Lung Cancer

Real-world outcome data from patients with advanced non–small cell lung cancer (NSCLC) treated with immunotherapy are robust enough to use for regulatory and payer decisions, suggests an analysis of six data sets and more than 13,000 patients.

“Study of routinely collected health care data is increasingly important for various stakeholders who are interested in better understanding particular patient populations, evaluating drug safety in the postmarketing setting, measuring health care use and clinical outcomes, performing comparative effectiveness research, and optimizing drug pricing models,” noted lead investigator Mark Stewart, PhD, Friends of Cancer Research, Washington, and coinvestigators. “However, before [real-world data] finds widespread use as an adjunct to – or in unique settings, an alternative for – [randomized clinical trials], the validity of readily extractable clinical outcomes measures – real-world endpoints – must be established.”

The investigators undertook a retrospective cohort study using administrative claims and electronic health records for patients with advanced NSCLC treated with inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) between January 2011 and October 2017 in real-world settings. They analyzed six data sets having 269 to 6,924 patients each (13,639 patients total).

Results reported in JCO Clinical Cancer Informatics showed that the real-world intermediate endpoints of time to treatment discontinuation and time to next treatment were moderately to highly correlated with real-world overall survival (Spearman’s rank correlation coefficient, 0.36 to 0.89, with most values 0.60 or higher).

In real-world settings, the 1-year rate of overall survival after starting immunotherapy ranged from 40% to 57%. Real-world data and trial data were similar with respect to median overall survival (8.6-13.5 months vs. 9.2-12.7 months).

The data sources used for the study have been extensively used for research and are curated on an ongoing basis to ensure the data are accurate and as complete as possible, Dr. Stewart and coinvestigators noted.

“These findings demonstrate that real-world endpoints are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision-making,” they maintained. “Differences observed likely reflect true differences between real-world and protocol-driven practices.

“Additional studies are needed to further support the use of [real-world evidence] and inform the development of regulatory guidance,” the investigators concluded. “Standardizing definitions for real-world endpoints and determining appropriate analytic methodologies for [real-world data] will be critical for broader adoption of real-world studies and will provide greater confidence in associated findings. As more refined and standardized approaches are developed that incorporate deep clinical and bioinformatics expertise, the greater the utility of [real-world data] will be for detecting even small, but important, differences in treatment effects.”

Dr. Stewart disclosed no conflicts of interest. The study was supported in part by the National Cancer Institute and the Patient Centered Outcomes Research Institute.

SOURCE: Stewart M et al. JCO Clin Cancer Inform. 2019 July 23. doi: 10.1200/CCI.18.00155.

Real-world outcome data from patients with advanced non–small cell lung cancer (NSCLC) treated with immunotherapy are robust enough to use for regulatory and payer decisions, suggests an analysis of six data sets and more than 13,000 patients.

“Study of routinely collected health care data is increasingly important for various stakeholders who are interested in better understanding particular patient populations, evaluating drug safety in the postmarketing setting, measuring health care use and clinical outcomes, performing comparative effectiveness research, and optimizing drug pricing models,” noted lead investigator Mark Stewart, PhD, Friends of Cancer Research, Washington, and coinvestigators. “However, before [real-world data] finds widespread use as an adjunct to – or in unique settings, an alternative for – [randomized clinical trials], the validity of readily extractable clinical outcomes measures – real-world endpoints – must be established.”

The investigators undertook a retrospective cohort study using administrative claims and electronic health records for patients with advanced NSCLC treated with inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) between January 2011 and October 2017 in real-world settings. They analyzed six data sets having 269 to 6,924 patients each (13,639 patients total).

Results reported in JCO Clinical Cancer Informatics showed that the real-world intermediate endpoints of time to treatment discontinuation and time to next treatment were moderately to highly correlated with real-world overall survival (Spearman’s rank correlation coefficient, 0.36 to 0.89, with most values 0.60 or higher).

In real-world settings, the 1-year rate of overall survival after starting immunotherapy ranged from 40% to 57%. Real-world data and trial data were similar with respect to median overall survival (8.6-13.5 months vs. 9.2-12.7 months).

The data sources used for the study have been extensively used for research and are curated on an ongoing basis to ensure the data are accurate and as complete as possible, Dr. Stewart and coinvestigators noted.

“These findings demonstrate that real-world endpoints are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision-making,” they maintained. “Differences observed likely reflect true differences between real-world and protocol-driven practices.

“Additional studies are needed to further support the use of [real-world evidence] and inform the development of regulatory guidance,” the investigators concluded. “Standardizing definitions for real-world endpoints and determining appropriate analytic methodologies for [real-world data] will be critical for broader adoption of real-world studies and will provide greater confidence in associated findings. As more refined and standardized approaches are developed that incorporate deep clinical and bioinformatics expertise, the greater the utility of [real-world data] will be for detecting even small, but important, differences in treatment effects.”

Dr. Stewart disclosed no conflicts of interest. The study was supported in part by the National Cancer Institute and the Patient Centered Outcomes Research Institute.

SOURCE: Stewart M et al. JCO Clin Cancer Inform. 2019 July 23. doi: 10.1200/CCI.18.00155.

Real-world outcome data from patients with advanced non–small cell lung cancer (NSCLC) treated with immunotherapy are robust enough to use for regulatory and payer decisions, suggests an analysis of six data sets and more than 13,000 patients.

“Study of routinely collected health care data is increasingly important for various stakeholders who are interested in better understanding particular patient populations, evaluating drug safety in the postmarketing setting, measuring health care use and clinical outcomes, performing comparative effectiveness research, and optimizing drug pricing models,” noted lead investigator Mark Stewart, PhD, Friends of Cancer Research, Washington, and coinvestigators. “However, before [real-world data] finds widespread use as an adjunct to – or in unique settings, an alternative for – [randomized clinical trials], the validity of readily extractable clinical outcomes measures – real-world endpoints – must be established.”

The investigators undertook a retrospective cohort study using administrative claims and electronic health records for patients with advanced NSCLC treated with inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) between January 2011 and October 2017 in real-world settings. They analyzed six data sets having 269 to 6,924 patients each (13,639 patients total).

Results reported in JCO Clinical Cancer Informatics showed that the real-world intermediate endpoints of time to treatment discontinuation and time to next treatment were moderately to highly correlated with real-world overall survival (Spearman’s rank correlation coefficient, 0.36 to 0.89, with most values 0.60 or higher).

In real-world settings, the 1-year rate of overall survival after starting immunotherapy ranged from 40% to 57%. Real-world data and trial data were similar with respect to median overall survival (8.6-13.5 months vs. 9.2-12.7 months).

The data sources used for the study have been extensively used for research and are curated on an ongoing basis to ensure the data are accurate and as complete as possible, Dr. Stewart and coinvestigators noted.

“These findings demonstrate that real-world endpoints are generally consistent with each other and with outcomes observed in randomized clinical trials, which substantiates the potential validity of real-world data to support regulatory and payer decision-making,” they maintained. “Differences observed likely reflect true differences between real-world and protocol-driven practices.

“Additional studies are needed to further support the use of [real-world evidence] and inform the development of regulatory guidance,” the investigators concluded. “Standardizing definitions for real-world endpoints and determining appropriate analytic methodologies for [real-world data] will be critical for broader adoption of real-world studies and will provide greater confidence in associated findings. As more refined and standardized approaches are developed that incorporate deep clinical and bioinformatics expertise, the greater the utility of [real-world data] will be for detecting even small, but important, differences in treatment effects.”

Dr. Stewart disclosed no conflicts of interest. The study was supported in part by the National Cancer Institute and the Patient Centered Outcomes Research Institute.

SOURCE: Stewart M et al. JCO Clin Cancer Inform. 2019 July 23. doi: 10.1200/CCI.18.00155.

The degree of tumor mutational burden can predict whether patients with non–small cell lung cancer will benefit from immunotherapy with a checkpoint inhibitor, but differences in TMB by tumor histology and metastatic sites suggest that clinicians still don’t fully understand the implications of this marker for clinical care, investigators say.

A study of nearly 3,500 unmatched non–small cell lung cancer (NSCLC) samples showed that TMB of 10 mutations per megabase (MB) or higher occurred more frequently in metastases (especially brain metastases) than in primary tumors, in squamous cell carcinomas (SCC), compared with adenocarcinomas, and in poorly differentiated tumors, compared with moderately or well-differentiated tumors, reported Matthew K. Stein, MD, of the University of Tennessee Health Sciences Center in Memphis and colleagues in JCO Precision Oncology.

“Further work is needed to elucidate the mutational differences implied by TMB with the hope of identifying additional ICI [immune checkpoint inhibitor] biomarkers, as well as exploring unique therapeutic approaches for brain metastases and other sites with high TMB,” they wrote.

To get a clearer picture of differences in TMB by biopsy sample location, histology, and other biomarkers, the investigators obtained 3,424 unique, unmatched specimens from multiple U.S. cancer centers. The specimens, including 2,351 adenocarcinomas and 1,073 SCCs, were identified by only age and sex, with histology confirmed by pathology review.

The investigators conducted next-generation sequencing of 592 cancer-related genes on each specimen, as well as programmed death ligand 1 (PD-L1) immunohistochemistry, and TMB. They used a TMB cutoff of 10 mutations/MB, which was established as predictive of response to immune checkpoint inhibitors in the Checkmate 568 and Checkmate 227 trials.

They found that 38% of metastatic adenocarcinoma samples had TMB of 10 mutations/MB or greater, compared with 25% of primary adenocarcinomas (P less than .001), a difference that was greatest for brain metastases, compared with other metastases (61% vs. 35%; P less than .001). The median TMBs were 13 mutations/MB vs. 6 mutations/MB, respectively.

Similarly, TMB above the cutoff was more frequent in SCC metastases than primaries (41% vs. 35%; P = .038).

TMB of 10 mutations/MB occurred significantly more often in SCC primary tumors (35%) than in adenocarcinoma primaries (25%; P less than .001).

They also saw variability in TMB among other sites, with adrenal metastases being the second–most likely site to have high TMB (51%) and bone metastases being least likely (19%).

In an analysis stratified by histology and primary or metastatic sample site, poorly differentiated tumors were significantly more likely to have TMB of 10 mutations/MB or greater both for adenocarcinomas (40% of poorly differentiated primaries vs. 19% for others, and 48% of poorly differentiated metastases vs. 35% for other metastases; P less than .001 for both), and for SCCs (40% vs. 33% of primaries; P = .028; and 42% vs. 31% of metastases; P = .025).

The investigators also detected site-specific differences in PD-L1 positivity, STK11 and KRAS mutation rates, and other markers along the 10 mutations/MB cutoff which they characterized as “clinically informative.”

“Practically, clinicians should consider obtaining metastasis samples when possible if assessing for high TMB. Furthermore, in addition to previously described intratumor heterogeneity, our data highlight significant intertumor heterogeneity in NSCLC. One possible solution to capture tumor heterogeneity is with blood TMB, which theoretically could depict a composite TMB score versus single-site tissue,” Dr. Stein and associates said.

The investigators did not report a study funding source. Dr. Stein reported no relevant disclosures. Several of the coauthors are employees of Caris Life Sciences, which performed the tumor profiling.

SOURCE: Stein MK et al. JCO Precision Oncology. 2019 Jul 26. doi: 10.1200/PO.18.00376.

The degree of tumor mutational burden can predict whether patients with non–small cell lung cancer will benefit from immunotherapy with a checkpoint inhibitor, but differences in TMB by tumor histology and metastatic sites suggest that clinicians still don’t fully understand the implications of this marker for clinical care, investigators say.

A study of nearly 3,500 unmatched non–small cell lung cancer (NSCLC) samples showed that TMB of 10 mutations per megabase (MB) or higher occurred more frequently in metastases (especially brain metastases) than in primary tumors, in squamous cell carcinomas (SCC), compared with adenocarcinomas, and in poorly differentiated tumors, compared with moderately or well-differentiated tumors, reported Matthew K. Stein, MD, of the University of Tennessee Health Sciences Center in Memphis and colleagues in JCO Precision Oncology.

“Further work is needed to elucidate the mutational differences implied by TMB with the hope of identifying additional ICI [immune checkpoint inhibitor] biomarkers, as well as exploring unique therapeutic approaches for brain metastases and other sites with high TMB,” they wrote.

To get a clearer picture of differences in TMB by biopsy sample location, histology, and other biomarkers, the investigators obtained 3,424 unique, unmatched specimens from multiple U.S. cancer centers. The specimens, including 2,351 adenocarcinomas and 1,073 SCCs, were identified by only age and sex, with histology confirmed by pathology review.

The investigators conducted next-generation sequencing of 592 cancer-related genes on each specimen, as well as programmed death ligand 1 (PD-L1) immunohistochemistry, and TMB. They used a TMB cutoff of 10 mutations/MB, which was established as predictive of response to immune checkpoint inhibitors in the Checkmate 568 and Checkmate 227 trials.

They found that 38% of metastatic adenocarcinoma samples had TMB of 10 mutations/MB or greater, compared with 25% of primary adenocarcinomas (P less than .001), a difference that was greatest for brain metastases, compared with other metastases (61% vs. 35%; P less than .001). The median TMBs were 13 mutations/MB vs. 6 mutations/MB, respectively.

Similarly, TMB above the cutoff was more frequent in SCC metastases than primaries (41% vs. 35%; P = .038).

TMB of 10 mutations/MB occurred significantly more often in SCC primary tumors (35%) than in adenocarcinoma primaries (25%; P less than .001).

They also saw variability in TMB among other sites, with adrenal metastases being the second–most likely site to have high TMB (51%) and bone metastases being least likely (19%).

In an analysis stratified by histology and primary or metastatic sample site, poorly differentiated tumors were significantly more likely to have TMB of 10 mutations/MB or greater both for adenocarcinomas (40% of poorly differentiated primaries vs. 19% for others, and 48% of poorly differentiated metastases vs. 35% for other metastases; P less than .001 for both), and for SCCs (40% vs. 33% of primaries; P = .028; and 42% vs. 31% of metastases; P = .025).

The investigators also detected site-specific differences in PD-L1 positivity, STK11 and KRAS mutation rates, and other markers along the 10 mutations/MB cutoff which they characterized as “clinically informative.”

“Practically, clinicians should consider obtaining metastasis samples when possible if assessing for high TMB. Furthermore, in addition to previously described intratumor heterogeneity, our data highlight significant intertumor heterogeneity in NSCLC. One possible solution to capture tumor heterogeneity is with blood TMB, which theoretically could depict a composite TMB score versus single-site tissue,” Dr. Stein and associates said.

The investigators did not report a study funding source. Dr. Stein reported no relevant disclosures. Several of the coauthors are employees of Caris Life Sciences, which performed the tumor profiling.

SOURCE: Stein MK et al. JCO Precision Oncology. 2019 Jul 26. doi: 10.1200/PO.18.00376.

The degree of tumor mutational burden can predict whether patients with non–small cell lung cancer will benefit from immunotherapy with a checkpoint inhibitor, but differences in TMB by tumor histology and metastatic sites suggest that clinicians still don’t fully understand the implications of this marker for clinical care, investigators say.

A study of nearly 3,500 unmatched non–small cell lung cancer (NSCLC) samples showed that TMB of 10 mutations per megabase (MB) or higher occurred more frequently in metastases (especially brain metastases) than in primary tumors, in squamous cell carcinomas (SCC), compared with adenocarcinomas, and in poorly differentiated tumors, compared with moderately or well-differentiated tumors, reported Matthew K. Stein, MD, of the University of Tennessee Health Sciences Center in Memphis and colleagues in JCO Precision Oncology.

“Further work is needed to elucidate the mutational differences implied by TMB with the hope of identifying additional ICI [immune checkpoint inhibitor] biomarkers, as well as exploring unique therapeutic approaches for brain metastases and other sites with high TMB,” they wrote.

To get a clearer picture of differences in TMB by biopsy sample location, histology, and other biomarkers, the investigators obtained 3,424 unique, unmatched specimens from multiple U.S. cancer centers. The specimens, including 2,351 adenocarcinomas and 1,073 SCCs, were identified by only age and sex, with histology confirmed by pathology review.

The investigators conducted next-generation sequencing of 592 cancer-related genes on each specimen, as well as programmed death ligand 1 (PD-L1) immunohistochemistry, and TMB. They used a TMB cutoff of 10 mutations/MB, which was established as predictive of response to immune checkpoint inhibitors in the Checkmate 568 and Checkmate 227 trials.

They found that 38% of metastatic adenocarcinoma samples had TMB of 10 mutations/MB or greater, compared with 25% of primary adenocarcinomas (P less than .001), a difference that was greatest for brain metastases, compared with other metastases (61% vs. 35%; P less than .001). The median TMBs were 13 mutations/MB vs. 6 mutations/MB, respectively.

Similarly, TMB above the cutoff was more frequent in SCC metastases than primaries (41% vs. 35%; P = .038).

TMB of 10 mutations/MB occurred significantly more often in SCC primary tumors (35%) than in adenocarcinoma primaries (25%; P less than .001).

They also saw variability in TMB among other sites, with adrenal metastases being the second–most likely site to have high TMB (51%) and bone metastases being least likely (19%).

In an analysis stratified by histology and primary or metastatic sample site, poorly differentiated tumors were significantly more likely to have TMB of 10 mutations/MB or greater both for adenocarcinomas (40% of poorly differentiated primaries vs. 19% for others, and 48% of poorly differentiated metastases vs. 35% for other metastases; P less than .001 for both), and for SCCs (40% vs. 33% of primaries; P = .028; and 42% vs. 31% of metastases; P = .025).

The investigators also detected site-specific differences in PD-L1 positivity, STK11 and KRAS mutation rates, and other markers along the 10 mutations/MB cutoff which they characterized as “clinically informative.”

“Practically, clinicians should consider obtaining metastasis samples when possible if assessing for high TMB. Furthermore, in addition to previously described intratumor heterogeneity, our data highlight significant intertumor heterogeneity in NSCLC. One possible solution to capture tumor heterogeneity is with blood TMB, which theoretically could depict a composite TMB score versus single-site tissue,” Dr. Stein and associates said.

The investigators did not report a study funding source. Dr. Stein reported no relevant disclosures. Several of the coauthors are employees of Caris Life Sciences, which performed the tumor profiling.

SOURCE: Stein MK et al. JCO Precision Oncology. 2019 Jul 26. doi: 10.1200/PO.18.00376.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

Natural disasters such as hurricanes cause delays in radiotherapy delivery for non–small cell lung cancer (NSCLC) that ultimately translate to poorer outcomes, suggests a retrospective cohort study.

“Radiotherapy is particularly vulnerable because it requires dependable electrical power and daily treatment,” lead investigator Leticia M. Nogueira, PhD, Surveillance and Health Services Research Program, American Cancer Society, and colleagues noted. “Disruptions are especially concerning for patients undergoing treatment for locally advanced ... NSCLC because treatment delays as little as 2 days negatively affect survival.”

The investigators used the National Cancer Database to identify patients receiving definitive radiotherapy for nonoperative locally advanced NSCLC between 2004 and 2014 who had at least 1 year of follow-up for vital status.

Each patient undergoing radiotherapy when a hurricane disaster was declared for their facility’s area was matched through propensity scoring with a patient treated during a declaration-free period having similar start month, sex, age, stage, nodal status, and income. Analyses compared 1,734 exposed patients with 1,734 unexposed patients.

Study results reported in JAMA showed that 101 hurricane disaster declarations were made during the study period, and they lasted from 1 day to 69 days. The radiation treatment duration was about 21 days (45%) longer for patients exposed to these declarations than for unexposed counterparts (66.9 vs. 46.2 days; P less than .001).

Over a median follow-up of 15 months, exposed patients were more likely to die (adjusted hazard ratio, 1.19; P = .001). Moreover, risk generally rose with the duration of the declaration, peaking for patients exposed to those lasting 27 days (adjusted relative risk, 1.27).

“Because data on other potentially explanatory factors are lacking, the relative contribution of treatment delay to the observed association cannot be quantified. However, treatment delay is one of the few hurricane-related disruptions that can be prevented,” Dr. Nogueira and colleagues maintain.

“Because no recommended correction for radiotherapy delays exists ... strategies for identifying patients, arranging for transferring treatment, and eliminating patient out-of-network insurance charges should be considered in disaster mitigation planning,” they recommend.

Dr. Nogueira disclosed no relevant conflicts of interest. The investigators conducted the study as part of the in-tramural research program at the American Cancer Society or contributed their time.

SOURCE: Nogueira LM et al. JAMA. 2019 Jul 16;322(3):269-71.

Natural disasters such as hurricanes cause delays in radiotherapy delivery for non–small cell lung cancer (NSCLC) that ultimately translate to poorer outcomes, suggests a retrospective cohort study.

“Radiotherapy is particularly vulnerable because it requires dependable electrical power and daily treatment,” lead investigator Leticia M. Nogueira, PhD, Surveillance and Health Services Research Program, American Cancer Society, and colleagues noted. “Disruptions are especially concerning for patients undergoing treatment for locally advanced ... NSCLC because treatment delays as little as 2 days negatively affect survival.”

The investigators used the National Cancer Database to identify patients receiving definitive radiotherapy for nonoperative locally advanced NSCLC between 2004 and 2014 who had at least 1 year of follow-up for vital status.

Each patient undergoing radiotherapy when a hurricane disaster was declared for their facility’s area was matched through propensity scoring with a patient treated during a declaration-free period having similar start month, sex, age, stage, nodal status, and income. Analyses compared 1,734 exposed patients with 1,734 unexposed patients.

Study results reported in JAMA showed that 101 hurricane disaster declarations were made during the study period, and they lasted from 1 day to 69 days. The radiation treatment duration was about 21 days (45%) longer for patients exposed to these declarations than for unexposed counterparts (66.9 vs. 46.2 days; P less than .001).

Over a median follow-up of 15 months, exposed patients were more likely to die (adjusted hazard ratio, 1.19; P = .001). Moreover, risk generally rose with the duration of the declaration, peaking for patients exposed to those lasting 27 days (adjusted relative risk, 1.27).

“Because data on other potentially explanatory factors are lacking, the relative contribution of treatment delay to the observed association cannot be quantified. However, treatment delay is one of the few hurricane-related disruptions that can be prevented,” Dr. Nogueira and colleagues maintain.

“Because no recommended correction for radiotherapy delays exists ... strategies for identifying patients, arranging for transferring treatment, and eliminating patient out-of-network insurance charges should be considered in disaster mitigation planning,” they recommend.

Dr. Nogueira disclosed no relevant conflicts of interest. The investigators conducted the study as part of the in-tramural research program at the American Cancer Society or contributed their time.

SOURCE: Nogueira LM et al. JAMA. 2019 Jul 16;322(3):269-71.

Natural disasters such as hurricanes cause delays in radiotherapy delivery for non–small cell lung cancer (NSCLC) that ultimately translate to poorer outcomes, suggests a retrospective cohort study.

“Radiotherapy is particularly vulnerable because it requires dependable electrical power and daily treatment,” lead investigator Leticia M. Nogueira, PhD, Surveillance and Health Services Research Program, American Cancer Society, and colleagues noted. “Disruptions are especially concerning for patients undergoing treatment for locally advanced ... NSCLC because treatment delays as little as 2 days negatively affect survival.”

The investigators used the National Cancer Database to identify patients receiving definitive radiotherapy for nonoperative locally advanced NSCLC between 2004 and 2014 who had at least 1 year of follow-up for vital status.

Each patient undergoing radiotherapy when a hurricane disaster was declared for their facility’s area was matched through propensity scoring with a patient treated during a declaration-free period having similar start month, sex, age, stage, nodal status, and income. Analyses compared 1,734 exposed patients with 1,734 unexposed patients.

Study results reported in JAMA showed that 101 hurricane disaster declarations were made during the study period, and they lasted from 1 day to 69 days. The radiation treatment duration was about 21 days (45%) longer for patients exposed to these declarations than for unexposed counterparts (66.9 vs. 46.2 days; P less than .001).

Over a median follow-up of 15 months, exposed patients were more likely to die (adjusted hazard ratio, 1.19; P = .001). Moreover, risk generally rose with the duration of the declaration, peaking for patients exposed to those lasting 27 days (adjusted relative risk, 1.27).

“Because data on other potentially explanatory factors are lacking, the relative contribution of treatment delay to the observed association cannot be quantified. However, treatment delay is one of the few hurricane-related disruptions that can be prevented,” Dr. Nogueira and colleagues maintain.

“Because no recommended correction for radiotherapy delays exists ... strategies for identifying patients, arranging for transferring treatment, and eliminating patient out-of-network insurance charges should be considered in disaster mitigation planning,” they recommend.

Dr. Nogueira disclosed no relevant conflicts of interest. The investigators conducted the study as part of the in-tramural research program at the American Cancer Society or contributed their time.

SOURCE: Nogueira LM et al. JAMA. 2019 Jul 16;322(3):269-71.

The majority of adult cigarette smokers in the United States try to quit each year, but there was little change in the rate of quit attempts from 2011 to 2017, according to the Centers for Disease Control and Prevention.

The median percentage of adult smokers who tried to quit cigarettes over the past year went from 64.9% in 2011 to 65.4% in 2017, CDC investigators reported in the Morbidity and Mortality Weekly Report, but the rate has gone down since 2014, when it reached 66.9%.

“The limited progress in increasing quit attempts … together with the variation in quit attempt prevalence among states, underscores the importance of enhanced efforts to motivate and help smokers to quit,” wrote Kimp Walton, MS, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion and associates.

State-specific trends in quit-attempt rates reflected the national situation. The prevalence of past-year cessation attempts went up significantly in four states (Kansas, Louisiana, Virginia, and West Virginia) from 2011 to 2017, went down significantly in two states (New York and Tennessee), and did not change significantly in the other 44 states and the District of Columbia, they wrote.

In 2017, cigarette smokers in Connecticut were the most likely to have tried to quit in the past year, with a rate of 71.6%. The only other places with rates greater than 70% were Delaware, D.C., New Jersey, and Texas. The lowest quit-attempt rate that year, 58.6%, belonged to Wisconsin, with Iowa and Missouri the only other states under 60%, the investigators reported based on data from annual Behavioral Risk Factor Surveillance System surveys.


“Because most smokers make multiple quit attempts before succeeding, as many as 30 on average, tobacco dependence is viewed as a chronic, relapsing condition that requires repeated intervention. Smokers should be encouraged to keep trying to quit until they succeed, and health care providers should be encouraged to keep supporting smokers until they quit,” investigators wrote.

rfranki@mdedge.com

SOURCE: Walton K et al. MMWR. 2019 Jul 19;68(28):621-6.

The majority of adult cigarette smokers in the United States try to quit each year, but there was little change in the rate of quit attempts from 2011 to 2017, according to the Centers for Disease Control and Prevention.

The median percentage of adult smokers who tried to quit cigarettes over the past year went from 64.9% in 2011 to 65.4% in 2017, CDC investigators reported in the Morbidity and Mortality Weekly Report, but the rate has gone down since 2014, when it reached 66.9%.

“The limited progress in increasing quit attempts … together with the variation in quit attempt prevalence among states, underscores the importance of enhanced efforts to motivate and help smokers to quit,” wrote Kimp Walton, MS, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion and associates.

State-specific trends in quit-attempt rates reflected the national situation. The prevalence of past-year cessation attempts went up significantly in four states (Kansas, Louisiana, Virginia, and West Virginia) from 2011 to 2017, went down significantly in two states (New York and Tennessee), and did not change significantly in the other 44 states and the District of Columbia, they wrote.

In 2017, cigarette smokers in Connecticut were the most likely to have tried to quit in the past year, with a rate of 71.6%. The only other places with rates greater than 70% were Delaware, D.C., New Jersey, and Texas. The lowest quit-attempt rate that year, 58.6%, belonged to Wisconsin, with Iowa and Missouri the only other states under 60%, the investigators reported based on data from annual Behavioral Risk Factor Surveillance System surveys.


“Because most smokers make multiple quit attempts before succeeding, as many as 30 on average, tobacco dependence is viewed as a chronic, relapsing condition that requires repeated intervention. Smokers should be encouraged to keep trying to quit until they succeed, and health care providers should be encouraged to keep supporting smokers until they quit,” investigators wrote.

rfranki@mdedge.com

SOURCE: Walton K et al. MMWR. 2019 Jul 19;68(28):621-6.

The majority of adult cigarette smokers in the United States try to quit each year, but there was little change in the rate of quit attempts from 2011 to 2017, according to the Centers for Disease Control and Prevention.

The median percentage of adult smokers who tried to quit cigarettes over the past year went from 64.9% in 2011 to 65.4% in 2017, CDC investigators reported in the Morbidity and Mortality Weekly Report, but the rate has gone down since 2014, when it reached 66.9%.

“The limited progress in increasing quit attempts … together with the variation in quit attempt prevalence among states, underscores the importance of enhanced efforts to motivate and help smokers to quit,” wrote Kimp Walton, MS, of the CDC’s National Center for Chronic Disease Prevention and Health Promotion and associates.

State-specific trends in quit-attempt rates reflected the national situation. The prevalence of past-year cessation attempts went up significantly in four states (Kansas, Louisiana, Virginia, and West Virginia) from 2011 to 2017, went down significantly in two states (New York and Tennessee), and did not change significantly in the other 44 states and the District of Columbia, they wrote.

In 2017, cigarette smokers in Connecticut were the most likely to have tried to quit in the past year, with a rate of 71.6%. The only other places with rates greater than 70% were Delaware, D.C., New Jersey, and Texas. The lowest quit-attempt rate that year, 58.6%, belonged to Wisconsin, with Iowa and Missouri the only other states under 60%, the investigators reported based on data from annual Behavioral Risk Factor Surveillance System surveys.


“Because most smokers make multiple quit attempts before succeeding, as many as 30 on average, tobacco dependence is viewed as a chronic, relapsing condition that requires repeated intervention. Smokers should be encouraged to keep trying to quit until they succeed, and health care providers should be encouraged to keep supporting smokers until they quit,” investigators wrote.

rfranki@mdedge.com

SOURCE: Walton K et al. MMWR. 2019 Jul 19;68(28):621-6.

Combination radiotherapy and pembrolizumab may improve clinical outcomes by means of synergy in the treatment of patients with non–small cell lung cancer (NSCLC), according to results from two recent studies.

“The best way to combine immunotherapy with ablative therapies in the curative setting is an area of active investigation,” wrote Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Dr. Bauml and colleagues recently reported the results of a phase 2 study exploring the addition of pembrolizumab following the completion of locally ablative therapy in patients with oligometastatic NSCLC in JAMA Oncology.

The single-arm trial included 51 patients who received intravenous pembrolizumab (200 mg every 21 days) for a total of 8 cycles within 4-12 weeks of local ablative therapy completion. Study participants were administered locally ablative therapy to all recognized sites of malignancy.

The researchers measured two primary efficacy outcomes: progression-free survival (PFS) from the initiation of ablative therapy and the PFS from initiation of pembrolizumab. Secondary endpoints were safety, quality of life, and overall survival (OS).

Among patients who received pembrolizumab after ablative therapy, the median PFS was 19.1 months (95% CI, 9.4-28.7 months), which was significantly longer than the historical outcome (median PFS, 6.6 months; P = .005). In addition, the 24-month OS was 77.5%. With respect to safety, no decrease in quality of life or new safety signals were reported in the study.

One key limitation of the study was the single-arm design. As a result, distinguishing the effects of pembrolizumab over ablative therapy alone is not possible with the present data.

“This study is the first to show improved outcomes for immunotherapy after locally ablative therapy in patients with oligometastatic NSCLC,” Dr. Bauml and his colleagues wrote.

In another phase 2 trial (PEMBRO-RT study) reported in the same issue, Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues examined the use of pembrolizumab after stereotactic body radiotherapy or pembrolizumab alone in patients with recurrent metastatic NSCLC.

“This study evaluates whether stereotactic body radiotherapy enhances the effect of immune checkpoint blockade,” wrote Dr. Theelen and colleagues.

The PEMBRO-RT study included 76 patients with recurrent metastatic NSCLC who were randomized to pembrolizumab following radiotherapy or pembrolizumab alone. Intravenous pembrolizumab was administered at 200 mg/kg every 3 weeks, with the first dose given within 7 days after completion of radiotherapy.

The primary outcome was the overall response rate (ORR) at 12 weeks. Secondary outcomes included OS, PFS, and safety.

Among patients who received pembrolizumab after radiotherapy versus pembrolizumab alone, the ORR at 12 weeks was 36% and 18%, respectively (P = .07). In addition, the median PFS and OS were not statistically significant (P = .19 and P = .16, respectively).

“Positive results were largely influenced by the PD-L1–negative subgroup, which had significantly improved progression-free survival and overall survival,” the researchers wrote.

With respect to safety, no differences in grade 3-5 adverse effects were observed between the treatment groups. In addition, no significant differences were seen in pulmonary toxicities.

One key limitation of the study was the lack of information regarding optimal radiotherapy dosing and schedule.

“The results of this study are encouraging, and further evaluation in a larger phase 2/3 trial is recommended,” Dr. Theelen and colleagues wrote.

Further studies are needed to fully understand the links between combination radiotherapy and pembrolizumab in patients with NSCLC.

The study by Dr. Bauml and colleagues was funded by the Abramson Cancer Center and Merck & Co. The authors reported financial affiliations with Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and several others.

The study by Dr. Theelen and colleagues was funded by Merck Sharp & Dohme. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Roche, Takeda, and several others.
 

SOURCE: Bauml JM et al. JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449. Theelen WSME et al. JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478.

Combination radiotherapy and pembrolizumab may improve clinical outcomes by means of synergy in the treatment of patients with non–small cell lung cancer (NSCLC), according to results from two recent studies.

“The best way to combine immunotherapy with ablative therapies in the curative setting is an area of active investigation,” wrote Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Dr. Bauml and colleagues recently reported the results of a phase 2 study exploring the addition of pembrolizumab following the completion of locally ablative therapy in patients with oligometastatic NSCLC in JAMA Oncology.

The single-arm trial included 51 patients who received intravenous pembrolizumab (200 mg every 21 days) for a total of 8 cycles within 4-12 weeks of local ablative therapy completion. Study participants were administered locally ablative therapy to all recognized sites of malignancy.

The researchers measured two primary efficacy outcomes: progression-free survival (PFS) from the initiation of ablative therapy and the PFS from initiation of pembrolizumab. Secondary endpoints were safety, quality of life, and overall survival (OS).

Among patients who received pembrolizumab after ablative therapy, the median PFS was 19.1 months (95% CI, 9.4-28.7 months), which was significantly longer than the historical outcome (median PFS, 6.6 months; P = .005). In addition, the 24-month OS was 77.5%. With respect to safety, no decrease in quality of life or new safety signals were reported in the study.

One key limitation of the study was the single-arm design. As a result, distinguishing the effects of pembrolizumab over ablative therapy alone is not possible with the present data.

“This study is the first to show improved outcomes for immunotherapy after locally ablative therapy in patients with oligometastatic NSCLC,” Dr. Bauml and his colleagues wrote.

In another phase 2 trial (PEMBRO-RT study) reported in the same issue, Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues examined the use of pembrolizumab after stereotactic body radiotherapy or pembrolizumab alone in patients with recurrent metastatic NSCLC.

“This study evaluates whether stereotactic body radiotherapy enhances the effect of immune checkpoint blockade,” wrote Dr. Theelen and colleagues.

The PEMBRO-RT study included 76 patients with recurrent metastatic NSCLC who were randomized to pembrolizumab following radiotherapy or pembrolizumab alone. Intravenous pembrolizumab was administered at 200 mg/kg every 3 weeks, with the first dose given within 7 days after completion of radiotherapy.

The primary outcome was the overall response rate (ORR) at 12 weeks. Secondary outcomes included OS, PFS, and safety.

Among patients who received pembrolizumab after radiotherapy versus pembrolizumab alone, the ORR at 12 weeks was 36% and 18%, respectively (P = .07). In addition, the median PFS and OS were not statistically significant (P = .19 and P = .16, respectively).

“Positive results were largely influenced by the PD-L1–negative subgroup, which had significantly improved progression-free survival and overall survival,” the researchers wrote.

With respect to safety, no differences in grade 3-5 adverse effects were observed between the treatment groups. In addition, no significant differences were seen in pulmonary toxicities.

One key limitation of the study was the lack of information regarding optimal radiotherapy dosing and schedule.

“The results of this study are encouraging, and further evaluation in a larger phase 2/3 trial is recommended,” Dr. Theelen and colleagues wrote.

Further studies are needed to fully understand the links between combination radiotherapy and pembrolizumab in patients with NSCLC.

The study by Dr. Bauml and colleagues was funded by the Abramson Cancer Center and Merck & Co. The authors reported financial affiliations with Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and several others.

The study by Dr. Theelen and colleagues was funded by Merck Sharp & Dohme. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Roche, Takeda, and several others.
 

SOURCE: Bauml JM et al. JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449. Theelen WSME et al. JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478.

Combination radiotherapy and pembrolizumab may improve clinical outcomes by means of synergy in the treatment of patients with non–small cell lung cancer (NSCLC), according to results from two recent studies.

“The best way to combine immunotherapy with ablative therapies in the curative setting is an area of active investigation,” wrote Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Dr. Bauml and colleagues recently reported the results of a phase 2 study exploring the addition of pembrolizumab following the completion of locally ablative therapy in patients with oligometastatic NSCLC in JAMA Oncology.

The single-arm trial included 51 patients who received intravenous pembrolizumab (200 mg every 21 days) for a total of 8 cycles within 4-12 weeks of local ablative therapy completion. Study participants were administered locally ablative therapy to all recognized sites of malignancy.

The researchers measured two primary efficacy outcomes: progression-free survival (PFS) from the initiation of ablative therapy and the PFS from initiation of pembrolizumab. Secondary endpoints were safety, quality of life, and overall survival (OS).

Among patients who received pembrolizumab after ablative therapy, the median PFS was 19.1 months (95% CI, 9.4-28.7 months), which was significantly longer than the historical outcome (median PFS, 6.6 months; P = .005). In addition, the 24-month OS was 77.5%. With respect to safety, no decrease in quality of life or new safety signals were reported in the study.

One key limitation of the study was the single-arm design. As a result, distinguishing the effects of pembrolizumab over ablative therapy alone is not possible with the present data.

“This study is the first to show improved outcomes for immunotherapy after locally ablative therapy in patients with oligometastatic NSCLC,” Dr. Bauml and his colleagues wrote.

In another phase 2 trial (PEMBRO-RT study) reported in the same issue, Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues examined the use of pembrolizumab after stereotactic body radiotherapy or pembrolizumab alone in patients with recurrent metastatic NSCLC.

“This study evaluates whether stereotactic body radiotherapy enhances the effect of immune checkpoint blockade,” wrote Dr. Theelen and colleagues.

The PEMBRO-RT study included 76 patients with recurrent metastatic NSCLC who were randomized to pembrolizumab following radiotherapy or pembrolizumab alone. Intravenous pembrolizumab was administered at 200 mg/kg every 3 weeks, with the first dose given within 7 days after completion of radiotherapy.

The primary outcome was the overall response rate (ORR) at 12 weeks. Secondary outcomes included OS, PFS, and safety.

Among patients who received pembrolizumab after radiotherapy versus pembrolizumab alone, the ORR at 12 weeks was 36% and 18%, respectively (P = .07). In addition, the median PFS and OS were not statistically significant (P = .19 and P = .16, respectively).

“Positive results were largely influenced by the PD-L1–negative subgroup, which had significantly improved progression-free survival and overall survival,” the researchers wrote.

With respect to safety, no differences in grade 3-5 adverse effects were observed between the treatment groups. In addition, no significant differences were seen in pulmonary toxicities.

One key limitation of the study was the lack of information regarding optimal radiotherapy dosing and schedule.

“The results of this study are encouraging, and further evaluation in a larger phase 2/3 trial is recommended,” Dr. Theelen and colleagues wrote.

Further studies are needed to fully understand the links between combination radiotherapy and pembrolizumab in patients with NSCLC.

The study by Dr. Bauml and colleagues was funded by the Abramson Cancer Center and Merck & Co. The authors reported financial affiliations with Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and several others.

The study by Dr. Theelen and colleagues was funded by Merck Sharp & Dohme. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Roche, Takeda, and several others.
 

SOURCE: Bauml JM et al. JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449. Theelen WSME et al. JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478.

Researchers say they have identified potential prognostic markers and targets for treatment in patients with non–small cell lung cancer (NSCLC) and brain metastases (BM).

There was “substantial” concordance in driver mutations, such as EGFR and KRAS, between BM and primary tumor samples but greater genomic instability in BM samples, reported Hong-Sheng Wang, PhD, of Sun Yat-Sen University in Guangzhou, China, and colleagues.

PI3K signaling was significantly associated with an increased risk of BM, and CDKs and PIK3CA were “potential druggable mutations,” they reported in Cancer.

The researchers conducted a retrospective study of 61 Chinese patients with NSCLC and BM. The patients had adenocarcinoma (n = 50), squamous cell carcinoma (n = 3), and mixed subtypes (n = 8). Less than half of patients (n = 28) had stage IV disease at diagnosis, 36 had metachronous disease, and 25 had synchronous disease. All patients had undergone surgery, 33 had received chemoradiation, 26 had received no systemic treatment, and 5 had been treated with tyrosine kinase inhibitors.

The researchers performed next-generation sequencing on primary tumors and matched BM samples from the 61 patients, targeting 416 cancer-relevant genes.

Results showed high concordance between the primary and BM samples with regard to major driver mutations – 92% for EGFR, 82% for KRAS, and 83% for TP53 mutations.

For nearly half of patients (48%), all mutations found in primary tumor samples were also found in BM samples. In fact, 18% of patients had the same mutational profiles in lung and brain lesions.

Conversely, 30% of patients had more brain-specific mutations, 13% had more lung-specific mutations, 28% had mixed profiles, and 11% had completely unique mutational profiles in lung and brain lesions.

Compared with primary tumor samples, BM samples had a significantly higher frequency of copy number variations (P = .0002); alterations in CDKN2A/2B, CCND1, CDK4, and RB1 (P = .0019); and alterations in PIK3CA, PTEN, STK11, RICTOR, and NF2 (P = .0037).

Patients with activated PI3K signaling in their primary tumors had significantly shorter BM-free survival. The hazard ratio (adjusted for baseline clinicopathologic parameters) was 8.49 (P = .0005).

There was no significant difference in BM-free survival between EGFR-/KRAS-mutated patients and patients with wild-type EGFR/KRAS (P = .29). However, there was a trend toward shorter BM-free survival in patients with TP53 mutations (P = .15).

There was a trend toward shorter BM-free intervals in patients with an activated WNT pathway via CTNNB1 mutations (P = .22) or APC and AXIN2 mutations (P = .015). However, the researchers said these findings should be treated with caution due to a small sample size.

The National Natural Science Foundation of China and the Natural Science Foundation of Guangdong Province supported the research. The researchers disclosed relationships with Geneseeq Technology Inc. in Toronto and Nanjing Geneseeq Technology Inc.

SOURCE: Wang H et al. Cancer. 2019 Jul 9. doi: 10.1002/cncr.32372.

Researchers say they have identified potential prognostic markers and targets for treatment in patients with non–small cell lung cancer (NSCLC) and brain metastases (BM).

There was “substantial” concordance in driver mutations, such as EGFR and KRAS, between BM and primary tumor samples but greater genomic instability in BM samples, reported Hong-Sheng Wang, PhD, of Sun Yat-Sen University in Guangzhou, China, and colleagues.

PI3K signaling was significantly associated with an increased risk of BM, and CDKs and PIK3CA were “potential druggable mutations,” they reported in Cancer.

The researchers conducted a retrospective study of 61 Chinese patients with NSCLC and BM. The patients had adenocarcinoma (n = 50), squamous cell carcinoma (n = 3), and mixed subtypes (n = 8). Less than half of patients (n = 28) had stage IV disease at diagnosis, 36 had metachronous disease, and 25 had synchronous disease. All patients had undergone surgery, 33 had received chemoradiation, 26 had received no systemic treatment, and 5 had been treated with tyrosine kinase inhibitors.

The researchers performed next-generation sequencing on primary tumors and matched BM samples from the 61 patients, targeting 416 cancer-relevant genes.

Results showed high concordance between the primary and BM samples with regard to major driver mutations – 92% for EGFR, 82% for KRAS, and 83% for TP53 mutations.

For nearly half of patients (48%), all mutations found in primary tumor samples were also found in BM samples. In fact, 18% of patients had the same mutational profiles in lung and brain lesions.

Conversely, 30% of patients had more brain-specific mutations, 13% had more lung-specific mutations, 28% had mixed profiles, and 11% had completely unique mutational profiles in lung and brain lesions.

Compared with primary tumor samples, BM samples had a significantly higher frequency of copy number variations (P = .0002); alterations in CDKN2A/2B, CCND1, CDK4, and RB1 (P = .0019); and alterations in PIK3CA, PTEN, STK11, RICTOR, and NF2 (P = .0037).

Patients with activated PI3K signaling in their primary tumors had significantly shorter BM-free survival. The hazard ratio (adjusted for baseline clinicopathologic parameters) was 8.49 (P = .0005).

There was no significant difference in BM-free survival between EGFR-/KRAS-mutated patients and patients with wild-type EGFR/KRAS (P = .29). However, there was a trend toward shorter BM-free survival in patients with TP53 mutations (P = .15).

There was a trend toward shorter BM-free intervals in patients with an activated WNT pathway via CTNNB1 mutations (P = .22) or APC and AXIN2 mutations (P = .015). However, the researchers said these findings should be treated with caution due to a small sample size.

The National Natural Science Foundation of China and the Natural Science Foundation of Guangdong Province supported the research. The researchers disclosed relationships with Geneseeq Technology Inc. in Toronto and Nanjing Geneseeq Technology Inc.

SOURCE: Wang H et al. Cancer. 2019 Jul 9. doi: 10.1002/cncr.32372.

Researchers say they have identified potential prognostic markers and targets for treatment in patients with non–small cell lung cancer (NSCLC) and brain metastases (BM).

There was “substantial” concordance in driver mutations, such as EGFR and KRAS, between BM and primary tumor samples but greater genomic instability in BM samples, reported Hong-Sheng Wang, PhD, of Sun Yat-Sen University in Guangzhou, China, and colleagues.

PI3K signaling was significantly associated with an increased risk of BM, and CDKs and PIK3CA were “potential druggable mutations,” they reported in Cancer.

The researchers conducted a retrospective study of 61 Chinese patients with NSCLC and BM. The patients had adenocarcinoma (n = 50), squamous cell carcinoma (n = 3), and mixed subtypes (n = 8). Less than half of patients (n = 28) had stage IV disease at diagnosis, 36 had metachronous disease, and 25 had synchronous disease. All patients had undergone surgery, 33 had received chemoradiation, 26 had received no systemic treatment, and 5 had been treated with tyrosine kinase inhibitors.

The researchers performed next-generation sequencing on primary tumors and matched BM samples from the 61 patients, targeting 416 cancer-relevant genes.

Results showed high concordance between the primary and BM samples with regard to major driver mutations – 92% for EGFR, 82% for KRAS, and 83% for TP53 mutations.

For nearly half of patients (48%), all mutations found in primary tumor samples were also found in BM samples. In fact, 18% of patients had the same mutational profiles in lung and brain lesions.

Conversely, 30% of patients had more brain-specific mutations, 13% had more lung-specific mutations, 28% had mixed profiles, and 11% had completely unique mutational profiles in lung and brain lesions.

Compared with primary tumor samples, BM samples had a significantly higher frequency of copy number variations (P = .0002); alterations in CDKN2A/2B, CCND1, CDK4, and RB1 (P = .0019); and alterations in PIK3CA, PTEN, STK11, RICTOR, and NF2 (P = .0037).

Patients with activated PI3K signaling in their primary tumors had significantly shorter BM-free survival. The hazard ratio (adjusted for baseline clinicopathologic parameters) was 8.49 (P = .0005).

There was no significant difference in BM-free survival between EGFR-/KRAS-mutated patients and patients with wild-type EGFR/KRAS (P = .29). However, there was a trend toward shorter BM-free survival in patients with TP53 mutations (P = .15).

There was a trend toward shorter BM-free intervals in patients with an activated WNT pathway via CTNNB1 mutations (P = .22) or APC and AXIN2 mutations (P = .015). However, the researchers said these findings should be treated with caution due to a small sample size.

The National Natural Science Foundation of China and the Natural Science Foundation of Guangdong Province supported the research. The researchers disclosed relationships with Geneseeq Technology Inc. in Toronto and Nanjing Geneseeq Technology Inc.

SOURCE: Wang H et al. Cancer. 2019 Jul 9. doi: 10.1002/cncr.32372.

Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to doublet or triplet regimens as first-line treatment for nonsquamous non–small cell lung cancer (NSCLC) is not cost effective, even by a long shot, concluded a Markov modeling study.

Positive results of the IMpower150 trial led the Food and Drug Administration to approve and the National Comprehensive Cancer Network to recommend the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) as an option for selected patients in this setting, noted the investigators, led by XiaoMin Wan, PhD, of the department of pharmacy at the Second Xiangya Hospital and the Institute of Clinical Pharmacy, both at Central South University, Changsha, China.

“Although adding atezolizumab to the combination of bevacizumab and chemotherapy results in significantly higher survival in patients with metastatic NSCLC, the question of whether its price reflects its potential benefit remains unclear from a value standpoint,” they wrote.

Dr. Wan and colleagues developed a Markov model to compare the lifetime cost and effectiveness of various combinations – the quadruplet ABCP regimen, the triplet BCP regimen (bevacizumab, carboplatin, and paclitaxel), and the doublet CP regimen (carboplatin and paclitaxel) – when used as first‐line treatment for metastatic nonsquamous NSCLC.

ABCP yielded an additional 0.413 quality-adjusted life-years (QALYs) and 0.460 life-years, compared with BCP, and an additional 0.738 QALYs and 0.956 life-years, compared with CP. Respective incremental costs were $234,998 and $381,116, the investigators reported in Cancer.

Ultimately, ABCP had an incremental cost‐effectiveness ratio (ICER) of $568,967 per QALY, compared with BCP, and $516,114 per QALY, compared with CP – both of which far exceeded the conventional $100,000 ICER per QALY willingness-to-pay threshold.

Although atezolizumab targets programmed death–ligand 1 (PD-L1), the ICER improved only modestly to $464,703 per QALY when treatment was given only to patients having PD‐L1 expression of at least 50% on tumor cells or at least 10% on immune cells. Findings were similar when the duration of atezolizumab therapy was restricted to 2 years.

However, steep reductions in the costs of the two targeted agents altered results. Specifically, ABCP had an ICER of $99,786 and $162,441 per QALY, compared with BCP and CP, respectively, when the costs of atezolizumab and bevacizumab were reduced by 70%, and ABCP fell below the $100,000 willingness-to-pay threshold, compared with both regimens, when those costs were reduced by 83%.

“To our knowledge, the current study is the first cost-effectiveness analysis of ABCP, compared with BCP, in the first-line setting for patients with metastatic NSCLC,” Dr. Wan and colleagues noted. “From the perspective of the U.S. payer, ABCP is estimated not to be cost effective, compared with BCP or CP, in the first-line setting for patients with metastatic, nonsquamous NSCLC at a [willingness-to-pay] threshold of $100,000 per QALY.”

“Although ABCP is not considered to be cost effective, this does not mean that patients should receive the less-effective treatment strategy of BCP,” they cautioned, noting that recent cost-effectiveness data appear to favor the first-line combination of another immune checkpoint inhibitor, pembrolizumab (Keytruda), with chemotherapy instead. “A price reduction is warranted to make ABCP cost effective and affordable.”

Dr. Wan did not report any relevant conflicts of interest. The study was supported by grants from the National Natural Science Foundation of China and the research project of the Health and Family Planning Commission of Hunan province.

SOURCE: Wan X et al. Cancer. 2019 Jul 9. doi: 10.1002/cncr.32368.

Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to doublet or triplet regimens as first-line treatment for nonsquamous non–small cell lung cancer (NSCLC) is not cost effective, even by a long shot, concluded a Markov modeling study.

Positive results of the IMpower150 trial led the Food and Drug Administration to approve and the National Comprehensive Cancer Network to recommend the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) as an option for selected patients in this setting, noted the investigators, led by XiaoMin Wan, PhD, of the department of pharmacy at the Second Xiangya Hospital and the Institute of Clinical Pharmacy, both at Central South University, Changsha, China.

“Although adding atezolizumab to the combination of bevacizumab and chemotherapy results in significantly higher survival in patients with metastatic NSCLC, the question of whether its price reflects its potential benefit remains unclear from a value standpoint,” they wrote.

Dr. Wan and colleagues developed a Markov model to compare the lifetime cost and effectiveness of various combinations – the quadruplet ABCP regimen, the triplet BCP regimen (bevacizumab, carboplatin, and paclitaxel), and the doublet CP regimen (carboplatin and paclitaxel) – when used as first‐line treatment for metastatic nonsquamous NSCLC.

ABCP yielded an additional 0.413 quality-adjusted life-years (QALYs) and 0.460 life-years, compared with BCP, and an additional 0.738 QALYs and 0.956 life-years, compared with CP. Respective incremental costs were $234,998 and $381,116, the investigators reported in Cancer.

Ultimately, ABCP had an incremental cost‐effectiveness ratio (ICER) of $568,967 per QALY, compared with BCP, and $516,114 per QALY, compared with CP – both of which far exceeded the conventional $100,000 ICER per QALY willingness-to-pay threshold.

Although atezolizumab targets programmed death–ligand 1 (PD-L1), the ICER improved only modestly to $464,703 per QALY when treatment was given only to patients having PD‐L1 expression of at least 50% on tumor cells or at least 10% on immune cells. Findings were similar when the duration of atezolizumab therapy was restricted to 2 years.

However, steep reductions in the costs of the two targeted agents altered results. Specifically, ABCP had an ICER of $99,786 and $162,441 per QALY, compared with BCP and CP, respectively, when the costs of atezolizumab and bevacizumab were reduced by 70%, and ABCP fell below the $100,000 willingness-to-pay threshold, compared with both regimens, when those costs were reduced by 83%.

“To our knowledge, the current study is the first cost-effectiveness analysis of ABCP, compared with BCP, in the first-line setting for patients with metastatic NSCLC,” Dr. Wan and colleagues noted. “From the perspective of the U.S. payer, ABCP is estimated not to be cost effective, compared with BCP or CP, in the first-line setting for patients with metastatic, nonsquamous NSCLC at a [willingness-to-pay] threshold of $100,000 per QALY.”

“Although ABCP is not considered to be cost effective, this does not mean that patients should receive the less-effective treatment strategy of BCP,” they cautioned, noting that recent cost-effectiveness data appear to favor the first-line combination of another immune checkpoint inhibitor, pembrolizumab (Keytruda), with chemotherapy instead. “A price reduction is warranted to make ABCP cost effective and affordable.”

Dr. Wan did not report any relevant conflicts of interest. The study was supported by grants from the National Natural Science Foundation of China and the research project of the Health and Family Planning Commission of Hunan province.

SOURCE: Wan X et al. Cancer. 2019 Jul 9. doi: 10.1002/cncr.32368.

Adding the immune checkpoint inhibitor atezolizumab (Tecentriq) to doublet or triplet regimens as first-line treatment for nonsquamous non–small cell lung cancer (NSCLC) is not cost effective, even by a long shot, concluded a Markov modeling study.

Positive results of the IMpower150 trial led the Food and Drug Administration to approve and the National Comprehensive Cancer Network to recommend the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) as an option for selected patients in this setting, noted the investigators, led by XiaoMin Wan, PhD, of the department of pharmacy at the Second Xiangya Hospital and the Institute of Clinical Pharmacy, both at Central South University, Changsha, China.

“Although adding atezolizumab to the combination of bevacizumab and chemotherapy results in significantly higher survival in patients with metastatic NSCLC, the question of whether its price reflects its potential benefit remains unclear from a value standpoint,” they wrote.

Dr. Wan and colleagues developed a Markov model to compare the lifetime cost and effectiveness of various combinations – the quadruplet ABCP regimen, the triplet BCP regimen (bevacizumab, carboplatin, and paclitaxel), and the doublet CP regimen (carboplatin and paclitaxel) – when used as first‐line treatment for metastatic nonsquamous NSCLC.

ABCP yielded an additional 0.413 quality-adjusted life-years (QALYs) and 0.460 life-years, compared with BCP, and an additional 0.738 QALYs and 0.956 life-years, compared with CP. Respective incremental costs were $234,998 and $381,116, the investigators reported in Cancer.

Ultimately, ABCP had an incremental cost‐effectiveness ratio (ICER) of $568,967 per QALY, compared with BCP, and $516,114 per QALY, compared with CP – both of which far exceeded the conventional $100,000 ICER per QALY willingness-to-pay threshold.

Although atezolizumab targets programmed death–ligand 1 (PD-L1), the ICER improved only modestly to $464,703 per QALY when treatment was given only to patients having PD‐L1 expression of at least 50% on tumor cells or at least 10% on immune cells. Findings were similar when the duration of atezolizumab therapy was restricted to 2 years.

However, steep reductions in the costs of the two targeted agents altered results. Specifically, ABCP had an ICER of $99,786 and $162,441 per QALY, compared with BCP and CP, respectively, when the costs of atezolizumab and bevacizumab were reduced by 70%, and ABCP fell below the $100,000 willingness-to-pay threshold, compared with both regimens, when those costs were reduced by 83%.

“To our knowledge, the current study is the first cost-effectiveness analysis of ABCP, compared with BCP, in the first-line setting for patients with metastatic NSCLC,” Dr. Wan and colleagues noted. “From the perspective of the U.S. payer, ABCP is estimated not to be cost effective, compared with BCP or CP, in the first-line setting for patients with metastatic, nonsquamous NSCLC at a [willingness-to-pay] threshold of $100,000 per QALY.”

“Although ABCP is not considered to be cost effective, this does not mean that patients should receive the less-effective treatment strategy of BCP,” they cautioned, noting that recent cost-effectiveness data appear to favor the first-line combination of another immune checkpoint inhibitor, pembrolizumab (Keytruda), with chemotherapy instead. “A price reduction is warranted to make ABCP cost effective and affordable.”

Dr. Wan did not report any relevant conflicts of interest. The study was supported by grants from the National Natural Science Foundation of China and the research project of the Health and Family Planning Commission of Hunan province.

SOURCE: Wan X et al. Cancer. 2019 Jul 9. doi: 10.1002/cncr.32368.

A combination of pembrolizumab and platinum chemotherapy is the most effective frontline treatment for patients with non–small cell lung cancer (NSCLC), according to a retrospective analysis of more than 16,000 patients.

The study showed that responses to therapy are best predicted by an aggregate of tumor mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, and proportion of CD8+ T-cell tumor-infiltrating lymphocytes (TILs), reported Yunfang Yu, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues.

“[I]mmunotherapy has produced inconsistent results in previous randomized clinical trials,” the investigators wrote, citing inconsistent survival outcomes in CheckMate-026 and publications by Takayama and Wu. “Moreover, independent immune-related biomarkers that are currently used, such as PD-L1 and TMB, have achieved clinical relevance for a selection of patients to some extent, but to our knowledge, they are still far from clear and established.” The report is in JAMA Network Open.

To gain clarity, the investigators performed a large-scale meta-analysis (n = 14,395) and individual patient-level study (n = 1,833) involving patients with NSCLC. Data were drawn from a variety of sources, including PubMed, EMBASE, Cochrane, conference proceedings, and others. Primary outcomes were median overall survival and progression-free survival. Secondary outcomes were objective response rate and durable clinical benefit. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was used as a reporting guideline.

Analysis showed the superiority of immunotherapy to conventional therapy with significantly extended median overall survival and progression-free survival, both with an immunotherapy-favoring hazard ratio (HR) of 0.76 (P less than .001). Immunotherapy survival advantages were also reported individually for checkpoint inhibitors (HR, 0.75), tumor vaccines (HR, 0.83), and cellular immunotherapy (HR, 0.40). Of these three, checkpoint inhibitors and tumor vaccines showed superiority for progression-free survival. For first-line therapy, a combination of a pembrolizumab and chemotherapy was associated with better progression-free and overall survival than were other immunotherapies.

For patients treated with checkpoint inhibitors, higher levels of PD-L1 expression, TMB, or neo-antigen burden (NAB) were each prognostically valuable; however, the most powerful predictive tool was a combination of PD-L1 expression, TMB, and proportion of CD8+ T-cell TILs, with a 3-year overall survival area under the curve of 0.659. In addition, RYR1 and MGAM mutations were independently associated with durable clinical benefits.

“Future development of an optimized, integrated predictive model for immunotherapy should consider the integration of multiple approaches involving biomarkers associated with the T cell–inflamed tumor microenvironment, such as PD-L1 expression, ICs, and those associated with tumor neoepitope burden,” the investigators wrote.

The study was funded by the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, and Guangzhou Science and Technology Program. The investigators disclosed no conflicts of interest.

SOURCE: Yu et al. JAMA Open. 2019 Jul 10. doi: 10.1001/jamanetworkopen.2019.6879.

A combination of pembrolizumab and platinum chemotherapy is the most effective frontline treatment for patients with non–small cell lung cancer (NSCLC), according to a retrospective analysis of more than 16,000 patients.

The study showed that responses to therapy are best predicted by an aggregate of tumor mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, and proportion of CD8+ T-cell tumor-infiltrating lymphocytes (TILs), reported Yunfang Yu, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues.

“[I]mmunotherapy has produced inconsistent results in previous randomized clinical trials,” the investigators wrote, citing inconsistent survival outcomes in CheckMate-026 and publications by Takayama and Wu. “Moreover, independent immune-related biomarkers that are currently used, such as PD-L1 and TMB, have achieved clinical relevance for a selection of patients to some extent, but to our knowledge, they are still far from clear and established.” The report is in JAMA Network Open.

To gain clarity, the investigators performed a large-scale meta-analysis (n = 14,395) and individual patient-level study (n = 1,833) involving patients with NSCLC. Data were drawn from a variety of sources, including PubMed, EMBASE, Cochrane, conference proceedings, and others. Primary outcomes were median overall survival and progression-free survival. Secondary outcomes were objective response rate and durable clinical benefit. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was used as a reporting guideline.

Analysis showed the superiority of immunotherapy to conventional therapy with significantly extended median overall survival and progression-free survival, both with an immunotherapy-favoring hazard ratio (HR) of 0.76 (P less than .001). Immunotherapy survival advantages were also reported individually for checkpoint inhibitors (HR, 0.75), tumor vaccines (HR, 0.83), and cellular immunotherapy (HR, 0.40). Of these three, checkpoint inhibitors and tumor vaccines showed superiority for progression-free survival. For first-line therapy, a combination of a pembrolizumab and chemotherapy was associated with better progression-free and overall survival than were other immunotherapies.

For patients treated with checkpoint inhibitors, higher levels of PD-L1 expression, TMB, or neo-antigen burden (NAB) were each prognostically valuable; however, the most powerful predictive tool was a combination of PD-L1 expression, TMB, and proportion of CD8+ T-cell TILs, with a 3-year overall survival area under the curve of 0.659. In addition, RYR1 and MGAM mutations were independently associated with durable clinical benefits.

“Future development of an optimized, integrated predictive model for immunotherapy should consider the integration of multiple approaches involving biomarkers associated with the T cell–inflamed tumor microenvironment, such as PD-L1 expression, ICs, and those associated with tumor neoepitope burden,” the investigators wrote.

The study was funded by the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, and Guangzhou Science and Technology Program. The investigators disclosed no conflicts of interest.

SOURCE: Yu et al. JAMA Open. 2019 Jul 10. doi: 10.1001/jamanetworkopen.2019.6879.

A combination of pembrolizumab and platinum chemotherapy is the most effective frontline treatment for patients with non–small cell lung cancer (NSCLC), according to a retrospective analysis of more than 16,000 patients.

The study showed that responses to therapy are best predicted by an aggregate of tumor mutational burden (TMB), programmed cell death ligand 1 (PD-L1) expression, and proportion of CD8+ T-cell tumor-infiltrating lymphocytes (TILs), reported Yunfang Yu, MD, of Sun Yat-sen University, Guangzhou, China, and colleagues.

“[I]mmunotherapy has produced inconsistent results in previous randomized clinical trials,” the investigators wrote, citing inconsistent survival outcomes in CheckMate-026 and publications by Takayama and Wu. “Moreover, independent immune-related biomarkers that are currently used, such as PD-L1 and TMB, have achieved clinical relevance for a selection of patients to some extent, but to our knowledge, they are still far from clear and established.” The report is in JAMA Network Open.

To gain clarity, the investigators performed a large-scale meta-analysis (n = 14,395) and individual patient-level study (n = 1,833) involving patients with NSCLC. Data were drawn from a variety of sources, including PubMed, EMBASE, Cochrane, conference proceedings, and others. Primary outcomes were median overall survival and progression-free survival. Secondary outcomes were objective response rate and durable clinical benefit. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) was used as a reporting guideline.

Analysis showed the superiority of immunotherapy to conventional therapy with significantly extended median overall survival and progression-free survival, both with an immunotherapy-favoring hazard ratio (HR) of 0.76 (P less than .001). Immunotherapy survival advantages were also reported individually for checkpoint inhibitors (HR, 0.75), tumor vaccines (HR, 0.83), and cellular immunotherapy (HR, 0.40). Of these three, checkpoint inhibitors and tumor vaccines showed superiority for progression-free survival. For first-line therapy, a combination of a pembrolizumab and chemotherapy was associated with better progression-free and overall survival than were other immunotherapies.

For patients treated with checkpoint inhibitors, higher levels of PD-L1 expression, TMB, or neo-antigen burden (NAB) were each prognostically valuable; however, the most powerful predictive tool was a combination of PD-L1 expression, TMB, and proportion of CD8+ T-cell TILs, with a 3-year overall survival area under the curve of 0.659. In addition, RYR1 and MGAM mutations were independently associated with durable clinical benefits.

“Future development of an optimized, integrated predictive model for immunotherapy should consider the integration of multiple approaches involving biomarkers associated with the T cell–inflamed tumor microenvironment, such as PD-L1 expression, ICs, and those associated with tumor neoepitope burden,” the investigators wrote.

The study was funded by the National Natural Science Foundation of China, Natural Science Foundation of Guangdong Province, and Guangzhou Science and Technology Program. The investigators disclosed no conflicts of interest.

SOURCE: Yu et al. JAMA Open. 2019 Jul 10. doi: 10.1001/jamanetworkopen.2019.6879.

In this edition of “How I will treat my next patient,” I take a look at recent studies that examined ways to predict important outcomes in two very different settings, acute leukemia and advanced non–small cell lung cancer (NSCLC). They share the virtue of helping cancer specialists to increase their vigilance for clinically relevant complications and situations and to educate patients and families.

VTE risk in acute leukemia

The risk of venous thromboembolism (VTE) in cancer patients depends upon multiple patient-, tumor-, anatomic-, and treatment-related factors. The Khorana score has become an accepted standard for predicting the risks of VTE and assessing the relative value of various anticoagulants in cancer patients. However, the only hematologic malignancy that is specifically listed among the primary cancer sites in the Khorana score is “lymphoma.” VTE can develop during treatment for acute leukemia, especially among patients with acute lymphoblastic leukemia (ALL).

At the 2019 annual congress of the European Hematology Association, Alejandro Lazo-Langer, MD, and his colleagues proposed a scoring system to quantify the risks of VTE based on a retrospective cohort study of more than 500 acute leukemia patients, diagnosed from 2006-2017. They identified 77 patients with a VTE event, with a median time from diagnosis to VTE of 64 days. Among 20 possible predictive factors, 3 emerged in the final multivariate model – platelet count greater than 50,000 (1 point), ALL (2 points), and prior history of VTE (3 points).

Over a period of 12 months, patients with a score of more than 3 points had a cumulative incidence of VTE of 44%, in comparison with 10.5% among patients with lower scores. They were unable to discern whether particular antineoplastic regimens or drugs enhanced the risk.

The authors proposed that, if verified in a validation cohort study, the scoring system could lead to better patient education about signs and symptoms, more intensive surveillance for high-risk patients, and preventive interventions.

What this means in practice

Although a large number of patient records were reviewed for Dr. Lazo-Langer’s study, there were just 74 ALL patients, and it is unclear whether particular treatment regimens or drugs (such as L-asparaginase in ALL) enhance risk. Further study with a validation cohort (as was performed for the Khorana score for patients with other malignancies), is warranted. The study is thought provoking, but for now, in my opinion, standard clinical vigilance, surveillance, and education regarding VTE in leukemia patients remain appropriate.

Steroid impact in NSCLC with ICI therapy

Patients with autoimmune disease and individuals requiring active treatment with steroids (prednisone at 10 mg/day or more or the equivalent) were excluded from clinical trials that led to Food and Drug Administration approval of immune checkpoint inhibitor (ICI) agents. Recently published data indicate that treatment with 10 mg or more of daily prednisone correlates with poor outcome in NSCLC patients receiving ICI therapy (J Clin Oncol. 2018;36:2872-8; J Thoracic Oncol. 2018;13:1771-5). However, at the 2019 annual meeting of the American Society of Clinical Oncology, analyses of the CancerLinQ database showed that, among NSCLC patients, autoimmune disease and treatment for autoimmune disease are surprisingly prevalent. Should oncologists refuse to treat these patients with ICI agents, alone and in combination with chemotherapy or CTLA4 inhibitors?

Biagio Ricciuti, MD, and colleagues published a retrospective, single-institution record review of 650 advanced NSCLC patients who were treated with ICI plus or minus CTLA-4 inhibition on a correlative intramural research study. Patients who received ICI with concurrent cytotoxic chemotherapy were excluded. They gathered clinical-pathologic information about whether patients received concurrent corticosteroids (10 mg/day or more vs. less than 10 mg/day of prednisone or the equivalent) and the reason for steroid use (oncologic vs. cancer-unrelated indications).

Importantly, they gathered information about programmed death-ligand 1 (PD-L1) tumor proportion scores and tumor mutational burden.

Among the 14.3% patients receiving prednisone 10 mg/day or more at the start of ICI therapy, progression-free survival and overall survival were significantly worse – but only among the 66 patients who needed steroids for oncologic reasons (pain, brain metastases, anorexia, cancer-associated dyspnea). Among the 27 patients who received steroids for cancer-unrelated reasons (autoimmune disease, chronic obstructive pulmonary disease, hypersensitivity pneumonitis), progression-free and overall survival were no different than for patients on prednisone 0-9 mg/day. Imbalances in PD-L1 tumor proportion scores among the groups analyzed did not clearly account for the differences in survival.

What this means in practice

The potential for great treatment outcomes with single-agent ICIs in a subset of advanced NSCLC patients, coupled with the lack of an air-tight biomarker for benefit, has changed the timing of discussions between oncologists and patients about stopping antineoplastic treatment. Since we cannot identify the patients for whom ICI use is futile, the default position has been lenient on using these expensive and potentially toxic therapies.

If verified in a multi-institutional setting, with larger numbers of NSCLC patients receiving steroids for cancer-unrelated reasons, the observations of Dr. Ricciuti and colleagues could help clinicians confidently identify the time to focus discussions on supportive care only. In patients with short survival and strong rationale for maximizing supportive care, analyses like this one could help us deliver more appropriate treatment, instead of more treatment, thereby furthering the goals of personalized cancer patient management.
 

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 recent studies that examined ways to predict important outcomes in two very different settings, acute leukemia and advanced non–small cell lung cancer (NSCLC). They share the virtue of helping cancer specialists to increase their vigilance for clinically relevant complications and situations and to educate patients and families.

VTE risk in acute leukemia

The risk of venous thromboembolism (VTE) in cancer patients depends upon multiple patient-, tumor-, anatomic-, and treatment-related factors. The Khorana score has become an accepted standard for predicting the risks of VTE and assessing the relative value of various anticoagulants in cancer patients. However, the only hematologic malignancy that is specifically listed among the primary cancer sites in the Khorana score is “lymphoma.” VTE can develop during treatment for acute leukemia, especially among patients with acute lymphoblastic leukemia (ALL).

At the 2019 annual congress of the European Hematology Association, Alejandro Lazo-Langer, MD, and his colleagues proposed a scoring system to quantify the risks of VTE based on a retrospective cohort study of more than 500 acute leukemia patients, diagnosed from 2006-2017. They identified 77 patients with a VTE event, with a median time from diagnosis to VTE of 64 days. Among 20 possible predictive factors, 3 emerged in the final multivariate model – platelet count greater than 50,000 (1 point), ALL (2 points), and prior history of VTE (3 points).

Over a period of 12 months, patients with a score of more than 3 points had a cumulative incidence of VTE of 44%, in comparison with 10.5% among patients with lower scores. They were unable to discern whether particular antineoplastic regimens or drugs enhanced the risk.

The authors proposed that, if verified in a validation cohort study, the scoring system could lead to better patient education about signs and symptoms, more intensive surveillance for high-risk patients, and preventive interventions.

What this means in practice

Although a large number of patient records were reviewed for Dr. Lazo-Langer’s study, there were just 74 ALL patients, and it is unclear whether particular treatment regimens or drugs (such as L-asparaginase in ALL) enhance risk. Further study with a validation cohort (as was performed for the Khorana score for patients with other malignancies), is warranted. The study is thought provoking, but for now, in my opinion, standard clinical vigilance, surveillance, and education regarding VTE in leukemia patients remain appropriate.

Steroid impact in NSCLC with ICI therapy

Patients with autoimmune disease and individuals requiring active treatment with steroids (prednisone at 10 mg/day or more or the equivalent) were excluded from clinical trials that led to Food and Drug Administration approval of immune checkpoint inhibitor (ICI) agents. Recently published data indicate that treatment with 10 mg or more of daily prednisone correlates with poor outcome in NSCLC patients receiving ICI therapy (J Clin Oncol. 2018;36:2872-8; J Thoracic Oncol. 2018;13:1771-5). However, at the 2019 annual meeting of the American Society of Clinical Oncology, analyses of the CancerLinQ database showed that, among NSCLC patients, autoimmune disease and treatment for autoimmune disease are surprisingly prevalent. Should oncologists refuse to treat these patients with ICI agents, alone and in combination with chemotherapy or CTLA4 inhibitors?

Biagio Ricciuti, MD, and colleagues published a retrospective, single-institution record review of 650 advanced NSCLC patients who were treated with ICI plus or minus CTLA-4 inhibition on a correlative intramural research study. Patients who received ICI with concurrent cytotoxic chemotherapy were excluded. They gathered clinical-pathologic information about whether patients received concurrent corticosteroids (10 mg/day or more vs. less than 10 mg/day of prednisone or the equivalent) and the reason for steroid use (oncologic vs. cancer-unrelated indications).

Importantly, they gathered information about programmed death-ligand 1 (PD-L1) tumor proportion scores and tumor mutational burden.

Among the 14.3% patients receiving prednisone 10 mg/day or more at the start of ICI therapy, progression-free survival and overall survival were significantly worse – but only among the 66 patients who needed steroids for oncologic reasons (pain, brain metastases, anorexia, cancer-associated dyspnea). Among the 27 patients who received steroids for cancer-unrelated reasons (autoimmune disease, chronic obstructive pulmonary disease, hypersensitivity pneumonitis), progression-free and overall survival were no different than for patients on prednisone 0-9 mg/day. Imbalances in PD-L1 tumor proportion scores among the groups analyzed did not clearly account for the differences in survival.

What this means in practice

The potential for great treatment outcomes with single-agent ICIs in a subset of advanced NSCLC patients, coupled with the lack of an air-tight biomarker for benefit, has changed the timing of discussions between oncologists and patients about stopping antineoplastic treatment. Since we cannot identify the patients for whom ICI use is futile, the default position has been lenient on using these expensive and potentially toxic therapies.

If verified in a multi-institutional setting, with larger numbers of NSCLC patients receiving steroids for cancer-unrelated reasons, the observations of Dr. Ricciuti and colleagues could help clinicians confidently identify the time to focus discussions on supportive care only. In patients with short survival and strong rationale for maximizing supportive care, analyses like this one could help us deliver more appropriate treatment, instead of more treatment, thereby furthering the goals of personalized cancer patient management.
 

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 recent studies that examined ways to predict important outcomes in two very different settings, acute leukemia and advanced non–small cell lung cancer (NSCLC). They share the virtue of helping cancer specialists to increase their vigilance for clinically relevant complications and situations and to educate patients and families.

VTE risk in acute leukemia

The risk of venous thromboembolism (VTE) in cancer patients depends upon multiple patient-, tumor-, anatomic-, and treatment-related factors. The Khorana score has become an accepted standard for predicting the risks of VTE and assessing the relative value of various anticoagulants in cancer patients. However, the only hematologic malignancy that is specifically listed among the primary cancer sites in the Khorana score is “lymphoma.” VTE can develop during treatment for acute leukemia, especially among patients with acute lymphoblastic leukemia (ALL).

At the 2019 annual congress of the European Hematology Association, Alejandro Lazo-Langer, MD, and his colleagues proposed a scoring system to quantify the risks of VTE based on a retrospective cohort study of more than 500 acute leukemia patients, diagnosed from 2006-2017. They identified 77 patients with a VTE event, with a median time from diagnosis to VTE of 64 days. Among 20 possible predictive factors, 3 emerged in the final multivariate model – platelet count greater than 50,000 (1 point), ALL (2 points), and prior history of VTE (3 points).

Over a period of 12 months, patients with a score of more than 3 points had a cumulative incidence of VTE of 44%, in comparison with 10.5% among patients with lower scores. They were unable to discern whether particular antineoplastic regimens or drugs enhanced the risk.

The authors proposed that, if verified in a validation cohort study, the scoring system could lead to better patient education about signs and symptoms, more intensive surveillance for high-risk patients, and preventive interventions.

What this means in practice

Although a large number of patient records were reviewed for Dr. Lazo-Langer’s study, there were just 74 ALL patients, and it is unclear whether particular treatment regimens or drugs (such as L-asparaginase in ALL) enhance risk. Further study with a validation cohort (as was performed for the Khorana score for patients with other malignancies), is warranted. The study is thought provoking, but for now, in my opinion, standard clinical vigilance, surveillance, and education regarding VTE in leukemia patients remain appropriate.

Steroid impact in NSCLC with ICI therapy

Patients with autoimmune disease and individuals requiring active treatment with steroids (prednisone at 10 mg/day or more or the equivalent) were excluded from clinical trials that led to Food and Drug Administration approval of immune checkpoint inhibitor (ICI) agents. Recently published data indicate that treatment with 10 mg or more of daily prednisone correlates with poor outcome in NSCLC patients receiving ICI therapy (J Clin Oncol. 2018;36:2872-8; J Thoracic Oncol. 2018;13:1771-5). However, at the 2019 annual meeting of the American Society of Clinical Oncology, analyses of the CancerLinQ database showed that, among NSCLC patients, autoimmune disease and treatment for autoimmune disease are surprisingly prevalent. Should oncologists refuse to treat these patients with ICI agents, alone and in combination with chemotherapy or CTLA4 inhibitors?

Biagio Ricciuti, MD, and colleagues published a retrospective, single-institution record review of 650 advanced NSCLC patients who were treated with ICI plus or minus CTLA-4 inhibition on a correlative intramural research study. Patients who received ICI with concurrent cytotoxic chemotherapy were excluded. They gathered clinical-pathologic information about whether patients received concurrent corticosteroids (10 mg/day or more vs. less than 10 mg/day of prednisone or the equivalent) and the reason for steroid use (oncologic vs. cancer-unrelated indications).

Importantly, they gathered information about programmed death-ligand 1 (PD-L1) tumor proportion scores and tumor mutational burden.

Among the 14.3% patients receiving prednisone 10 mg/day or more at the start of ICI therapy, progression-free survival and overall survival were significantly worse – but only among the 66 patients who needed steroids for oncologic reasons (pain, brain metastases, anorexia, cancer-associated dyspnea). Among the 27 patients who received steroids for cancer-unrelated reasons (autoimmune disease, chronic obstructive pulmonary disease, hypersensitivity pneumonitis), progression-free and overall survival were no different than for patients on prednisone 0-9 mg/day. Imbalances in PD-L1 tumor proportion scores among the groups analyzed did not clearly account for the differences in survival.

What this means in practice

The potential for great treatment outcomes with single-agent ICIs in a subset of advanced NSCLC patients, coupled with the lack of an air-tight biomarker for benefit, has changed the timing of discussions between oncologists and patients about stopping antineoplastic treatment. Since we cannot identify the patients for whom ICI use is futile, the default position has been lenient on using these expensive and potentially toxic therapies.

If verified in a multi-institutional setting, with larger numbers of NSCLC patients receiving steroids for cancer-unrelated reasons, the observations of Dr. Ricciuti and colleagues could help clinicians confidently identify the time to focus discussions on supportive care only. In patients with short survival and strong rationale for maximizing supportive care, analyses like this one could help us deliver more appropriate treatment, instead of more treatment, thereby furthering the goals of personalized cancer patient management.
 

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.