHA facilities for EBB. The remaining 72% of respondents favor use of conventional EBRT.

Respondents were presented with a case of a male patient aged 70 years who smoked and had widely metastatic NSCLC, a life expectancy of about 3 months, and 10/10 chest wall pain from direct tumor invasion. All respondents recommended palliative radiotherapy. The preferred fractionation was 20 Gray (Gy) in 5 fractions, which was recommended by 69% of respondents. The remainder recommended 30 Gy in 10 fractions (22%) or a single fraction of 10 Gy (9%). No respondent recommended the longer fractionation options of 60 Gy in 30 fractions, 45 Gy in 15 fractions, or 40 Gy in 20 fractions. The majority (98%) did not recommend concurrent chemotherapy.

When the above case was modified for an endobronchial lesion requiring palliation with associated lung collapse, rather than chest wall invasion, 20 respondents (38%) reported they would refer for EBB, and 20 respondents reported they would refer for YAG laser. As > 1 answer could be selected for this question, there were 12 respondents who selected both EBB and YAG laser; 8 selected only EBB, and 8 selected only YAG laser. Many respondents added comments about treating with EBRT, which had not been presented as an answer choice. Nearly half of respondents (49%) were amenable to referral for the use of EBB or YAG laser for lung reexpansion prior to radiotherapy. Three respondents mentioned referral for an endobronchial stent prior to palliative radiotherapy to address this question.

Discussion

This survey was conducted to evaluate concordance of management of metastatic lung cancer in the VHA with ASTRO guidelines. The relationship between respondents’ familiarity with the guidelines and responses also was evaluated to determine the impact such guidelines have on decision-making. The ASTRO guidelines for palliative thoracic radiation make recommendations regarding 3 issues: (1) radiation doses and fractionations for palliation; (2) the role of EBB; and (3) the use of concurrent chemotherapy.^5,6

Radiation Dose and Fractionation for Palliation

A variety of dose/fractionation schemes are considered appropriate in the ASTRO guideline statement, including more prolonged courses such as 30 Gy/10 fractions as well as more hypofractionated regimens (ie, 20 Gy/5 fractions, 17 Gy/2 fractions, and a single fraction of 10 Gy). Higher dose regimens, such as 30 Gy/10 fractions, have been associated with prolonged survival, as well as increased toxicities such as radiation esophagitis.⁸ Therefore, the guidelines support use of 30 Gy/10 fractions for patients with good performance status while encouraging use of more hypofractionated regimens for patients with poor performance status. In considering more hypofractionated regimens, one must consider the possibility of adverse effects that can be associated with higher dose per fraction. For instance, 17 Gy/2 fractions has been associated with myelopathy; therefore it should be used with caution and careful treatment planning.⁹

For the survey case example (a male aged 70 years with a 3-month life expectancy who required palliation for chest wall pain), all respondents selected hypofractionated regimens; with no respondent selected the more prolonged fractionations of 60 Gy/30 fractions, 45 Gy/15 fractions, or 40 Gy/20 fractions. These more prolonged fractionations are not endorsed by the guidelines in general, and particularly not for a patient with poor life expectancy. All responses for this case selected by survey respondents are considered appropriate per the consensus guideline statement.

Role of Concurrent Chemotherapy

The ASTRO guidelines do not support use of concurrent chemotherapy for palliation of stage IV NSCLC.^5,6 The 2018 updated guidelines established a role for concurrent chemotherapy for patients with stage III NSCLC with good performance status and life expectancy of > 3 months. This updated recommendation is based on data from 2 randomized trials demonstrating improvement in overall survival with the addition of chemotherapy for patients with stage III NSCLC undergoing palliative radiotherapy.^10-12

These newer studies are in contrast to an older randomized study by Ball and colleagues that demonstrated greater toxicity from concurrent chemotherapy, with no improvement in outcomes such as palliation of symptoms, overall survival, or progression free survival.¹³ In contrast to the newer studies that included only patients with stage III NSCLC, about half of the patients in the Ball and colleagues study had known metastatic disease.^10-13 Of note, staging for metastatic disease was not carried out routinely, so it is possible that a greater proportion of patients had metastatic disease that would have been seen on imaging. In concordance with the guidelines, 98% of the survey respondents did not recommend concurrent chemotherapy for palliation of intrathoracic symptom; only 1 respondent recommended use of chemotherapy for palliation.

Role of Endobronchial Brachytherapy

EBB involves implantation of radioactive sources for treatment of endobronchial lesions causing obstructive symptoms.¹⁴ Given the lack of randomized data that demonstrate a benefit of EBB over EBRT, the ASTRO guidelines do not endorse routine use of EBB for initial palliative management.^15,16 The ASTRO guidelines reference a Cochrane Review of 13 trials that concluded that EBRT alone is superior to EBB alone for initial palliation of symptoms from endobronchial NSCLC.¹⁷

Of respondents surveyed, only 1 facility offered onsite EBB. The majority of respondents (72%) preferred the use of conventional EBRT techniques, while 26% refer to non-VHA centers for EBB. Lack of incorporation of EBB into routine VHA practice likely is a reflection of the unclear role of this technology based on the available literature and ASTRO guidelines. In the setting of a right lower lung collapse, more respondents (49%) would consider use of EBB or YAG laser technology for lung reexpansion prior to EBRT.

The ASTRO guidelines recommend that initial EBB in conjunction with EBRT be considered based on randomized data demonstrating significant improvement in lung reexpansion and in patient reported dyspnea with addition of EBB to EBRT over EBRT alone.¹⁸ However, the guidelines do not mandate the use of EBB in this situation. It is possible that targeted education regarding the role of EBB would improve knowledge of the potential benefit in the setting of lung collapse and increase the percentage of VHA ROs who would recommend this procedure.

Limitations

The study is limited by lack of generalizability of these findings to all ROs in the country. It is also possible that physician responses do not represent practice patterns with complete accuracy. The use of EBB varied among practitioners. Further study of this technology is necessary to clarify its role in the management of endobronchial obstructive symptoms and to determine whether efforts should be made to increase access to EBB within the VHA.

Conclusions

Most of the ROs who responded to our survey were cognizant and compliant with current ASTRO guidelines on management of lung cancer. Furthermore, familiarity with ASTRO guidelines and management choices were not associated with the respondents’ years in practice, academic appointment, full-time vs part-time status, or familiarity with ASTRO guidelines. This study is a nationwide survey of ROs in the VHA system that reflects the radiation-related care received by veterans with metastatic lung cancer. Responses were obtained from 93% of the 40 radiation oncology centers, so it is likely that the survey accurately represents the decision-making process at the majority of centers. It is possible that those who did not respond to the survey do not treat thoracic cases.

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types. But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed “hyperprogressive disease” (HPD). It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a “provocative phenomenon,” wrote the authors of a recent commentary entitled “Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?”

“This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease,” said the author of another commentary.

But the tide is now turning toward acceptance of HPD, said Kartik Sehgal, MD, an oncologist at Dana-Farber Cancer Institute and Harvard University, both in Boston.

“With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease,” Dr. Sehgal said.

He authored an invited commentary in JAMA Network Openabout one of the latest meta-analyses (JAMA Netw Open. 2021;4[3]:e211136) to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. Dr. Sehgal emphasized the need to study hyperprogression in well-designed prospective studies.
 

Existing data on HPD

HPD was described as “a new pattern of progression” seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited “anecdotal occurrences” of HPD among patients in phase 1 trials of anti–PD-1/PD-L1 agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti–PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and reported at the time by this news organization, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population – worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

However, there is little so far to show for those efforts, Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

“Many questions remain to be answered,” said Dr. Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the division of cancer medicine at MD Anderson. He was the senior author of the “Fact, Fiction, or Alternative Fact?” commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, Dr. Subbiah and colleagues noted.

Other “proposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways,” noted Dr. Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Dr. Subbiah said.

The main challenge is defining HPD, he added. Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Dr. Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3,100 patients ranged from 5.9% to 43.1%.

“Hyperprogressive disease could be overestimated or underestimated based on current assessment,” Dr. Park and colleagues concluded. They highlighted the importance of “establishing uniform and clinically relevant criteria based on currently available evidence.”
 

Steps for solving the HPD mystery

“I think we need to come up with consensus criteria for an HPD definition. We need a unified definition,” Dr. Subbiah said. “We also need to design prospective studies to prove or disprove the immunotherapy-HPD association.”

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

“We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk,” he said. “We also need to know what to do if they are at risk.”

Dr. Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes “colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful,” he said.

Dr. Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, “sufficiently quantitative” criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Dr. Sehgal said.

“Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this ... so that interventions can be brought on earlier,” he said.

“If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD,” he said.

Dr. Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimated the true incidence of immunotherapy-related HPD will be in the 9%-10% range.

“This is a substantial number of patients, so it’s important that we try to understand this phenomenon, using, again, uniform criteria,” he said.
 

Current treatment decision-making

Until more is known, Dr. Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision-making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

“Is that the only factor that is going to make me choose one thing or another? No,” Dr. Sehgal said. However, he said it would make him more “proactive in making sure the patient is doing clinically okay” and in determining when to obtain on-treatment imaging studies.

Dr. Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

“Immunotherapy has been a game changer; it has been transformative in the lives of these patients,” Dr. Subbiah said. “So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD.”

A version of this article first appeared on Medscape.com.

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types. But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed “hyperprogressive disease” (HPD). It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a “provocative phenomenon,” wrote the authors of a recent commentary entitled “Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?”

“This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease,” said the author of another commentary.

But the tide is now turning toward acceptance of HPD, said Kartik Sehgal, MD, an oncologist at Dana-Farber Cancer Institute and Harvard University, both in Boston.

“With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease,” Dr. Sehgal said.

He authored an invited commentary in JAMA Network Openabout one of the latest meta-analyses (JAMA Netw Open. 2021;4[3]:e211136) to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. Dr. Sehgal emphasized the need to study hyperprogression in well-designed prospective studies.
 

Existing data on HPD

HPD was described as “a new pattern of progression” seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited “anecdotal occurrences” of HPD among patients in phase 1 trials of anti–PD-1/PD-L1 agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti–PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and reported at the time by this news organization, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population – worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

However, there is little so far to show for those efforts, Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

“Many questions remain to be answered,” said Dr. Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the division of cancer medicine at MD Anderson. He was the senior author of the “Fact, Fiction, or Alternative Fact?” commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, Dr. Subbiah and colleagues noted.

Other “proposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways,” noted Dr. Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Dr. Subbiah said.

The main challenge is defining HPD, he added. Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Dr. Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3,100 patients ranged from 5.9% to 43.1%.

“Hyperprogressive disease could be overestimated or underestimated based on current assessment,” Dr. Park and colleagues concluded. They highlighted the importance of “establishing uniform and clinically relevant criteria based on currently available evidence.”
 

Steps for solving the HPD mystery

“I think we need to come up with consensus criteria for an HPD definition. We need a unified definition,” Dr. Subbiah said. “We also need to design prospective studies to prove or disprove the immunotherapy-HPD association.”

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

“We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk,” he said. “We also need to know what to do if they are at risk.”

Dr. Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes “colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful,” he said.

Dr. Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, “sufficiently quantitative” criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Dr. Sehgal said.

“Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this ... so that interventions can be brought on earlier,” he said.

“If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD,” he said.

Dr. Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimated the true incidence of immunotherapy-related HPD will be in the 9%-10% range.

“This is a substantial number of patients, so it’s important that we try to understand this phenomenon, using, again, uniform criteria,” he said.
 

Current treatment decision-making

Until more is known, Dr. Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision-making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

“Is that the only factor that is going to make me choose one thing or another? No,” Dr. Sehgal said. However, he said it would make him more “proactive in making sure the patient is doing clinically okay” and in determining when to obtain on-treatment imaging studies.

Dr. Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

“Immunotherapy has been a game changer; it has been transformative in the lives of these patients,” Dr. Subbiah said. “So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD.”

A version of this article first appeared on Medscape.com.

Immunotherapy with checkpoint inhibitors has ushered in a new era of cancer therapy, with some patients showing dramatic responses and significantly better outcomes than with other therapies across many cancer types. But some patients do worse, sometimes much worse.

A subset of patients who undergo immunotherapy experience unexpected, rapid disease progression, with a dramatic acceleration of disease trajectory. They also have a shorter progression-free survival and overall survival than would have been expected.

This has been described as hyperprogression and has been termed “hyperprogressive disease” (HPD). It has been seen in a variety of cancers; the incidence ranges from 4% to 29% in the studies reported to date.

There has been some debate over whether this is a real phenomenon or whether it is part of the natural course of disease.

HPD is a “provocative phenomenon,” wrote the authors of a recent commentary entitled “Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?”

“This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease,” said the author of another commentary.

But the tide is now turning toward acceptance of HPD, said Kartik Sehgal, MD, an oncologist at Dana-Farber Cancer Institute and Harvard University, both in Boston.

“With publication of multiple clinical reports of different cancer types worldwide, hyperprogression is now accepted by most oncologists to be a true phenomenon rather than natural progression of disease,” Dr. Sehgal said.

He authored an invited commentary in JAMA Network Openabout one of the latest meta-analyses (JAMA Netw Open. 2021;4[3]:e211136) to investigate HPD during immunotherapy. One of the biggest issues is that the studies that have reported on HPD have been retrospective, with a lack of comparator groups and a lack of a standardized definition of hyperprogression. Dr. Sehgal emphasized the need to study hyperprogression in well-designed prospective studies.
 

Existing data on HPD

HPD was described as “a new pattern of progression” seen in patients undergoing immune checkpoint inhibitor therapy in a 2017 article published in Clinical Cancer Research. Authors Stephane Champiat, MD, PhD, of Institut Gustave Roussy, Universite Paris Saclay, Villejuif, France, and colleagues cited “anecdotal occurrences” of HPD among patients in phase 1 trials of anti–PD-1/PD-L1 agents.

In that study, HPD was defined by tumor growth rate ratio. The incidence was 9% among 213 patients.

The findings raised concerns about treating elderly patients with anti–PD-1/PD-L1 monotherapy, according to the authors, who called for further study.

That same year, Roberto Ferrara, MD, and colleagues from the Insitut Gustave Roussy reported additional data indicating an incidence of HPD of 16% among 333 patients with non–small cell lung cancer who underwent immunotherapy at eight centers from 2012 to 2017. The findings, which were presented at the 2017 World Conference on Lung Cancer and reported at the time by this news organization, also showed that the incidence of HPD was higher with immunotherapy than with single-agent chemotherapy (5%).

Median overall survival (OS) was just 3.4 months among those with HPD, compared with 13 months in the overall study population – worse, even, than the median 5.4-month OS observed among patients with progressive disease who received immunotherapy.

In the wake of these findings, numerous researchers have attempted to better define HPD, its incidence, and patient factors associated with developing HPD while undergoing immunotherapy.

However, there is little so far to show for those efforts, Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, Houston, said in an interview.

“Many questions remain to be answered,” said Dr. Subbiah, clinical medical director of the Clinical Center for Targeted Therapy in the division of cancer medicine at MD Anderson. He was the senior author of the “Fact, Fiction, or Alternative Fact?” commentary.

Work is underway to elucidate biological mechanisms. Some groups have implicated the Fc region of antibodies. Another group has reported EGFR and MDM2/MDM4 amplifications in patients with HPD, Dr. Subbiah and colleagues noted.

Other “proposed contributing pathological mechanisms include modulation of tumor immune microenvironment through macrophages and regulatory T cells as well as activation of oncogenic signaling pathways,” noted Dr. Sehgal.

Both groups of authors emphasize the urgent need for prospective studies.

It is imperative to confirm underlying biology, predict which patients are at risk, and identify therapeutic directions for patients who experience HPD, Dr. Subbiah said.

The main challenge is defining HPD, he added. Definitions that have been proposed include tumor growth at least two times greater than in control persons, a 15% increase in tumor burden in a set period, and disease progression of 50% from the first evaluation before treatment, he said.

The recent meta-analysis by Hyo Jung Park, MD, PhD, and colleagues, which Dr. Sehgal addressed in his invited commentary, highlights the many approaches used for defining HPD.

Depending on the definition used, the incidence of HPD across 24 studies involving more than 3,100 patients ranged from 5.9% to 43.1%.

“Hyperprogressive disease could be overestimated or underestimated based on current assessment,” Dr. Park and colleagues concluded. They highlighted the importance of “establishing uniform and clinically relevant criteria based on currently available evidence.”
 

Steps for solving the HPD mystery

“I think we need to come up with consensus criteria for an HPD definition. We need a unified definition,” Dr. Subbiah said. “We also need to design prospective studies to prove or disprove the immunotherapy-HPD association.”

Prospective registries with independent review of patients with suspected immunotherapy-related HPD would be useful for assessing the true incidence and the biology of HPD among patients undergoing immunotherapy, he suggested.

“We need to know the immunologic signals of HPD. This can give us an idea if patients can be prospectively identified for being at risk,” he said. “We also need to know what to do if they are at risk.”

Dr. Sehgal also called for consensus on an HPD definition, with input from a multidisciplinary group that includes “colleagues from radiology, medical oncology, radiation oncology. Getting expertise from different disciplines would be helpful,” he said.

Dr. Park and colleagues suggested several key requirements for an optimal HP definition, such as the inclusion of multiple variables for measuring tumor growth acceleration, “sufficiently quantitative” criteria for determining time to failure, and establishment of a standardized measure of tumor growth acceleration.

The agreed-upon definition of HPD could be applied to patients in a prospective registry and to existing trial data, Dr. Sehgal said.

“Eventually, the goal of this exercise is to [determine] how we can help our patients the best, having a biomarker that can at least inform us in terms of being aware and being proactive in terms of looking for this ... so that interventions can be brought on earlier,” he said.

“If we know what may be a biological mechanism, we can design trials that are designed to look at how to overcome that HPD,” he said.

Dr. Sehgal said he believes HPD is triggered in some way by treatment, including immunotherapy, chemotherapy, and targeted therapy, but perhaps in different ways for each.

He estimated the true incidence of immunotherapy-related HPD will be in the 9%-10% range.

“This is a substantial number of patients, so it’s important that we try to understand this phenomenon, using, again, uniform criteria,” he said.
 

Current treatment decision-making

Until more is known, Dr. Sehgal said he considers the potential risk factors when treating patients with immunotherapy.

For example, the presence of MDM2 or MDM4 amplification on a genomic profile may factor into his treatment decision-making when it comes to using immunotherapy or immunotherapy in combination with chemotherapy, he said.

“Is that the only factor that is going to make me choose one thing or another? No,” Dr. Sehgal said. However, he said it would make him more “proactive in making sure the patient is doing clinically okay” and in determining when to obtain on-treatment imaging studies.

Dr. Subbiah emphasized the relative benefit of immunotherapy, noting that survival with chemotherapy for many difficult-to-treat cancers in the relapsed/refractory metastatic setting is less than 2 years.

Immunotherapy with checkpoint inhibitors has allowed some of these patients to live longer (with survival reported to be more than 10 years for patients with metastatic melanoma).

“Immunotherapy has been a game changer; it has been transformative in the lives of these patients,” Dr. Subbiah said. “So unless there is any other contraindication, the benefit of receiving immunotherapy for an approved indication far outweighs the risk of HPD.”

A version of this article first appeared on Medscape.com.

Second-line treatment with sintilimab improved survival, when compared with docetaxel, in patients with advanced/metastatic squamous non–small cell lung cancer (sqNSCLC) in a phase 3 trial.

Sintilimab improved both overall survival (OS) and progression-free survival (PFS), according to Yuankai Shi, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.

Dr. Shi presented these findings, from the ORIENT-3 study, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT041).

ORIENT-3 enrolled and randomized 290 patients with stage IIIB/IIIC or IV sqNSCLC and disease progression during or after first-line platimum-based chemotherapy. They were randomized 1:1 to receive sintilimab at 200 mg or docetaxel at 75 mg/m²intravenously every 3 weeks until disease progression or intolerable toxicity.

The median age was 60 years in the sintilimab arm and 61 years in the docetaxel arm. A majority of patients were men (94% in the sintilimab arm and 90% in the docetaxel arm), most were current or former smokers (90% and 80%, respectively), and more than three-quarters had an ECOG performance status of 1 (76% and 77%, respectively). More than half of patients had a PD-L1 tumor proportion score (TPS) of 1% or greater (57% and 47%, respectively), and 81% of patients in both arms had stage IV disease.

Results: Survival and safety

Patients in the sintilimab arm received a median of 8.0 cycles of therapy (range, 1-45), and those in the docetaxel arm received a median of 2.0 cycles of therapy (range, 1-15).

At a median follow-up of 23.56 months, the median OS was significantly longer in the sintilimab arm than in the docetaxel arm – 11.79 months and 8.25 months, respectively (hazard ratio, 0.74; P = .02489). OS benefits were generally consistent across subgroups.

The secondary endpoints of PFS and objective response rate also favored sintilimab, Dr. Shi reported.

The median PFS was 4.30 months in the sintilimab arm and 2.79 months in the docetaxel arm (HR, 0.52; P < .00001). Confirmed objective response rates were 25.5% and 2.2%, respectively; the median duration of response was 12.45 months and 4.14 months, respectively; and disease control rates were 65.5% and 37.8%, respectively.

“Sintilimab had a favorable safety profile over docetaxel, with a lower frequency of grade 3 or higher treatment-related adverse events, with no new safety signals observed,” Dr. Shi said.

Treatment-related adverse events (TRAEs) occurred in 84.7% of patients receiving sintilimab and 83.1% of those receiving docetaxel. Hypothyroidism was the most common TRAE in the sintilimab arm (18.1%), and alopecia was the most common TRAE in the docetaxel arm (34.6%).

Grade 3 or higher TRAEs were less frequent in the sintilimab arm than in the docetaxel arm (18.1% vs. 36.2%). Rates of discontinuation because of TRAEs were 12.5% and 5.4% in the sintilimab and docetaxel arms, respectively. TRAEs leading to death occurred in five patients in the sintilimab arm and one in the docetaxel arm.

Use in the real world

Noting sintilimab’s significant OS and PFS benefits as well as superior response rate and duration of response, Dr. Shi concluded, “Sintilimab might provide an alternative second-line treatment option for advanced and metastatic sqNSCLC.”

AACR moderator Marina Garassino, MD, of the University of Chicago, commented on the potential utility of sintilimab and tislelizumab, another checkpoint inhibitor that was evaluated in NSCLC in the RATIONALE 303 trial (AACR 2021, Abstract CT039). Dr. Garassino observed that both drugs have demonstrated superiority to docetaxel as second-line therapy in NSCLC.

Although there have been no head-to-head trials, sintilimab and tislelizumab appear to be very similar to the already approved immune checkpoint inhibitors, which are currently being used as first-line treatment.

“That similarity would make them inappropriate for second-line treatment, except in countries where immune checkpoint inhibitors are not yet approved for first-line therapy,” Dr. Garassino noted.

When asked to comment on the higher treatment-related death rate observed with sintilimab, Dr. Garassino said, “We need to remember that these drugs were developed in China with a population that may have a side effect profile differing from that of a Western population. Also, we are very familiar with this class of drugs and know how to treat their side effects. Similar drugs but different populations and different trials, so it’s very hard to judge.”

Dr. Garassino speculated that with the “super expensive” price tags on the new checkpoint inhibitors, having additional agents that could provide choice and drive prices down would be welcome.

ORIENT-3 was funded by Innovent Biologics and Eli Lilly. Dr. Shi disclosed consultancy for Innovent Biologics. Dr. Garassino disclosed relationships with Eli Lilly, AstraZeneca, Novartis, and several other companies, not including Innovent Biologics.

Second-line treatment with sintilimab improved survival, when compared with docetaxel, in patients with advanced/metastatic squamous non–small cell lung cancer (sqNSCLC) in a phase 3 trial.

Sintilimab improved both overall survival (OS) and progression-free survival (PFS), according to Yuankai Shi, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.

Dr. Shi presented these findings, from the ORIENT-3 study, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT041).

ORIENT-3 enrolled and randomized 290 patients with stage IIIB/IIIC or IV sqNSCLC and disease progression during or after first-line platimum-based chemotherapy. They were randomized 1:1 to receive sintilimab at 200 mg or docetaxel at 75 mg/m²intravenously every 3 weeks until disease progression or intolerable toxicity.

The median age was 60 years in the sintilimab arm and 61 years in the docetaxel arm. A majority of patients were men (94% in the sintilimab arm and 90% in the docetaxel arm), most were current or former smokers (90% and 80%, respectively), and more than three-quarters had an ECOG performance status of 1 (76% and 77%, respectively). More than half of patients had a PD-L1 tumor proportion score (TPS) of 1% or greater (57% and 47%, respectively), and 81% of patients in both arms had stage IV disease.

Results: Survival and safety

Patients in the sintilimab arm received a median of 8.0 cycles of therapy (range, 1-45), and those in the docetaxel arm received a median of 2.0 cycles of therapy (range, 1-15).

At a median follow-up of 23.56 months, the median OS was significantly longer in the sintilimab arm than in the docetaxel arm – 11.79 months and 8.25 months, respectively (hazard ratio, 0.74; P = .02489). OS benefits were generally consistent across subgroups.

The secondary endpoints of PFS and objective response rate also favored sintilimab, Dr. Shi reported.

The median PFS was 4.30 months in the sintilimab arm and 2.79 months in the docetaxel arm (HR, 0.52; P < .00001). Confirmed objective response rates were 25.5% and 2.2%, respectively; the median duration of response was 12.45 months and 4.14 months, respectively; and disease control rates were 65.5% and 37.8%, respectively.

“Sintilimab had a favorable safety profile over docetaxel, with a lower frequency of grade 3 or higher treatment-related adverse events, with no new safety signals observed,” Dr. Shi said.

Treatment-related adverse events (TRAEs) occurred in 84.7% of patients receiving sintilimab and 83.1% of those receiving docetaxel. Hypothyroidism was the most common TRAE in the sintilimab arm (18.1%), and alopecia was the most common TRAE in the docetaxel arm (34.6%).

Grade 3 or higher TRAEs were less frequent in the sintilimab arm than in the docetaxel arm (18.1% vs. 36.2%). Rates of discontinuation because of TRAEs were 12.5% and 5.4% in the sintilimab and docetaxel arms, respectively. TRAEs leading to death occurred in five patients in the sintilimab arm and one in the docetaxel arm.

Use in the real world

Noting sintilimab’s significant OS and PFS benefits as well as superior response rate and duration of response, Dr. Shi concluded, “Sintilimab might provide an alternative second-line treatment option for advanced and metastatic sqNSCLC.”

AACR moderator Marina Garassino, MD, of the University of Chicago, commented on the potential utility of sintilimab and tislelizumab, another checkpoint inhibitor that was evaluated in NSCLC in the RATIONALE 303 trial (AACR 2021, Abstract CT039). Dr. Garassino observed that both drugs have demonstrated superiority to docetaxel as second-line therapy in NSCLC.

Although there have been no head-to-head trials, sintilimab and tislelizumab appear to be very similar to the already approved immune checkpoint inhibitors, which are currently being used as first-line treatment.

“That similarity would make them inappropriate for second-line treatment, except in countries where immune checkpoint inhibitors are not yet approved for first-line therapy,” Dr. Garassino noted.

When asked to comment on the higher treatment-related death rate observed with sintilimab, Dr. Garassino said, “We need to remember that these drugs were developed in China with a population that may have a side effect profile differing from that of a Western population. Also, we are very familiar with this class of drugs and know how to treat their side effects. Similar drugs but different populations and different trials, so it’s very hard to judge.”

Dr. Garassino speculated that with the “super expensive” price tags on the new checkpoint inhibitors, having additional agents that could provide choice and drive prices down would be welcome.

ORIENT-3 was funded by Innovent Biologics and Eli Lilly. Dr. Shi disclosed consultancy for Innovent Biologics. Dr. Garassino disclosed relationships with Eli Lilly, AstraZeneca, Novartis, and several other companies, not including Innovent Biologics.

Second-line treatment with sintilimab improved survival, when compared with docetaxel, in patients with advanced/metastatic squamous non–small cell lung cancer (sqNSCLC) in a phase 3 trial.

Sintilimab improved both overall survival (OS) and progression-free survival (PFS), according to Yuankai Shi, MD, of the Chinese Academy of Medical Sciences & Peking Union Medical College in Beijing.

Dr. Shi presented these findings, from the ORIENT-3 study, at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT041).

ORIENT-3 enrolled and randomized 290 patients with stage IIIB/IIIC or IV sqNSCLC and disease progression during or after first-line platimum-based chemotherapy. They were randomized 1:1 to receive sintilimab at 200 mg or docetaxel at 75 mg/m²intravenously every 3 weeks until disease progression or intolerable toxicity.

The median age was 60 years in the sintilimab arm and 61 years in the docetaxel arm. A majority of patients were men (94% in the sintilimab arm and 90% in the docetaxel arm), most were current or former smokers (90% and 80%, respectively), and more than three-quarters had an ECOG performance status of 1 (76% and 77%, respectively). More than half of patients had a PD-L1 tumor proportion score (TPS) of 1% or greater (57% and 47%, respectively), and 81% of patients in both arms had stage IV disease.

Results: Survival and safety

Patients in the sintilimab arm received a median of 8.0 cycles of therapy (range, 1-45), and those in the docetaxel arm received a median of 2.0 cycles of therapy (range, 1-15).

At a median follow-up of 23.56 months, the median OS was significantly longer in the sintilimab arm than in the docetaxel arm – 11.79 months and 8.25 months, respectively (hazard ratio, 0.74; P = .02489). OS benefits were generally consistent across subgroups.

The secondary endpoints of PFS and objective response rate also favored sintilimab, Dr. Shi reported.

The median PFS was 4.30 months in the sintilimab arm and 2.79 months in the docetaxel arm (HR, 0.52; P < .00001). Confirmed objective response rates were 25.5% and 2.2%, respectively; the median duration of response was 12.45 months and 4.14 months, respectively; and disease control rates were 65.5% and 37.8%, respectively.

“Sintilimab had a favorable safety profile over docetaxel, with a lower frequency of grade 3 or higher treatment-related adverse events, with no new safety signals observed,” Dr. Shi said.

Treatment-related adverse events (TRAEs) occurred in 84.7% of patients receiving sintilimab and 83.1% of those receiving docetaxel. Hypothyroidism was the most common TRAE in the sintilimab arm (18.1%), and alopecia was the most common TRAE in the docetaxel arm (34.6%).

Grade 3 or higher TRAEs were less frequent in the sintilimab arm than in the docetaxel arm (18.1% vs. 36.2%). Rates of discontinuation because of TRAEs were 12.5% and 5.4% in the sintilimab and docetaxel arms, respectively. TRAEs leading to death occurred in five patients in the sintilimab arm and one in the docetaxel arm.

Use in the real world

Noting sintilimab’s significant OS and PFS benefits as well as superior response rate and duration of response, Dr. Shi concluded, “Sintilimab might provide an alternative second-line treatment option for advanced and metastatic sqNSCLC.”

AACR moderator Marina Garassino, MD, of the University of Chicago, commented on the potential utility of sintilimab and tislelizumab, another checkpoint inhibitor that was evaluated in NSCLC in the RATIONALE 303 trial (AACR 2021, Abstract CT039). Dr. Garassino observed that both drugs have demonstrated superiority to docetaxel as second-line therapy in NSCLC.

Although there have been no head-to-head trials, sintilimab and tislelizumab appear to be very similar to the already approved immune checkpoint inhibitors, which are currently being used as first-line treatment.

“That similarity would make them inappropriate for second-line treatment, except in countries where immune checkpoint inhibitors are not yet approved for first-line therapy,” Dr. Garassino noted.

When asked to comment on the higher treatment-related death rate observed with sintilimab, Dr. Garassino said, “We need to remember that these drugs were developed in China with a population that may have a side effect profile differing from that of a Western population. Also, we are very familiar with this class of drugs and know how to treat their side effects. Similar drugs but different populations and different trials, so it’s very hard to judge.”

Dr. Garassino speculated that with the “super expensive” price tags on the new checkpoint inhibitors, having additional agents that could provide choice and drive prices down would be welcome.

ORIENT-3 was funded by Innovent Biologics and Eli Lilly. Dr. Shi disclosed consultancy for Innovent Biologics. Dr. Garassino disclosed relationships with Eli Lilly, AstraZeneca, Novartis, and several other companies, not including Innovent Biologics.

The Food and Drug Administration said that within a year it will ban menthol in cigarettes and ban all flavors including menthol in cigars.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Menthol makes it easier to start smoking, and also enhances the effects of nicotine, making it more addictive and harder to quit, the FDA said in announcing its actions on Thursday.

Nineteen organizations – including the American Academy of Pediatrics, American Cancer Society, American College of Chest Physicians, American Medical Association, American Heart Association, and the National Medical Association – have pushed the FDA to ban menthol for years. The agency banned all flavors in cigarettes in 2009 but did not take any action against menthol. In 2013, the groups filed a petition demanding that the FDA ban menthol, too. The agency responded months later with a notice that it would start the process.

But it never took any action. Action on Smoking and Health and the African American Tobacco Control Leadership Council, later joined by the AMA and the NMA, sued in 2020 to compel the agency to do something. Now it has finally agreed to act.

The African American Tobacco Control Leadership Council welcomed the move but said the fight is not over and encouraged tobacco control activists to fight to ban menthol tobacco products at the local, state and federal level. “We know that this rule-making process could take years and we know that the tobacco industry will continue to do everything in their power to derail any attempt to remove their deadly products from the market,” Phillip Gardiner, MD, council cochair, said in a statement.

The AMA is urging the FDA to quickly implement the ban and remove the products “without further delay,” AMA President Susan R. Bailey, MD, said in a statement.

“FDA’s long-awaited decision to take action to eliminate menthol flavoring in cigarettes and all flavors in cigars ends a decades-long deference to the tobacco industry, which has repeatedly demonstrated its willingness to profit from products that result in death,” Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said in her own statement.

Ms. Lacasse said banning menthol will help eliminate health disparities. She said 86% of Black people who smoke use menthol cigarettes, compared with 46% of Hispanic people who smoke, 39% of Asian people who smoke, and 29% of White people who smoke. “FDA’s actions today send a clear message that Big Tobacco’s strategy to profit off addicting Black communities will no longer be tolerated,” she said.

Not all groups are on board, however. The American Civil Liberties Union and several other organizations wrote to the country’s top health officials urging them to reconsider.

“Such a ban will trigger criminal penalties which will disproportionately impact people of color, as well as prioritize criminalization over public health and harm reduction,” the letter says. “A ban will also lead to unconstitutional policing and other negative interactions with local law enforcement.”

The letter calls the proposed ban “well intentioned,” but said any effort to reduce death and disease from tobacco “must avoid solutions that will create yet another reason for armed police to engage citizens on the street based on pretext or conduct that does not pose a threat to public safety.”

Instead of a ban, the organizations said, policy makers should consider increased education for adults and minors, stop-smoking programs, and increased funding for health centers in communities of color.

The Biden administration, however, pressed the point that banning menthol will bring many positives. Acting FDA Commissioner Janet Woodcock, MD said in a statement that banning menthol “will help significantly reduce youth initiation, increase the chances of smoking cessation among current smokers, and address health disparities experienced by communities of color, low-income populations, and LGBTQ-plus individuals, all of whom are far more likely to use these tobacco products.”

The FDA cited data showing that, in the first year or so after a ban goes into effect, an additional 923,000 smokers would quit, including 230,000 African Americans. Another study suggests that 633,000 deaths would be averted, including 237,000 Black Americans.

Dr. Woodcock added that, “armed with strong scientific evidence, and with full support from the [Biden] administration, we believe these actions will launch us on a trajectory toward ending tobacco-related disease and death in the U.S.”

The FDA estimates that 18.6 million Americans who are current smokers use menthol cigarettes, with a disproportionately high number being Black people. Menthol cigarette use among Black and Hispanic youth increased from 2011 to 2018, but declined for non-Hispanic White youth.

Flavored mass-produced cigars and cigarillos are disproportionately popular among youth, especially non-Hispanic Black high school students, who in 2020 reported past 30-day cigar smoking at levels twice as high as their White counterparts, said the FDA. Three-quarters of 12- to 17-year-olds reported they smoke cigars because they like the flavors. In 2020, more young people tried a cigar every day than tried a cigarette, reports the agency.

“This long-overdue decision will protect future generations of young people from nicotine addiction, especially Black children and communities, which have disproportionately suffered from menthol tobacco use due to targeted efforts from the tobacco industry,” Lee Savio Beers, MD, president of the American Academy of Pediatrics, said in a statement.

The FDA’s announcement “is only a first step that must be followed with urgent, comprehensive action to remove these flavored products from the market,” he said.

A version of this article first appeared on WebMD.com.

The Food and Drug Administration said that within a year it will ban menthol in cigarettes and ban all flavors including menthol in cigars.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Menthol makes it easier to start smoking, and also enhances the effects of nicotine, making it more addictive and harder to quit, the FDA said in announcing its actions on Thursday.

Nineteen organizations – including the American Academy of Pediatrics, American Cancer Society, American College of Chest Physicians, American Medical Association, American Heart Association, and the National Medical Association – have pushed the FDA to ban menthol for years. The agency banned all flavors in cigarettes in 2009 but did not take any action against menthol. In 2013, the groups filed a petition demanding that the FDA ban menthol, too. The agency responded months later with a notice that it would start the process.

But it never took any action. Action on Smoking and Health and the African American Tobacco Control Leadership Council, later joined by the AMA and the NMA, sued in 2020 to compel the agency to do something. Now it has finally agreed to act.

The African American Tobacco Control Leadership Council welcomed the move but said the fight is not over and encouraged tobacco control activists to fight to ban menthol tobacco products at the local, state and federal level. “We know that this rule-making process could take years and we know that the tobacco industry will continue to do everything in their power to derail any attempt to remove their deadly products from the market,” Phillip Gardiner, MD, council cochair, said in a statement.

The AMA is urging the FDA to quickly implement the ban and remove the products “without further delay,” AMA President Susan R. Bailey, MD, said in a statement.

“FDA’s long-awaited decision to take action to eliminate menthol flavoring in cigarettes and all flavors in cigars ends a decades-long deference to the tobacco industry, which has repeatedly demonstrated its willingness to profit from products that result in death,” Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said in her own statement.

Ms. Lacasse said banning menthol will help eliminate health disparities. She said 86% of Black people who smoke use menthol cigarettes, compared with 46% of Hispanic people who smoke, 39% of Asian people who smoke, and 29% of White people who smoke. “FDA’s actions today send a clear message that Big Tobacco’s strategy to profit off addicting Black communities will no longer be tolerated,” she said.

Not all groups are on board, however. The American Civil Liberties Union and several other organizations wrote to the country’s top health officials urging them to reconsider.

“Such a ban will trigger criminal penalties which will disproportionately impact people of color, as well as prioritize criminalization over public health and harm reduction,” the letter says. “A ban will also lead to unconstitutional policing and other negative interactions with local law enforcement.”

The letter calls the proposed ban “well intentioned,” but said any effort to reduce death and disease from tobacco “must avoid solutions that will create yet another reason for armed police to engage citizens on the street based on pretext or conduct that does not pose a threat to public safety.”

Instead of a ban, the organizations said, policy makers should consider increased education for adults and minors, stop-smoking programs, and increased funding for health centers in communities of color.

The Biden administration, however, pressed the point that banning menthol will bring many positives. Acting FDA Commissioner Janet Woodcock, MD said in a statement that banning menthol “will help significantly reduce youth initiation, increase the chances of smoking cessation among current smokers, and address health disparities experienced by communities of color, low-income populations, and LGBTQ-plus individuals, all of whom are far more likely to use these tobacco products.”

The FDA cited data showing that, in the first year or so after a ban goes into effect, an additional 923,000 smokers would quit, including 230,000 African Americans. Another study suggests that 633,000 deaths would be averted, including 237,000 Black Americans.

Dr. Woodcock added that, “armed with strong scientific evidence, and with full support from the [Biden] administration, we believe these actions will launch us on a trajectory toward ending tobacco-related disease and death in the U.S.”

The FDA estimates that 18.6 million Americans who are current smokers use menthol cigarettes, with a disproportionately high number being Black people. Menthol cigarette use among Black and Hispanic youth increased from 2011 to 2018, but declined for non-Hispanic White youth.

Flavored mass-produced cigars and cigarillos are disproportionately popular among youth, especially non-Hispanic Black high school students, who in 2020 reported past 30-day cigar smoking at levels twice as high as their White counterparts, said the FDA. Three-quarters of 12- to 17-year-olds reported they smoke cigars because they like the flavors. In 2020, more young people tried a cigar every day than tried a cigarette, reports the agency.

“This long-overdue decision will protect future generations of young people from nicotine addiction, especially Black children and communities, which have disproportionately suffered from menthol tobacco use due to targeted efforts from the tobacco industry,” Lee Savio Beers, MD, president of the American Academy of Pediatrics, said in a statement.

The FDA’s announcement “is only a first step that must be followed with urgent, comprehensive action to remove these flavored products from the market,” he said.

A version of this article first appeared on WebMD.com.

The Food and Drug Administration said that within a year it will ban menthol in cigarettes and ban all flavors including menthol in cigars.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

Menthol makes it easier to start smoking, and also enhances the effects of nicotine, making it more addictive and harder to quit, the FDA said in announcing its actions on Thursday.

Nineteen organizations – including the American Academy of Pediatrics, American Cancer Society, American College of Chest Physicians, American Medical Association, American Heart Association, and the National Medical Association – have pushed the FDA to ban menthol for years. The agency banned all flavors in cigarettes in 2009 but did not take any action against menthol. In 2013, the groups filed a petition demanding that the FDA ban menthol, too. The agency responded months later with a notice that it would start the process.

But it never took any action. Action on Smoking and Health and the African American Tobacco Control Leadership Council, later joined by the AMA and the NMA, sued in 2020 to compel the agency to do something. Now it has finally agreed to act.

The African American Tobacco Control Leadership Council welcomed the move but said the fight is not over and encouraged tobacco control activists to fight to ban menthol tobacco products at the local, state and federal level. “We know that this rule-making process could take years and we know that the tobacco industry will continue to do everything in their power to derail any attempt to remove their deadly products from the market,” Phillip Gardiner, MD, council cochair, said in a statement.

The AMA is urging the FDA to quickly implement the ban and remove the products “without further delay,” AMA President Susan R. Bailey, MD, said in a statement.

“FDA’s long-awaited decision to take action to eliminate menthol flavoring in cigarettes and all flavors in cigars ends a decades-long deference to the tobacco industry, which has repeatedly demonstrated its willingness to profit from products that result in death,” Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said in her own statement.

Ms. Lacasse said banning menthol will help eliminate health disparities. She said 86% of Black people who smoke use menthol cigarettes, compared with 46% of Hispanic people who smoke, 39% of Asian people who smoke, and 29% of White people who smoke. “FDA’s actions today send a clear message that Big Tobacco’s strategy to profit off addicting Black communities will no longer be tolerated,” she said.

Not all groups are on board, however. The American Civil Liberties Union and several other organizations wrote to the country’s top health officials urging them to reconsider.

“Such a ban will trigger criminal penalties which will disproportionately impact people of color, as well as prioritize criminalization over public health and harm reduction,” the letter says. “A ban will also lead to unconstitutional policing and other negative interactions with local law enforcement.”

The letter calls the proposed ban “well intentioned,” but said any effort to reduce death and disease from tobacco “must avoid solutions that will create yet another reason for armed police to engage citizens on the street based on pretext or conduct that does not pose a threat to public safety.”

Instead of a ban, the organizations said, policy makers should consider increased education for adults and minors, stop-smoking programs, and increased funding for health centers in communities of color.

The Biden administration, however, pressed the point that banning menthol will bring many positives. Acting FDA Commissioner Janet Woodcock, MD said in a statement that banning menthol “will help significantly reduce youth initiation, increase the chances of smoking cessation among current smokers, and address health disparities experienced by communities of color, low-income populations, and LGBTQ-plus individuals, all of whom are far more likely to use these tobacco products.”

The FDA cited data showing that, in the first year or so after a ban goes into effect, an additional 923,000 smokers would quit, including 230,000 African Americans. Another study suggests that 633,000 deaths would be averted, including 237,000 Black Americans.

Dr. Woodcock added that, “armed with strong scientific evidence, and with full support from the [Biden] administration, we believe these actions will launch us on a trajectory toward ending tobacco-related disease and death in the U.S.”

The FDA estimates that 18.6 million Americans who are current smokers use menthol cigarettes, with a disproportionately high number being Black people. Menthol cigarette use among Black and Hispanic youth increased from 2011 to 2018, but declined for non-Hispanic White youth.

Flavored mass-produced cigars and cigarillos are disproportionately popular among youth, especially non-Hispanic Black high school students, who in 2020 reported past 30-day cigar smoking at levels twice as high as their White counterparts, said the FDA. Three-quarters of 12- to 17-year-olds reported they smoke cigars because they like the flavors. In 2020, more young people tried a cigar every day than tried a cigarette, reports the agency.

“This long-overdue decision will protect future generations of young people from nicotine addiction, especially Black children and communities, which have disproportionately suffered from menthol tobacco use due to targeted efforts from the tobacco industry,” Lee Savio Beers, MD, president of the American Academy of Pediatrics, said in a statement.

The FDA’s announcement “is only a first step that must be followed with urgent, comprehensive action to remove these flavored products from the market,” he said.

A version of this article first appeared on WebMD.com.

Nivolumab continues to demonstrate a substantial survival benefit over docetaxel at 5 years in advanced non-small cell lung cancer (NSCLC) patients who progressed on platinum-based therapies, according to a pooled analysis of two phase 3 trials published in the Journal of Clinical Oncology.

Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.

At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.

The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.

There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.

According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”

“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.

Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”

No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.

The optimal duration of nivolumab treatment beyond 1 year is also uncertain.

The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.

The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.

They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.

Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.

This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.

aotto@mdedge.com

Nivolumab continues to demonstrate a substantial survival benefit over docetaxel at 5 years in advanced non-small cell lung cancer (NSCLC) patients who progressed on platinum-based therapies, according to a pooled analysis of two phase 3 trials published in the Journal of Clinical Oncology.

Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.

At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.

The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.

There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.

According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”

“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.

Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”

No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.

The optimal duration of nivolumab treatment beyond 1 year is also uncertain.

The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.

The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.

They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.

Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.

This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.

aotto@mdedge.com

Nivolumab continues to demonstrate a substantial survival benefit over docetaxel at 5 years in advanced non-small cell lung cancer (NSCLC) patients who progressed on platinum-based therapies, according to a pooled analysis of two phase 3 trials published in the Journal of Clinical Oncology.

Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m² once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.

At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.

The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.

There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.

According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”

“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.

Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”

No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.

The optimal duration of nivolumab treatment beyond 1 year is also uncertain.

The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.

The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.

They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.

Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.

This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.

aotto@mdedge.com

As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.

The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.

Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.

In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.

The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
 

Study details

RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.

The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.

Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).

Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m² every 3 weeks (n = 270) until unacceptable toxicity or disease progression.

The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
 

Survival and safety

In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.

The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).

In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.

The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.

In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).

The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.

The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
 

‘Very important trial’

“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.

Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”

Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”

RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.

As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.

The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.

Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.

In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.

The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
 

Study details

RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.

The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.

Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).

Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m² every 3 weeks (n = 270) until unacceptable toxicity or disease progression.

The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
 

Survival and safety

In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.

The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).

In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.

The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.

In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).

The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.

The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
 

‘Very important trial’

“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.

Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”

Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”

RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.

As second- or third-line therapy in patients with locally advanced non–small cell lung cancer (NSCLC), tislelizumab was well tolerated and prolonged overall survival (OS), compared with docetaxel in the phase 3 RATIONALE 303 study.

The results were presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT039).

Tislelizumab is an anti–PD-1 antibody engineered to minimize Fc-gamma receptor binding on macrophages, a mechanism of T-cell clearance and potential anti–PD-1 resistance, according to investigator Caicun Zhou, MD, PhD, of Shanghai (China) Pulmonary Hospital.

Tislelizumab is approved for the treatment of relapsed/refractory classical Hodgkin lymphoma, the second-line treatment of locally advanced or metastatic urothelial carcinoma, and first-line treatment of advanced squamous NSCLC in China.

In patients with locally advanced or metastatic NSCLC whose disease has progressed after initial platinum-based chemotherapy, anti–PD-1/PD-L1 therapies have been shown to improve OS by 2-4 months versus docetaxel, Dr. Zhou said. A phase 1/2 study of second-line tislelizumab demonstrated antitumor activity in multiple advanced solid tumors, including NSCLC.

The phase 3 RATIONALE 303 study (NCT3358875) was designed to investigate the efficacy and safety of tislelizumab, compared with docetaxel in patients with locally advanced or metastatic NSCLC whose disease had progressed during or after platinum-containing doublet chemotherapy.
 

Study details

RATIONALE 303 enrolled 805 patients who had received up to two prior lines of systemic therapy and had no known EGFR mutations or ALK fusions.

The patients’ median age was 61 years, about 77% were male, about 80% were Asian, and about 70% were current or former smokers. Roughly 46% of patients had squamous histology, and about 43% had PD-L1 expression of 25% or greater.

Patients were stratified according to histology (squamous vs. nonsquamous), lines of prior therapy (second vs. third), and PD-L1 status (<25% vs. ≥25%).

Patients were randomized 2:1 to receive IV tislelizumab at 200 mg every 3 weeks (n = 535) or IV docetaxel at 75 mg/m² every 3 weeks (n = 270) until unacceptable toxicity or disease progression.

The dual primary endpoints were OS in the intention-to-treat (ITT) population and in patients with PD-L1 expression of 25% or higher.
 

Survival and safety

In the ITT population, the 1-year OS rate was 61.9% in the tislelizumab arm and 49.8% in the docetaxel arm. At 2 years, the OS rates were 39.4% and 25.0%, respectively.

The median OS was 17.2 months in the tislelizumab arm and 11.9 months in the docetaxel arm (hazard ratio, 0.64; 95% CI, 0.53-0.78; P < .0001).

In the PD-L1–high subgroup, the median OS was 19.1 months with tislelizumab and 11.9 months with docetaxel (HR, 0.52; 95% CI, 0.38-0.71; P < .0001). The 1-year OS rates in this group were 67.5% and 49.1%, respectively, and the 2-year OS rates were 44.7% and 24.5%, respectively.

The OS benefit with tislelizumab was observed across nearly all subgroups, Dr. Zhou noted.

In the ITT population, benefits were seen with tislelizumab over docetaxel for progression-free survival (4.1 months vs. 2.6 months, P < .0001), objective response rate (21.9% vs. 7.1%, P < .0001), and median duration of response (13.5 months vs. 6.2 months, P < .0001).

The rate of treatment-related adverse events (TRAEs) was 73.0% in the tislelizumab arm and 93.8% in the docetaxel arm. Rates of grade 3 or higher TRAEs were 14.4% and 66.3%, respectively. Rates of TRAEs leading to permanent discontinuation of treatment were 6.0% and 9.7%, respectively, and rates of TRAEs leading to death were 1.5% and 1.6%, respectively.

The most common treatment-emergent adverse events were anemia in the tislelizumab arm (28.5%) and alopecia in the docetaxel arm (47.3%). The most common grade 3 or higher treatment-emergent adverse event was neutropenia in the docetaxel arm (27.9% vs. 0.6% with tislelizumab).
 

‘Very important trial’

“RATIONALE 303 demonstrated that, as second- or third-line therapy in patients with advanced NSCLC, tislelizumab was tolerable and prolonged overall survival by 5-7 months. It also improved progression-free survival and objective response rate versus docetaxel, regardless of histology or PD-L1 expression,” Dr. Zhou concluded.

Session moderator Marina Chiara Garassino, MD, of the University of Chicago called RATIONALE 303 a “very important trial.”

Citing the range of immunotherapies available for NSCLC, Dr. Garassino said, “We have a very crowded space in the treatment of NSCLC. ... It is difficult to do a direct comparison [of immunotherapy trials] because we know that populations can be different and other factors can play a role. In the near future, we have to understand if they are all the same and interchangeable or if they are different.”

RATIONALE 303 was funded by BeiGene. Dr. Zhou disclosed relationships with Lily China, Sanofi, Roche, and several other companies, not including BeiGene. Dr. Garassino disclosed relationships with AstraZeneca, Novartis, Bristol-Myers Squibb, and several other companies, not including BeiGene.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Research suggests certain gut bacteria can reduce the efficacy of radiotherapy against cancers, but targeting those bacteria with vancomycin can reverse this effect.

Andrea Facciabene, PhD, of the University of Pennsylvania, Philadelphia, and colleagues conducted a preclinical study in which vancomycin enhanced the efficacy of radiotherapy against melanoma and lung cancer. Now, researchers are conducting a clinical trial to determine if vancomycin can have the same effect in patients with non–small cell lung cancer.

Dr. Facciabene reviewed this research at the AACR Virtual Special Conference: Radiation Science and Medicine.

According to Dr. Facciabene, “gut microbiota” includes the more than 1,000 different strains of bacteria living in human intestines. He indicated that the average human has 10 times more bacteria than cells in the body and 150 times more genes in the gut microbiome than in the human genome.

In healthy individuals, the gut microbiota play a key role in intestinal function and digestive processes, modulation of hormones and vitamin secretion, energy extraction from food, and development and maintenance of a balanced immune system.

“Dysbiosis” is the term applied to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to one associated with disease. Antibiotic therapy is a classic cause of dysbiosis, and dysbiosis has been implicated in a variety of inflammatory diseases.

The mechanisms by which the gut microbiome could influence systemic immunity is not known but is relevant to cancer therapy response. Augmenting the frequency and durability of response to immune-targeted treatments – potentially by manipulating the influence of gut microbiota on the immune system – could be highly impactful.
 

Gut microbiota and radiation-induced cell death

Immunogenic cell death – a process by which tumors die and release their intracellular molecular contents – is one of the mechanisms by which radiotherapy kills cancer cells.

Tumor cells succumbing to immunogenic cell death stimulate antigen presenting cells, such as dendritic cells, that engulf tumor antigens and cross-present them to CD8+ cytotoxic T lymphocytes. This process culminates in the generation of a specific immune response capable of killing the malignant cells in the irradiated area, but it also impacts distant nonirradiated tumors – an abscopal effect.

Dr. Facciabene and colleagues hypothesized that alterations of the gut microbiota could have an impact on the effect of radiotherapy. To investigate this, they studied mouse models of melanoma.

The team allowed B16-OVA tumors to grow for 9-12 days, then delivered a single dose of radiotherapy (21 Gy) to one – but not all – tumors. Simultaneously with the delivery of radiotherapy, the investigators started some animals on oral vancomycin. The team chose vancomycin because its effects are localized and impact the gut microbiota directly, without any known systemic effects.

Results showed that vancomycin significantly augmented the impact of radiotherapy in the irradiated area and was associated with regression of remote tumors.

The effects of the combination treatment on tumor volume were significantly greater than the effects of either treatment alone. Since manipulation of the gut microbiome potentiated radiotherapy effects both locally and distantly, the investigators concluded that immunogenic cell death may be involved in both the local and abscopal effects of radiotherapy.

When the experiment was repeated with a lung tumor model, similar findings were observed.
 

Involvement of cytotoxic T cells and interferon-gamma

Dr. Facciabene and colleagues found that the irradiated and unirradiated B16 OVA melanoma tumors treated with the radiotherapy-vancomycin combination were infiltrated by CD3+ and CD8+ T cells.

The investigators selectively depleted CD8+ T cells by pretreating the mice with an anti-CD8 monoclonal antibody. Depletion of CD8+ cells prior to administering radiotherapy plus vancomycin abrogated the antitumor effects of the combination treatment, demonstrating that the CD8+ T cells were required.

To characterize the antigen specificity of the tumor-infiltrating CD8+ T cells, Dr. Facciabene and colleagues used OVA MHC class 1 tetramer. Tumors from mice treated with vancomycin alone, radiotherapy alone, or the combination were dissected. Individual dendritic cells were assayed for OVA tetramer by flow cytometry.

The investigators found that tumors from mice treated with radiotherapy plus vancomycin had a significantly higher number of OVA-specific CD8+ T cells, in comparison with untreated tumors or tumors treated with either vancomycin alone or radiotherapy alone. Since antibody that impaired recognition of MHC class I peptides by T cells ablated the effect, it was clear that antigen recognition was vital.

Interferon-gamma (IFN-gamma) is known to play a critical role in both differentiation and effector functions of CD8+ cytolytic T cells in the antitumor immune response. To determine whether IFN-gamma is involved in the antitumor effects of the radiotherapy-vancomycin combination, the investigators measured intratumoral expression of IFN-gamma in the tumors 5 days after radiotherapy.

IFN-gamma messenger RNA expression levels were significantly elevated in the combination treatment group when compared with either treatment alone. In B16-OVA melanoma–challenged knockout mice, the enhancement of the radiotherapy effects by vancomycin was ablated.

The investigators concluded that vancomycin remodels the tumor microenvironment and increases the functionality of tumor-infiltrating, tumor-specific, CD8+ T cells. Furthermore, IFN-gamma is required to augment the radiotherapy-induced immune effect against the tumor.
 

Potential biochemical mediators of immune effects

The gut microbiota aid host digestion and generate a large repertoire of metabolites after defermentation of fiber. Short-chain fatty acids (SCFAs) constitute the major products of bacterial fermentation.

Acetic acid, propionic acid, and butyric acid represent 95% of total SCFAs present in the intestine. SCFAs are known to directly modulate cytokine production and dendritic cell function.

In their study, Dr. Facciabene and colleagues focused on butyric acid. Using mass spectroscopy, they demonstrated that vancomycin treatment reduces butyrate concentrations in tumor and tumor-draining lymph nodes by eradicating the major families of SCFA-producing Clostridia species.

To test whether supplementing butyrate could influence the synergy of the radiotherapy-vancomycin combination in vivo, the investigators added sodium butyrate to the mice’s drinking water when starting vancomycin treatment. The team then challenged the mice with B16-OVA tumors and treated them with radiotherapy.

In agreement with the group’s prior findings, vancomycin enhanced the tumor-inhibitory effects of radiotherapy, but dietary butyrate inhibited the benefit. The investigators found a significant decrease in the population of B16-OVA–presenting dendritic cells in the lymph nodes of mice receiving the supplemental butyrate.

Dr. Facciabene said these findings were supported by a recent publication. The authors observed that butyrate inhibited type I IFN expression in dendritic cells and radiotherapy-induced, tumor-specific cytotoxic T-cell immune responses without directly protecting tumor cells from the cytotoxic effects of radiotherapy.
 

Wide-ranging implications

Overall, Dr. Facciabene’s research has shown that:

• Vancomycin significantly enhances the tumor inhibitory effect of targeted radiation, including abscopal effects.
• The synergistic effects are dependent upon IFN-gamma and CD8+ cells.
• Depletion of some gut microbiome species increases antigen presentation by dendritic cells. This is mediated by SCFAs produced by certain bacterial families.
• There are promising new strategies to improve responses to radiotherapy, including targeting gut microbiota.

A clinical trial (NCT03546829) of vancomycin plus stereotactic body radiation in patients with locally advanced non–small cell lung cancer has been launched to investigate these findings further. Early data analysis has shown a significant impact of vancomycin on several species of gut microbiota, according to Dr. Facciabene.

Revolutionary results from immune-targeted therapy in the recent past have highlighted the important role the immune system can play in fighting cancer. Still, up to one-third of cancer patients fail to respond to overtly immune-targeted therapy.

The ability to inhibit cancer cells from evading immune surveillance by using new adjuvants – including those acting on non-traditional targets like gut microbiota – could herald the next major advances in cancer therapy. During his presentation, Dr. Facciabene gave participants an enticing hint of what could be coming for cancer patients in the years ahead.

Dr. Facciabene reported having no relevant disclosures.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Hopes for a new category of agents recently hailed as “a triumph of drug discovery” have been dimmed somewhat by new data showing many types of acquired resistance.

KRAS is one of the most frequently mutated oncogenes in human cancer and has long been thought “undruggable” – but novel drugs acting specifically on the KRAS G12C mutation have shown promise in clinical trials.

Early results with the experimental KRAS inhibitors sotorasib and adagrasib were deemed promising, but new data presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB002) have splashed cold water on that enthusiasm.

The efficacy of these new drugs looks to be threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Mark M. Awad, MD, PhD, from the Dana-Farber Cancer Institute in Boston, reported data from 30 patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) bearing the KRAS G12C mutation who had disease progression while being treated with adagrasib in clinical trials. Investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to adagrasib in these patients.

“Diverse mechanisms confer resistance to the KRAS G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” Dr. Awad said in a mini-symposium presentation.

“Several cases displayed multiple resistance mechanisms, and novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” he said.

Inactivating KRAS

The KRAS G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form.

But the mutation has been considered too tough to target because of the KRAS gene’s strong binding affinity for guanosine triphosphate, an essential building block of RNA synthesis, and by a lack of accessible drug-binding sites.

Sotorasib and adagrasib are small-molecule, specific, and irreversible inhibitors of KRAS that interact with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drugs inhibit oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

Multiple mutations, histologic transformations

Dr. Awad and colleagues studied biopsy samples and circulating tumor DNA (ctDNA) from 30 patients both at baseline and after administration of adagrasib monotherapy. The patients all had initial responses to the drug but then experienced disease progression.

The investigators used mutagenesis screens to identify mechanisms of resistance to KRAS G12C inhibitors.

The 30 patients included 23 with NSCLC and 7 with CRC. Eighteen had unknown mechanisms of resistance, and putative resistance mechanisms were identified in the other 12 patients. Of this latter group, seven appeared to have single resistance mechanisms, and five had multiple mechanisms of resistance.

One patient with NSCLC who had radiographic evidence of response followed by progression was found to have had a novel KRAS Y96C mutation, and three had novel KRAS mutations in other gene regions, with multiple concurrent alterations in genes implicated in other forms of cancer, such as PTEN, BRAF, and MAP2K1.

The investigators also identified amplifications of the KRAS G12C allele, and MET.

In two patients, NSCLC underwent histologic transformation from adenocarcinoma at baseline to squamous cell carcinoma at the time of acquired resistance to the drug. No genomic resistance mechanisms were detected in either of these patients, Dr. Awad said.

“In several cases, we see multiple mechanisms or co-occurring alterations in each individual patient, with the suggestion that perhaps the multiple mutations or resistance mechanism may be more common in the colorectal population, particularly with acquired gene fusions, than in the lung cancer population, although larger datasets will be needed to confirm this observation,” he said.
 

Does duration of response matter?

In the question-and-answer session following his presentation, Dr. Awad was asked about clinical responses in the patients who developed resistance.

“In this initial reporting of resistance mechanisms we did not overlay or report out the clinical outcomes, including the durations of response or the time to disease progression, in part because this is an ongoing clinical trial, and those data will be reported in full at a later time,” Dr. Awad replied. “But I think it will be really important to identify whether patients are more likely to develop resistance earlier versus later or have different resistance mechanisms.”

Dr. Awad commented further that the resistance to adagrasib appeared to be acquired. “These resistance mutations were not detected to the level of detection at the baseline samples. So presumably they may be present at some low levels at the time of initial diagnosis, or they emerge over the course of therapy,” he said.

“Many of the resistance mechanisms appear to be more subclonal, occurring at an allele fraction lower than the original KRAS G12C mutation, which we know is the clonal event in the entire population of the cancer, and I think when we’re seeing these multiple resistance mechanisms emerging, they are potentially each representing different subclones that can develop simultaneously,” he added.

Adagrasib trials are supported by Mirati Therapeutics. Dr. Awad disclosed consulting for Mirati and others, and institutional research support from several different companies.

A version of this article first appeared on Medscape.com.

Hopes for a new category of agents recently hailed as “a triumph of drug discovery” have been dimmed somewhat by new data showing many types of acquired resistance.

KRAS is one of the most frequently mutated oncogenes in human cancer and has long been thought “undruggable” – but novel drugs acting specifically on the KRAS G12C mutation have shown promise in clinical trials.

Early results with the experimental KRAS inhibitors sotorasib and adagrasib were deemed promising, but new data presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB002) have splashed cold water on that enthusiasm.

The efficacy of these new drugs looks to be threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Mark M. Awad, MD, PhD, from the Dana-Farber Cancer Institute in Boston, reported data from 30 patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) bearing the KRAS G12C mutation who had disease progression while being treated with adagrasib in clinical trials. Investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to adagrasib in these patients.

“Diverse mechanisms confer resistance to the KRAS G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” Dr. Awad said in a mini-symposium presentation.

“Several cases displayed multiple resistance mechanisms, and novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” he said.

Inactivating KRAS

The KRAS G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form.

But the mutation has been considered too tough to target because of the KRAS gene’s strong binding affinity for guanosine triphosphate, an essential building block of RNA synthesis, and by a lack of accessible drug-binding sites.

Sotorasib and adagrasib are small-molecule, specific, and irreversible inhibitors of KRAS that interact with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drugs inhibit oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

Multiple mutations, histologic transformations

Dr. Awad and colleagues studied biopsy samples and circulating tumor DNA (ctDNA) from 30 patients both at baseline and after administration of adagrasib monotherapy. The patients all had initial responses to the drug but then experienced disease progression.

The investigators used mutagenesis screens to identify mechanisms of resistance to KRAS G12C inhibitors.

The 30 patients included 23 with NSCLC and 7 with CRC. Eighteen had unknown mechanisms of resistance, and putative resistance mechanisms were identified in the other 12 patients. Of this latter group, seven appeared to have single resistance mechanisms, and five had multiple mechanisms of resistance.

One patient with NSCLC who had radiographic evidence of response followed by progression was found to have had a novel KRAS Y96C mutation, and three had novel KRAS mutations in other gene regions, with multiple concurrent alterations in genes implicated in other forms of cancer, such as PTEN, BRAF, and MAP2K1.

The investigators also identified amplifications of the KRAS G12C allele, and MET.

In two patients, NSCLC underwent histologic transformation from adenocarcinoma at baseline to squamous cell carcinoma at the time of acquired resistance to the drug. No genomic resistance mechanisms were detected in either of these patients, Dr. Awad said.

“In several cases, we see multiple mechanisms or co-occurring alterations in each individual patient, with the suggestion that perhaps the multiple mutations or resistance mechanism may be more common in the colorectal population, particularly with acquired gene fusions, than in the lung cancer population, although larger datasets will be needed to confirm this observation,” he said.
 

Does duration of response matter?

In the question-and-answer session following his presentation, Dr. Awad was asked about clinical responses in the patients who developed resistance.

“In this initial reporting of resistance mechanisms we did not overlay or report out the clinical outcomes, including the durations of response or the time to disease progression, in part because this is an ongoing clinical trial, and those data will be reported in full at a later time,” Dr. Awad replied. “But I think it will be really important to identify whether patients are more likely to develop resistance earlier versus later or have different resistance mechanisms.”

Dr. Awad commented further that the resistance to adagrasib appeared to be acquired. “These resistance mutations were not detected to the level of detection at the baseline samples. So presumably they may be present at some low levels at the time of initial diagnosis, or they emerge over the course of therapy,” he said.

“Many of the resistance mechanisms appear to be more subclonal, occurring at an allele fraction lower than the original KRAS G12C mutation, which we know is the clonal event in the entire population of the cancer, and I think when we’re seeing these multiple resistance mechanisms emerging, they are potentially each representing different subclones that can develop simultaneously,” he added.

Adagrasib trials are supported by Mirati Therapeutics. Dr. Awad disclosed consulting for Mirati and others, and institutional research support from several different companies.

A version of this article first appeared on Medscape.com.

Hopes for a new category of agents recently hailed as “a triumph of drug discovery” have been dimmed somewhat by new data showing many types of acquired resistance.

KRAS is one of the most frequently mutated oncogenes in human cancer and has long been thought “undruggable” – but novel drugs acting specifically on the KRAS G12C mutation have shown promise in clinical trials.

Early results with the experimental KRAS inhibitors sotorasib and adagrasib were deemed promising, but new data presented at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB002) have splashed cold water on that enthusiasm.

The efficacy of these new drugs looks to be threatened by the development of resistance caused by a wide range of genomic and histologic mechanisms.

Mark M. Awad, MD, PhD, from the Dana-Farber Cancer Institute in Boston, reported data from 30 patients with non–small cell lung cancer (NSCLC) or colorectal cancer (CRC) bearing the KRAS G12C mutation who had disease progression while being treated with adagrasib in clinical trials. Investigators found multiple on-target KRAS alterations and off-target bypass mechanisms of acquired resistance to adagrasib in these patients.

“Diverse mechanisms confer resistance to the KRAS G12C inhibitors, including secondary KRAS mutations, MAP [mitogen-activated protein] kinase pathway alterations, acquired genomic rearrangements, and histologic transformation,” Dr. Awad said in a mini-symposium presentation.

“Several cases displayed multiple resistance mechanisms, and novel combinatorial strategies will be necessary to delay or overcome resistance in KRAS G12C-mutant cancers,” he said.

Inactivating KRAS

The KRAS G12C mutation is a glycine-to-cysteine substitution that results in the oncogene being switched on in its active form.

But the mutation has been considered too tough to target because of the KRAS gene’s strong binding affinity for guanosine triphosphate, an essential building block of RNA synthesis, and by a lack of accessible drug-binding sites.

Sotorasib and adagrasib are small-molecule, specific, and irreversible inhibitors of KRAS that interact with a “pocket” on the gene’s surface that is present only in an inactive conformation of KRAS. The drugs inhibit oncogenic signaling and tumorigenesis by preventing cycling of the oncogene into its active form.

Multiple mutations, histologic transformations

Dr. Awad and colleagues studied biopsy samples and circulating tumor DNA (ctDNA) from 30 patients both at baseline and after administration of adagrasib monotherapy. The patients all had initial responses to the drug but then experienced disease progression.

The investigators used mutagenesis screens to identify mechanisms of resistance to KRAS G12C inhibitors.

The 30 patients included 23 with NSCLC and 7 with CRC. Eighteen had unknown mechanisms of resistance, and putative resistance mechanisms were identified in the other 12 patients. Of this latter group, seven appeared to have single resistance mechanisms, and five had multiple mechanisms of resistance.

One patient with NSCLC who had radiographic evidence of response followed by progression was found to have had a novel KRAS Y96C mutation, and three had novel KRAS mutations in other gene regions, with multiple concurrent alterations in genes implicated in other forms of cancer, such as PTEN, BRAF, and MAP2K1.

The investigators also identified amplifications of the KRAS G12C allele, and MET.

In two patients, NSCLC underwent histologic transformation from adenocarcinoma at baseline to squamous cell carcinoma at the time of acquired resistance to the drug. No genomic resistance mechanisms were detected in either of these patients, Dr. Awad said.

“In several cases, we see multiple mechanisms or co-occurring alterations in each individual patient, with the suggestion that perhaps the multiple mutations or resistance mechanism may be more common in the colorectal population, particularly with acquired gene fusions, than in the lung cancer population, although larger datasets will be needed to confirm this observation,” he said.
 

Does duration of response matter?

In the question-and-answer session following his presentation, Dr. Awad was asked about clinical responses in the patients who developed resistance.

“In this initial reporting of resistance mechanisms we did not overlay or report out the clinical outcomes, including the durations of response or the time to disease progression, in part because this is an ongoing clinical trial, and those data will be reported in full at a later time,” Dr. Awad replied. “But I think it will be really important to identify whether patients are more likely to develop resistance earlier versus later or have different resistance mechanisms.”

Dr. Awad commented further that the resistance to adagrasib appeared to be acquired. “These resistance mutations were not detected to the level of detection at the baseline samples. So presumably they may be present at some low levels at the time of initial diagnosis, or they emerge over the course of therapy,” he said.

“Many of the resistance mechanisms appear to be more subclonal, occurring at an allele fraction lower than the original KRAS G12C mutation, which we know is the clonal event in the entire population of the cancer, and I think when we’re seeing these multiple resistance mechanisms emerging, they are potentially each representing different subclones that can develop simultaneously,” he added.

Adagrasib trials are supported by Mirati Therapeutics. Dr. Awad disclosed consulting for Mirati and others, and institutional research support from several different companies.

A version of this article first appeared on Medscape.com.