Alan P. Lyss, MD

In this edition of “How I Will Treat My Next Patient,” I highlight two articles that demonstrate the safety of established treatments – nephrectomy and stereotactic ablative body radiotherapy (SABR) – in patient populations that previously may have been excluded from those treatments at many centers.

Nephrectomy in advanced RCC

Nirmish Singla, MD, and colleagues reported a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced renal cell carcinoma (RCC) who had received front- or later-line immune checkpoint inhibitor therapy (ICIs). Half had received nivolumab alone; the others received nivolumab plus ipilimumab. Surgery was performed laparoscopically in five cases (Urol Oncol. 2019 Dec;37[12]:924-31).

No patient experienced a major intraoperative complication. Four experienced postoperative complications, the majority of which were addressed with interventional radiology procedures. The median hospital stay was 4 days. One patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism and sepsis. Six of the 10 patients did not have any complications or readmissions. There were no immune-related toxicities and no wound-healing issues. ICI therapy was resumed postoperatively in six patients.

At nephrectomy (plus or minus metastatectomy), one patient achieved a response to immunotherapy in the primary tumor, and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer. All surgical margins were negative.

During a median postoperative follow-up of 180 days, nephrectomy following ICI was safe. Pathologic response in both the primary tumor and metastatic sites was encouraging.

What this means in clinical practice

In medical school, all of us are admonished not to be afraid to unlearn something and to learn something new. Historically, nephrectomy was felt to be helpful in improving overall survival in patients with advanced RCC. Effective targeted therapies and ICIs have caused us to question the role of nephrectomy and its timing, since 20%-40% of patients who have apparently localized RCC at the time of nephrectomy develop recurrences within 3 years. Preoperative therapy could mitigate potentially aggressive tumor biology, treat micrometastatic disease, and help select patients who should not be treated surgically.

In the CARMENA trial of the treatment of advanced RCC patients with the tyrosine kinase inhibitor sunitinib versus nephrectomy followed by sunitinib, most patients could avoid nephrectomy without compromising survival (N Engl J Med. 2018; 379:417-27). Results were updated at the 2019 annual meeting of the American Society of Clinical Oncology. Overall, nephrectomy was not beneficial. However, delayed nephrectomy (after sunitinib) appeared be beneficial for good responders with only one IMDC (International Metastatic RCC Database Consortium) risk factor and only one metastatic site.

The small study by Dr. Singla and colleagues illustrates that nephrectomy is feasible after ICI, plus or minus anti-CTLA4-targeted treatment, and that favorable histologic results can be achieved. With ICI plus or minus anti-CTLA4-targeted treatment, no patient had progressive disease prior to surgery. This experience is germane in view of recently updated results of the CheckMate 214 trial, showing superior overall survival, response rates, and response duration for nivolumab plus ipilimumab, in comparison with sunitinib.

There are still unresolved questions, including whether these favorable outcomes can be achieved in community practice and whether there are genomic or immunohistochemistry expression profiles to select patients who can benefit from this approach. It’s unclear whether there are practical issues that influence outcome, such as type of ICI, number of preoperative treatment cycles, and additional systemic therapies including postoperative treatment. However, the current series rings the starting bell for the study of those questions and a promising era for patients with this deadly disease.
 

SABR in moderately central NSCLC

SABR to peripheral, small non–small cell lung cancers (NSCLCs) produces high local control rates, with low grade 3-4 toxicity, and is an alternative to resection in patients who are unfit for surgery. In a pragmatic, community-based, prospective cohort experience in Scotland, Robert Rulach, MBChB, and colleagues, treated 50 T1-2N0M0 NSCLC patients with SABR 50-Gy in five fractions (Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055). The dose and fractionation schedule was safe and effective in the phase 1/2 RTOG 0813 trial and is concordant with guidelines from the National Comprehensive Cancer Network (NCCN).

All of the tumors were moderately central, as in the RTOG trial. One patient had an additional tumor that was ultracentral. Notably, 84% of patients were deemed medically unfit for surgery.

All patients completed radiotherapy without treatment delays. Two patients died within 90 days of treatment. There were no grade 4 or grade 5 toxicities and the overall rate of grade 3 toxicity was 4%. With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The median overall survival was 27 months. The 2-year overall survival rate was 67.6%, commensurate with the rate seen in RTOG 0813.

The researchers concluded that, for frail patients with centrally-located NSCLC treated uniformly in a community practice, SABR with the RTOG 0813 treatment protocol produced acceptable toxicity and overall survival comparable with the published literature.

What this means in clinical practice

The results and conclusions of the study by Dr. Rulach and colleagues are straightforward: SABR can be used for centrally-located NSCLC without producing massive hemoptysis, bronchial stricture, and fistula formation. Since the majority of patients had no histologic diagnosis, T1N0 lesions, and no routine follow-up CT scans beyond 3 months post treatment, conclusions beyond that are unjustified.

In a community-based practice, NCCN guideline–concordant SABR treatment in moderately centrally-located NSCLC was safely delivered. For the burgeoning population of medically inoperable and/or elderly NSCLC patients, this alone is reassuring for clinicians and is helpful information for patients who require and/or desire nonsurgical treatment.
 

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 highlight two articles that demonstrate the safety of established treatments – nephrectomy and stereotactic ablative body radiotherapy (SABR) – in patient populations that previously may have been excluded from those treatments at many centers.

Nephrectomy in advanced RCC

Nirmish Singla, MD, and colleagues reported a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced renal cell carcinoma (RCC) who had received front- or later-line immune checkpoint inhibitor therapy (ICIs). Half had received nivolumab alone; the others received nivolumab plus ipilimumab. Surgery was performed laparoscopically in five cases (Urol Oncol. 2019 Dec;37[12]:924-31).

No patient experienced a major intraoperative complication. Four experienced postoperative complications, the majority of which were addressed with interventional radiology procedures. The median hospital stay was 4 days. One patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism and sepsis. Six of the 10 patients did not have any complications or readmissions. There were no immune-related toxicities and no wound-healing issues. ICI therapy was resumed postoperatively in six patients.

At nephrectomy (plus or minus metastatectomy), one patient achieved a response to immunotherapy in the primary tumor, and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer. All surgical margins were negative.

During a median postoperative follow-up of 180 days, nephrectomy following ICI was safe. Pathologic response in both the primary tumor and metastatic sites was encouraging.

What this means in clinical practice

In medical school, all of us are admonished not to be afraid to unlearn something and to learn something new. Historically, nephrectomy was felt to be helpful in improving overall survival in patients with advanced RCC. Effective targeted therapies and ICIs have caused us to question the role of nephrectomy and its timing, since 20%-40% of patients who have apparently localized RCC at the time of nephrectomy develop recurrences within 3 years. Preoperative therapy could mitigate potentially aggressive tumor biology, treat micrometastatic disease, and help select patients who should not be treated surgically.

In the CARMENA trial of the treatment of advanced RCC patients with the tyrosine kinase inhibitor sunitinib versus nephrectomy followed by sunitinib, most patients could avoid nephrectomy without compromising survival (N Engl J Med. 2018; 379:417-27). Results were updated at the 2019 annual meeting of the American Society of Clinical Oncology. Overall, nephrectomy was not beneficial. However, delayed nephrectomy (after sunitinib) appeared be beneficial for good responders with only one IMDC (International Metastatic RCC Database Consortium) risk factor and only one metastatic site.

The small study by Dr. Singla and colleagues illustrates that nephrectomy is feasible after ICI, plus or minus anti-CTLA4-targeted treatment, and that favorable histologic results can be achieved. With ICI plus or minus anti-CTLA4-targeted treatment, no patient had progressive disease prior to surgery. This experience is germane in view of recently updated results of the CheckMate 214 trial, showing superior overall survival, response rates, and response duration for nivolumab plus ipilimumab, in comparison with sunitinib.

There are still unresolved questions, including whether these favorable outcomes can be achieved in community practice and whether there are genomic or immunohistochemistry expression profiles to select patients who can benefit from this approach. It’s unclear whether there are practical issues that influence outcome, such as type of ICI, number of preoperative treatment cycles, and additional systemic therapies including postoperative treatment. However, the current series rings the starting bell for the study of those questions and a promising era for patients with this deadly disease.
 

SABR in moderately central NSCLC

SABR to peripheral, small non–small cell lung cancers (NSCLCs) produces high local control rates, with low grade 3-4 toxicity, and is an alternative to resection in patients who are unfit for surgery. In a pragmatic, community-based, prospective cohort experience in Scotland, Robert Rulach, MBChB, and colleagues, treated 50 T1-2N0M0 NSCLC patients with SABR 50-Gy in five fractions (Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055). The dose and fractionation schedule was safe and effective in the phase 1/2 RTOG 0813 trial and is concordant with guidelines from the National Comprehensive Cancer Network (NCCN).

All of the tumors were moderately central, as in the RTOG trial. One patient had an additional tumor that was ultracentral. Notably, 84% of patients were deemed medically unfit for surgery.

All patients completed radiotherapy without treatment delays. Two patients died within 90 days of treatment. There were no grade 4 or grade 5 toxicities and the overall rate of grade 3 toxicity was 4%. With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The median overall survival was 27 months. The 2-year overall survival rate was 67.6%, commensurate with the rate seen in RTOG 0813.

The researchers concluded that, for frail patients with centrally-located NSCLC treated uniformly in a community practice, SABR with the RTOG 0813 treatment protocol produced acceptable toxicity and overall survival comparable with the published literature.

What this means in clinical practice

The results and conclusions of the study by Dr. Rulach and colleagues are straightforward: SABR can be used for centrally-located NSCLC without producing massive hemoptysis, bronchial stricture, and fistula formation. Since the majority of patients had no histologic diagnosis, T1N0 lesions, and no routine follow-up CT scans beyond 3 months post treatment, conclusions beyond that are unjustified.

In a community-based practice, NCCN guideline–concordant SABR treatment in moderately centrally-located NSCLC was safely delivered. For the burgeoning population of medically inoperable and/or elderly NSCLC patients, this alone is reassuring for clinicians and is helpful information for patients who require and/or desire nonsurgical treatment.
 

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 highlight two articles that demonstrate the safety of established treatments – nephrectomy and stereotactic ablative body radiotherapy (SABR) – in patient populations that previously may have been excluded from those treatments at many centers.

Nephrectomy in advanced RCC

Nirmish Singla, MD, and colleagues reported a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced renal cell carcinoma (RCC) who had received front- or later-line immune checkpoint inhibitor therapy (ICIs). Half had received nivolumab alone; the others received nivolumab plus ipilimumab. Surgery was performed laparoscopically in five cases (Urol Oncol. 2019 Dec;37[12]:924-31).

No patient experienced a major intraoperative complication. Four experienced postoperative complications, the majority of which were addressed with interventional radiology procedures. The median hospital stay was 4 days. One patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism and sepsis. Six of the 10 patients did not have any complications or readmissions. There were no immune-related toxicities and no wound-healing issues. ICI therapy was resumed postoperatively in six patients.

At nephrectomy (plus or minus metastatectomy), one patient achieved a response to immunotherapy in the primary tumor, and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer. All surgical margins were negative.

During a median postoperative follow-up of 180 days, nephrectomy following ICI was safe. Pathologic response in both the primary tumor and metastatic sites was encouraging.

What this means in clinical practice

In medical school, all of us are admonished not to be afraid to unlearn something and to learn something new. Historically, nephrectomy was felt to be helpful in improving overall survival in patients with advanced RCC. Effective targeted therapies and ICIs have caused us to question the role of nephrectomy and its timing, since 20%-40% of patients who have apparently localized RCC at the time of nephrectomy develop recurrences within 3 years. Preoperative therapy could mitigate potentially aggressive tumor biology, treat micrometastatic disease, and help select patients who should not be treated surgically.

In the CARMENA trial of the treatment of advanced RCC patients with the tyrosine kinase inhibitor sunitinib versus nephrectomy followed by sunitinib, most patients could avoid nephrectomy without compromising survival (N Engl J Med. 2018; 379:417-27). Results were updated at the 2019 annual meeting of the American Society of Clinical Oncology. Overall, nephrectomy was not beneficial. However, delayed nephrectomy (after sunitinib) appeared be beneficial for good responders with only one IMDC (International Metastatic RCC Database Consortium) risk factor and only one metastatic site.

The small study by Dr. Singla and colleagues illustrates that nephrectomy is feasible after ICI, plus or minus anti-CTLA4-targeted treatment, and that favorable histologic results can be achieved. With ICI plus or minus anti-CTLA4-targeted treatment, no patient had progressive disease prior to surgery. This experience is germane in view of recently updated results of the CheckMate 214 trial, showing superior overall survival, response rates, and response duration for nivolumab plus ipilimumab, in comparison with sunitinib.

There are still unresolved questions, including whether these favorable outcomes can be achieved in community practice and whether there are genomic or immunohistochemistry expression profiles to select patients who can benefit from this approach. It’s unclear whether there are practical issues that influence outcome, such as type of ICI, number of preoperative treatment cycles, and additional systemic therapies including postoperative treatment. However, the current series rings the starting bell for the study of those questions and a promising era for patients with this deadly disease.
 

SABR in moderately central NSCLC

SABR to peripheral, small non–small cell lung cancers (NSCLCs) produces high local control rates, with low grade 3-4 toxicity, and is an alternative to resection in patients who are unfit for surgery. In a pragmatic, community-based, prospective cohort experience in Scotland, Robert Rulach, MBChB, and colleagues, treated 50 T1-2N0M0 NSCLC patients with SABR 50-Gy in five fractions (Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055). The dose and fractionation schedule was safe and effective in the phase 1/2 RTOG 0813 trial and is concordant with guidelines from the National Comprehensive Cancer Network (NCCN).

All of the tumors were moderately central, as in the RTOG trial. One patient had an additional tumor that was ultracentral. Notably, 84% of patients were deemed medically unfit for surgery.

All patients completed radiotherapy without treatment delays. Two patients died within 90 days of treatment. There were no grade 4 or grade 5 toxicities and the overall rate of grade 3 toxicity was 4%. With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The median overall survival was 27 months. The 2-year overall survival rate was 67.6%, commensurate with the rate seen in RTOG 0813.

The researchers concluded that, for frail patients with centrally-located NSCLC treated uniformly in a community practice, SABR with the RTOG 0813 treatment protocol produced acceptable toxicity and overall survival comparable with the published literature.

What this means in clinical practice

The results and conclusions of the study by Dr. Rulach and colleagues are straightforward: SABR can be used for centrally-located NSCLC without producing massive hemoptysis, bronchial stricture, and fistula formation. Since the majority of patients had no histologic diagnosis, T1N0 lesions, and no routine follow-up CT scans beyond 3 months post treatment, conclusions beyond that are unjustified.

In a community-based practice, NCCN guideline–concordant SABR treatment in moderately centrally-located NSCLC was safely delivered. For the burgeoning population of medically inoperable and/or elderly NSCLC patients, this alone is reassuring for clinicians and is helpful information for patients who require and/or desire nonsurgical treatment.
 

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 highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).

Osimertinib in advanced NSCLC

In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.

At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).

More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.

The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.

What this means in clinical practice

The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”

For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.

In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.

MONARCH 2: Abemaciclib plus fulvestrant

In the MONARCH 2, randomized, placebo-controlled, phase 3 trial, abemaciclib plus fulvestrant (abema-F) significantly improved PFS, in comparison with placebo plus fulvestrant (placebo-F; 16.9 months vs. 9.3 months; HR, 0.563) in 669 premenopausal (with concurrent ovarian function suppression) and postmenopausal women with metastatic breast cancer (mBC) who had disease progression on one to two lines of prior hormonal therapy (J Clin Oncol. 2017;35[25]:2875-84).

At ESMO 2019, George W. Sledge Jr., MD, of Stanford (Calif.) Medical Center, and colleagues reported the OS results, a secondary endpoint for the trial (JAMA Oncol. 2019 Sep 29. doi. 10.1001/jamaoncol.2019.4782). At the prespecified interim analysis point, median OS for abema-F was 46.7 months vs. 37.3 months for placebo-F (HR, 0.757; 95% CI 0.505-0.945; P = .0137). Patients with greatest benefit from abema-F were exactly the patients who needed the most help – those with visceral metastases (HR 0.675) and with primary resistance to prior hormonal therapy (HR, 0.686).

At 3 years, at least three times as many patients remained progression free with abema-F, compared with placebo-F, and the abema-F patients experienced prolongation in time to eventual chemotherapy (50.2 months vs. 22.1 months; HR, 0.625).

What this means in clinical practice

Many times I find myself sitting at the annual meeting of the American Society of Clinical Oncology and thinking, “Only a medical oncologist like me would find this result exciting.” Prior to ESMO 2019, MONARCH 2 (and a similar study presented at ESMO 2019, MONALEESA-3, which employed an alternative CDK 4/6 inhibitor, ribociclib, with similar OS results) added to the body of literature that caused NCCN guidelines to list all of the approved CDK 4/6 inhibitors plus endocrine therapy for first- or second-line use in patients with hormone-receptor positive, HER2/neu-negative mBC. NCCN guidelines have the caveat that, among patients with disease progression on CDK 4/6 inhibitors in the first-line setting, there are no data to support continuing the CDK 4/6 inhibitor or switching to an alternative CDK 4/6 inhibitor thereafter.

For that shrinking group of patients and doctors who choose to avoid CDK 4/6 inhibitors for first-line treatment, as we describe risks and benefits of using a CDK 4/6 inhibitor for second- or third-line therapy, we have high-quality OS information from ESMO 2019 to answer the “Is it worth it?” question.

Are the results of MONARCH 2 and MONALEESA-3 practice changing? No. We were already convinced. Should we be excited that we have this new information for discussions with our patients? Absolutely.
 

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 highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).

Osimertinib in advanced NSCLC

In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.

At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).

More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.

The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.

What this means in clinical practice

The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”

For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.

In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.

MONARCH 2: Abemaciclib plus fulvestrant

In the MONARCH 2, randomized, placebo-controlled, phase 3 trial, abemaciclib plus fulvestrant (abema-F) significantly improved PFS, in comparison with placebo plus fulvestrant (placebo-F; 16.9 months vs. 9.3 months; HR, 0.563) in 669 premenopausal (with concurrent ovarian function suppression) and postmenopausal women with metastatic breast cancer (mBC) who had disease progression on one to two lines of prior hormonal therapy (J Clin Oncol. 2017;35[25]:2875-84).

At ESMO 2019, George W. Sledge Jr., MD, of Stanford (Calif.) Medical Center, and colleagues reported the OS results, a secondary endpoint for the trial (JAMA Oncol. 2019 Sep 29. doi. 10.1001/jamaoncol.2019.4782). At the prespecified interim analysis point, median OS for abema-F was 46.7 months vs. 37.3 months for placebo-F (HR, 0.757; 95% CI 0.505-0.945; P = .0137). Patients with greatest benefit from abema-F were exactly the patients who needed the most help – those with visceral metastases (HR 0.675) and with primary resistance to prior hormonal therapy (HR, 0.686).

At 3 years, at least three times as many patients remained progression free with abema-F, compared with placebo-F, and the abema-F patients experienced prolongation in time to eventual chemotherapy (50.2 months vs. 22.1 months; HR, 0.625).

What this means in clinical practice

Many times I find myself sitting at the annual meeting of the American Society of Clinical Oncology and thinking, “Only a medical oncologist like me would find this result exciting.” Prior to ESMO 2019, MONARCH 2 (and a similar study presented at ESMO 2019, MONALEESA-3, which employed an alternative CDK 4/6 inhibitor, ribociclib, with similar OS results) added to the body of literature that caused NCCN guidelines to list all of the approved CDK 4/6 inhibitors plus endocrine therapy for first- or second-line use in patients with hormone-receptor positive, HER2/neu-negative mBC. NCCN guidelines have the caveat that, among patients with disease progression on CDK 4/6 inhibitors in the first-line setting, there are no data to support continuing the CDK 4/6 inhibitor or switching to an alternative CDK 4/6 inhibitor thereafter.

For that shrinking group of patients and doctors who choose to avoid CDK 4/6 inhibitors for first-line treatment, as we describe risks and benefits of using a CDK 4/6 inhibitor for second- or third-line therapy, we have high-quality OS information from ESMO 2019 to answer the “Is it worth it?” question.

Are the results of MONARCH 2 and MONALEESA-3 practice changing? No. We were already convinced. Should we be excited that we have this new information for discussions with our patients? Absolutely.
 

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 highlight two studies that previously reported significant progression-free survival (PFS) improvements and more recently, at the European Society for Medical Oncology Congress, overall survival (OS) benefit. I reflect on the significance of these new reports in the wake of previously reported data and guidelines from the National Comprehensive Cancer Network (NCCN).

Osimertinib in advanced NSCLC

In the double-blind, phase 3 FLAURA trial, 556 patients with EGFR-mutated (EGFRm), advanced non–small cell lung cancer (NSCLC) received osimertinib or a standard tyrosine kinase inhibitor (TKI) as initial treatment. PFS, the primary endpoint, was clinically and statistically better for osimertinib (18.9 months vs. 10.2 months; hazard ratio 0.46; P less than .001), overall and in all major subgroups. There were fewer grade 3-4 adverse events and fewer permanent treatment discontinuations with osimertinib.

At the time of initial publication, OS data were immature, but because of the substantial survival improvements previously noted, osimertinib was approved by the Food and Drug Administration for first-line treatment of EGFRm stage IV NSCLC patients in April 2018 (N Engl J Med. 2018; 378:113-25).

More recently, at ESMO 2019, Suresh Ramalingam, MD, of the department of hematology and medical oncology at Emory University, Atlanta, and colleagues reported the OS results. Crossover to osimertinib was allowed for patients on the standard TKI arm when they had progressive disease and a T790M mutation. Osimertinib produced a median OS of 38.6 months, compared with 31.8 months for standard TKI (HR, 0.799; P = .0462), a 24-month OS rate of 74% vs. 59% (with no overlap in the 95% confidence intervals), and a 36-month OS rate of 54% vs. 44%. These benefits were interpreted to be statistically significant and clinically meaningful.

The 31.8-month median OS for standard TKI was competitive with the highest reported OS for standard therapy, perhaps because crossover to osimertinib was permitted.

What this means in clinical practice

The report by Dr. Ramalingam and colleagues – and the next abstract I will review – remind me of the famous “You had me at Hello” line from “Jerry Maguire.”

For patient education – and perhaps for some national regulatory agencies – it is good that we now have definition of what the average OS is with osimertinib, compared with standard TKI followed by osimertinib. However, very few oncologists in the United States likely use the latter strategy anymore. It was clear when the impressive PFS and toxicity information appeared in 2018 in the New England Journal of Medicine that osimertinib is the best tolerated, most durably effective front-line treatment for EGFRm mNSCLC, regardless of disease extent, sex, nationality, type of EGFRm (L858R amino acid substitution in exon 21 or exon 19 deletion), or presence/absence of central nervous system metastases.

In NCCN guidelines, osimertinib was listed as the preferred TKI, prior to the OS report at ESMO 2019. The challenges going forward will be to identify high-risk patient subsets who might benefit from drug combinations or novel new agents.

MONARCH 2: Abemaciclib plus fulvestrant

In the MONARCH 2, randomized, placebo-controlled, phase 3 trial, abemaciclib plus fulvestrant (abema-F) significantly improved PFS, in comparison with placebo plus fulvestrant (placebo-F; 16.9 months vs. 9.3 months; HR, 0.563) in 669 premenopausal (with concurrent ovarian function suppression) and postmenopausal women with metastatic breast cancer (mBC) who had disease progression on one to two lines of prior hormonal therapy (J Clin Oncol. 2017;35[25]:2875-84).

At ESMO 2019, George W. Sledge Jr., MD, of Stanford (Calif.) Medical Center, and colleagues reported the OS results, a secondary endpoint for the trial (JAMA Oncol. 2019 Sep 29. doi. 10.1001/jamaoncol.2019.4782). At the prespecified interim analysis point, median OS for abema-F was 46.7 months vs. 37.3 months for placebo-F (HR, 0.757; 95% CI 0.505-0.945; P = .0137). Patients with greatest benefit from abema-F were exactly the patients who needed the most help – those with visceral metastases (HR 0.675) and with primary resistance to prior hormonal therapy (HR, 0.686).

At 3 years, at least three times as many patients remained progression free with abema-F, compared with placebo-F, and the abema-F patients experienced prolongation in time to eventual chemotherapy (50.2 months vs. 22.1 months; HR, 0.625).

What this means in clinical practice

Many times I find myself sitting at the annual meeting of the American Society of Clinical Oncology and thinking, “Only a medical oncologist like me would find this result exciting.” Prior to ESMO 2019, MONARCH 2 (and a similar study presented at ESMO 2019, MONALEESA-3, which employed an alternative CDK 4/6 inhibitor, ribociclib, with similar OS results) added to the body of literature that caused NCCN guidelines to list all of the approved CDK 4/6 inhibitors plus endocrine therapy for first- or second-line use in patients with hormone-receptor positive, HER2/neu-negative mBC. NCCN guidelines have the caveat that, among patients with disease progression on CDK 4/6 inhibitors in the first-line setting, there are no data to support continuing the CDK 4/6 inhibitor or switching to an alternative CDK 4/6 inhibitor thereafter.

For that shrinking group of patients and doctors who choose to avoid CDK 4/6 inhibitors for first-line treatment, as we describe risks and benefits of using a CDK 4/6 inhibitor for second- or third-line therapy, we have high-quality OS information from ESMO 2019 to answer the “Is it worth it?” question.

Are the results of MONARCH 2 and MONALEESA-3 practice changing? No. We were already convinced. Should we be excited that we have this new information for discussions with our patients? Absolutely.
 

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 review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.

Metastatic CRPC

Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).

Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.

Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).

Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).

PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.

 

What this means in practice

During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.

Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.

For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.
 

Advanced ovarian cancer

The randomized, double-blind, placebo-controlled, phase 3 PAOLA-1/ENGOT-ov25 trial studied patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer who had surgery, platinum-taxane chemotherapy, and at least 3 months of bevacizumab. Patients were randomized to maintenance treatment with an additional 12 months of bevacizumab plus 24 months of PARPi with olaparib or placebo. Germline BRCA mutations were not required (Ray-Coquard I et al. ESMO 2019, Abstract LBA2).

As reported at ESMO, adding PARPi to bevacizumab maintenance provided a clinically meaningful PFS benefit of 22.1 months, in comparison with 16.6 months for bevacizumab alone. The difference was statistically significant.

For patients with tumor BRCA mutations (tBRCAm), PFS was 37.2 months with olaparib vs. 21.7 months for placebo (HR, 0.31). The PFS benefit was even more impressive for homologous recombination deficient (HRD)–positive patients, inclusive of those with tBRCAm (PFS 37.2 months for PARPi vs. 17.7 months for placebo; and in the 152 HRD-positive patients without tBRCAm, (median PFS 28.1 months vs. 16.6 months; HR, 0.43).

The improved PFS in patients with tBRCAm is similar to that reported in the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer (N Engl J Med. 2018; 379:2495-2505), but the PFS in the control arm was longer in PAOLA-1 than in SOLO1, perhaps because of the use of bevacizumab in PAOLA-1. PARPi did not affect tolerance to bevacizumab.

In PAOLA-1, the HRD-positive patients who lacked tBRCAm and, by extension, lacked germline BRCA mutations – a new population of patients – was identified who benefited substantially from maintenance PARPi in the first-line setting.
 

What this means in practice

PAOLA-1 demonstrates that PARPi can improve outcomes in first-line treatment – and in patients beyond those with germline BRCA mutations. As a result, PAOLA-1 potentially changes the standard of care for initial treatment of the respectable fraction of patients with previously untreated, advanced müllerian cancers who have either tBRCAm or HRD positive tumors.

Importantly, PAOLA-1 is one of many published trials that stimulates the discussion of cost vs. value for combinations of biologics. The incremental benefit from the second biologic (in this case PARPi) is almost never completely additive or supra-additive to the benefit associated with the first biologic (in this case, bevacizumab). In that regard, despite the fact that PARPi showed a PFS benefit in the intent-to-treat population overall, precisely defining the patient population that has the greatest benefit will facilitate the goal of getting the treatments of greatest “value for cost” to our patients in the most responsible way.

Additional research will hopefully define the relative contribution of bevacizumab to PARPi in patients who benefited so dramatically from PARPi in PAOLA-1.
 

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 review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.

Metastatic CRPC

Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).

Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.

Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).

Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).

PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.

 

What this means in practice

During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.

Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.

For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.
 

Advanced ovarian cancer

The randomized, double-blind, placebo-controlled, phase 3 PAOLA-1/ENGOT-ov25 trial studied patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer who had surgery, platinum-taxane chemotherapy, and at least 3 months of bevacizumab. Patients were randomized to maintenance treatment with an additional 12 months of bevacizumab plus 24 months of PARPi with olaparib or placebo. Germline BRCA mutations were not required (Ray-Coquard I et al. ESMO 2019, Abstract LBA2).

As reported at ESMO, adding PARPi to bevacizumab maintenance provided a clinically meaningful PFS benefit of 22.1 months, in comparison with 16.6 months for bevacizumab alone. The difference was statistically significant.

For patients with tumor BRCA mutations (tBRCAm), PFS was 37.2 months with olaparib vs. 21.7 months for placebo (HR, 0.31). The PFS benefit was even more impressive for homologous recombination deficient (HRD)–positive patients, inclusive of those with tBRCAm (PFS 37.2 months for PARPi vs. 17.7 months for placebo; and in the 152 HRD-positive patients without tBRCAm, (median PFS 28.1 months vs. 16.6 months; HR, 0.43).

The improved PFS in patients with tBRCAm is similar to that reported in the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer (N Engl J Med. 2018; 379:2495-2505), but the PFS in the control arm was longer in PAOLA-1 than in SOLO1, perhaps because of the use of bevacizumab in PAOLA-1. PARPi did not affect tolerance to bevacizumab.

In PAOLA-1, the HRD-positive patients who lacked tBRCAm and, by extension, lacked germline BRCA mutations – a new population of patients – was identified who benefited substantially from maintenance PARPi in the first-line setting.
 

What this means in practice

PAOLA-1 demonstrates that PARPi can improve outcomes in first-line treatment – and in patients beyond those with germline BRCA mutations. As a result, PAOLA-1 potentially changes the standard of care for initial treatment of the respectable fraction of patients with previously untreated, advanced müllerian cancers who have either tBRCAm or HRD positive tumors.

Importantly, PAOLA-1 is one of many published trials that stimulates the discussion of cost vs. value for combinations of biologics. The incremental benefit from the second biologic (in this case PARPi) is almost never completely additive or supra-additive to the benefit associated with the first biologic (in this case, bevacizumab). In that regard, despite the fact that PARPi showed a PFS benefit in the intent-to-treat population overall, precisely defining the patient population that has the greatest benefit will facilitate the goal of getting the treatments of greatest “value for cost” to our patients in the most responsible way.

Additional research will hopefully define the relative contribution of bevacizumab to PARPi in patients who benefited so dramatically from PARPi in PAOLA-1.
 

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 review two recent presentations at the European Society of Medical Oncology Congress regarding the expanded use of poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) in patients with advanced solid tumors, potentially broadening the indications for this important class of agents.

Metastatic CRPC

Perhaps 25% of prostate cancer patients have loss-of-function mutations – BRCA1, BRCA2, and ATM – or alterations in homologous recombinant repair (HRR) genes. In the PROfound trial, men with metastatic castration-resistant prostate cancer (mCRPC) who had progressed on either abiraterone or enzalutamide and who had DNA-repair mutations were randomized to either olaparib (300 mg b.i.d.) or treatment of physician’s choice (TPC) with either abiraterone or enzalutamide plus prednisone (Hussain M et al. ESMO 2019, Abstract LBA-12).

Two cohorts were enrolled. Cohort A included 245 men with BRCA1, BRCA2, or ATM mutations, and cohort B included 142 men with other alterations (BARD1, BIRP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD15B, RAD15C, RAD15D, or RAD54L). After disease progression, patients could cross over to receive PARPi, which more than 80% of patients eventually did.

Median radiographic progression-free survival (PFS) in cohort A was 7.39 months with PARPi, compared with 3.55 months with TPC, for a hazard ratio for progression on PARPi of 0.34 (P less than .0001). A significant benefit was seen for PARPi in the overall population (both cohorts), with a median radiographic PFS of 5.82 months va. 3.52 months, respectively (HR, 0.49; P less than .0001).

Among patients in cohort A, the objective response rate (ORR) was 33.3% with PARPi, compared with 2.3% for TPC, resulting in an odds ratio for ORR of 20.86 (P less than .0001).

PARPi demonstrated a longer time to pain progression in cohort A, with the median not reached, compared with 9.92 months with TPC (HR, 0.44; P = .0192). Perhaps because of the high proportion of TPC patients who eventually received PARPi, no statistically significant differences in overall survival have yet been seen.

 

What this means in practice

During my fellowship, a mentor taught that “because quality of life is generally better before progression than afterwards, PFS is a worthy endpoint in its own right.” For that reason, although I would have liked to see the data for cohort B alone, it appears worthwhile for physicians to make every effort to obtain PARPi. The difference in ORR, pain progression, and PFS at 12 months is clinically dramatic.

Of equal significance, however, is that PROfound is the first positive phase 3 biomarker-selected study evaluating a targeted treatment in patients with mCRPC. For prostate cancer – as for breast, ovarian, pancreatic, and several other cancers – the molecular biology and genetic background of our patients dictates the other tumors for which they and their family members are at risk, and expands the treatment armamentarium for them.

For those clinicians who needed to be convinced that “precision medicine” for prostate cancer patients was worthwhile, the PROfound trial should have a profound impact.
 

Advanced ovarian cancer

The randomized, double-blind, placebo-controlled, phase 3 PAOLA-1/ENGOT-ov25 trial studied patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer who had surgery, platinum-taxane chemotherapy, and at least 3 months of bevacizumab. Patients were randomized to maintenance treatment with an additional 12 months of bevacizumab plus 24 months of PARPi with olaparib or placebo. Germline BRCA mutations were not required (Ray-Coquard I et al. ESMO 2019, Abstract LBA2).

As reported at ESMO, adding PARPi to bevacizumab maintenance provided a clinically meaningful PFS benefit of 22.1 months, in comparison with 16.6 months for bevacizumab alone. The difference was statistically significant.

For patients with tumor BRCA mutations (tBRCAm), PFS was 37.2 months with olaparib vs. 21.7 months for placebo (HR, 0.31). The PFS benefit was even more impressive for homologous recombination deficient (HRD)–positive patients, inclusive of those with tBRCAm (PFS 37.2 months for PARPi vs. 17.7 months for placebo; and in the 152 HRD-positive patients without tBRCAm, (median PFS 28.1 months vs. 16.6 months; HR, 0.43).

The improved PFS in patients with tBRCAm is similar to that reported in the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer (N Engl J Med. 2018; 379:2495-2505), but the PFS in the control arm was longer in PAOLA-1 than in SOLO1, perhaps because of the use of bevacizumab in PAOLA-1. PARPi did not affect tolerance to bevacizumab.

In PAOLA-1, the HRD-positive patients who lacked tBRCAm and, by extension, lacked germline BRCA mutations – a new population of patients – was identified who benefited substantially from maintenance PARPi in the first-line setting.
 

What this means in practice

PAOLA-1 demonstrates that PARPi can improve outcomes in first-line treatment – and in patients beyond those with germline BRCA mutations. As a result, PAOLA-1 potentially changes the standard of care for initial treatment of the respectable fraction of patients with previously untreated, advanced müllerian cancers who have either tBRCAm or HRD positive tumors.

Importantly, PAOLA-1 is one of many published trials that stimulates the discussion of cost vs. value for combinations of biologics. The incremental benefit from the second biologic (in this case PARPi) is almost never completely additive or supra-additive to the benefit associated with the first biologic (in this case, bevacizumab). In that regard, despite the fact that PARPi showed a PFS benefit in the intent-to-treat population overall, precisely defining the patient population that has the greatest benefit will facilitate the goal of getting the treatments of greatest “value for cost” to our patients in the most responsible way.

Additional research will hopefully define the relative contribution of bevacizumab to PARPi in patients who benefited so dramatically from PARPi in PAOLA-1.
 

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.

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 highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.

TMB in nonsquamous NSCLC

Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.

Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.

In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.

Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.

Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.

How these results influence clinical practice

TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.

While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.

PD-L1 expression and overall survival

Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.

Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).

In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.

How these results influence clinical practice

As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.

To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.

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 highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.

TMB in nonsquamous NSCLC

Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.

Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.

In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.

Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.

Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.

How these results influence clinical practice

TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.

While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.

PD-L1 expression and overall survival

Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.

Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).

In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.

How these results influence clinical practice

As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.

To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.

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 highlight three studies presented at the World Conference on Lung Cancer (WCLC 2019) regarding the use of tissue biomarkers to predict benefit when immune checkpoint inhibitors (ICIs) are combined with chemotherapy in the treatment of stage IV non–small cell lung cancer (NSCLC) patients.

TMB in nonsquamous NSCLC

Marina C. Garassino, MD, and colleagues examined tumor mutation burden (TMB) to predict benefit from pembrolizumab in the KEYNOTE-189 study. KEYNOTE-189 was a double-blind comparison of first-line chemotherapy plus either pembrolizumab or placebo in 616 patients with stage IV nonsquamous NSCLC who were randomized 2:1 to the treatment arms.

Overall, adding pembrolizumab to pemetrexed and platinum significantly improved overall survival (hazard ratio, 0.49), progression-free survival (HR, 0.52), and overall response rate (47.6% vs. 18.9%). Benefit was observed in all analyzed subgroups, including patients with programmed death-ligand 1 (PD-L1) of less than 1%, 1%-49%, and 50% or greater.

In 293 patients – less than 50% of the total participants in the trial – with evaluable TMB data, TMB as a continuous variable showed no significant association with overall survival, progression-free survival, or overall response rate. There was no cut point at which TMB predicted outcome from treatment.

Similarly, Corey Langer, MD, and colleagues presented an exploratory analysis of the randomized, phase 2 KEYNOTE-021 trial (open label, pembrolizumab plus chemotherapy in 70 stage IV nonsquamous NSCLC patients). There was no association between tissue TMB and overall survival, progression-free survival, or overall response rate. In patients with tissue TMB greater than 175 mutations/exome and less than 175 mutations/exome, the overall response rate was 71% and 61%, respectively.

Both presenters recommended that tissue TMB not yet be used in therapeutic decision making.

How these results influence clinical practice

TMB has been associated with response to ICIs, but there is little information regarding whether TMB predicts for response to chemotherapy, either given alone or with ICIs. Logistical issues have limited the clinical utility of TMB. There are a variety of methodologies to measure TMB and no consensus on the ideal cut point for defining benefit from ICI therapy.

While TMB remains a marker of interest, the two presentations at WCLC 2019 demonstrate that additional research is needed to define whether TMB needs to be combined with other markers in an algorithm or matrix to guide decision making or whether we should focus entirely on identifying better biomarkers of immunogenicity.

PD-L1 expression and overall survival

Federico Cappuzzo, MD, and colleagues reported a subset analysis of IMpower131, a randomized, phase 3 trial of chemotherapy plus or minus atezolizumab as first-line therapy in 1,021 patients with stage IV squamous NSCLC. Patients were randomized to arm A (atezolizumab plus carboplatin plus paclitaxel), arm B (atezolizumab plus carboplatin plus nab-paclitaxel) or arm C (carboplatin plus nab-paclitaxel). Investigator-assessed progression-free survival, reported at the 2018 annual meeting of the American Society of Clinical Oncology, showed a small (about 21 days), but statistically significant, improvement in median progression-free survival in arm B versus arm C. The progression-free survival benefit was seen in all PD-L1-positive subgroups. At WCLC 2019, he reported the final overall survival results of arms B versus C.

Median overall survival in the intent-to-treat population was 14.2 months with atezolizumab versus 13.5 months without it (HR, 0.88). Patients with high PD-L1 expression (14% and 13% of patients in the groups, respectively), experienced dramatic, clinically important improvement in overall survival with atezolizumab plus chemotherapy, compared with chemotherapy alone (median of 23.4 vs. 10.2 months; HR, 0.48).

In IMpower 131, PD-L1-high expression was defined as TC3 or IC3 – expression on greater than 50% of tumor cells or greater than 10% of immune cells. Patients were also categorized as PD-L1 positive (TC 1/2/3 or IC 1/2/3 – expression of PD-L1 on 1% or greater of tumor cells or immune cells) or PD-LI negative (TC 0 or IC 0 – expression on less than 1% of cells). The PD-L1-positive and negative subsets did not demonstrate improved overall survival with atezolizumab.

How these results influence clinical practice

As noted above, in NSCLC patients (regardless of histology), we need biomarkers that predict benefit from ICIs alone and additive benefit when ICIs are combined with other, potentially toxic therapies. In the subset analysis of IMpower 131, despite clinically relevant differences in overall survival for the “PD-L1-high” patients, the PD-L1-positive patients did not benefit, so PD-L1 tumor proportion score remains an imperfect biomarker.

To put this report in its proper context, it will be important to analyze the details of the final manuscript of IMpower 131, particularly the comparison of arms A plus B versus C and the proportion of arm C patients who ultimately received an ICI in the second- or later-line setting. In the meantime, clinicians will select their ICI and chemotherapy regimen of choice, utilizing PD-L1 expression as an “eyebrow raiser,” but not an exclusionary criteria – as they did prior to WCLC 2019.

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 highlight two studies addressing long-term survival for patients with stage IV non–small cell lung cancer (NSCLC). One summarizes survival of patients who received nivolumab therapy in the second- or later-line setting. The other is a retrospective database query regarding whether local consolidation (LC) improves survival after systemic treatment of patients with oligometastatic NSCLC.

Nivolumab therapy

Scott J. Antonia, MD, PhD, and colleagues sought to determine the frequency of long-term survival among advanced NSCLC patients who received nivolumab in the second-line or later settings (Lancet Oncol. 2019 Aug 14. doi: 10.1016/S1470-2045[19]30407-3). They aggregated the results of four trials. Checkmate 017 and 057 were phase 3 comparisons of nivolumab with docetaxel for nonsquamous and squamous NSCLC, respectively – with crossover from docetaxel to nivolumab permitted. Checkmate 003 was a dose-escalation trial and Checkmate 063 was a phase 2 study of nivolumab in advanced, refractory squamous NSCLC. A minimum follow-up of 4 years was required.

In total, 664 patients participated in the four trials, more than 85% of whom received the fairly standard dose of 3 mg/kg every 2 weeks. In a very data-dense analysis, among all patients who received nivolumab, the 4-year overall survival was 14% (95% confidence interval, 11%-17%). Four-year overall survival was higher (19%; 95% CI, 15%-24%) in patients with at least 1% programmed death-ligand 1 (PD-L1) expression. There was no difference by histology (squamous vs. nonsquamous). Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, PD-L1 greater than 10%, and absence of liver metastases were more likely to achieve 4-year overall survival.

Although progression-free survival was low (8%, overall; 19% for patients achieving complete remission or partial remission), depth of response correlated with the 4-year overall survival rate. Those patients in complete or partial remission at 6 months had an overall survival at 4 years of 56%. Stable disease at 6 months showed an overall survival at 4 years of 19%, which was superior to the results for patients with partial disease as best response (4%).

There were two treatment-related deaths with nivolumab, with no unexpected safety signals. Despite allowing continuous treatment in three of the four studies, most potentially immune-related toxic events occurred in the first 2-3 years of therapy. In the two randomized studies (017 and 057), 4-year overall survival was higher with nivolumab (14%) than with docetaxel (5%), with no overlap in the 95% confidence intervals.

What this means in practice

British prime minister, Benjamin Disraeli (and, later, Mark Twain) said, “There are three kinds of lies: lies, damned lies, and statistics.” There are no lies in Dr. Antonia’s paper, but there are plenty of statistics – which oncologists love. The reported data enable us to put some boundaries on the figures we quote when patients ask us, “How well could I do with this treatment?” Dr. Antonia’s paper significantly assists with these very practical discussions. For patients who want more detail, the boundaries can be further refined. Dr. Antonia and colleagues have given us clinical (depth of response, performance status, sites of metastasis) and molecular (proportion of cells with PD-L1) refinements to personalize our consultations with patients.

Unfortunately, the data do not allow us to predict who should not receive an immune checkpoint inhibitor and, instead, receive late-line chemotherapy or early hospice referral. The data summarize well-executed clinical trials, but it is well known that (as reported at the Quality Care Symposium 2019) NSCLC patients participating in clinical trials have significantly improved survival rates – perhaps as much as two times – compared with those not enrolled in trials. These realities, however, should not obscure the fact that immune checkpoint inhibitors are a major advance for metastatic NSCLC patients, including those who have progressed after prior treatment. They offer hope for cancer-free or cancer-controlled survival that would have properly been placed in the category of “a miracle” just a few years ago.

Local consolidation

Johannes Uhlig, MD, and colleagues analyzed 6 years of National Cancer Database records, identifying 34,887 stage IV NSCLC patients who had fewer than two distant metastatic lesions in the liver, lung, brain, or bone (JAMA Netw Open. 2019 Aug 21. doi: 10.1001/jamanetworkopen.2019.9702). Treatment groups were divided into patients who received systemic therapy alone (70.3% of the total patients), had surgical resection of the primary site plus systemic therapy (2.4%), or received external beam radiation therapy or thermal ablation (EBRT/TA) of the primary site plus systemic therapy (27.3%). Multivariable Cox proportional hazards models, incorporating a number of clinical variables, were used to compare overall survival between the three groups at a median follow-up of approximately 39 months.

They found that patients treated with surgical consolidation had a 41% lower mortality, in comparison with systemic therapy alone. EBRT/TA was also associated with lower mortality (by 5%), in comparison with systemic therapy alone, but the benefit was more nuanced. For instance, patients with squamous cell histology with low tumor bulk, low nodal burden, and fewer distant sites of disease benefited, but patients with adenocarcinoma and bulkier disease or more than two distant sites did not benefit.

The discussion emphasized all of the caveats that would be appropriate for a retrospective, telescopic record review – patient selection factors; lack of detail about systemic therapy; small numbers of patients in various subsets; exclusion of patients who had consolidative treatment of metastatic sites; and the potential for unbalanced allocation of patients with various actionable, prognostically relevant mutations. Further research, including ongoing trials such as NRG-LU002, was encouraged.

How these results influence clinical practice

Ralph R. Weichselbaum, MD, in his Karnofsky lecture at the 2018 annual meeting of the American Society of Clinical Oncology highlighted the hypothesis that metastatic tumors are enriched differentially for oligometastatic or polymetastatic miRNAs and that these miRNAs could influence future clinical behavior (J Clin Oncol. 2018;36[32]:3240-50). This work, coupled with clinical features (number of sites of disease, pace of progression) could elucidate which oligometastatic NSCLC patients might benefit from aggressive local treatment and achieve long-term, disease-free survival.

As previously reported, Daniel R. Gomez, MD, and colleagues found improved median progression-free survival (14.2 vs. 4.4 months; P = .022) and overall survival (41.2 vs. 17.0 months; P = .017) among patients with oligometastatic NSCLC who were randomized to local consolidation versus standard maintenance therapy/observation (J Clin Oncol. 8 May 2019. doi: 10. 1200/JCO.19.00201). Joshua M. Bauml and colleagues reported impressive results for systemically treated stage IV NSCLC patients who received local consolidation and checkpoint inhibitors for “oligo-remnant disease” (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449).

At the present time, clinical practice should remain governed by the general tendency to discourage aggressive local treatment except in highly selected cases with poorly resolved or impending life-altering symptoms. The publication by Dr. Uhlig and colleagues and the previously reported phase 2 trials, support phase 3 randomized trials of local treatment of isolated sites in oligometastatic NSCLC patients, particularly in an era of immune-based systemic treatment that offers finite potential for long-term survival.

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 highlight two studies addressing long-term survival for patients with stage IV non–small cell lung cancer (NSCLC). One summarizes survival of patients who received nivolumab therapy in the second- or later-line setting. The other is a retrospective database query regarding whether local consolidation (LC) improves survival after systemic treatment of patients with oligometastatic NSCLC.

Nivolumab therapy

Scott J. Antonia, MD, PhD, and colleagues sought to determine the frequency of long-term survival among advanced NSCLC patients who received nivolumab in the second-line or later settings (Lancet Oncol. 2019 Aug 14. doi: 10.1016/S1470-2045[19]30407-3). They aggregated the results of four trials. Checkmate 017 and 057 were phase 3 comparisons of nivolumab with docetaxel for nonsquamous and squamous NSCLC, respectively – with crossover from docetaxel to nivolumab permitted. Checkmate 003 was a dose-escalation trial and Checkmate 063 was a phase 2 study of nivolumab in advanced, refractory squamous NSCLC. A minimum follow-up of 4 years was required.

In total, 664 patients participated in the four trials, more than 85% of whom received the fairly standard dose of 3 mg/kg every 2 weeks. In a very data-dense analysis, among all patients who received nivolumab, the 4-year overall survival was 14% (95% confidence interval, 11%-17%). Four-year overall survival was higher (19%; 95% CI, 15%-24%) in patients with at least 1% programmed death-ligand 1 (PD-L1) expression. There was no difference by histology (squamous vs. nonsquamous). Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, PD-L1 greater than 10%, and absence of liver metastases were more likely to achieve 4-year overall survival.

Although progression-free survival was low (8%, overall; 19% for patients achieving complete remission or partial remission), depth of response correlated with the 4-year overall survival rate. Those patients in complete or partial remission at 6 months had an overall survival at 4 years of 56%. Stable disease at 6 months showed an overall survival at 4 years of 19%, which was superior to the results for patients with partial disease as best response (4%).

There were two treatment-related deaths with nivolumab, with no unexpected safety signals. Despite allowing continuous treatment in three of the four studies, most potentially immune-related toxic events occurred in the first 2-3 years of therapy. In the two randomized studies (017 and 057), 4-year overall survival was higher with nivolumab (14%) than with docetaxel (5%), with no overlap in the 95% confidence intervals.

What this means in practice

British prime minister, Benjamin Disraeli (and, later, Mark Twain) said, “There are three kinds of lies: lies, damned lies, and statistics.” There are no lies in Dr. Antonia’s paper, but there are plenty of statistics – which oncologists love. The reported data enable us to put some boundaries on the figures we quote when patients ask us, “How well could I do with this treatment?” Dr. Antonia’s paper significantly assists with these very practical discussions. For patients who want more detail, the boundaries can be further refined. Dr. Antonia and colleagues have given us clinical (depth of response, performance status, sites of metastasis) and molecular (proportion of cells with PD-L1) refinements to personalize our consultations with patients.

Unfortunately, the data do not allow us to predict who should not receive an immune checkpoint inhibitor and, instead, receive late-line chemotherapy or early hospice referral. The data summarize well-executed clinical trials, but it is well known that (as reported at the Quality Care Symposium 2019) NSCLC patients participating in clinical trials have significantly improved survival rates – perhaps as much as two times – compared with those not enrolled in trials. These realities, however, should not obscure the fact that immune checkpoint inhibitors are a major advance for metastatic NSCLC patients, including those who have progressed after prior treatment. They offer hope for cancer-free or cancer-controlled survival that would have properly been placed in the category of “a miracle” just a few years ago.

Local consolidation

Johannes Uhlig, MD, and colleagues analyzed 6 years of National Cancer Database records, identifying 34,887 stage IV NSCLC patients who had fewer than two distant metastatic lesions in the liver, lung, brain, or bone (JAMA Netw Open. 2019 Aug 21. doi: 10.1001/jamanetworkopen.2019.9702). Treatment groups were divided into patients who received systemic therapy alone (70.3% of the total patients), had surgical resection of the primary site plus systemic therapy (2.4%), or received external beam radiation therapy or thermal ablation (EBRT/TA) of the primary site plus systemic therapy (27.3%). Multivariable Cox proportional hazards models, incorporating a number of clinical variables, were used to compare overall survival between the three groups at a median follow-up of approximately 39 months.

They found that patients treated with surgical consolidation had a 41% lower mortality, in comparison with systemic therapy alone. EBRT/TA was also associated with lower mortality (by 5%), in comparison with systemic therapy alone, but the benefit was more nuanced. For instance, patients with squamous cell histology with low tumor bulk, low nodal burden, and fewer distant sites of disease benefited, but patients with adenocarcinoma and bulkier disease or more than two distant sites did not benefit.

The discussion emphasized all of the caveats that would be appropriate for a retrospective, telescopic record review – patient selection factors; lack of detail about systemic therapy; small numbers of patients in various subsets; exclusion of patients who had consolidative treatment of metastatic sites; and the potential for unbalanced allocation of patients with various actionable, prognostically relevant mutations. Further research, including ongoing trials such as NRG-LU002, was encouraged.

How these results influence clinical practice

Ralph R. Weichselbaum, MD, in his Karnofsky lecture at the 2018 annual meeting of the American Society of Clinical Oncology highlighted the hypothesis that metastatic tumors are enriched differentially for oligometastatic or polymetastatic miRNAs and that these miRNAs could influence future clinical behavior (J Clin Oncol. 2018;36[32]:3240-50). This work, coupled with clinical features (number of sites of disease, pace of progression) could elucidate which oligometastatic NSCLC patients might benefit from aggressive local treatment and achieve long-term, disease-free survival.

As previously reported, Daniel R. Gomez, MD, and colleagues found improved median progression-free survival (14.2 vs. 4.4 months; P = .022) and overall survival (41.2 vs. 17.0 months; P = .017) among patients with oligometastatic NSCLC who were randomized to local consolidation versus standard maintenance therapy/observation (J Clin Oncol. 8 May 2019. doi: 10. 1200/JCO.19.00201). Joshua M. Bauml and colleagues reported impressive results for systemically treated stage IV NSCLC patients who received local consolidation and checkpoint inhibitors for “oligo-remnant disease” (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449).

At the present time, clinical practice should remain governed by the general tendency to discourage aggressive local treatment except in highly selected cases with poorly resolved or impending life-altering symptoms. The publication by Dr. Uhlig and colleagues and the previously reported phase 2 trials, support phase 3 randomized trials of local treatment of isolated sites in oligometastatic NSCLC patients, particularly in an era of immune-based systemic treatment that offers finite potential for long-term survival.

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 highlight two studies addressing long-term survival for patients with stage IV non–small cell lung cancer (NSCLC). One summarizes survival of patients who received nivolumab therapy in the second- or later-line setting. The other is a retrospective database query regarding whether local consolidation (LC) improves survival after systemic treatment of patients with oligometastatic NSCLC.

Nivolumab therapy

Scott J. Antonia, MD, PhD, and colleagues sought to determine the frequency of long-term survival among advanced NSCLC patients who received nivolumab in the second-line or later settings (Lancet Oncol. 2019 Aug 14. doi: 10.1016/S1470-2045[19]30407-3). They aggregated the results of four trials. Checkmate 017 and 057 were phase 3 comparisons of nivolumab with docetaxel for nonsquamous and squamous NSCLC, respectively – with crossover from docetaxel to nivolumab permitted. Checkmate 003 was a dose-escalation trial and Checkmate 063 was a phase 2 study of nivolumab in advanced, refractory squamous NSCLC. A minimum follow-up of 4 years was required.

In total, 664 patients participated in the four trials, more than 85% of whom received the fairly standard dose of 3 mg/kg every 2 weeks. In a very data-dense analysis, among all patients who received nivolumab, the 4-year overall survival was 14% (95% confidence interval, 11%-17%). Four-year overall survival was higher (19%; 95% CI, 15%-24%) in patients with at least 1% programmed death-ligand 1 (PD-L1) expression. There was no difference by histology (squamous vs. nonsquamous). Patients with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, PD-L1 greater than 10%, and absence of liver metastases were more likely to achieve 4-year overall survival.

Although progression-free survival was low (8%, overall; 19% for patients achieving complete remission or partial remission), depth of response correlated with the 4-year overall survival rate. Those patients in complete or partial remission at 6 months had an overall survival at 4 years of 56%. Stable disease at 6 months showed an overall survival at 4 years of 19%, which was superior to the results for patients with partial disease as best response (4%).

There were two treatment-related deaths with nivolumab, with no unexpected safety signals. Despite allowing continuous treatment in three of the four studies, most potentially immune-related toxic events occurred in the first 2-3 years of therapy. In the two randomized studies (017 and 057), 4-year overall survival was higher with nivolumab (14%) than with docetaxel (5%), with no overlap in the 95% confidence intervals.

What this means in practice

British prime minister, Benjamin Disraeli (and, later, Mark Twain) said, “There are three kinds of lies: lies, damned lies, and statistics.” There are no lies in Dr. Antonia’s paper, but there are plenty of statistics – which oncologists love. The reported data enable us to put some boundaries on the figures we quote when patients ask us, “How well could I do with this treatment?” Dr. Antonia’s paper significantly assists with these very practical discussions. For patients who want more detail, the boundaries can be further refined. Dr. Antonia and colleagues have given us clinical (depth of response, performance status, sites of metastasis) and molecular (proportion of cells with PD-L1) refinements to personalize our consultations with patients.

Unfortunately, the data do not allow us to predict who should not receive an immune checkpoint inhibitor and, instead, receive late-line chemotherapy or early hospice referral. The data summarize well-executed clinical trials, but it is well known that (as reported at the Quality Care Symposium 2019) NSCLC patients participating in clinical trials have significantly improved survival rates – perhaps as much as two times – compared with those not enrolled in trials. These realities, however, should not obscure the fact that immune checkpoint inhibitors are a major advance for metastatic NSCLC patients, including those who have progressed after prior treatment. They offer hope for cancer-free or cancer-controlled survival that would have properly been placed in the category of “a miracle” just a few years ago.

Local consolidation

Johannes Uhlig, MD, and colleagues analyzed 6 years of National Cancer Database records, identifying 34,887 stage IV NSCLC patients who had fewer than two distant metastatic lesions in the liver, lung, brain, or bone (JAMA Netw Open. 2019 Aug 21. doi: 10.1001/jamanetworkopen.2019.9702). Treatment groups were divided into patients who received systemic therapy alone (70.3% of the total patients), had surgical resection of the primary site plus systemic therapy (2.4%), or received external beam radiation therapy or thermal ablation (EBRT/TA) of the primary site plus systemic therapy (27.3%). Multivariable Cox proportional hazards models, incorporating a number of clinical variables, were used to compare overall survival between the three groups at a median follow-up of approximately 39 months.

They found that patients treated with surgical consolidation had a 41% lower mortality, in comparison with systemic therapy alone. EBRT/TA was also associated with lower mortality (by 5%), in comparison with systemic therapy alone, but the benefit was more nuanced. For instance, patients with squamous cell histology with low tumor bulk, low nodal burden, and fewer distant sites of disease benefited, but patients with adenocarcinoma and bulkier disease or more than two distant sites did not benefit.

The discussion emphasized all of the caveats that would be appropriate for a retrospective, telescopic record review – patient selection factors; lack of detail about systemic therapy; small numbers of patients in various subsets; exclusion of patients who had consolidative treatment of metastatic sites; and the potential for unbalanced allocation of patients with various actionable, prognostically relevant mutations. Further research, including ongoing trials such as NRG-LU002, was encouraged.

How these results influence clinical practice

Ralph R. Weichselbaum, MD, in his Karnofsky lecture at the 2018 annual meeting of the American Society of Clinical Oncology highlighted the hypothesis that metastatic tumors are enriched differentially for oligometastatic or polymetastatic miRNAs and that these miRNAs could influence future clinical behavior (J Clin Oncol. 2018;36[32]:3240-50). This work, coupled with clinical features (number of sites of disease, pace of progression) could elucidate which oligometastatic NSCLC patients might benefit from aggressive local treatment and achieve long-term, disease-free survival.

As previously reported, Daniel R. Gomez, MD, and colleagues found improved median progression-free survival (14.2 vs. 4.4 months; P = .022) and overall survival (41.2 vs. 17.0 months; P = .017) among patients with oligometastatic NSCLC who were randomized to local consolidation versus standard maintenance therapy/observation (J Clin Oncol. 8 May 2019. doi: 10. 1200/JCO.19.00201). Joshua M. Bauml and colleagues reported impressive results for systemically treated stage IV NSCLC patients who received local consolidation and checkpoint inhibitors for “oligo-remnant disease” (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449).

At the present time, clinical practice should remain governed by the general tendency to discourage aggressive local treatment except in highly selected cases with poorly resolved or impending life-altering symptoms. The publication by Dr. Uhlig and colleagues and the previously reported phase 2 trials, support phase 3 randomized trials of local treatment of isolated sites in oligometastatic NSCLC patients, particularly in an era of immune-based systemic treatment that offers finite potential for long-term survival.

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 examine two recently published efforts to enlighten our sensitivity to the seriousness of immune-related adverse events (IrAEs) in patients on immune checkpoint inhibitors (ICIs) and the effect of delays in initiating systemic adjuvant therapy on the long-term outcomes of patients with resected pancreatic cancer.

IrAEs requiring hospitalization

Investigators led by Aanika Balaji of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, reviewed a 6-month audit of inpatient oncology admissions of solid-tumor patients who had ever received ICIs and ascertained the prevalence of hospitalization for management of IrAEs (J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703). To determine that an IrAE had occurred they required: consensus among two oncologists, clinical improvement with immune-directed therapy, exclusion of alternative diagnoses or pathologic confirmation of an IrAE, or chronic management of an IrAE for more than 6 months.

The bottom line: They found a cumulative incidence of a confirmed IrAEs among hospitalized ICI-treated solid tumor patients of 23%. As expected, the majority (65%) were grade 3-4 in severity. In total, 91% required multidisciplinary management, and 65% improved or resolved. But 87% of patients never received an ICI again.

Patients with preexisting autoimmune disease (25% of patients, although they included hypothyroidism in that group) were not more vulnerable to an IrAE with ICI therapy (odds ratio, 1.0; 95% confidence interval, 0.3-4.0). Not unsurprisingly, the median age was higher for ICI-treated patients who were admitted for IrAEs than for those not admitted (68 years vs. 59 years; OR, 5.4; 95% CI, 1.6-17.8), and more admitted patients had received combination ICIs than single agents (OR, 6.8; 95% CI, 2.0-23.2).

The median time from beginning ICIs to an IrAE-related hospitalization was 64 days, and the median number of ICI doses was one, with a wide range for both days and doses. The authors were quick to comment that this is a small, academic, single-institution survey over a brief period of time and that the generalizability of the results is uncertain.

What this means in practice

This publication changes very little for most practicing oncologists, but it does reinforce that ICI therapy can cause unpredictable, severe IrAEs. Clinical markers for selecting patients at highest risk are imperfect. As with chemotherapy, the patients we worry about the most – older individuals and patients treated with drug combinations – are, in fact, the ones we should be worrying about the most.

In view of the potential severity and impact of IrAEs, research efforts should place equal priority on identifying biomarkers of toxicity, such as tumor mutation burden, and biomarkers of efficacy (JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.3221). The potential financial and societal effects, as well as lost opportunity costs in the form of alternative therapies and early referral to hospice, demand no less, particularly in an era of value-based health care reimbursement.
 

Timing of adjuvant treatment

Sung Jun Ma, MD, department of radiation medicine at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues analyzed data from the more than 7,500 stage I-II resected pancreatic cancer patients in the National Cancer Database, of whom more than 5,400 ultimately received adjuvant therapy (chemotherapy with or without radiation). The patients were treated during 2004-2015. Appropriately, the investigators focused on correlating survival duration with the interval between surgery and initiation of adjuvant therapy. Other endpoints would be hard to accurately measure and verify without detailed clinical information (JAMA Network Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9126).

They found that the best overall survival was associated with starting adjuvant treatment 28-59 days after surgery – not earlier (17% higher mortality) and not later (9% higher). Patients who did not start adjuvant treatment until more than 90 days post operatively still had an overall survival benefit (hazard ratio, 0.75; 95% confidence interval, 0.66-0.85; P less than .001), a more impressive hazard ratio than that seen for any particular interval between surgery and adjuvant treatment. Overall survival at 2 years was 47.2% versus 38% for the adjuvant therapy and surgery alone cohorts, respectively, with no overlap in the 95% confidence intervals.

As expected, longer delays to receive adjuvant treatment were associated with longer inpatient surgical stays, advanced age, black race, lower income, and a readmission for a postoperative complication within 30 days.

What this means in practice

This is another study that verifies that the patients we worry about most – older patients, those with a complicated recovery from surgery, and those with fewer supportive resources – are exactly the patients we should worry about most. It changes very little for most practicing oncologists. The analysis validates the importance of adjuvant therapy for patients who are able to receive it – whenever that is.

The data collection in this publication precedes recent improvements in adjuvant chemotherapy for resected pancreatic cancer, such as FOLFIRINOX or gemcitabine plus capecitabine. In an era of improved treatment, delays in initiating therapy may be less important since better treatment overcomes many prognostic variables that are significant for less effective therapy.

In my opinion, this large-data analysis is not really hypothesis-generating or practice-changing, but it does compel us to continue research efforts to improve surgical morbidity, identify better adjuvant and advanced disease regimens, and consider neoadjuvant treatment so that more than 72% of patients can receive all components of the multimodality treatment they need.
 

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 examine two recently published efforts to enlighten our sensitivity to the seriousness of immune-related adverse events (IrAEs) in patients on immune checkpoint inhibitors (ICIs) and the effect of delays in initiating systemic adjuvant therapy on the long-term outcomes of patients with resected pancreatic cancer.

IrAEs requiring hospitalization

Investigators led by Aanika Balaji of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, reviewed a 6-month audit of inpatient oncology admissions of solid-tumor patients who had ever received ICIs and ascertained the prevalence of hospitalization for management of IrAEs (J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703). To determine that an IrAE had occurred they required: consensus among two oncologists, clinical improvement with immune-directed therapy, exclusion of alternative diagnoses or pathologic confirmation of an IrAE, or chronic management of an IrAE for more than 6 months.

The bottom line: They found a cumulative incidence of a confirmed IrAEs among hospitalized ICI-treated solid tumor patients of 23%. As expected, the majority (65%) were grade 3-4 in severity. In total, 91% required multidisciplinary management, and 65% improved or resolved. But 87% of patients never received an ICI again.

Patients with preexisting autoimmune disease (25% of patients, although they included hypothyroidism in that group) were not more vulnerable to an IrAE with ICI therapy (odds ratio, 1.0; 95% confidence interval, 0.3-4.0). Not unsurprisingly, the median age was higher for ICI-treated patients who were admitted for IrAEs than for those not admitted (68 years vs. 59 years; OR, 5.4; 95% CI, 1.6-17.8), and more admitted patients had received combination ICIs than single agents (OR, 6.8; 95% CI, 2.0-23.2).

The median time from beginning ICIs to an IrAE-related hospitalization was 64 days, and the median number of ICI doses was one, with a wide range for both days and doses. The authors were quick to comment that this is a small, academic, single-institution survey over a brief period of time and that the generalizability of the results is uncertain.

What this means in practice

This publication changes very little for most practicing oncologists, but it does reinforce that ICI therapy can cause unpredictable, severe IrAEs. Clinical markers for selecting patients at highest risk are imperfect. As with chemotherapy, the patients we worry about the most – older individuals and patients treated with drug combinations – are, in fact, the ones we should be worrying about the most.

In view of the potential severity and impact of IrAEs, research efforts should place equal priority on identifying biomarkers of toxicity, such as tumor mutation burden, and biomarkers of efficacy (JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.3221). The potential financial and societal effects, as well as lost opportunity costs in the form of alternative therapies and early referral to hospice, demand no less, particularly in an era of value-based health care reimbursement.
 

Timing of adjuvant treatment

Sung Jun Ma, MD, department of radiation medicine at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues analyzed data from the more than 7,500 stage I-II resected pancreatic cancer patients in the National Cancer Database, of whom more than 5,400 ultimately received adjuvant therapy (chemotherapy with or without radiation). The patients were treated during 2004-2015. Appropriately, the investigators focused on correlating survival duration with the interval between surgery and initiation of adjuvant therapy. Other endpoints would be hard to accurately measure and verify without detailed clinical information (JAMA Network Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9126).

They found that the best overall survival was associated with starting adjuvant treatment 28-59 days after surgery – not earlier (17% higher mortality) and not later (9% higher). Patients who did not start adjuvant treatment until more than 90 days post operatively still had an overall survival benefit (hazard ratio, 0.75; 95% confidence interval, 0.66-0.85; P less than .001), a more impressive hazard ratio than that seen for any particular interval between surgery and adjuvant treatment. Overall survival at 2 years was 47.2% versus 38% for the adjuvant therapy and surgery alone cohorts, respectively, with no overlap in the 95% confidence intervals.

As expected, longer delays to receive adjuvant treatment were associated with longer inpatient surgical stays, advanced age, black race, lower income, and a readmission for a postoperative complication within 30 days.

What this means in practice

This is another study that verifies that the patients we worry about most – older patients, those with a complicated recovery from surgery, and those with fewer supportive resources – are exactly the patients we should worry about most. It changes very little for most practicing oncologists. The analysis validates the importance of adjuvant therapy for patients who are able to receive it – whenever that is.

The data collection in this publication precedes recent improvements in adjuvant chemotherapy for resected pancreatic cancer, such as FOLFIRINOX or gemcitabine plus capecitabine. In an era of improved treatment, delays in initiating therapy may be less important since better treatment overcomes many prognostic variables that are significant for less effective therapy.

In my opinion, this large-data analysis is not really hypothesis-generating or practice-changing, but it does compel us to continue research efforts to improve surgical morbidity, identify better adjuvant and advanced disease regimens, and consider neoadjuvant treatment so that more than 72% of patients can receive all components of the multimodality treatment they need.
 

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 examine two recently published efforts to enlighten our sensitivity to the seriousness of immune-related adverse events (IrAEs) in patients on immune checkpoint inhibitors (ICIs) and the effect of delays in initiating systemic adjuvant therapy on the long-term outcomes of patients with resected pancreatic cancer.

IrAEs requiring hospitalization

Investigators led by Aanika Balaji of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, reviewed a 6-month audit of inpatient oncology admissions of solid-tumor patients who had ever received ICIs and ascertained the prevalence of hospitalization for management of IrAEs (J Oncol Pract. 2019 Aug 6. doi: 10.1200/JOP.18.00703). To determine that an IrAE had occurred they required: consensus among two oncologists, clinical improvement with immune-directed therapy, exclusion of alternative diagnoses or pathologic confirmation of an IrAE, or chronic management of an IrAE for more than 6 months.

The bottom line: They found a cumulative incidence of a confirmed IrAEs among hospitalized ICI-treated solid tumor patients of 23%. As expected, the majority (65%) were grade 3-4 in severity. In total, 91% required multidisciplinary management, and 65% improved or resolved. But 87% of patients never received an ICI again.

Patients with preexisting autoimmune disease (25% of patients, although they included hypothyroidism in that group) were not more vulnerable to an IrAE with ICI therapy (odds ratio, 1.0; 95% confidence interval, 0.3-4.0). Not unsurprisingly, the median age was higher for ICI-treated patients who were admitted for IrAEs than for those not admitted (68 years vs. 59 years; OR, 5.4; 95% CI, 1.6-17.8), and more admitted patients had received combination ICIs than single agents (OR, 6.8; 95% CI, 2.0-23.2).

The median time from beginning ICIs to an IrAE-related hospitalization was 64 days, and the median number of ICI doses was one, with a wide range for both days and doses. The authors were quick to comment that this is a small, academic, single-institution survey over a brief period of time and that the generalizability of the results is uncertain.

What this means in practice

This publication changes very little for most practicing oncologists, but it does reinforce that ICI therapy can cause unpredictable, severe IrAEs. Clinical markers for selecting patients at highest risk are imperfect. As with chemotherapy, the patients we worry about the most – older individuals and patients treated with drug combinations – are, in fact, the ones we should be worrying about the most.

In view of the potential severity and impact of IrAEs, research efforts should place equal priority on identifying biomarkers of toxicity, such as tumor mutation burden, and biomarkers of efficacy (JAMA Oncol. 2019 Aug 22. doi: 10.1001/jamaoncol.2019.3221). The potential financial and societal effects, as well as lost opportunity costs in the form of alternative therapies and early referral to hospice, demand no less, particularly in an era of value-based health care reimbursement.
 

Timing of adjuvant treatment

Sung Jun Ma, MD, department of radiation medicine at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., and colleagues analyzed data from the more than 7,500 stage I-II resected pancreatic cancer patients in the National Cancer Database, of whom more than 5,400 ultimately received adjuvant therapy (chemotherapy with or without radiation). The patients were treated during 2004-2015. Appropriately, the investigators focused on correlating survival duration with the interval between surgery and initiation of adjuvant therapy. Other endpoints would be hard to accurately measure and verify without detailed clinical information (JAMA Network Open. 2019 Aug 14. doi: 10.1001/jamanetworkopen.2019.9126).

They found that the best overall survival was associated with starting adjuvant treatment 28-59 days after surgery – not earlier (17% higher mortality) and not later (9% higher). Patients who did not start adjuvant treatment until more than 90 days post operatively still had an overall survival benefit (hazard ratio, 0.75; 95% confidence interval, 0.66-0.85; P less than .001), a more impressive hazard ratio than that seen for any particular interval between surgery and adjuvant treatment. Overall survival at 2 years was 47.2% versus 38% for the adjuvant therapy and surgery alone cohorts, respectively, with no overlap in the 95% confidence intervals.

As expected, longer delays to receive adjuvant treatment were associated with longer inpatient surgical stays, advanced age, black race, lower income, and a readmission for a postoperative complication within 30 days.

What this means in practice

This is another study that verifies that the patients we worry about most – older patients, those with a complicated recovery from surgery, and those with fewer supportive resources – are exactly the patients we should worry about most. It changes very little for most practicing oncologists. The analysis validates the importance of adjuvant therapy for patients who are able to receive it – whenever that is.

The data collection in this publication precedes recent improvements in adjuvant chemotherapy for resected pancreatic cancer, such as FOLFIRINOX or gemcitabine plus capecitabine. In an era of improved treatment, delays in initiating therapy may be less important since better treatment overcomes many prognostic variables that are significant for less effective therapy.

In my opinion, this large-data analysis is not really hypothesis-generating or practice-changing, but it does compel us to continue research efforts to improve surgical morbidity, identify better adjuvant and advanced disease regimens, and consider neoadjuvant treatment so that more than 72% of patients can receive all components of the multimodality treatment they need.
 

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 examine the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement regarding screening for pancreatic cancer in normal-risk populations. I also review newly published information regarding low-dose CT screening (LDCT) for lung cancer in a commonly screened population – individuals with chronic obstructive pulmonary disease (COPD). Both publications highlight the complexity of implementing shared decision making in clinicians’ efforts to find these highly lethal cancers in their earliest, most curable stages.

Pancreatic cancer screening

In their recommendation, the USPSTF considered data relevant to the benefits and harms (exclusive of costs) of screening for pancreatic cancer in the 85%-90% of individuals who are at normal risk because they lack a known familial or genetic syndrome and do not have at least two affected relatives or one first-degree affected relative (JAMA. 2019;322[5]:438-44).

After reviewing 13 cohort studies employing image-based technologies (CT, MRI, endoscopic ultrasound) and biomarkers for screening, the USPSTF reaffirmed its 2004 recommendation against pancreatic cancer screening. They found no new evidence of sufficient strength and quality to alter their previous “D grade” for screening (i.e., “Don’t do it.”). There were at least moderate harms of screening and subsequent treatment in normal-risk populations. These recommendations apply to asymptomatic individuals with new-onset diabetes mellitus, smokers, older adults, obese patients, and patients with a history of chronic pancreatitis.

What this means in practice

In the nicely written and comprehensive recommendation statement and in the two accompanying editorials (JAMA Surg. 2019 Aug 6. doi: 10.1001/jamasurg.2019.2832; JAMA. 2019;322[5]:407-8), the authors were explicit that the “D grade” for pancreatic cancer screening did not apply to individuals from familial pancreatic cancer kindreds and those with germline mutations and Lynch syndrome mismatch repair genes. For them, the relative risk of pancreatic cancer (greater than 5%) may justify the morbidity of available surveillance technologies, especially since U.S. and International screening studies in these high-risk individuals have generated data suggesting a benefit for treatment of screen-detected cancers.

The USPSTF and the editorial authors were strongly supportive of, and enthusiastic about, ongoing research efforts. Recently, a joint effort at the National Institutes of Health began recruiting centers for a study to assess the sensitivity of novel biomarkers in detecting pancreatic cancer among adults with new-onset diabetes (A211701).

To me, it is clear that the pathway to identifying effective screening for pancreatic cancer – which is forecast to become the second leading cause of cancer death in the United States by 2020 – will focus on high-risk populations first, enabling accurate determination of sensitivity and specificity before being applied to the general population. This is as it should be.
 

Lung cancer screening

Currently, guidelines from the National Comprehensive Cancer Network recommend LDCT screening annually for high-risk smokers, former smokers, and individuals with additional risk factors aged 55-77 years. The National Lung Screening Trial indicated that LDCT screening achieved a 20% relative reduction in lung cancer mortality and 6.7% relative reduction in overall mortality in a similar population. NCCN guidelines stress the importance of shared decision making and include a table of risks and benefits that should be considered.

Jonathan M. Iaccarino, MD, and colleagues quantified the risks of screening among COPD patients in a secondary analysis of the more than 75,000 LDCT scans that were performed among the more than 26,000 participants in the National Lung Screening Trial (Chest 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016). In comparison with participants who did not self-report a diagnosis of COPD, the 4,632 participants with self-reported COPD were significantly more likely to require further diagnostic studies, have an invasive procedure, have a complication of any type from the invasive procedure, and suffer a serious complication. The establishment of a lung cancer diagnosis from the invasive procedure, however, occurred in just 6.1% of COPD patients versus 3.6% of patients without COPD.

What this means in practice

At a consensus conference convened by the National Quality Forum, shared decision making was defined as a process of communication in which clinicians and patients work together to make decisions that align with what matters most to patients. Ideally, shared decision making requires clear, accurate, unbiased medical evidence about reasonable alternatives; tailored evidence for individual patients; and the incorporation of patient values, goals, informed preferences and concerns, including a discussion of treatment burdens. All of us wrestle with the challenge of conducting these conversations in a comprehensive and unbiased manner. I am not sure that I have ever achieved an ideal shared decision-making conversation in my practice.

Despite the limitations acknowledged by the authors – self-reported diagnosis of COPD, outcomes that were not the primary focus of the trial, failure to incorporate other important comorbid conditions – the study by Dr. Iaccarino and colleagues helps to quantify risks and benefits for a commonly screened population, specifically COPD patients. Most importantly, it focuses our attention on the key goal of all cancer-screening efforts – applying our personal and technological resources to patients who benefit the most and will suffer the least harm from our efforts.
 

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 examine the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement regarding screening for pancreatic cancer in normal-risk populations. I also review newly published information regarding low-dose CT screening (LDCT) for lung cancer in a commonly screened population – individuals with chronic obstructive pulmonary disease (COPD). Both publications highlight the complexity of implementing shared decision making in clinicians’ efforts to find these highly lethal cancers in their earliest, most curable stages.

Pancreatic cancer screening

In their recommendation, the USPSTF considered data relevant to the benefits and harms (exclusive of costs) of screening for pancreatic cancer in the 85%-90% of individuals who are at normal risk because they lack a known familial or genetic syndrome and do not have at least two affected relatives or one first-degree affected relative (JAMA. 2019;322[5]:438-44).

After reviewing 13 cohort studies employing image-based technologies (CT, MRI, endoscopic ultrasound) and biomarkers for screening, the USPSTF reaffirmed its 2004 recommendation against pancreatic cancer screening. They found no new evidence of sufficient strength and quality to alter their previous “D grade” for screening (i.e., “Don’t do it.”). There were at least moderate harms of screening and subsequent treatment in normal-risk populations. These recommendations apply to asymptomatic individuals with new-onset diabetes mellitus, smokers, older adults, obese patients, and patients with a history of chronic pancreatitis.

What this means in practice

In the nicely written and comprehensive recommendation statement and in the two accompanying editorials (JAMA Surg. 2019 Aug 6. doi: 10.1001/jamasurg.2019.2832; JAMA. 2019;322[5]:407-8), the authors were explicit that the “D grade” for pancreatic cancer screening did not apply to individuals from familial pancreatic cancer kindreds and those with germline mutations and Lynch syndrome mismatch repair genes. For them, the relative risk of pancreatic cancer (greater than 5%) may justify the morbidity of available surveillance technologies, especially since U.S. and International screening studies in these high-risk individuals have generated data suggesting a benefit for treatment of screen-detected cancers.

The USPSTF and the editorial authors were strongly supportive of, and enthusiastic about, ongoing research efforts. Recently, a joint effort at the National Institutes of Health began recruiting centers for a study to assess the sensitivity of novel biomarkers in detecting pancreatic cancer among adults with new-onset diabetes (A211701).

To me, it is clear that the pathway to identifying effective screening for pancreatic cancer – which is forecast to become the second leading cause of cancer death in the United States by 2020 – will focus on high-risk populations first, enabling accurate determination of sensitivity and specificity before being applied to the general population. This is as it should be.
 

Lung cancer screening

Currently, guidelines from the National Comprehensive Cancer Network recommend LDCT screening annually for high-risk smokers, former smokers, and individuals with additional risk factors aged 55-77 years. The National Lung Screening Trial indicated that LDCT screening achieved a 20% relative reduction in lung cancer mortality and 6.7% relative reduction in overall mortality in a similar population. NCCN guidelines stress the importance of shared decision making and include a table of risks and benefits that should be considered.

Jonathan M. Iaccarino, MD, and colleagues quantified the risks of screening among COPD patients in a secondary analysis of the more than 75,000 LDCT scans that were performed among the more than 26,000 participants in the National Lung Screening Trial (Chest 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016). In comparison with participants who did not self-report a diagnosis of COPD, the 4,632 participants with self-reported COPD were significantly more likely to require further diagnostic studies, have an invasive procedure, have a complication of any type from the invasive procedure, and suffer a serious complication. The establishment of a lung cancer diagnosis from the invasive procedure, however, occurred in just 6.1% of COPD patients versus 3.6% of patients without COPD.

What this means in practice

At a consensus conference convened by the National Quality Forum, shared decision making was defined as a process of communication in which clinicians and patients work together to make decisions that align with what matters most to patients. Ideally, shared decision making requires clear, accurate, unbiased medical evidence about reasonable alternatives; tailored evidence for individual patients; and the incorporation of patient values, goals, informed preferences and concerns, including a discussion of treatment burdens. All of us wrestle with the challenge of conducting these conversations in a comprehensive and unbiased manner. I am not sure that I have ever achieved an ideal shared decision-making conversation in my practice.

Despite the limitations acknowledged by the authors – self-reported diagnosis of COPD, outcomes that were not the primary focus of the trial, failure to incorporate other important comorbid conditions – the study by Dr. Iaccarino and colleagues helps to quantify risks and benefits for a commonly screened population, specifically COPD patients. Most importantly, it focuses our attention on the key goal of all cancer-screening efforts – applying our personal and technological resources to patients who benefit the most and will suffer the least harm from our efforts.
 

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 examine the U.S. Preventive Services Task Force Reaffirmation Recommendation Statement regarding screening for pancreatic cancer in normal-risk populations. I also review newly published information regarding low-dose CT screening (LDCT) for lung cancer in a commonly screened population – individuals with chronic obstructive pulmonary disease (COPD). Both publications highlight the complexity of implementing shared decision making in clinicians’ efforts to find these highly lethal cancers in their earliest, most curable stages.

Pancreatic cancer screening

In their recommendation, the USPSTF considered data relevant to the benefits and harms (exclusive of costs) of screening for pancreatic cancer in the 85%-90% of individuals who are at normal risk because they lack a known familial or genetic syndrome and do not have at least two affected relatives or one first-degree affected relative (JAMA. 2019;322[5]:438-44).

After reviewing 13 cohort studies employing image-based technologies (CT, MRI, endoscopic ultrasound) and biomarkers for screening, the USPSTF reaffirmed its 2004 recommendation against pancreatic cancer screening. They found no new evidence of sufficient strength and quality to alter their previous “D grade” for screening (i.e., “Don’t do it.”). There were at least moderate harms of screening and subsequent treatment in normal-risk populations. These recommendations apply to asymptomatic individuals with new-onset diabetes mellitus, smokers, older adults, obese patients, and patients with a history of chronic pancreatitis.

What this means in practice

In the nicely written and comprehensive recommendation statement and in the two accompanying editorials (JAMA Surg. 2019 Aug 6. doi: 10.1001/jamasurg.2019.2832; JAMA. 2019;322[5]:407-8), the authors were explicit that the “D grade” for pancreatic cancer screening did not apply to individuals from familial pancreatic cancer kindreds and those with germline mutations and Lynch syndrome mismatch repair genes. For them, the relative risk of pancreatic cancer (greater than 5%) may justify the morbidity of available surveillance technologies, especially since U.S. and International screening studies in these high-risk individuals have generated data suggesting a benefit for treatment of screen-detected cancers.

The USPSTF and the editorial authors were strongly supportive of, and enthusiastic about, ongoing research efforts. Recently, a joint effort at the National Institutes of Health began recruiting centers for a study to assess the sensitivity of novel biomarkers in detecting pancreatic cancer among adults with new-onset diabetes (A211701).

To me, it is clear that the pathway to identifying effective screening for pancreatic cancer – which is forecast to become the second leading cause of cancer death in the United States by 2020 – will focus on high-risk populations first, enabling accurate determination of sensitivity and specificity before being applied to the general population. This is as it should be.
 

Lung cancer screening

Currently, guidelines from the National Comprehensive Cancer Network recommend LDCT screening annually for high-risk smokers, former smokers, and individuals with additional risk factors aged 55-77 years. The National Lung Screening Trial indicated that LDCT screening achieved a 20% relative reduction in lung cancer mortality and 6.7% relative reduction in overall mortality in a similar population. NCCN guidelines stress the importance of shared decision making and include a table of risks and benefits that should be considered.

Jonathan M. Iaccarino, MD, and colleagues quantified the risks of screening among COPD patients in a secondary analysis of the more than 75,000 LDCT scans that were performed among the more than 26,000 participants in the National Lung Screening Trial (Chest 2019 Jul 5. doi: 10.1016/j.chest.2019.06.016). In comparison with participants who did not self-report a diagnosis of COPD, the 4,632 participants with self-reported COPD were significantly more likely to require further diagnostic studies, have an invasive procedure, have a complication of any type from the invasive procedure, and suffer a serious complication. The establishment of a lung cancer diagnosis from the invasive procedure, however, occurred in just 6.1% of COPD patients versus 3.6% of patients without COPD.

What this means in practice

At a consensus conference convened by the National Quality Forum, shared decision making was defined as a process of communication in which clinicians and patients work together to make decisions that align with what matters most to patients. Ideally, shared decision making requires clear, accurate, unbiased medical evidence about reasonable alternatives; tailored evidence for individual patients; and the incorporation of patient values, goals, informed preferences and concerns, including a discussion of treatment burdens. All of us wrestle with the challenge of conducting these conversations in a comprehensive and unbiased manner. I am not sure that I have ever achieved an ideal shared decision-making conversation in my practice.

Despite the limitations acknowledged by the authors – self-reported diagnosis of COPD, outcomes that were not the primary focus of the trial, failure to incorporate other important comorbid conditions – the study by Dr. Iaccarino and colleagues helps to quantify risks and benefits for a commonly screened population, specifically COPD patients. Most importantly, it focuses our attention on the key goal of all cancer-screening efforts – applying our personal and technological resources to patients who benefit the most and will suffer the least harm from our efforts.
 

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 take a look at two phase 2 trials in stage IV non–small cell lung cancer (NSCLC) patients that appeared recently in JAMA Oncology. One summarizes a trial in stage IV NSCLC with four or fewer sites of metastasis (oligometastatic disease or OM), in which pembrolizumab is added to locally ablative therapy (LAT). The other examines whether LAT potentiates the response to immuno-oncology (I/O) in distant sites that were unexposed to LAT.

©Sergey Nivens/thinkstockphotos

I/O added to LAT in OM-NSCLC

Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues, published findings from a nonrandomized phase 2 trial in OM-NSCLC in which patients could receive LAT by any technique (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449). Patients could have synchronous or metachronous OM-NSCLC, any histology, and any PD-L1 tumor proportion score. Patients with more than four sites of metastatic disease that regressed to OM-NSCLC after prior therapy (i.e., “oligoremnant NSCLC”) were excluded.

They reported on 51 patients who received conventional-dose pembrolizumab for eight cycles after LAT. Patients without toxicity or progression were allowed to receive up to eight additional cycles of pembrolizumab. The median progression-free survival (PFS) was 19.1 months (95% confidence interval, 9.4-28.7 months), significantly longer than the historical comparison group (median PFS, 6.6 months; P = .005). Additionally, the 24-month overall survival (OS) was 77.5%. With respect to safety, no quality of life decrement or new safety signals were seen.
 

What this means in practice

As Dr. Bauml and colleagues suggest, there is strong theoretical rationale for believing that OM-NSCLC represents a special, potentially curable, population of stage IV NSCLC patients. Like the recently published work of Daniel R. Gomez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues (J Clin Oncol. 2019 Jun 20;37[18]:1558-65), who studied LAT in comparison with consolidative/maintenance chemotherapy in a slightly different population of OM-NSCLC patients, the current trial moves clinical research forward.

Practically, this study has limitations that should temper a clinician’s enthusiasm for adopting the strategy of LAT, followed by I/O, as standard practice: small patient numbers, most with only one site of OM-NSCLC; comparison with historical controls; and no meaningful information about patient subsets who benefit from I/O and who do not. As the authors suggest, this study provides a strong rationale for a phase 3 trial with stratification for variables that could influence outcome. It does not inform clinical practice at the present time.
 

LAT added to I/O in stage IV NSCLC

We have limited ability to identify (the majority of) patients with metastatic NSCLC who will not benefit from I/O and no proven interventions to augment benefit in (the majority of) patients with low PD-L1 tumor proportion scores and/or low tumor mutation burden. However, the PEMBRO-RT study was designed to investigate whether LAT with stereotactic body radiation therapy (SBRT) could exploit the hypothesized increase in tumor antigen release and antigen presentation that could lead to better responses to I/O in untreated sites of disease among all patients with stage IV NSCLC.

As reported by Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues, the PEMBRO-RT study randomized 76 patients with stage IV NSCLC to pembro following SBRT to a single metastatic site (the experimental arm of the trial) or pembrolizumab alone. Pembrolizumab was given in a conventional dose and schedule in both arms of the trial and was administered within 7 days after SBRT on the experimental arm (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478).

The primary outcome was the overall response rate (ORR) at 12 weeks. Among patients on the experimental versus control arms, the ORR was 36% and 18%, respectively (P = .07). This did not meet the prespecified endpoint of improving ORR from 20% to 50% at 12 weeks. Additionally, although improved on the pembro plus SBRT arm of the trial, the median PFS and OS did not meet statistical criteria for improvement over the control arm, except among the 47 patients in the PD-L1 negative subset.

What this means in practice

There are a lot of potentially relevant variables in this small, randomized phase 2 study. As the authors discuss, if there is a dose and schedule of RT that facilitates antigen release and presentation and or an ideal latent period after radiotherapy that promotes an “abscopal effect” from I/O, it is unclear whether the ideal schema was used in the PEMBRO-RT trial.

At present, if a patient with stage IV NSCLC requires LAT for clinical reasons during I/O treatment, the patient can receive it safely, but without the expectation that the LAT will augment overall benefit from I/O. Additional preclinical work will need to help guide us about a rational way to design the next trial to test the concept of supra-additive benefit from these modalities. Not only is this combination “not ready for prime time” in clinical care, but it’s not ready for the large numbers of patients in a phase 3 clinical trial.
 

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 take a look at two phase 2 trials in stage IV non–small cell lung cancer (NSCLC) patients that appeared recently in JAMA Oncology. One summarizes a trial in stage IV NSCLC with four or fewer sites of metastasis (oligometastatic disease or OM), in which pembrolizumab is added to locally ablative therapy (LAT). The other examines whether LAT potentiates the response to immuno-oncology (I/O) in distant sites that were unexposed to LAT.

©Sergey Nivens/thinkstockphotos

I/O added to LAT in OM-NSCLC

Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues, published findings from a nonrandomized phase 2 trial in OM-NSCLC in which patients could receive LAT by any technique (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449). Patients could have synchronous or metachronous OM-NSCLC, any histology, and any PD-L1 tumor proportion score. Patients with more than four sites of metastatic disease that regressed to OM-NSCLC after prior therapy (i.e., “oligoremnant NSCLC”) were excluded.

They reported on 51 patients who received conventional-dose pembrolizumab for eight cycles after LAT. Patients without toxicity or progression were allowed to receive up to eight additional cycles of pembrolizumab. The median progression-free survival (PFS) was 19.1 months (95% confidence interval, 9.4-28.7 months), significantly longer than the historical comparison group (median PFS, 6.6 months; P = .005). Additionally, the 24-month overall survival (OS) was 77.5%. With respect to safety, no quality of life decrement or new safety signals were seen.
 

What this means in practice

As Dr. Bauml and colleagues suggest, there is strong theoretical rationale for believing that OM-NSCLC represents a special, potentially curable, population of stage IV NSCLC patients. Like the recently published work of Daniel R. Gomez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues (J Clin Oncol. 2019 Jun 20;37[18]:1558-65), who studied LAT in comparison with consolidative/maintenance chemotherapy in a slightly different population of OM-NSCLC patients, the current trial moves clinical research forward.

Practically, this study has limitations that should temper a clinician’s enthusiasm for adopting the strategy of LAT, followed by I/O, as standard practice: small patient numbers, most with only one site of OM-NSCLC; comparison with historical controls; and no meaningful information about patient subsets who benefit from I/O and who do not. As the authors suggest, this study provides a strong rationale for a phase 3 trial with stratification for variables that could influence outcome. It does not inform clinical practice at the present time.
 

LAT added to I/O in stage IV NSCLC

We have limited ability to identify (the majority of) patients with metastatic NSCLC who will not benefit from I/O and no proven interventions to augment benefit in (the majority of) patients with low PD-L1 tumor proportion scores and/or low tumor mutation burden. However, the PEMBRO-RT study was designed to investigate whether LAT with stereotactic body radiation therapy (SBRT) could exploit the hypothesized increase in tumor antigen release and antigen presentation that could lead to better responses to I/O in untreated sites of disease among all patients with stage IV NSCLC.

As reported by Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues, the PEMBRO-RT study randomized 76 patients with stage IV NSCLC to pembro following SBRT to a single metastatic site (the experimental arm of the trial) or pembrolizumab alone. Pembrolizumab was given in a conventional dose and schedule in both arms of the trial and was administered within 7 days after SBRT on the experimental arm (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478).

The primary outcome was the overall response rate (ORR) at 12 weeks. Among patients on the experimental versus control arms, the ORR was 36% and 18%, respectively (P = .07). This did not meet the prespecified endpoint of improving ORR from 20% to 50% at 12 weeks. Additionally, although improved on the pembro plus SBRT arm of the trial, the median PFS and OS did not meet statistical criteria for improvement over the control arm, except among the 47 patients in the PD-L1 negative subset.

What this means in practice

There are a lot of potentially relevant variables in this small, randomized phase 2 study. As the authors discuss, if there is a dose and schedule of RT that facilitates antigen release and presentation and or an ideal latent period after radiotherapy that promotes an “abscopal effect” from I/O, it is unclear whether the ideal schema was used in the PEMBRO-RT trial.

At present, if a patient with stage IV NSCLC requires LAT for clinical reasons during I/O treatment, the patient can receive it safely, but without the expectation that the LAT will augment overall benefit from I/O. Additional preclinical work will need to help guide us about a rational way to design the next trial to test the concept of supra-additive benefit from these modalities. Not only is this combination “not ready for prime time” in clinical care, but it’s not ready for the large numbers of patients in a phase 3 clinical trial.
 

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 take a look at two phase 2 trials in stage IV non–small cell lung cancer (NSCLC) patients that appeared recently in JAMA Oncology. One summarizes a trial in stage IV NSCLC with four or fewer sites of metastasis (oligometastatic disease or OM), in which pembrolizumab is added to locally ablative therapy (LAT). The other examines whether LAT potentiates the response to immuno-oncology (I/O) in distant sites that were unexposed to LAT.

©Sergey Nivens/thinkstockphotos

I/O added to LAT in OM-NSCLC

Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues, published findings from a nonrandomized phase 2 trial in OM-NSCLC in which patients could receive LAT by any technique (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449). Patients could have synchronous or metachronous OM-NSCLC, any histology, and any PD-L1 tumor proportion score. Patients with more than four sites of metastatic disease that regressed to OM-NSCLC after prior therapy (i.e., “oligoremnant NSCLC”) were excluded.

They reported on 51 patients who received conventional-dose pembrolizumab for eight cycles after LAT. Patients without toxicity or progression were allowed to receive up to eight additional cycles of pembrolizumab. The median progression-free survival (PFS) was 19.1 months (95% confidence interval, 9.4-28.7 months), significantly longer than the historical comparison group (median PFS, 6.6 months; P = .005). Additionally, the 24-month overall survival (OS) was 77.5%. With respect to safety, no quality of life decrement or new safety signals were seen.
 

What this means in practice

As Dr. Bauml and colleagues suggest, there is strong theoretical rationale for believing that OM-NSCLC represents a special, potentially curable, population of stage IV NSCLC patients. Like the recently published work of Daniel R. Gomez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues (J Clin Oncol. 2019 Jun 20;37[18]:1558-65), who studied LAT in comparison with consolidative/maintenance chemotherapy in a slightly different population of OM-NSCLC patients, the current trial moves clinical research forward.

Practically, this study has limitations that should temper a clinician’s enthusiasm for adopting the strategy of LAT, followed by I/O, as standard practice: small patient numbers, most with only one site of OM-NSCLC; comparison with historical controls; and no meaningful information about patient subsets who benefit from I/O and who do not. As the authors suggest, this study provides a strong rationale for a phase 3 trial with stratification for variables that could influence outcome. It does not inform clinical practice at the present time.
 

LAT added to I/O in stage IV NSCLC

We have limited ability to identify (the majority of) patients with metastatic NSCLC who will not benefit from I/O and no proven interventions to augment benefit in (the majority of) patients with low PD-L1 tumor proportion scores and/or low tumor mutation burden. However, the PEMBRO-RT study was designed to investigate whether LAT with stereotactic body radiation therapy (SBRT) could exploit the hypothesized increase in tumor antigen release and antigen presentation that could lead to better responses to I/O in untreated sites of disease among all patients with stage IV NSCLC.

As reported by Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues, the PEMBRO-RT study randomized 76 patients with stage IV NSCLC to pembro following SBRT to a single metastatic site (the experimental arm of the trial) or pembrolizumab alone. Pembrolizumab was given in a conventional dose and schedule in both arms of the trial and was administered within 7 days after SBRT on the experimental arm (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478).

The primary outcome was the overall response rate (ORR) at 12 weeks. Among patients on the experimental versus control arms, the ORR was 36% and 18%, respectively (P = .07). This did not meet the prespecified endpoint of improving ORR from 20% to 50% at 12 weeks. Additionally, although improved on the pembro plus SBRT arm of the trial, the median PFS and OS did not meet statistical criteria for improvement over the control arm, except among the 47 patients in the PD-L1 negative subset.

What this means in practice

There are a lot of potentially relevant variables in this small, randomized phase 2 study. As the authors discuss, if there is a dose and schedule of RT that facilitates antigen release and presentation and or an ideal latent period after radiotherapy that promotes an “abscopal effect” from I/O, it is unclear whether the ideal schema was used in the PEMBRO-RT trial.

At present, if a patient with stage IV NSCLC requires LAT for clinical reasons during I/O treatment, the patient can receive it safely, but without the expectation that the LAT will augment overall benefit from I/O. Additional preclinical work will need to help guide us about a rational way to design the next trial to test the concept of supra-additive benefit from these modalities. Not only is this combination “not ready for prime time” in clinical care, but it’s not ready for the large numbers of patients in a phase 3 clinical trial.
 

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 highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

SC-Dara in myeloma

At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.

Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
 

What this means in practice

It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.

However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.

Acalabrutinib in CLL/SLL

Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).

Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.

Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.

What this means in practice

The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.

With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.

With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.

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 highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

SC-Dara in myeloma

At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.

Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
 

What this means in practice

It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.

However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.

Acalabrutinib in CLL/SLL

Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).

Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.

Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.

What this means in practice

The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.

With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.

With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.

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 highlight two recent presentations regarding potential improvements in the convenience and tolerability of treatment for two hematologic malignancies: multiple myeloma and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

SC-Dara in myeloma

At the 2019 annual meeting of the American Society of Clinical Oncology, Maria-Victoria Mateos, MD, PhD, and colleagues, reported the results of COLUMBA, a phase 3 evaluation in 522 patients with multiple myeloma who were randomized to subcutaneous daratumumab (SC-Dara) or standard intravenous infusions of daratumumab (IV-Dara). A previous phase 1b study (Blood. 2017;130:838) had suggested comparable efficacy from the more convenient SC regime. Whereas conventional infusions of IV-Dara (16 mg/kg) take several hours, the SC formulation (1,800 mg–flat dose) is delivered in minutes. In COLUMBA, patients were randomized between SC- and IV-Dara weekly (cycles 1-2), then every 2 weeks (cycles 3-6), then every 4 weeks until disease progression.

Among the IV-Dara patients, the median duration of the first infusion was 421 minutes in cycle 1, 255 minutes in cycle 2, and 205 minutes in subsequent cycles – compatible with standard practice in the United States. As reported, at a median follow-up of 7.46 months, the efficacy (overall response rate, complete response rate, stringent-complete response rate, very good-partial response rate, progression-free survival, and 6-month overall survival) and safety profile were non-inferior for SC-Dara. SC-Dara patients also reported higher satisfaction with therapy.
 

What this means in practice

It is always a good idea to await publication of the manuscript because there may be study details and statistical nuances that make SC-Dara appear better than it will prove to be. For example, patient characteristics were slightly different between the two arms. Peer review of the final manuscript could be important in placing these results in context.

However, for treatments that demand frequent office visits over many months, reducing treatment burden for patients has value. Based on COLUMBA, it appears likely that SC-Dara will be a major convenience for patients, without obvious drawbacks in efficacy or toxicity. Meanwhile, flat dosing will be a time-saver for physicians, nursing, and pharmacy staff. If the price of the SC formulation is not exorbitant, I would expect a “win-win” that will support converting from IV- to SC-Dara as standard practice.

Acalabrutinib in CLL/SLL

Preclinical studies have shown acalabrutinib (Acala) to be more selective for Bruton’s tyrosine kinase (BTK) than the first-in-class agent ibrutinib, with less off-target kinase inhibition. As reported at the 2019 annual congress of the European Hematology Association by Paolo Ghia, MD, PhD, and colleagues in the phase 3 ASCEND trial, 310 patients with previously treated CLL were randomized between oral Acala twice daily and treatment of physician’s choice (TPC) – either idelalisib plus rituximab (maximum of seven infusions) or bendamustine plus rituximab (maximum of six cycles).

Progression-free survival was the primary endpoint. At a median of 16.1 months, progression-free survival had not been reached for Acala, in comparison with 16.5 months for TPC. Significant benefit of Acala was observed in all prognostic subsets.

Although there was no difference in overall survival at a median follow-up of about 16 months, 85% of Acala patients had a response lasting at least 12 months, compared with 60% of TPC patients. Adverse events of any grade occurred in 94% of patients treated with Acala, with 45% being grade 3-4 toxicities and six treatment-related deaths.

What this means in practice

The vast majority of CLL/SLL patients will relapse after primary therapy and will require further treatment, so the progression-free survival improvement associated with Acala in ASCEND is eye-catching. However, there are important considerations that demand closer scrutiny.

With oral agents administered until progression or unacceptable toxicity, low-grade toxicities can influence patient adherence, quality of life, and potentially the need for dose reduction or treatment interruptions. Regimens of finite duration and easy adherence monitoring may be, on balance, preferred by patients and providers – especially if the oral agent can be given in later-line with comparable overall survival.

With ibrutinib (Blood. 2017;129:2612-5), Paul M. Barr, MD, and colleagues demonstrated that higher dose intensity was associated with improved progression-free survival and that holds were associated with worsened progression-free survival. Acala’s promise of high efficacy and lower off-target toxicity will be solidified if the large (more than 500 patients) phase 3 ACE-CL-006 study (Acala vs. ibrutinib) demonstrates its relative benefit from efficacy, toxicity, and adherence perspectives, in comparison with a standard therapy that similarly demands adherence until disease progression or unacceptable toxicity.

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.