Meeting News

High mutation burden improves nivolumab efficacy for small cell lung cancer

Naiyer Rizvi

Nivolumab with or without ipilimumab demonstrated greater efficacy among patients with small cell lung cancer who had a high mutation burden, according to results of an exploratory analysis from CheckMate 032 presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.

“Patients with small cell lung cancer have limited treatment options, and it’s a very aggressive cancer,” Naiyer Rizvi, MD, director of thoracic oncology and director of immunotherapeutics for the division of hematology and oncology at Columbia University Medical Center, said during his presentation. “Chemotherapy resistance is rapid.”

As HemOnc Today previously reported, first data from CheckMate 032 showed a 2-year OS rate of 26% with nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb), and 14% with nivolumab alone.

“These data were really encouraging and certainly addressed an unmet need in the United States,” Rizvi said. “The National Comprehensive Cancer Network deemed the data important enough to include in guidelines for the treatment of small cell lung cancer in the United States.”

Because not all patients with small cell lung cancer respond to nivolumab with or without ipilimumab, researchers seek to identify a biomarker that can help predict response. However, 82% of patients with small cell lung cancer do not express PD-L1, a biomarker that has predicted response to immunotherapy in other disease states.

“This remains a puzzling factor considering small cell lung cancer has other similarities to non-small cell lung cancer,” Rizvi said.

Of 401 patients in the intent-to-treat population of CheckMate 032, 211 (53%) had evaluable tumor mutation burden data gathered from whole-exome sequencing on tumor and matched blood samples. This cohort included 133 patients (median age, 63 years; 59% men) treated with nivolumab alone and 78 (median age, 65 years; 67% men) treated with nivolumab plus ipilimumab.

Researchers characterized patients’ tumor mutation burden — defined as total number of nonsynonymous somatic mutations — as low, medium or high.

Regardless of treatment arm, a greater proportion of patients with high vs. medium or low mutation burden demonstrated an overall response (nivolumab, 21.3% vs. 6.8% vs. 4.8%; combination, 46.2% vs. 16% vs. 22.2%), achieved 1-year PFS (nivolumab, 21.2% vs. 3.1% vs. not calculable; combination, 30% vs. 8% vs. 6.2%) and achieved 1-year OS (nivolumab, 35.2% vs. 26% vs. 22.1%; combination, 62.4% vs. 19.6% vs. 23.4%).

“It’s clear that patients with the upper-third highest mutation burden, irrespective of PD-L1 expression, have improved activity measured by response, PFS and OS, for monotherapy and more robustly with nivolumab plus ipilimumab,” Rizvi said. “This is the first study to evaluate the impact of tumor mutation burden on outcomes with this combination immunotherapy, and it supports the relative contribution of CTLA-4 on PD-1.

“This opens the door to a lot of future analyses to determine the optimal tumor mutation burden cutoff, whether we can extrapolate these data to more targeted gene panels that will give the same predictive capacity with a more limited and real-time set of next-generation sequencing, and whether we can do this off cell-free DNA with blood,” Rizvi added. “There are a lot of questions, but tumor mutation burden is a relevant predictive biomarker for lung cancers, and now, we can say it is for small cell and combination immunotherapy.” – by Alexandra Todak

Reference: Antonia S, et al. Abstract OA 07.03a. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Oct. 15-18, 2017; Yokohama, Japan.

Disclosures: Rizvi reports consultant roles with AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis and Pfizer; a co-founder and shareholder role with Gritstone Oncology; scientific advisory board roles with Neogenomics and Nilogen Oncosystems, and a board of directors role with ARMO BioSciences. Please see the abstract for a list of all other authors’ relevant financial disclosures.

Naiyer Rizvi

Nivolumab with or without ipilimumab demonstrated greater efficacy among patients with small cell lung cancer who had a high mutation burden, according to results of an exploratory analysis from CheckMate 032 presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.

“Patients with small cell lung cancer have limited treatment options, and it’s a very aggressive cancer,” Naiyer Rizvi, MD, director of thoracic oncology and director of immunotherapeutics for the division of hematology and oncology at Columbia University Medical Center, said during his presentation. “Chemotherapy resistance is rapid.”

As HemOnc Today previously reported, first data from CheckMate 032 showed a 2-year OS rate of 26% with nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb), and 14% with nivolumab alone.

“These data were really encouraging and certainly addressed an unmet need in the United States,” Rizvi said. “The National Comprehensive Cancer Network deemed the data important enough to include in guidelines for the treatment of small cell lung cancer in the United States.”

Because not all patients with small cell lung cancer respond to nivolumab with or without ipilimumab, researchers seek to identify a biomarker that can help predict response. However, 82% of patients with small cell lung cancer do not express PD-L1, a biomarker that has predicted response to immunotherapy in other disease states.

“This remains a puzzling factor considering small cell lung cancer has other similarities to non-small cell lung cancer,” Rizvi said.

Of 401 patients in the intent-to-treat population of CheckMate 032, 211 (53%) had evaluable tumor mutation burden data gathered from whole-exome sequencing on tumor and matched blood samples. This cohort included 133 patients (median age, 63 years; 59% men) treated with nivolumab alone and 78 (median age, 65 years; 67% men) treated with nivolumab plus ipilimumab.

Researchers characterized patients’ tumor mutation burden — defined as total number of nonsynonymous somatic mutations — as low, medium or high.

Regardless of treatment arm, a greater proportion of patients with high vs. medium or low mutation burden demonstrated an overall response (nivolumab, 21.3% vs. 6.8% vs. 4.8%; combination, 46.2% vs. 16% vs. 22.2%), achieved 1-year PFS (nivolumab, 21.2% vs. 3.1% vs. not calculable; combination, 30% vs. 8% vs. 6.2%) and achieved 1-year OS (nivolumab, 35.2% vs. 26% vs. 22.1%; combination, 62.4% vs. 19.6% vs. 23.4%).

“It’s clear that patients with the upper-third highest mutation burden, irrespective of PD-L1 expression, have improved activity measured by response, PFS and OS, for monotherapy and more robustly with nivolumab plus ipilimumab,” Rizvi said. “This is the first study to evaluate the impact of tumor mutation burden on outcomes with this combination immunotherapy, and it supports the relative contribution of CTLA-4 on PD-1.

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“This opens the door to a lot of future analyses to determine the optimal tumor mutation burden cutoff, whether we can extrapolate these data to more targeted gene panels that will give the same predictive capacity with a more limited and real-time set of next-generation sequencing, and whether we can do this off cell-free DNA with blood,” Rizvi added. “There are a lot of questions, but tumor mutation burden is a relevant predictive biomarker for lung cancers, and now, we can say it is for small cell and combination immunotherapy.” – by Alexandra Todak

Reference: Antonia S, et al. Abstract OA 07.03a. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Oct. 15-18, 2017; Yokohama, Japan.

Disclosures: Rizvi reports consultant roles with AbbVie, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Merck, Novartis and Pfizer; a co-founder and shareholder role with Gritstone Oncology; scientific advisory board roles with Neogenomics and Nilogen Oncosystems, and a board of directors role with ARMO BioSciences. Please see the abstract for a list of all other authors’ relevant financial disclosures.