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Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.
Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).
A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).
In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
Details of CheckMate 9LA
CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.
The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.
If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.
Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.
The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
Results prompt FDA approval
Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).
With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).
Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.
One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.
Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.
Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.
Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.
Challenges to overcome
In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.
Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.
With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).
Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
Better by design
In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.
Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.
Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.
Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.
Longer follow-up needed
In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.
As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.
It would be ideal to know whether the tail of the OS curve will flatten out.
Do the best you can
Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.
In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.
Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Reck M et al. ASCO 2020, Abstract 9501.
Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.
Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).
A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).
In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
Details of CheckMate 9LA
CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.
The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.
If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.
Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.
The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
Results prompt FDA approval
Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).
With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).
Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.
One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.
Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.
Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.
Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.
Challenges to overcome
In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.
Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.
With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).
Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
Better by design
In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.
Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.
Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.
Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.
Longer follow-up needed
In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.
As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.
It would be ideal to know whether the tail of the OS curve will flatten out.
Do the best you can
Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.
In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.
Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Reck M et al. ASCO 2020, Abstract 9501.
Data from the CheckMate 9LA study suggest the combination amplifies the rapid response expected from chemotherapy and the long-term benefit from immunotherapy. Furthermore, the very limited exposure to chemotherapy appears to mitigate long-term risks.
Martin Reck, MD, PhD, of LungenClinic Grosshansdorf in Germany, reported the data as part of the American Society of Clinical Oncology virtual scientific program (Abstract 9501).
A prior trial, CheckMate 227, demonstrated that nivolumab plus ipilimumab improved overall survival (OS) and durability of response in comparison with conventional chemotherapy in advanced NSCLC, regardless of PD-L1 expression (N Engl J Med 2019; 381:2020-31).
In CheckMate 9LA, researchers tested whether adding a limited course of chemotherapy – just two cycles – could improve outcomes further. Dr. Reck reported that, at the first preplanned interim analysis, the combination met its primary goal of improving OS as well as meeting multiple secondary endpoints.
Details of CheckMate 9LA
CheckMate 9LA included 719 treatment-naive patients with histologically confirmed stage IV or recurrent NSCLC and no known sensitizing alterations in EGFR or ALK. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.
Patients received either nivolumab plus ipilimumab at standard NSCLC doses plus two cycles of chemotherapy or chemotherapy alone for four cycles.
The chemotherapy regimen was tailored by histology. Pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance, was administered to patients with non-squamous histology. Paclitaxel plus carboplatin was chosen for patients with squamous disease.
If there was no disease progression or unacceptable toxicity, patients receiving nivolumab plus ipilimumab could continue immunotherapy for up to 2 years.
Patients were stratified by PD-L1 expression (< 1% vs. ≥ 1%), gender, and histology (squamous vs. non-squamous). Tumor and clinical characteristics were balanced across the trial arms.
The primary endpoint was OS, with secondary endpoints of progression-free survival, objective response rate by blinded independent central review, and efficacy by PD-L1 subgroups. Exploratory endpoints included safety/tolerability.
Results prompt FDA approval
Dr. Reck and colleagues found significantly better OS with nivolumab-ipilimumab plus chemotherapy, in comparison with chemotherapy alone (hazard ratio, 0.69; P = .0006).
With longer follow-up (minimum 12.7 months), nivolumab-ipilimumab plus chemotherapy continued to provide longer OS compared with chemotherapy alone. The median OS was 15.6 months and 10.9 months, respectively (HR, 0.66).
Despite more patients receiving subsequent systemic therapy in the chemotherapy-alone arm (34% of whom eventually received an immune checkpoint inhibitor), the immunotherapy-chemotherapy arm still yielded superior OS in the overall population.
One-year OS rates were 63% in the immunotherapy arm and 47% in the chemotherapy-alone arm.
Statistically significant improvements in progression-free survival and objective response rate were seen. The median response duration was 11.3 months in the immunotherapy arm and 5.6 months in the chemotherapy-alone arm.
Benefit was consistent by all efficacy measures and in all subgroups, including by PD-L1 expression and histology.
Based on the strength of these results, in May, the Food and Drug Administration approved nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy for the frontline treatment of patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.
Challenges to overcome
In the forest plots for OS, the 70 patients who were 75 years of age and older had inferior survival with the combination regimen, compared with chemotherapy alone.
Grade 3-4 treatment-related toxicity was reported in 47% of patients in the immunotherapy arm and 38% of those in the chemotherapy-alone arm.
With nivolumab-ipilimumab plus chemotherapy, more adverse events were considered serious (25.4% vs. 15%). Furthermore, grade 3-4 adverse events led to a higher rate of treatment discontinuation in the immunotherapy arm than in the chemotherapy-alone arm (16% vs. 5%).
Although cross-trial comparisons are treacherous, in CheckMate 227, only 12% of patients receiving nivolumab plus ipilimumab stopped treatment because of a grade 3-4 adverse event.
Better by design
In the updated analysis of CheckMate 227 (ASCO 2020, Abstract 9500), the nivolumab-ipilimumab regimen showed inferior OS results for the first 6 months of treatment, with more disease progression during that time. However, at 6 months, the OS curves crossed over to become consistently superior for the immunotherapy regimen thereafter.
Platinum-based chemotherapy is thought to augment antitumor immunity by inducing immunogenic cell death, increasing tumor neoantigen expression, and disturbing the immunosuppressive tumor microenvironment that prevents immune detection.
Therefore, CheckMate 9LA incorporated a short exposure to chemotherapy for the patients receiving nivolumab-ipilimumab in an effort to attain rapid disease control and retain the durable OS benefit that was seen with dual immunotherapy in CheckMate 227.
Indeed, in CheckMate 9LA, the Kaplan-Meier curves in both the initial and follow-up OS analyses diverged early in favor of the nivolumab-ipilimumab plus chemotherapy regimen and never crossed the curve for chemotherapy alone. Progressive disease was observed in fewer patients with the immunotherapy combination than with chemotherapy alone.
Longer follow-up needed
In recent years, a large number of treatment options for stage IV NSCLC patients have emerged. In the current report of CheckMate 9LA, the OS curve extended only to 27 months.
As was noted by invited discussant Benjamin Levy, MD, of Johns Hopkins University in Baltimore, it may be premature to put the regimen of two cycles of chemotherapy plus dual checkpoint/CTLA4 blockade in its proper context until follow-up extends for 3-5 years.
It would be ideal to know whether the tail of the OS curve will flatten out.
Do the best you can
Clinical investigators have a responsibility to retain the successes of prior regimens while overcoming the challenges of adverse events. New regimens also need to be practical when applied in general oncology practice.
In 2014, the American poet Maya Angelou advised, “Do the best you can until you know better. Then, when you know better, do better.” In many regards, the immunotherapy-chemotherapy combination tested in CheckMate 9LA appears to do better than preceding regimens.
Further refinements in dose, schedule, and supportive care, as well as real-time reporting of and response to patient-reported outcomes, will likely help us build on the CheckMate 9LA regimen and do even better.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
SOURCE: Reck M et al. ASCO 2020, Abstract 9501.
FROM ASCO 2020