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Fluoroscopic system can improve targeting of lung lesions
NEW ORLEANS – A novel according to an industry-sponsored, prospective study.
The system, which incorporates fluoroscopic navigation, increased the percentage of cases in which the target overlapped with the lesion, from 60% to 83%. The percentage of cases without any target overlap decreased from 32% to 5%.
“Tomosynthesis-based fluoroscopic navigation … improves the three-dimensional convergence between the virtual target and the actual target,” said Krish Bhadra, MD, of CHI Memorial Medical Group in Chattanooga, Tenn.
Dr. Bhadra presented results with this system at the annual meeting of the American College of Chest Physicians.
He and his colleagues conducted a study of Medtronic’s superDimension navigation system (version 7.2), which provides real-time imaging with three-dimensional fluoroscopy. The system has a “local registration” feature, which uses fluoroscopy and an algorithm to update the virtual target location during the procedure. This allows the user to reposition the catheter based on the location of the lesion.
The researchers tested the system in 50 patients from two centers (NCT03585959). Patients’ lesions had to be larger than 10 mm, not visible endobronchially, and not reachable by convex endobronchial ultrasound. Lesions within 10 mm of the diaphragm were excluded.
The median lesion size was 17.0 mm, 61.2% were smaller than 20 mm, 65.3% were in the upper lobe, and 53.1% had a bronchus sign present. The median distance from lesion to pleura was 5.9 mm.
Dr. Bhadra said the system performed as designed in all cases, and the protocol-defined technical success rate was 95.9% (47/49). Local registration was attempted in 49 patients and was successful in 47 patients (95.9%). In the unsuccessful cases, local registration was not completed based on the system design because the correction distance was greater than 3.0 cm.
The study’s primary endpoint was three-dimensional overlap of the virtual target and the actual lesion, as confirmed by cone-beam computed tomography. Success was defined as greater than 0% overlap after location correction. Target overlap was achieved in 59.6% (28/47) of cases before local registration and 83.0% (39/47) of cases after.
There were six cases in which local registration was successful, but these subjects weren’t evaluable because of failed procedure recording. When those subjects were excluded, target overlap was achieved in 95.1% (39/41) of cases after local registration.
The median percent overlap between the virtual target and the actual lesion was 11.4% before local registration and 32.8% after. The percentage of cases without any target overlap decreased from 31.7% (13/41) before local registration to 4.9% (2/41) after.
Focusing on the two cases without target overlap, Dr. Bhadra noted that he was able to get a biopsy that proved a malignancy in one of those patients. In the other patient, Dr. Bhadra was able to identify features of organizing pneumonia.
“Even though we did not have overlap, we must have been close enough that we were able to get malignant tissue in one [patient] and features of organizing pneumonia in a patient who’s got no history of organizing pneumonia,” Dr. Bhadra said.
He and his colleagues did not evaluate diagnostic yield in this study, but they did assess complications up to 7 days after the procedure.
The team reported one case of pneumothorax, but the patient didn’t require a chest tube. Additionally, there were two cases of bronchopulmonary hemorrhage, but the patients didn’t require any interventions.
This study was sponsored by Medtronic. Dr. Bhadra disclosed relationships with Medtronic, Boston Scientific, BodyVision, Auris Surgical Robotics, Intuitive Surgical, Veracyte, Biodesix, Merit Medical Endotek, and Johnson & Johnson.
SOURCE: Bhadra K et al. CHEST 2019. doi: 10.1016/j.chest.2019.08.314.
NEW ORLEANS – A novel according to an industry-sponsored, prospective study.
The system, which incorporates fluoroscopic navigation, increased the percentage of cases in which the target overlapped with the lesion, from 60% to 83%. The percentage of cases without any target overlap decreased from 32% to 5%.
“Tomosynthesis-based fluoroscopic navigation … improves the three-dimensional convergence between the virtual target and the actual target,” said Krish Bhadra, MD, of CHI Memorial Medical Group in Chattanooga, Tenn.
Dr. Bhadra presented results with this system at the annual meeting of the American College of Chest Physicians.
He and his colleagues conducted a study of Medtronic’s superDimension navigation system (version 7.2), which provides real-time imaging with three-dimensional fluoroscopy. The system has a “local registration” feature, which uses fluoroscopy and an algorithm to update the virtual target location during the procedure. This allows the user to reposition the catheter based on the location of the lesion.
The researchers tested the system in 50 patients from two centers (NCT03585959). Patients’ lesions had to be larger than 10 mm, not visible endobronchially, and not reachable by convex endobronchial ultrasound. Lesions within 10 mm of the diaphragm were excluded.
The median lesion size was 17.0 mm, 61.2% were smaller than 20 mm, 65.3% were in the upper lobe, and 53.1% had a bronchus sign present. The median distance from lesion to pleura was 5.9 mm.
Dr. Bhadra said the system performed as designed in all cases, and the protocol-defined technical success rate was 95.9% (47/49). Local registration was attempted in 49 patients and was successful in 47 patients (95.9%). In the unsuccessful cases, local registration was not completed based on the system design because the correction distance was greater than 3.0 cm.
The study’s primary endpoint was three-dimensional overlap of the virtual target and the actual lesion, as confirmed by cone-beam computed tomography. Success was defined as greater than 0% overlap after location correction. Target overlap was achieved in 59.6% (28/47) of cases before local registration and 83.0% (39/47) of cases after.
There were six cases in which local registration was successful, but these subjects weren’t evaluable because of failed procedure recording. When those subjects were excluded, target overlap was achieved in 95.1% (39/41) of cases after local registration.
The median percent overlap between the virtual target and the actual lesion was 11.4% before local registration and 32.8% after. The percentage of cases without any target overlap decreased from 31.7% (13/41) before local registration to 4.9% (2/41) after.
Focusing on the two cases without target overlap, Dr. Bhadra noted that he was able to get a biopsy that proved a malignancy in one of those patients. In the other patient, Dr. Bhadra was able to identify features of organizing pneumonia.
“Even though we did not have overlap, we must have been close enough that we were able to get malignant tissue in one [patient] and features of organizing pneumonia in a patient who’s got no history of organizing pneumonia,” Dr. Bhadra said.
He and his colleagues did not evaluate diagnostic yield in this study, but they did assess complications up to 7 days after the procedure.
The team reported one case of pneumothorax, but the patient didn’t require a chest tube. Additionally, there were two cases of bronchopulmonary hemorrhage, but the patients didn’t require any interventions.
This study was sponsored by Medtronic. Dr. Bhadra disclosed relationships with Medtronic, Boston Scientific, BodyVision, Auris Surgical Robotics, Intuitive Surgical, Veracyte, Biodesix, Merit Medical Endotek, and Johnson & Johnson.
SOURCE: Bhadra K et al. CHEST 2019. doi: 10.1016/j.chest.2019.08.314.
NEW ORLEANS – A novel according to an industry-sponsored, prospective study.
The system, which incorporates fluoroscopic navigation, increased the percentage of cases in which the target overlapped with the lesion, from 60% to 83%. The percentage of cases without any target overlap decreased from 32% to 5%.
“Tomosynthesis-based fluoroscopic navigation … improves the three-dimensional convergence between the virtual target and the actual target,” said Krish Bhadra, MD, of CHI Memorial Medical Group in Chattanooga, Tenn.
Dr. Bhadra presented results with this system at the annual meeting of the American College of Chest Physicians.
He and his colleagues conducted a study of Medtronic’s superDimension navigation system (version 7.2), which provides real-time imaging with three-dimensional fluoroscopy. The system has a “local registration” feature, which uses fluoroscopy and an algorithm to update the virtual target location during the procedure. This allows the user to reposition the catheter based on the location of the lesion.
The researchers tested the system in 50 patients from two centers (NCT03585959). Patients’ lesions had to be larger than 10 mm, not visible endobronchially, and not reachable by convex endobronchial ultrasound. Lesions within 10 mm of the diaphragm were excluded.
The median lesion size was 17.0 mm, 61.2% were smaller than 20 mm, 65.3% were in the upper lobe, and 53.1% had a bronchus sign present. The median distance from lesion to pleura was 5.9 mm.
Dr. Bhadra said the system performed as designed in all cases, and the protocol-defined technical success rate was 95.9% (47/49). Local registration was attempted in 49 patients and was successful in 47 patients (95.9%). In the unsuccessful cases, local registration was not completed based on the system design because the correction distance was greater than 3.0 cm.
The study’s primary endpoint was three-dimensional overlap of the virtual target and the actual lesion, as confirmed by cone-beam computed tomography. Success was defined as greater than 0% overlap after location correction. Target overlap was achieved in 59.6% (28/47) of cases before local registration and 83.0% (39/47) of cases after.
There were six cases in which local registration was successful, but these subjects weren’t evaluable because of failed procedure recording. When those subjects were excluded, target overlap was achieved in 95.1% (39/41) of cases after local registration.
The median percent overlap between the virtual target and the actual lesion was 11.4% before local registration and 32.8% after. The percentage of cases without any target overlap decreased from 31.7% (13/41) before local registration to 4.9% (2/41) after.
Focusing on the two cases without target overlap, Dr. Bhadra noted that he was able to get a biopsy that proved a malignancy in one of those patients. In the other patient, Dr. Bhadra was able to identify features of organizing pneumonia.
“Even though we did not have overlap, we must have been close enough that we were able to get malignant tissue in one [patient] and features of organizing pneumonia in a patient who’s got no history of organizing pneumonia,” Dr. Bhadra said.
He and his colleagues did not evaluate diagnostic yield in this study, but they did assess complications up to 7 days after the procedure.
The team reported one case of pneumothorax, but the patient didn’t require a chest tube. Additionally, there were two cases of bronchopulmonary hemorrhage, but the patients didn’t require any interventions.
This study was sponsored by Medtronic. Dr. Bhadra disclosed relationships with Medtronic, Boston Scientific, BodyVision, Auris Surgical Robotics, Intuitive Surgical, Veracyte, Biodesix, Merit Medical Endotek, and Johnson & Johnson.
SOURCE: Bhadra K et al. CHEST 2019. doi: 10.1016/j.chest.2019.08.314.
REPORTING FROM CHEST 2019
Levothyroxine dose for checkpoint inhibitor toxicity may be too high
CHICAGO – both for patients with preexisting and de novo hypothyroidism.
The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.
Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.
Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.
The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.
The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.
However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.
To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.
The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.
At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.
For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.
The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.
For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).
Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.
For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.
However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.
Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.
The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.
Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.
Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.
CHICAGO – both for patients with preexisting and de novo hypothyroidism.
The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.
Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.
Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.
The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.
The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.
However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.
To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.
The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.
At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.
For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.
The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.
For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).
Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.
For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.
However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.
Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.
The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.
Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.
Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.
CHICAGO – both for patients with preexisting and de novo hypothyroidism.
The real-world data, presented by Megan Kristan, MD, at the annual meeting of the American Thyroid Association, refine recommendations for dosing by body weight for levothyroxine in patients receiving checkpoint inhibitor therapy.
Immune checkpoint inhibitors stand a good chance of turning the tide against melanoma, some lung cancers, and other malignancies that have long been considered lethal. However, as more patients are exposed to the therapies, endocrinologists are seeing a wave of thyroid abnormalities, and must decide when, and at what doses, to treat hypothyroidism, said Dr. Kristan, a diabetes, endocrinology, and nutrition fellow at the University of Maryland, Baltimore.
Six checkpoint inhibitors are currently approved to hit a variety of molecular targets, and the prevalence of thyroid toxicity and hypothyroidism across the drug class ranges from a reported 9% to 40%, said Dr. Kristan.
The acknowledged thyroid toxicity of these drugs led the American Society for Clinical Oncology (ASCO) to issue guidelines advising that oncologists obtain baseline thyroid function tests before initiating checkpoint inhibitors, and that values be rechecked frequently – every 4-6 weeks – during therapy.
The guidelines advise dosing levothyroxine at approximately 1.6 mcg/kg per day, based on ideal patient body weight. The recommendation is limited to patients without risk factors, and approximates full levothyroxine replacement.
However, some patients enter cancer treatment with hypothyroidism, and some develop it de novo after beginning checkpoint inhibitor therapy. It is not known how best to treat each group, said Dr. Kristan.
To help answer that question, she and her collaborators at Georgetown University Hospital, McLean, Va., made use of a database drawn from five hospitals to perform a retrospective chart review. They looked at 822 patients who had received checkpoint inhibitor therapy, and from those patients, they selected 118 who had a diagnosis of hypothyroidism, or who received a prescription for levothyroxine during the 8-year study period.
The investigators assembled all available relevant data for each patient, including thyroid function tests, levothyroxine dosing, type of cancer, and type of therapy. They sorted participants into those who had received a diagnosis of hypothyroidism before or after receiving the first dose of checkpoint inhibitor therapy.
At baseline, 81 patients had preexisting hypothyroidism and were receiving a mean levothyroxine dose of 88.2 mcg. After treatment, the mean dose was 94.3 mcg, a nonsignificant difference. The median dose for this group remained at 88 mcg through treatment.
For the 37 patients who developed hypothyroidism de novo during checkpoint inhibitor therapy, the final observed levothyroxine dose was 71.2 mcg.
The mean age of the patients at baseline was 69 years. About half were women, and 91% were white. Either nivolumab or pembrolizumab was used in 72% of patients, making them the most commonly used checkpoint inhibitors, though 90% of patients received combination therapy. Taken together, melanoma and lung cancer accounted for about two-thirds of the cancers seen.
For both groups, the on-treatment levothyroxine dose was considerably lower than the ASCO-recommended, weight-based dosing, which would have been 122.9 mcg for those with preexisting hypothyroidism and 115.7 mcg for those who developed hypothyroidism on treatment (P less than .001 for both).
Dr. Kristan noted that thyroid stimulating hormone (TSH) values for patients with pretreatment hypothyroidism peaked between weeks 12 and 20, though there was no preemptive adjustment of levothyroxine dosing.
For those who developed on-treatment hypothyroidism, TSH values peaked at a series of times, at about weeks 8, 16, and 32. These waves of TSH elevation, she said, support the 4- to 6-week follow-up interval recommended in the ASCO guidelines.
However, she said, patients with de novo hypothyroidism “should not be started on the 1.6-mcg/kg-a-day weight-based dosing.” The cohort with de novo hypothyroidism in Dr. Kristan’s analysis required a daily dose of about 1 mcg/kg, she said. These real-world results support the idea that many patients on checkpoint inhibitors retain some thyroid reserve.
Dr. Kristan said that based on these findings, she and her collaborators recommend monitoring thyroid function every 4-6 weeks for patients taking immune checkpoint inhibitors. Patients with preexisting thyroid disease should not have an empiric adjustment of levothyroxine dose on checkpoint inhibitor initiation. For patients who develop thyroiditis after starting therapy, initiating a dose at 1 mcg/kg per day of ideal body weight is a good place to start, and treatment response should be monitored.
The study was limited by its retrospective nature and the small sample size, acknowledged Dr. Kristan. In addition, there were confounding variables and different frequencies of testing across institutions, and antibody status was not available and may have affected the results. Testing was performable for all participants.
Dr. Kristan said that the analysis opens up areas for further study, such as which patient populations are at risk for developing thyroid toxicity, what baseline characteristics can help predict which patients develop toxicity, and whether particular checkpoint inhibitors are more likely to cause toxicity. In addition, she said, a subset of patients will develop hyperthyroidism on checkpoint inhibitor therapy, and little is known about how to treat that complication.
Dr. Kristan reported no conflicts of interest. The research she presented was completed during her residency at Georgetown University.
SOURCE: Kristan M et al. ATA 2019, Oral Abstract 25.
REPORTING FROM ATA 2019
Immune checkpoint inhibition in SCLC: Modest outcomes, many questions
BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.
That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.
“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
The state of the art
Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.
A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.
An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.
Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”
Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.
The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.
“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”
The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.
“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.
When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.
One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.
Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.
“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:
- Combination immunotherapy is necessary.
- Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
- Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
- PD-1 blockade should continue.
- Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.
Clinical and molecular biomarkers
Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.
Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”
“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”
Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.
Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.
TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.
“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.
“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”
IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.
PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.
“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.
In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.
“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.
Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.
In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.
That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”
DDR is also garnering attention.
“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.
The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.
“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.
“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”
At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
The SCLC immune microenvironment
The immune microenvironment will be an integral part of that journey, according to Dr. Liu.
“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.
“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.
Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.
Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.
Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.
“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.
Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.
“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).
Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.
“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.
“All of these will need to be accounted for in various patients.”
These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.
In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.
“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.
Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.
“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.
But many questions remain, he said.
For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?
And importantly, “how will we choose between these various molecules we have?” he asked.
“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”
It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.
However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.
“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.
Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.
“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”
As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.
“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”
Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.
BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.
That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.
“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
The state of the art
Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.
A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.
An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.
Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”
Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.
The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.
“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”
The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.
“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.
When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.
One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.
Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.
“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:
- Combination immunotherapy is necessary.
- Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
- Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
- PD-1 blockade should continue.
- Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.
Clinical and molecular biomarkers
Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.
Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”
“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”
Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.
Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.
TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.
“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.
“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”
IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.
PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.
“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.
In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.
“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.
Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.
In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.
That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”
DDR is also garnering attention.
“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.
The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.
“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.
“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”
At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
The SCLC immune microenvironment
The immune microenvironment will be an integral part of that journey, according to Dr. Liu.
“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.
“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.
Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.
Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.
Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.
“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.
Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.
“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).
Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.
“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.
“All of these will need to be accounted for in various patients.”
These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.
In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.
“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.
Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.
“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.
But many questions remain, he said.
For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?
And importantly, “how will we choose between these various molecules we have?” he asked.
“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”
It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.
However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.
“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.
Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.
“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”
As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.
“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”
Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.
BARCELONA – Immune checkpoint inhibitors demonstrate activity in small cell lung cancer (SCLC), but achieving more durable disease control and better survival requires improved understanding of biomarkers and the immune microenvironment.
That was the overarching message from experts speaking at a minisymposium on immunotherapy in SCLC at the World Conference on Lung Cancer.
“None of us are disputing that immunotherapy is clearly active in this space, but I think that we can all agree that the outcomes have been somewhat modest in an unselected population, and there is certainly room to grow,” said Dr. Stephen V. Liu, MD. “Moving forward, while we will look for any advances we can, we also feel strongly that these incremental gains are probably not enough.”
The state of the art
Hints that immunotherapy could be clinically efficacious in SCLC emerged in 2016 when interim findings from the CheckMate 032 study showed that the programmed cell death-1 (PD-1) inhibitor nivolumab, either alone or in combination with the anti-CTLA4 antibody ipilimumab, had efficacy in recurrent SCLC. Efficacy was seen regardless of programmed death-ligand 1 (PD-L1) status, which is “a good thing since PD-L1 is expressed much less frequently in SCLC than in non-SCLC,” Scott J. Antonia, MD, of Duke Cancer Institute, Durham, N.C., who was the first author on that study, said during the symposium.
A particularly encouraging finding was that responders included patients with platinum-refractory SCLC for whom treatments in the relapse setting are lacking, Dr Antonia said.
An exploratory analysis of CheckMate 032 also showed better responses among patients in the highest tumor mutation burden (TMB) tertile, especially in the combination therapy group, leading to the hypothesis-generating finding that TMB may predict response, he said.
Another suggestion of nivolumab’s potential came from the randomized CheckMate 331 study comparing the checkpoint inhibitor with chemotherapy in relapsed SCLC patients. As reported in 2018 at the European Society for Medical Oncology (ESMO), no overall survival (OS) benefit was apparent at 12 months (37% vs. 34%), but a separation of the curves at 36 months suggested a possible OS benefit with nivolumab, Dr. Antonia noted, adding that the difference was “obviously small” and requires “a lot more work related to that.”
Subgroup analyses in that study also were “perhaps revealing” in that patients without liver metastases derived benefit (hazard ratio, 0.75), as did those who were platinum resistant (HR, 0.71), he said.
The phase 1b KEYNOTE-028 study showed that the anti–PD-1 monoclonal antibody pembrolizumab also has activity in PD-L1–positive SCLC patients in the relapsed setting, and pooled data from that study and KEYNOTE-158, which included both PD-L1–positive and –negative patients, showed promising antitumor activity and durable responses with pembrolizumab. The pooled data, as presented at the 2019 annual meeting of the American Association for Cancer Research, showed an objective response rate (ORR) of 19%, including complete and partial response rates of 2% and 17%, respectively.
“And there appears to be, at least preliminarily, some durability to the responses,” he said, noting that 9 of 16 patients experienced at least an 18-month response. “Progression-free survival was 2 months, and overall survival was 7.7 months.”
The IMpower133 study showed significantly longer OS and progression-free survival (PFS) with the addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage SCLC (HR, 0.70). Some late merging of the survival curves was apparent, but the data haven’t matured.
“Hopefully there will be some evidence of a lifting of the tail of the survival curve with some durability of responsiveness like we see in non–small cell lung cancer,” he said.
When it comes to “making the next leap” toward improved clinical efficacy with immunotherapy for SCLC, “we need to think about three general categories of how it is that tumors evade rejection by the immune system,” he said.
One category involves SCLC patients with an insufficient numbers of T cells generated within the lymphoid compartment; in those patients, an immunotherapeutic approach directed at the tumor microenvironment won’t lead to a response. Another category includes patients who generate enough T cells within the lymphoid compartment but in whom those cells aren’t driven into the tumor parenchyma. The third involves those whose T cells may make it into the tumor parenchyma, but are inhibited in the tumor microenvironment, he explained.
Strategies to increase the number of T cells generated in the lymphoid compartment – such as vaccines, radiation, adoptive cell therapy with chimeric antigen receptors, to name a few – were a focus of research efforts more than a decade ago, but the pendulum swung more toward addressing the tumor microenvironment.
“I think that the pendulum needs to swing back to the middle, and we do need to develop combination immunotherapies paying attention to the lymphoid compartment as well as the tumor microenvironment,” Dr. Antonia said, listing these “guiding principles” for the development of effective SCLC immunotherapy:
- Combination immunotherapy is necessary.
- Mechanisms exploited by SCLC to evade immune-mediated rejection need to be identified.
- Inclusion of strategies for driving tumor-reactive T cells into the tumor microenvironment should be considered.
- PD-1 blockade should continue.
- Biomarkers should be identified for selecting patients for tumor microenvironment–targeted agents.
Clinical and molecular biomarkers
Indeed, there is much work to do with respect to biomarkers, but their use in the selection of SCLC patients for immunotherapy is “finally starting to evolve and evolve more rapidly,” according to Lauren Averett Byers, MD, of the University of Texas MD Anderson Cancer Center, Houston.
Numerous groups are identifying biomarkers for both targeted therapy and immunotherapy, Dr. Byers said, noting that “this has been a really incredible time for those of us who take care of small cell lung cancer patients.”
“It’s been many decades since we’ve had a new option for our patients ... and so I think with the landmark clinical trials ... we really do have a new option in terms of a new standard of care,” she said of immunotherapy. “But I think we also recognize that there is significant room for further improvement.”
Many patients don’t respond or don’t respond as well as hoped, and therefore an “incredible need” exists for personalized biomarker-driven therapy for SCLC and its distinct molecular subsets, she said.
Emerging and potential biomarkers and other factors to guide treatment decisions include TMB, PD-L1, clinical history/duration of response in immunotherapy-naive relapsed patients, gene expression profile–driven SCLC subgroup identification, and DNA damage response (DDR) inhibitors such as Chk1, PARP, and Wee1 inhibitors.
TMB, as described by Dr. Antonia with respect to the CheckMate 032 findings of improved outcomes in those in the highest TMB tertile, is one potentially helpful biomarker for response.
“In thinking about how we apply this, though, we have to think about what we’re deciding between,” Dr. Byers said, explaining that the responses in patients with medium or low TMB – between 0% and 10% in most studies in the relapsed SCLC setting – aren’t that different from those seen with other treatment options.
“Currently we’re not routinely ordering TMB to decide on immunotherapy because there are still patients that can be as likely to benefit from immunotherapy as they are from chemotherapy, and potentially with more durable responses,” she said. “But certainly, it is a way to potentially identify patients where immunotherapy alone may have very high rates of response.”
IMPower133 showed no difference in hazard ratios for death based on TMB detected in the blood in SCLC patients treated with first-line atezolizumab plus chemotherapy, but “this still supports using the immunotherapy/chemotherapy combination broadly, and also emphasizes the need for an improved – and probably expanded – look at other biomarkers that may help predict response,” she said.
PD-L1 appears to have a role as a biomarker in this setting as well, she said, citing the KEYNOTE-028 findings of numerically improved responses in PD-L1–positive SCLC patients treated with pembrolizumab.
“We should be looking at PD-L1 levels, but we need further information to know how we might use this,” she said.
In immunotherapy-naive patients who relapse after front-line chemotherapy, the most important biomarker is clinical history and duration of response to platinum, which helps guide second-line treatment, Dr. Byers said.
“I think there’s consensus among most of us that patients who have platinum-refractory disease and are unlikely to respond to further platinum therapy or other chemotherapy agents are patients who really should get immunotherapy,” she added, explaining that the available data suggest there is no cross-resistance and that there may actually be enhanced benefit with immunotherapy in such patients.
Using molecular data to identify SCLC subtypes based on gene expression profiles is another area of interest, she said.
In fact, new data presented at the WCLC conference by Carl Gay, MD, PhD, a former fellow in her lab and now a junior faculty member at MD Anderson, identified four specific SCLC subgroups; three were driven by activation of the known transcription factors ASCL1, NEUROD1, and POU2F3, but an additional “inflamed” group without expression of those three transcription factors was also identified.
That “triple-negative” group had significantly higher expression of human leukocyte antigen and very high T-cell activation with expression of multiple immune checkpoints representing candidate targets, she said, adding: “We hypothesize that this group may be the group in SCLC that gets relatively greater benefit from immune checkpoint blockade.”
DDR is also garnering attention.
“Since there was this signal that [patients with] DNA damage ... tend to be more sensitive to immunotherapy ... we looked at whether or not targeted agents that prevented repair of DNA damage and induced increased levels of DNA damage ... might activate the innate immune system through the STING pathway and if that could be a potential approach to enhance immunotherapy response,” she said.
The approach showed promise in cell lines in a mouse model and also in an immunocompetent SCLC mouse model.
“It was really interesting to see how these drugs might potentially enhance response to immunotherapy,” Dr. Byers said, noting that the same phenomenon has been seen with PARP inhibitors in breast and colon cancer models and in other solid tumors.
“So I think that there is something there, and fortunately we’re now at a point now where we can start looking at some of these combinations in the clinic across many different cancer types,” she said. “I think we’ll be learning a lot more about what’s happening with these patients.”
At present, however, “there is more that we don’t know about the immune landscape of small cell lung cancer than what we do know, and that’s a real opportunity where, over the next several years, we will gain a deeper understanding ... that will direct where we’re going in terms of translating that back into the clinic.”
The SCLC immune microenvironment
The immune microenvironment will be an integral part of that journey, according to Dr. Liu.
“We consider small cell lung cancer – a carcinogen-associated cancer – to be one that has a high somatic mutation rate, but what we’ve learned over the past few years is that tumor neoantigens are certainly necessary – but not sufficient,” he said, noting that mutational burden represents the potential for immune-mediated antitumor responses, but is not a guarantee.
“As a group, we need to develop strategies to overcome the powerful immunosuppressive microenvironment in small cell lung cancer,” he added.
Lessons learned from studying PD-L1 provided the first insight into the importance of the immune microenvironment: PD-L1 expression, as measured by tumor proportion score (TPS) holds predictive value in non–small cell lung cancer patients treated with PD-1 inhibitors, but the SCLC story is much more complex, he said.
Only 18% of SCLC patients in CheckMate 032 were PD-L1–positive, and “paradoxically, we see responses were better in the PD-L1–negative group,” he explained. The response rates for nivolumab/ipilimumab were 32% in the PD-L1–negative group and 10% in the PD-L1–positive group.
Recent findings regarding the use of the combined positive score (CPS), which unlike the TPS for determining PD-L1 status, includes PD-L1 expression on stromal cells, are also notable. In a phase 2 study of maintenance pembrolizumab in SCLC, for example, 3 of 30 patients were PD-L1 positive by TPS, and 8 of 20 were positive by CPS.
“And that did predict outcomes: We see a higher response rate [38% vs. 8%], better PFS [6.5 vs. 1.3 months], and better overall survival [13 months vs. 8 months] in pretreated small cell lung cancer,” he said.
Similarly, in KEYNOTE-158 when looking at pembrolizumab in previously treated SCLC, the overall response was modest at 18.7%, and median PFS was 2.0 months.
“Again, breaking it down by CPS, we see a different story,” Dr. Liu said. “We see better outcomes in the PD-L1–positive [group] if you’re factoring in expression in the microenvironment.” When assessed by CPS, 39% of patients were PD-L1 positive; those patients, when compared with PD-L1–negative patients, had improved 12-month PFS (28.5% vs. 8.2%, respectively), 12-month OS (53.3% vs. 30.7%), and median OS (14.9 vs. 5.9 months).
Checkpoint expression in tumor-infiltrating lymphocytes (TILs) also has been shown to vary when compared with tumor expression. SCLC tissue microarrays in a study presented at ASCO 2017 (Rivalland et al. Abstract 8569), for example, showed that tumor expression versus TIL expression of PD-L1, TIMS3, and LAG3 was 18% vs. 67%, 0% vs. 59%, and 0% vs. 45%, respectively, and the TIL expression correlated with survival, Dr. Liu said.
“So when we consider things like PD-L1 expression, looking at a narrow scope of just the tumor is not enough. We need to consider the stromal cells, the microenvironment,” he said. “And even larger than that, PD-1/PD-L1 interaction is but a fraction of powerful, dynamic, immunosuppressive factors in small cell lung cancer.
“All of these will need to be accounted for in various patients.”
These findings and others, like those from a recent study showing differentially expressed genes and pathways in the stromal cells of longer- versus shorter-term survivors, raise questions about whether the lymphoid compartment can be manipulated in SCLC to improve immune responses using the strategies discussed by Dr. Antonia and Dr. Byers, he said.
In “cold” tumor phenotypes, one hypothesis has tumor-associated macrophages (TAMs) preventing infiltration of the cytotoxic T lymphocytes, which raises the possibility that TAMs are a therapeutic target, he said.
“At this meeting and others we’ve heard of lurbinectedin as a possible active drug in SCLC,” he said, noting that preclinical data also demonstrate that lurbinectedin targets TAMs. Perhaps the agent’s future role will be that of an immune modulator rather than a cytotoxic agent, he suggested.
Regulatory T cells (Tregs) are another potential immunomodulatory target, but the problem is their redundancy and the lack of good models to identify which ones are active, he said.
“Myeloid-derived suppressor cells [MDSC] are another important part of the microenvironment and could be potential targets to restore immune responses,” he added.
But many questions remain, he said.
For example: How can we overcome an immunosuppressive tumor microenvironment? Can we inhibit arginine or adenosine? Can we restore interleukin-2? Can we target things like LAG3? Can we eliminate the Treg and MDSC population? Which strategies are appropriate? Are they the same in immunotherapy-naive vs. immunotherapy-experienced patients – is intrinsic resistance the same as acquired resistance? Are they the same in each patient, or even throughout each tumor?
And importantly, “how will we choose between these various molecules we have?” he asked.
“At this point we’ve learned that empiric strategies are unlikely to yield meaningful results. We’ve been through empiric strategies in SCLC for years, and it doesn’t work because of that heterogeneity – unless there’s a universal underlying mechanism,” he said. “I think more than likely the studies have to be enriched for the right patients; we need to apply everything we’ve learned from non–small cell lung cancer and apply the principles of targeted therapy to immunotherapy – and that requires the identification of predictive biomarkers.”
It’s a challenging task in SCLC, but “it still needs to be done,” he said, noting that the lack of “perfect models” means relying on cell lines in surgical specimens.
However, while surgical tissue banks are an important resource, there is doubt about whether the specimens are representative of patients in the clinic, he noted.
“At best need to confirm what we know; at worst we may need to rework a lot of the underlying maps,” he said.
Therefore, future SCLC studies “are simply going to need more biopsies,” and that is yet another challenge, he added, explaining that the largely central tumors and fairly aggressive, rapid course of disease in SCLC make it difficult to obtain meaningful biopsies.
“But it’s the only way to move forward,” he said. “As a community we have to stand up and obtain more biopsies and tissue for in-depth analysis.”
As much as that will advance the field, the greatest impact for SCLC will be through prevention, including by smoking cessation, he added.
“Our overarching goal for small cell lung cancer remains achieving durable disease control and long-term survival for our patients,” Dr. Liu said. “That certainly is a lofty goal, but those are probably the only goals worth having.”
Dr. Liu, Dr. Byers, and Dr. Antonia reported relationships with numerous pharmaceutical companies.
EXPERT ANALYSIS FROM WCLC 2019
Patients have good recall on lung cancer screening scan benefits, not risks
NEW ORLEANS – in a recent survey, underscoring the need for ongoing patient education beyond the initial shared decision-making encounter, a researcher said.
While about 9 in 10 patients recalled key information on the benefits, only about 4 in 10 recalled information on risks, according to Erin Hirsch, MSPH, of the Colorado School of Public Health in Aurora.
“This may mean we need ongoing clinician involvement or continued education about this important information, especially if the patients aren’t screening annually,” Ms. Hirsch said in a podium presentation at the annual meeting of the American College of Chest Physicians.
Even fewer patients could correctly recall eligibility criteria for lung cancer screening, which suggests “ongoing clinician involvement” is needed to identify appropriate patients, Hirsch added in her presentation.
Shared decision making about lung cancer screening, which is supposed to entail a balanced patient-provider conversation about eligibility, risks, and benefits, is required by the Centers for Medicare & Medicaid Services to cover the cost of lung cancer screening as a preventative service, Hirsch noted in her presentation.
However, it’s largely unknown to what extent patients due for an annual screening recall information that should have been imparted in that initial discussion.
“The gap in knowledge centers around the fact that shared decision making is only required for baseline scan, but screening is recommended on an annual basis,” she said.
To test patient recall, Hirsch and colleagues developed a knowledge survey including 34 questions about lung cancer screening eligibility, risks, and benefits. The surveys went out by mail or email to 228 patients who had a baseline screening CT scan 6-12 months earlier; a total of 53 complete responses were included in the analysis, which focused on seven key questions about benefit, risk, and eligibility.
Recall was “excellent” for the benefit questions, Ms. Hirsch said, with 91% of patients able to recall that a computed tomography (CT) scan is better at detecting a possible lung cancer than a chest x-ray, while 87% recalled that without screening lung cancer is often found at a later stage when cure is less likely.
By contrast, a “moderate” amount (40%) remembered that a CT scan can suggest the patient has lung cancer when in fact they do not, she said, and only 38% recalled that radiation exposure was one of the harms of lung cancer screening, she added.
Eligibility recall was “poor,” she added, with only 21% affirming that not all current and former smokers need to be screened for lung cancer. Just 8% recalled that 55 years is the age at which beginning lung cancer screening is recommended, and 4% knew that 30 is the minimum number of pack-years required to be eligible for screening.
While these results may have clinical implications, Ms. Hirsch acknowledged a number of limitations to this pilot study. Among those was the fact that the content of the initial shared decision-making conversation could not be assessed: “We assumed that the patients were exposed to the information asked about in the survey ahead of time, but we can’t say for sure if that was true,” she explained.
Ms. Hirsch and coauthors disclosed no relationships relevant to their study.
SOURCE: Hirsch E et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.107.
NEW ORLEANS – in a recent survey, underscoring the need for ongoing patient education beyond the initial shared decision-making encounter, a researcher said.
While about 9 in 10 patients recalled key information on the benefits, only about 4 in 10 recalled information on risks, according to Erin Hirsch, MSPH, of the Colorado School of Public Health in Aurora.
“This may mean we need ongoing clinician involvement or continued education about this important information, especially if the patients aren’t screening annually,” Ms. Hirsch said in a podium presentation at the annual meeting of the American College of Chest Physicians.
Even fewer patients could correctly recall eligibility criteria for lung cancer screening, which suggests “ongoing clinician involvement” is needed to identify appropriate patients, Hirsch added in her presentation.
Shared decision making about lung cancer screening, which is supposed to entail a balanced patient-provider conversation about eligibility, risks, and benefits, is required by the Centers for Medicare & Medicaid Services to cover the cost of lung cancer screening as a preventative service, Hirsch noted in her presentation.
However, it’s largely unknown to what extent patients due for an annual screening recall information that should have been imparted in that initial discussion.
“The gap in knowledge centers around the fact that shared decision making is only required for baseline scan, but screening is recommended on an annual basis,” she said.
To test patient recall, Hirsch and colleagues developed a knowledge survey including 34 questions about lung cancer screening eligibility, risks, and benefits. The surveys went out by mail or email to 228 patients who had a baseline screening CT scan 6-12 months earlier; a total of 53 complete responses were included in the analysis, which focused on seven key questions about benefit, risk, and eligibility.
Recall was “excellent” for the benefit questions, Ms. Hirsch said, with 91% of patients able to recall that a computed tomography (CT) scan is better at detecting a possible lung cancer than a chest x-ray, while 87% recalled that without screening lung cancer is often found at a later stage when cure is less likely.
By contrast, a “moderate” amount (40%) remembered that a CT scan can suggest the patient has lung cancer when in fact they do not, she said, and only 38% recalled that radiation exposure was one of the harms of lung cancer screening, she added.
Eligibility recall was “poor,” she added, with only 21% affirming that not all current and former smokers need to be screened for lung cancer. Just 8% recalled that 55 years is the age at which beginning lung cancer screening is recommended, and 4% knew that 30 is the minimum number of pack-years required to be eligible for screening.
While these results may have clinical implications, Ms. Hirsch acknowledged a number of limitations to this pilot study. Among those was the fact that the content of the initial shared decision-making conversation could not be assessed: “We assumed that the patients were exposed to the information asked about in the survey ahead of time, but we can’t say for sure if that was true,” she explained.
Ms. Hirsch and coauthors disclosed no relationships relevant to their study.
SOURCE: Hirsch E et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.107.
NEW ORLEANS – in a recent survey, underscoring the need for ongoing patient education beyond the initial shared decision-making encounter, a researcher said.
While about 9 in 10 patients recalled key information on the benefits, only about 4 in 10 recalled information on risks, according to Erin Hirsch, MSPH, of the Colorado School of Public Health in Aurora.
“This may mean we need ongoing clinician involvement or continued education about this important information, especially if the patients aren’t screening annually,” Ms. Hirsch said in a podium presentation at the annual meeting of the American College of Chest Physicians.
Even fewer patients could correctly recall eligibility criteria for lung cancer screening, which suggests “ongoing clinician involvement” is needed to identify appropriate patients, Hirsch added in her presentation.
Shared decision making about lung cancer screening, which is supposed to entail a balanced patient-provider conversation about eligibility, risks, and benefits, is required by the Centers for Medicare & Medicaid Services to cover the cost of lung cancer screening as a preventative service, Hirsch noted in her presentation.
However, it’s largely unknown to what extent patients due for an annual screening recall information that should have been imparted in that initial discussion.
“The gap in knowledge centers around the fact that shared decision making is only required for baseline scan, but screening is recommended on an annual basis,” she said.
To test patient recall, Hirsch and colleagues developed a knowledge survey including 34 questions about lung cancer screening eligibility, risks, and benefits. The surveys went out by mail or email to 228 patients who had a baseline screening CT scan 6-12 months earlier; a total of 53 complete responses were included in the analysis, which focused on seven key questions about benefit, risk, and eligibility.
Recall was “excellent” for the benefit questions, Ms. Hirsch said, with 91% of patients able to recall that a computed tomography (CT) scan is better at detecting a possible lung cancer than a chest x-ray, while 87% recalled that without screening lung cancer is often found at a later stage when cure is less likely.
By contrast, a “moderate” amount (40%) remembered that a CT scan can suggest the patient has lung cancer when in fact they do not, she said, and only 38% recalled that radiation exposure was one of the harms of lung cancer screening, she added.
Eligibility recall was “poor,” she added, with only 21% affirming that not all current and former smokers need to be screened for lung cancer. Just 8% recalled that 55 years is the age at which beginning lung cancer screening is recommended, and 4% knew that 30 is the minimum number of pack-years required to be eligible for screening.
While these results may have clinical implications, Ms. Hirsch acknowledged a number of limitations to this pilot study. Among those was the fact that the content of the initial shared decision-making conversation could not be assessed: “We assumed that the patients were exposed to the information asked about in the survey ahead of time, but we can’t say for sure if that was true,” she explained.
Ms. Hirsch and coauthors disclosed no relationships relevant to their study.
SOURCE: Hirsch E et al. CHEST 2019. Abstract, doi: 10.1016/j.chest.2019.08.107.
REPORTING FROM CHEST 2019
Stereotactic body radiation therapy safe, effective for moderately central NSCLC
Trial success with a stereotactic body radiation therapy (SBRT) regimen for centrally located non–small cell lung cancer (NSCLC) can be largely replicated in real-world practice, suggests a prospective cohort study published in Clinical Oncology.
The Radiation Therapy Oncology Group (RTOG) 0813 trial established the safety and efficacy of 50 Gy or 60 Gy given in five fractions to patients with early-stage central NSCLC (J Clin Oncol. 2019;37:1316-25). But whether similar outcomes can be achieved in routine care and how the degree of tumor centrality affects outcomes remain unclear.
Investigators led by Robert Rulach, MBChB, from the Beatson West of Scotland Cancer Centre, Glasgow, analyzed outcomes for 50 patients treated with the regimen of 50-Gy in five fractions at their institution for T1-2N0M0 stage NSCLC. All had tumors that were moderately central (within 2 cm of the trachea, bronchi, or proximal bronchial tree or having a planning target volume that abutted mediastinal pleura or pericardium); one had an additional tumor that was ultracentral (having a planning target volume that abutted the trachea).
The patients had a median age of 75.1 years. Notably, the majority were medically unfit for surgery (84%) and had an Eastern Cooperative Oncology Group performance status score of 2 or worse (56%). In 60% of patients, the diagnosis was made radiographically using PET/CT imaging; in the rest, the diagnosis was biopsy proven.
Study results showed that all patients completed the radiotherapy regimen of 50 Gy in 5 fractions on alternate days as planned, without treatment delays.
Two patients (4%) died within 90 days of treatment (1 from a chest infection, 1 from an unknown cause). A single patient each experienced early grade 3 esophagitis and grade 3 late dyspnea, for an overall rate of grade 3 toxicity of 4%. None of the patients experienced grade 4 toxicity. The 90-day rate of hospital admission was 20%.
With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The cohort had a median overall survival of 27.0 months and a median cancer-specific survival of 39.8 months. The 2-year overall survival rate was 67.6%.
“For patients with early stage moderately central NSCLC, SABR [stereotactic ablative body radiotherapy] using a schedule of 50 Gy/five fractions has acceptable toxicity and overall survival comparable with the published literature, despite treating a majority of patients with a performance status of 2 or worse,” the investigators concluded.
Dr. Rulach disclosed no conflicts of interest. The study did not receive any specific funding.
SOURCE: Rulach R et al. Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055.
Trial success with a stereotactic body radiation therapy (SBRT) regimen for centrally located non–small cell lung cancer (NSCLC) can be largely replicated in real-world practice, suggests a prospective cohort study published in Clinical Oncology.
The Radiation Therapy Oncology Group (RTOG) 0813 trial established the safety and efficacy of 50 Gy or 60 Gy given in five fractions to patients with early-stage central NSCLC (J Clin Oncol. 2019;37:1316-25). But whether similar outcomes can be achieved in routine care and how the degree of tumor centrality affects outcomes remain unclear.
Investigators led by Robert Rulach, MBChB, from the Beatson West of Scotland Cancer Centre, Glasgow, analyzed outcomes for 50 patients treated with the regimen of 50-Gy in five fractions at their institution for T1-2N0M0 stage NSCLC. All had tumors that were moderately central (within 2 cm of the trachea, bronchi, or proximal bronchial tree or having a planning target volume that abutted mediastinal pleura or pericardium); one had an additional tumor that was ultracentral (having a planning target volume that abutted the trachea).
The patients had a median age of 75.1 years. Notably, the majority were medically unfit for surgery (84%) and had an Eastern Cooperative Oncology Group performance status score of 2 or worse (56%). In 60% of patients, the diagnosis was made radiographically using PET/CT imaging; in the rest, the diagnosis was biopsy proven.
Study results showed that all patients completed the radiotherapy regimen of 50 Gy in 5 fractions on alternate days as planned, without treatment delays.
Two patients (4%) died within 90 days of treatment (1 from a chest infection, 1 from an unknown cause). A single patient each experienced early grade 3 esophagitis and grade 3 late dyspnea, for an overall rate of grade 3 toxicity of 4%. None of the patients experienced grade 4 toxicity. The 90-day rate of hospital admission was 20%.
With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The cohort had a median overall survival of 27.0 months and a median cancer-specific survival of 39.8 months. The 2-year overall survival rate was 67.6%.
“For patients with early stage moderately central NSCLC, SABR [stereotactic ablative body radiotherapy] using a schedule of 50 Gy/five fractions has acceptable toxicity and overall survival comparable with the published literature, despite treating a majority of patients with a performance status of 2 or worse,” the investigators concluded.
Dr. Rulach disclosed no conflicts of interest. The study did not receive any specific funding.
SOURCE: Rulach R et al. Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055.
Trial success with a stereotactic body radiation therapy (SBRT) regimen for centrally located non–small cell lung cancer (NSCLC) can be largely replicated in real-world practice, suggests a prospective cohort study published in Clinical Oncology.
The Radiation Therapy Oncology Group (RTOG) 0813 trial established the safety and efficacy of 50 Gy or 60 Gy given in five fractions to patients with early-stage central NSCLC (J Clin Oncol. 2019;37:1316-25). But whether similar outcomes can be achieved in routine care and how the degree of tumor centrality affects outcomes remain unclear.
Investigators led by Robert Rulach, MBChB, from the Beatson West of Scotland Cancer Centre, Glasgow, analyzed outcomes for 50 patients treated with the regimen of 50-Gy in five fractions at their institution for T1-2N0M0 stage NSCLC. All had tumors that were moderately central (within 2 cm of the trachea, bronchi, or proximal bronchial tree or having a planning target volume that abutted mediastinal pleura or pericardium); one had an additional tumor that was ultracentral (having a planning target volume that abutted the trachea).
The patients had a median age of 75.1 years. Notably, the majority were medically unfit for surgery (84%) and had an Eastern Cooperative Oncology Group performance status score of 2 or worse (56%). In 60% of patients, the diagnosis was made radiographically using PET/CT imaging; in the rest, the diagnosis was biopsy proven.
Study results showed that all patients completed the radiotherapy regimen of 50 Gy in 5 fractions on alternate days as planned, without treatment delays.
Two patients (4%) died within 90 days of treatment (1 from a chest infection, 1 from an unknown cause). A single patient each experienced early grade 3 esophagitis and grade 3 late dyspnea, for an overall rate of grade 3 toxicity of 4%. None of the patients experienced grade 4 toxicity. The 90-day rate of hospital admission was 20%.
With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The cohort had a median overall survival of 27.0 months and a median cancer-specific survival of 39.8 months. The 2-year overall survival rate was 67.6%.
“For patients with early stage moderately central NSCLC, SABR [stereotactic ablative body radiotherapy] using a schedule of 50 Gy/five fractions has acceptable toxicity and overall survival comparable with the published literature, despite treating a majority of patients with a performance status of 2 or worse,” the investigators concluded.
Dr. Rulach disclosed no conflicts of interest. The study did not receive any specific funding.
SOURCE: Rulach R et al. Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055.
FROM CLINICAL ONCOLOGY
Adding ramucirumab extends PFS in EGFR-mutated lung cancer
For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.
Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.
Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”
The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.
After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.
Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.
Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”
The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.
SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.
The study by Nakagawa et al. suggests that epidermal growth factor receptor tyrosine kinase inhibitors may feasibly be combined with other drugs, but concerns remain about the infrequency of complete responses, which were uncommon in this trial, at 1%, and only slightly higher, at 7%, in a previous, similar trial that involved the addition of bevacizumab to erlotinib (Lancet Oncol. 2019 Apr 8. doi: 10.1016/S1470-2045(19)30035-X). A lack of complete responses may be caused by vascular endothelial growth factor inhibition, which reduces tumor burden, but also may increase risks of tumor invasion, metastases, hypoxia, and other malignant processes.
Hypothetically, multitargeted receptor tyrosine kinases, such as cabozantinib or foretinib, could counteract the above drawbacks, but this remains to be seen. In the meantime, investigators should aim to design trials based on preclinical data instead of empirical reasoning. Despite the complexity of the molecular pathophysiology involved, research is bringing us closer to a clear understanding of the network of relationships between pathways, which could ultimately enable effective use of available combinations.
Rafael Rosell, MD, PhD, and Carlos Pedraz-Valdunciel are with Germans Trias i Pujol Research Institute and Hospital and the Universitat Autónoma de Barcelona. Both authors declared no competing interests. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30636-9).
The study by Nakagawa et al. suggests that epidermal growth factor receptor tyrosine kinase inhibitors may feasibly be combined with other drugs, but concerns remain about the infrequency of complete responses, which were uncommon in this trial, at 1%, and only slightly higher, at 7%, in a previous, similar trial that involved the addition of bevacizumab to erlotinib (Lancet Oncol. 2019 Apr 8. doi: 10.1016/S1470-2045(19)30035-X). A lack of complete responses may be caused by vascular endothelial growth factor inhibition, which reduces tumor burden, but also may increase risks of tumor invasion, metastases, hypoxia, and other malignant processes.
Hypothetically, multitargeted receptor tyrosine kinases, such as cabozantinib or foretinib, could counteract the above drawbacks, but this remains to be seen. In the meantime, investigators should aim to design trials based on preclinical data instead of empirical reasoning. Despite the complexity of the molecular pathophysiology involved, research is bringing us closer to a clear understanding of the network of relationships between pathways, which could ultimately enable effective use of available combinations.
Rafael Rosell, MD, PhD, and Carlos Pedraz-Valdunciel are with Germans Trias i Pujol Research Institute and Hospital and the Universitat Autónoma de Barcelona. Both authors declared no competing interests. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30636-9).
The study by Nakagawa et al. suggests that epidermal growth factor receptor tyrosine kinase inhibitors may feasibly be combined with other drugs, but concerns remain about the infrequency of complete responses, which were uncommon in this trial, at 1%, and only slightly higher, at 7%, in a previous, similar trial that involved the addition of bevacizumab to erlotinib (Lancet Oncol. 2019 Apr 8. doi: 10.1016/S1470-2045(19)30035-X). A lack of complete responses may be caused by vascular endothelial growth factor inhibition, which reduces tumor burden, but also may increase risks of tumor invasion, metastases, hypoxia, and other malignant processes.
Hypothetically, multitargeted receptor tyrosine kinases, such as cabozantinib or foretinib, could counteract the above drawbacks, but this remains to be seen. In the meantime, investigators should aim to design trials based on preclinical data instead of empirical reasoning. Despite the complexity of the molecular pathophysiology involved, research is bringing us closer to a clear understanding of the network of relationships between pathways, which could ultimately enable effective use of available combinations.
Rafael Rosell, MD, PhD, and Carlos Pedraz-Valdunciel are with Germans Trias i Pujol Research Institute and Hospital and the Universitat Autónoma de Barcelona. Both authors declared no competing interests. Their remarks are adapted from an accompanying editorial (Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30636-9).
For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.
Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.
Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”
The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.
After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.
Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.
Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”
The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.
SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.
For patients with epidermal growth factor receptor–mutated non–small cell lung cancer (NSCLC), adding the vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitor ramucirumab to standard erlotinib therapy may extend progression-free survival, based on results from the phase 3 RELAY trial.
Considering the acceptable safety profile, this dual regimen should be considered for first-line treatment of epidermal growth factor receptor (EGFR)–mutated disease, according to lead author Kazuhiko Nakagawa, MD, PhD, of the Kindai University faculty of medicine in Osaka, Japan, and colleagues.
Dual blockade of the EGFR and VEGF pathways is supported by previous studies which pointed to efficacy among EGFR-mutated subgroups, the investigators explained in Lancet Oncology, noting that ramucirumab appeared to be the best candidate for VEGF pathway inhibition. “Ramucirumab, a human monoclonal IgG1 antibody, selectively targets VEGFR-2, thereby blocking signaling mediated by VEGF-A, VEGF-C, and VEGF-D in NSCLC,” the investigators wrote. “Therefore, ramucirumab has the potential for broader antitumor activity than inhibitors of VEGF-A.”
The trial involved 449 patients with stage IV NSCLC and an EGFR exon 21 substitution or exon 19 deletion. Patients were randomized in a 1:1 ratio to receive either erlotinib (150 mg/day) plus placebo, or erlotinib plus ramucirumab (10 mg/kg every 2 weeks). The primary endpoint was progression-free survival. Secondary endpoints included safety and toxicity, overall survival, and various measures of response.
After a median follow-up of 20.7 months, the addition of ramucirumab was associated with a significantly better median progression-free survival, at 19.4 months, compared with 12.4 months among patients who received erlotinib alone, which translates to a hazard ratio of 0.59 (P less than .0001). In each cohort, 1% of patients achieved a complete response. Partial responses were also highly similar at 75% for ramucirumab versus 74% for placebo.
Turning to safety, ramucirumab was associated with more safety concerns, including a higher rate of grade 3-4 treatment-emergent adverse events (72% vs. 54%), most often hypertension. Serious adverse events were also more frequent with ramucirumab at a rate of 29%, compared with 21% among those who received erlotinib alone.
Despite these differences, the investigators concluded that the dual regimen still offers acceptable tolerability. “Safety was consistent with the established safety profiles of the individual compounds and a metastatic NSCLC population,” they wrote. “The RELAY regimen is therefore a viable new treatment option for the initial treatment of patients with metastatic EGFR-mutated NSCLC.”
The RELAY trial was funded by Eli Lilly. The investigators reported additional relationships with AstraZeneca, Bristol-Myers Squibb, Novartis, and others.
SOURCE: Nakagawa K et al. Lancet Oncol. 2019 Oct 4. doi: 10.1016/S1470-2045(19)30634-5.
FROM LANCET ONCOLOGY
Lazertinib has good showing in EGFR-mutated advanced NSCLC
Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.
Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.
Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.
“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.
“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.
The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.
Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).
Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.
On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.
The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).
Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.
Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.
SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.
“[W]hy should anyone care about all these data for lazertinib?” Tejas Patil, MD, and D. Ross Camidge, MD, PhD, asked in a commentary, noting that another third-generation EGFR TKI, osimertinib (Tagrisso), has already received Food and Drug Administration approval for use in this setting and has generally similar activity and tolerability.
“Beyond any potential competitive price advantage that could be introduced after licensing, or idiosyncratic tolerance of one drug over another in individual patients, the real potential advantage of lazertinib might be hiding in plain sight. Specifically, lazertinib’s incompletely explored potential to treat CNS metastases,” they noted.
Although osimertinib appears to have good CNS activity, patients with CNS metastases continue to experience poorer progression-free survival. And even at higher doses causing greater toxicity, CNS penetration of that drug is limited.
“[T]he ideal drug for dedicated CNS dose regimen exploration is one in which the standard dosing has been set in the absence of substantial toxicity and in the absence of any plateauing of pharmacokinetic exposures,” Dr. Patil and Dr. Camidge maintained. And lazertinib appears to fit that bill.
The 44% intracranial response rate “is encouraging but still leaves a substantial amount of important data to be generated,” they contended. Although progression in the CNS was uncommon among patients without CNS metastases at baseline, the longer median progression-free survival at higher doses may indicate better CNS control and support further dose escalation.
“Lazertinib could be one of the pioneer drugs for redefining how we optimally address the CNS in oncology drug development,” they concluded. “Taking full advantage of the early drug-development process to explore the CNS potential of any oncology drug being considered in disease types with a high rate of CNS metastases should be part of a future that we can all look forward to.”
Dr. Patil is instructor of medicine, and Dr. Camidge is professor of medicine, in the division of medical oncology, department of medicine, at the University of Colorado, Anschutz Medical Campus, Aurora.
“[W]hy should anyone care about all these data for lazertinib?” Tejas Patil, MD, and D. Ross Camidge, MD, PhD, asked in a commentary, noting that another third-generation EGFR TKI, osimertinib (Tagrisso), has already received Food and Drug Administration approval for use in this setting and has generally similar activity and tolerability.
“Beyond any potential competitive price advantage that could be introduced after licensing, or idiosyncratic tolerance of one drug over another in individual patients, the real potential advantage of lazertinib might be hiding in plain sight. Specifically, lazertinib’s incompletely explored potential to treat CNS metastases,” they noted.
Although osimertinib appears to have good CNS activity, patients with CNS metastases continue to experience poorer progression-free survival. And even at higher doses causing greater toxicity, CNS penetration of that drug is limited.
“[T]he ideal drug for dedicated CNS dose regimen exploration is one in which the standard dosing has been set in the absence of substantial toxicity and in the absence of any plateauing of pharmacokinetic exposures,” Dr. Patil and Dr. Camidge maintained. And lazertinib appears to fit that bill.
The 44% intracranial response rate “is encouraging but still leaves a substantial amount of important data to be generated,” they contended. Although progression in the CNS was uncommon among patients without CNS metastases at baseline, the longer median progression-free survival at higher doses may indicate better CNS control and support further dose escalation.
“Lazertinib could be one of the pioneer drugs for redefining how we optimally address the CNS in oncology drug development,” they concluded. “Taking full advantage of the early drug-development process to explore the CNS potential of any oncology drug being considered in disease types with a high rate of CNS metastases should be part of a future that we can all look forward to.”
Dr. Patil is instructor of medicine, and Dr. Camidge is professor of medicine, in the division of medical oncology, department of medicine, at the University of Colorado, Anschutz Medical Campus, Aurora.
“[W]hy should anyone care about all these data for lazertinib?” Tejas Patil, MD, and D. Ross Camidge, MD, PhD, asked in a commentary, noting that another third-generation EGFR TKI, osimertinib (Tagrisso), has already received Food and Drug Administration approval for use in this setting and has generally similar activity and tolerability.
“Beyond any potential competitive price advantage that could be introduced after licensing, or idiosyncratic tolerance of one drug over another in individual patients, the real potential advantage of lazertinib might be hiding in plain sight. Specifically, lazertinib’s incompletely explored potential to treat CNS metastases,” they noted.
Although osimertinib appears to have good CNS activity, patients with CNS metastases continue to experience poorer progression-free survival. And even at higher doses causing greater toxicity, CNS penetration of that drug is limited.
“[T]he ideal drug for dedicated CNS dose regimen exploration is one in which the standard dosing has been set in the absence of substantial toxicity and in the absence of any plateauing of pharmacokinetic exposures,” Dr. Patil and Dr. Camidge maintained. And lazertinib appears to fit that bill.
The 44% intracranial response rate “is encouraging but still leaves a substantial amount of important data to be generated,” they contended. Although progression in the CNS was uncommon among patients without CNS metastases at baseline, the longer median progression-free survival at higher doses may indicate better CNS control and support further dose escalation.
“Lazertinib could be one of the pioneer drugs for redefining how we optimally address the CNS in oncology drug development,” they concluded. “Taking full advantage of the early drug-development process to explore the CNS potential of any oncology drug being considered in disease types with a high rate of CNS metastases should be part of a future that we can all look forward to.”
Dr. Patil is instructor of medicine, and Dr. Camidge is professor of medicine, in the division of medical oncology, department of medicine, at the University of Colorado, Anschutz Medical Campus, Aurora.
Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.
Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.
Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.
“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.
“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.
The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.
Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).
Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.
On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.
The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).
Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.
Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.
SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.
Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.
Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.
Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.
“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.
“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.
The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.
Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).
Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.
On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.
The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).
Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.
Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.
SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.
FROM LANCET ONCOLOGY
Next-gen genomic test plus bronchoscopy may improve lung nodule management
NEW ORLEANS – The use of a results of a recent clinical validation study suggest.
The Percepta Genomic Sequencing Classifier (GSC) was able to up- and down-classify probability of malignancy for a considerable proportion of nondiagnostic bronchoscopies in the study, Peter J. Mazzone MD, FCCP, reported at the annual meeting of the American College of Chest Physicians.
The test is seen as complementary to bronchoscopy, improving the sensitivity of bronchoscopy overall and showing a combined sensitivity of greater than 95% in low- and intermediate-risk groups, according to Dr. Mazzone.
While the clinical utility of this genomic test needs to be further tested, the eventual goal is to improve clinician decision making when bronchoscopy results don’t clearly classify nodules as malignant or benign, Dr. Mazzone said in an interview.
“In that situation, you’re often left wondering, ‘what should I do next? Can I just watch this, and see if it grows and changes, or do I have to be even more aggressive – do another biopsy, or have a surgery to take it out?’ ” he explained. “So the test hopes to help make a more informed decision by further stratifying those patients as being quite low risk and maybe safe to follow, or quite high risk and maybe you should be considering more aggressive management.”
The GSC improves on the performance of an earlier molecular test, the Percepta Bronchial Genomic Classifier, which uses a brushing of bronchial epithelium to enhance nodule management in smokers, according to the researcher.
The next-generation GSC uses 1,232 gene transcripts from whole-transcriptome RNA sequencing, along with clinical factors, to help with nodule diagnosis, he said.
To establish the diagnostic accuracy of the GSC, Dr. Mazzone and colleagues evaluated data on 412 patients from three independent cohorts, all of whom had bronchoscopies for lung nodule evaluation that were nondiagnostic. Of those patients, 5% had nodules that physicians had deemed as low probability of malignancy prior to bronchoscopy, 28% deemed intermediate risk, and 74% high risk.
They found that the Percepta GSC down-classified the low–pretest risk patients with 100% negative predictive value (NPV) and down-classified intermediate–pretest risk patients with a 91.0% NPV, Dr. Mazzone reported, while patients with intermediate pretest risk were up-classified with a 65.4% positive predictive value (PPV) and patients with high pretest risk were upclassified with a 91.5% PPV.
The proportion of patients reclassified was about 55% for the low-risk group, 42% for the intermediate-risk group, and 27% for the high-risk group, according to the report at the meeting.
These results suggest the Percepta GSC could help in the “sticky situation” where a bronchoscopy result is inconclusive, Dr. Mazzone told attendees.
“When a bronchoscopy is recommended, despite fantastic advances in navigation systems to get to those nodules, we often come back without a solid answer, and that leaves the clinician in a bit of a predicament,” he said in a late-breaking clinical trial presentation.
Dr. Mazzone provided disclosures related to Veracyte, Exact Sciences, SEER, Tencent, and PCORI (research support to institution).
SOURCE: Mazzone PJ et al. CHEST 2019, Abstract. doi: 10.1016/j.chest.2019.08.307.
NEW ORLEANS – The use of a results of a recent clinical validation study suggest.
The Percepta Genomic Sequencing Classifier (GSC) was able to up- and down-classify probability of malignancy for a considerable proportion of nondiagnostic bronchoscopies in the study, Peter J. Mazzone MD, FCCP, reported at the annual meeting of the American College of Chest Physicians.
The test is seen as complementary to bronchoscopy, improving the sensitivity of bronchoscopy overall and showing a combined sensitivity of greater than 95% in low- and intermediate-risk groups, according to Dr. Mazzone.
While the clinical utility of this genomic test needs to be further tested, the eventual goal is to improve clinician decision making when bronchoscopy results don’t clearly classify nodules as malignant or benign, Dr. Mazzone said in an interview.
“In that situation, you’re often left wondering, ‘what should I do next? Can I just watch this, and see if it grows and changes, or do I have to be even more aggressive – do another biopsy, or have a surgery to take it out?’ ” he explained. “So the test hopes to help make a more informed decision by further stratifying those patients as being quite low risk and maybe safe to follow, or quite high risk and maybe you should be considering more aggressive management.”
The GSC improves on the performance of an earlier molecular test, the Percepta Bronchial Genomic Classifier, which uses a brushing of bronchial epithelium to enhance nodule management in smokers, according to the researcher.
The next-generation GSC uses 1,232 gene transcripts from whole-transcriptome RNA sequencing, along with clinical factors, to help with nodule diagnosis, he said.
To establish the diagnostic accuracy of the GSC, Dr. Mazzone and colleagues evaluated data on 412 patients from three independent cohorts, all of whom had bronchoscopies for lung nodule evaluation that were nondiagnostic. Of those patients, 5% had nodules that physicians had deemed as low probability of malignancy prior to bronchoscopy, 28% deemed intermediate risk, and 74% high risk.
They found that the Percepta GSC down-classified the low–pretest risk patients with 100% negative predictive value (NPV) and down-classified intermediate–pretest risk patients with a 91.0% NPV, Dr. Mazzone reported, while patients with intermediate pretest risk were up-classified with a 65.4% positive predictive value (PPV) and patients with high pretest risk were upclassified with a 91.5% PPV.
The proportion of patients reclassified was about 55% for the low-risk group, 42% for the intermediate-risk group, and 27% for the high-risk group, according to the report at the meeting.
These results suggest the Percepta GSC could help in the “sticky situation” where a bronchoscopy result is inconclusive, Dr. Mazzone told attendees.
“When a bronchoscopy is recommended, despite fantastic advances in navigation systems to get to those nodules, we often come back without a solid answer, and that leaves the clinician in a bit of a predicament,” he said in a late-breaking clinical trial presentation.
Dr. Mazzone provided disclosures related to Veracyte, Exact Sciences, SEER, Tencent, and PCORI (research support to institution).
SOURCE: Mazzone PJ et al. CHEST 2019, Abstract. doi: 10.1016/j.chest.2019.08.307.
NEW ORLEANS – The use of a results of a recent clinical validation study suggest.
The Percepta Genomic Sequencing Classifier (GSC) was able to up- and down-classify probability of malignancy for a considerable proportion of nondiagnostic bronchoscopies in the study, Peter J. Mazzone MD, FCCP, reported at the annual meeting of the American College of Chest Physicians.
The test is seen as complementary to bronchoscopy, improving the sensitivity of bronchoscopy overall and showing a combined sensitivity of greater than 95% in low- and intermediate-risk groups, according to Dr. Mazzone.
While the clinical utility of this genomic test needs to be further tested, the eventual goal is to improve clinician decision making when bronchoscopy results don’t clearly classify nodules as malignant or benign, Dr. Mazzone said in an interview.
“In that situation, you’re often left wondering, ‘what should I do next? Can I just watch this, and see if it grows and changes, or do I have to be even more aggressive – do another biopsy, or have a surgery to take it out?’ ” he explained. “So the test hopes to help make a more informed decision by further stratifying those patients as being quite low risk and maybe safe to follow, or quite high risk and maybe you should be considering more aggressive management.”
The GSC improves on the performance of an earlier molecular test, the Percepta Bronchial Genomic Classifier, which uses a brushing of bronchial epithelium to enhance nodule management in smokers, according to the researcher.
The next-generation GSC uses 1,232 gene transcripts from whole-transcriptome RNA sequencing, along with clinical factors, to help with nodule diagnosis, he said.
To establish the diagnostic accuracy of the GSC, Dr. Mazzone and colleagues evaluated data on 412 patients from three independent cohorts, all of whom had bronchoscopies for lung nodule evaluation that were nondiagnostic. Of those patients, 5% had nodules that physicians had deemed as low probability of malignancy prior to bronchoscopy, 28% deemed intermediate risk, and 74% high risk.
They found that the Percepta GSC down-classified the low–pretest risk patients with 100% negative predictive value (NPV) and down-classified intermediate–pretest risk patients with a 91.0% NPV, Dr. Mazzone reported, while patients with intermediate pretest risk were up-classified with a 65.4% positive predictive value (PPV) and patients with high pretest risk were upclassified with a 91.5% PPV.
The proportion of patients reclassified was about 55% for the low-risk group, 42% for the intermediate-risk group, and 27% for the high-risk group, according to the report at the meeting.
These results suggest the Percepta GSC could help in the “sticky situation” where a bronchoscopy result is inconclusive, Dr. Mazzone told attendees.
“When a bronchoscopy is recommended, despite fantastic advances in navigation systems to get to those nodules, we often come back without a solid answer, and that leaves the clinician in a bit of a predicament,” he said in a late-breaking clinical trial presentation.
Dr. Mazzone provided disclosures related to Veracyte, Exact Sciences, SEER, Tencent, and PCORI (research support to institution).
SOURCE: Mazzone PJ et al. CHEST 2019, Abstract. doi: 10.1016/j.chest.2019.08.307.
REPORTING FROM CHEST 2019
The law of unintended consequences
In this edition of “How I will treat my next patient,” I focus on a recent presentation at the American Society for Radiation Oncology meeting regarding the association of recent closures in women’s health clinics with cervical cancer outcomes and on a publication regarding guideline-concordant radiation exposure and organizational characteristics of lung cancer screening programs.
Cervical cancer screening and outcomes
Between 2010 and 2013, nearly 100 women’s health clinics closed in the United States because of a variety of factors, including concerns by state legislatures about reproductive services. Amar J. Srivastava, MD, and colleagues, performed a database search to determine the effect of closures on cervical cancer screening, stage, and mortality (ASTRO 2019, Abstract 202). The researchers used the Behavioral Risk Factors Surveillance Study, which provided data from 197,143 cases, to assess differences in screening availability in 2008-2009 (before the closures). They used the Surveillance, Epidemiology, and End Results (SEER) registry data from 2014-2015 (after) on 10,652 patients to compare stage at diagnosis and disease-specific mortality in states with women’s health clinic closures and states without closures.
They found that the cervical cancer screening rate in states that had a decline in the number of women’s health clinics was 1.63% lower than in states that did not lose clinics. The disparity was greater in medically underserved subgroups: Hispanic women, women aged 21-34 years, unmarried women, and uninsured women.
Early-stage diagnosis was also significantly less common in states that had a decreased number of women’s health clinics – a 13.2% drop – and the overall mortality rate from cervical cancer was 36% higher. The difference was even higher (40%) when comparing only metro residents. All of these differences between states with and without closures were statistically significant.
How these results influence clinical practice
The law of unintended consequences is that the actions of people, and especially of governments, will have effects that are unanticipated or unintended. All oncologists understand this law – we live it every day.
The data generated by Dr. Srivastava and colleagues bring to mind two presentations at the 2019 annual meeting of the American Society of Clinical Oncology: the impact of Medicaid Expansion on racial disparities in time to cancer treatment (LBA 1) and the impact of the Affordable Care Act on early-stage diagnosis and treatment for women with ovarian cancer (LBA 5563). Collectively, they remind us that health care policy changes influence the timeliness of cancer care delivery and disparities in cancer care. Of course, these analyses describe associations, not necessarily causation. Large databases have quality and completeness limitations. Nonetheless, these abstracts and the associated presentations and discussions support the concept that improved access can be associated with improved cancer care outcomes.
In 1936, American sociologist Robert K. Merton described “imperious immediacy of interest,” referring to instances in which an individual wants the intended consequence of an action so badly that he or she purposefully chooses to ignore unintended effects. As a clinical and research community, we are obliged to highlight those effects when they influence our patients’ suffering.
Lung cancer screening
As a component of the Centers for Medicare & Medicaid Services’ requirements for lung cancer screening payment, institutions performing screening must use low-dose techniques and participate in a dose registry. The American College of Radiology (ACR) recommends the dose levels per CT slice (CTDIvol; 3 mGy or lower) and the effective dose (ED; 1 mSr or lower) that would qualify an examination as “low dose,” thereby hoping to minimize the risk of radiation-induced cancers.
Joshua Demb, PhD, and colleagues prospectively collected lung cancer screening examination dose metrics at U.S. institutions in the University of California, San Francisco, International Dose Registry (JAMA Intern Med. 2019 Sep 23. doi: 10.1001/jamainternmed.2019.3893). Only U.S. institutions that performed more than 24 lung cancer screening scans from 2016-2017 were included in the survey (n = 72, more than 12,500 patients). Institution-level factors were collected via the Partnership for Dose trial, including how CT scans are performed and how CT protocols are established at the institutional level.
In a data-dense analysis, the authors found that 65% of institutions delivered, and more than half of patients received, radiation doses above ACR targets. This suggests that both the potential screening benefits and the margins of benefits over risks might be reduced for patients at those institutions. Factors associated with exceeding ACR guidelines for radiation dose were using an “external” medical physicist, although having a medical physicist of any type was more beneficial than not having one; allowing any radiologist to establish or modify the screening protocol, instead of limiting that role to “lead” radiologists; and updating CT protocols as needed, compared with updating the protocols annually.
How these results influence clinical practice
As with the ASTRO 2019 presentation, the law of unintended consequences applies here. Whenever potentially healthy people are subjected to medical procedures to prevent illness or detect disease at early stages, protecting safety is paramount. For that reason, National Comprehensive Cancer Network (NCCN) guidelines are explicit that all lung cancer screening and follow-up scans should use low-dose techniques, unless evaluating mediastinal abnormalities or adenopathy.
The study by Dr. Demb and colleagues critically examined the proportion of lung cancer screening participants receiving guideline-concordant, low-dose examinations and several factors that could influence conformance with ACR guidelines. The results are instructive despite some of the study’s limits including the fact that the database used did not enable long-term follow-up of screened individuals for lung cancer detection or mortality, the survey relied on self-reporting, and the institutional level data was not solely focused on lung cancer screening examinations.
The survey reminds us that the logistics, quality control, and periodic review of well-intentioned programs like lung cancer screening require the thoughtful, regular involvement of teams of professionals who are cognizant of, adherent to, and vigilant about the guidelines that protect the individuals who entrust their care to us.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I focus on a recent presentation at the American Society for Radiation Oncology meeting regarding the association of recent closures in women’s health clinics with cervical cancer outcomes and on a publication regarding guideline-concordant radiation exposure and organizational characteristics of lung cancer screening programs.
Cervical cancer screening and outcomes
Between 2010 and 2013, nearly 100 women’s health clinics closed in the United States because of a variety of factors, including concerns by state legislatures about reproductive services. Amar J. Srivastava, MD, and colleagues, performed a database search to determine the effect of closures on cervical cancer screening, stage, and mortality (ASTRO 2019, Abstract 202). The researchers used the Behavioral Risk Factors Surveillance Study, which provided data from 197,143 cases, to assess differences in screening availability in 2008-2009 (before the closures). They used the Surveillance, Epidemiology, and End Results (SEER) registry data from 2014-2015 (after) on 10,652 patients to compare stage at diagnosis and disease-specific mortality in states with women’s health clinic closures and states without closures.
They found that the cervical cancer screening rate in states that had a decline in the number of women’s health clinics was 1.63% lower than in states that did not lose clinics. The disparity was greater in medically underserved subgroups: Hispanic women, women aged 21-34 years, unmarried women, and uninsured women.
Early-stage diagnosis was also significantly less common in states that had a decreased number of women’s health clinics – a 13.2% drop – and the overall mortality rate from cervical cancer was 36% higher. The difference was even higher (40%) when comparing only metro residents. All of these differences between states with and without closures were statistically significant.
How these results influence clinical practice
The law of unintended consequences is that the actions of people, and especially of governments, will have effects that are unanticipated or unintended. All oncologists understand this law – we live it every day.
The data generated by Dr. Srivastava and colleagues bring to mind two presentations at the 2019 annual meeting of the American Society of Clinical Oncology: the impact of Medicaid Expansion on racial disparities in time to cancer treatment (LBA 1) and the impact of the Affordable Care Act on early-stage diagnosis and treatment for women with ovarian cancer (LBA 5563). Collectively, they remind us that health care policy changes influence the timeliness of cancer care delivery and disparities in cancer care. Of course, these analyses describe associations, not necessarily causation. Large databases have quality and completeness limitations. Nonetheless, these abstracts and the associated presentations and discussions support the concept that improved access can be associated with improved cancer care outcomes.
In 1936, American sociologist Robert K. Merton described “imperious immediacy of interest,” referring to instances in which an individual wants the intended consequence of an action so badly that he or she purposefully chooses to ignore unintended effects. As a clinical and research community, we are obliged to highlight those effects when they influence our patients’ suffering.
Lung cancer screening
As a component of the Centers for Medicare & Medicaid Services’ requirements for lung cancer screening payment, institutions performing screening must use low-dose techniques and participate in a dose registry. The American College of Radiology (ACR) recommends the dose levels per CT slice (CTDIvol; 3 mGy or lower) and the effective dose (ED; 1 mSr or lower) that would qualify an examination as “low dose,” thereby hoping to minimize the risk of radiation-induced cancers.
Joshua Demb, PhD, and colleagues prospectively collected lung cancer screening examination dose metrics at U.S. institutions in the University of California, San Francisco, International Dose Registry (JAMA Intern Med. 2019 Sep 23. doi: 10.1001/jamainternmed.2019.3893). Only U.S. institutions that performed more than 24 lung cancer screening scans from 2016-2017 were included in the survey (n = 72, more than 12,500 patients). Institution-level factors were collected via the Partnership for Dose trial, including how CT scans are performed and how CT protocols are established at the institutional level.
In a data-dense analysis, the authors found that 65% of institutions delivered, and more than half of patients received, radiation doses above ACR targets. This suggests that both the potential screening benefits and the margins of benefits over risks might be reduced for patients at those institutions. Factors associated with exceeding ACR guidelines for radiation dose were using an “external” medical physicist, although having a medical physicist of any type was more beneficial than not having one; allowing any radiologist to establish or modify the screening protocol, instead of limiting that role to “lead” radiologists; and updating CT protocols as needed, compared with updating the protocols annually.
How these results influence clinical practice
As with the ASTRO 2019 presentation, the law of unintended consequences applies here. Whenever potentially healthy people are subjected to medical procedures to prevent illness or detect disease at early stages, protecting safety is paramount. For that reason, National Comprehensive Cancer Network (NCCN) guidelines are explicit that all lung cancer screening and follow-up scans should use low-dose techniques, unless evaluating mediastinal abnormalities or adenopathy.
The study by Dr. Demb and colleagues critically examined the proportion of lung cancer screening participants receiving guideline-concordant, low-dose examinations and several factors that could influence conformance with ACR guidelines. The results are instructive despite some of the study’s limits including the fact that the database used did not enable long-term follow-up of screened individuals for lung cancer detection or mortality, the survey relied on self-reporting, and the institutional level data was not solely focused on lung cancer screening examinations.
The survey reminds us that the logistics, quality control, and periodic review of well-intentioned programs like lung cancer screening require the thoughtful, regular involvement of teams of professionals who are cognizant of, adherent to, and vigilant about the guidelines that protect the individuals who entrust their care to us.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I focus on a recent presentation at the American Society for Radiation Oncology meeting regarding the association of recent closures in women’s health clinics with cervical cancer outcomes and on a publication regarding guideline-concordant radiation exposure and organizational characteristics of lung cancer screening programs.
Cervical cancer screening and outcomes
Between 2010 and 2013, nearly 100 women’s health clinics closed in the United States because of a variety of factors, including concerns by state legislatures about reproductive services. Amar J. Srivastava, MD, and colleagues, performed a database search to determine the effect of closures on cervical cancer screening, stage, and mortality (ASTRO 2019, Abstract 202). The researchers used the Behavioral Risk Factors Surveillance Study, which provided data from 197,143 cases, to assess differences in screening availability in 2008-2009 (before the closures). They used the Surveillance, Epidemiology, and End Results (SEER) registry data from 2014-2015 (after) on 10,652 patients to compare stage at diagnosis and disease-specific mortality in states with women’s health clinic closures and states without closures.
They found that the cervical cancer screening rate in states that had a decline in the number of women’s health clinics was 1.63% lower than in states that did not lose clinics. The disparity was greater in medically underserved subgroups: Hispanic women, women aged 21-34 years, unmarried women, and uninsured women.
Early-stage diagnosis was also significantly less common in states that had a decreased number of women’s health clinics – a 13.2% drop – and the overall mortality rate from cervical cancer was 36% higher. The difference was even higher (40%) when comparing only metro residents. All of these differences between states with and without closures were statistically significant.
How these results influence clinical practice
The law of unintended consequences is that the actions of people, and especially of governments, will have effects that are unanticipated or unintended. All oncologists understand this law – we live it every day.
The data generated by Dr. Srivastava and colleagues bring to mind two presentations at the 2019 annual meeting of the American Society of Clinical Oncology: the impact of Medicaid Expansion on racial disparities in time to cancer treatment (LBA 1) and the impact of the Affordable Care Act on early-stage diagnosis and treatment for women with ovarian cancer (LBA 5563). Collectively, they remind us that health care policy changes influence the timeliness of cancer care delivery and disparities in cancer care. Of course, these analyses describe associations, not necessarily causation. Large databases have quality and completeness limitations. Nonetheless, these abstracts and the associated presentations and discussions support the concept that improved access can be associated with improved cancer care outcomes.
In 1936, American sociologist Robert K. Merton described “imperious immediacy of interest,” referring to instances in which an individual wants the intended consequence of an action so badly that he or she purposefully chooses to ignore unintended effects. As a clinical and research community, we are obliged to highlight those effects when they influence our patients’ suffering.
Lung cancer screening
As a component of the Centers for Medicare & Medicaid Services’ requirements for lung cancer screening payment, institutions performing screening must use low-dose techniques and participate in a dose registry. The American College of Radiology (ACR) recommends the dose levels per CT slice (CTDIvol; 3 mGy or lower) and the effective dose (ED; 1 mSr or lower) that would qualify an examination as “low dose,” thereby hoping to minimize the risk of radiation-induced cancers.
Joshua Demb, PhD, and colleagues prospectively collected lung cancer screening examination dose metrics at U.S. institutions in the University of California, San Francisco, International Dose Registry (JAMA Intern Med. 2019 Sep 23. doi: 10.1001/jamainternmed.2019.3893). Only U.S. institutions that performed more than 24 lung cancer screening scans from 2016-2017 were included in the survey (n = 72, more than 12,500 patients). Institution-level factors were collected via the Partnership for Dose trial, including how CT scans are performed and how CT protocols are established at the institutional level.
In a data-dense analysis, the authors found that 65% of institutions delivered, and more than half of patients received, radiation doses above ACR targets. This suggests that both the potential screening benefits and the margins of benefits over risks might be reduced for patients at those institutions. Factors associated with exceeding ACR guidelines for radiation dose were using an “external” medical physicist, although having a medical physicist of any type was more beneficial than not having one; allowing any radiologist to establish or modify the screening protocol, instead of limiting that role to “lead” radiologists; and updating CT protocols as needed, compared with updating the protocols annually.
How these results influence clinical practice
As with the ASTRO 2019 presentation, the law of unintended consequences applies here. Whenever potentially healthy people are subjected to medical procedures to prevent illness or detect disease at early stages, protecting safety is paramount. For that reason, National Comprehensive Cancer Network (NCCN) guidelines are explicit that all lung cancer screening and follow-up scans should use low-dose techniques, unless evaluating mediastinal abnormalities or adenopathy.
The study by Dr. Demb and colleagues critically examined the proportion of lung cancer screening participants receiving guideline-concordant, low-dose examinations and several factors that could influence conformance with ACR guidelines. The results are instructive despite some of the study’s limits including the fact that the database used did not enable long-term follow-up of screened individuals for lung cancer detection or mortality, the survey relied on self-reporting, and the institutional level data was not solely focused on lung cancer screening examinations.
The survey reminds us that the logistics, quality control, and periodic review of well-intentioned programs like lung cancer screening require the thoughtful, regular involvement of teams of professionals who are cognizant of, adherent to, and vigilant about the guidelines that protect the individuals who entrust their care to us.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
Treatment of Unresectable Stage III Non-small Cell Lung Cancer
With a recent renaissance in cancer diagnostics and treatment, there is hope for many fighting the disease. In this article, Dr. M. Patricia Rivera discusses screening and diagnostic procedures as well as the treatment options that are available for patients with unresectable stage III non-small cell lung cancer.
This article is sponsored by AstraZeneca.
US-33194 Last Updated 9/19
With a recent renaissance in cancer diagnostics and treatment, there is hope for many fighting the disease. In this article, Dr. M. Patricia Rivera discusses screening and diagnostic procedures as well as the treatment options that are available for patients with unresectable stage III non-small cell lung cancer.
This article is sponsored by AstraZeneca.
US-33194 Last Updated 9/19
With a recent renaissance in cancer diagnostics and treatment, there is hope for many fighting the disease. In this article, Dr. M. Patricia Rivera discusses screening and diagnostic procedures as well as the treatment options that are available for patients with unresectable stage III non-small cell lung cancer.
This article is sponsored by AstraZeneca.
US-33194 Last Updated 9/19
