Tumor Mutation Burden Shows Promise as a Response Biomarker in Small Cell Lung Cancer


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Patients with small cell lung cancer (SCLC) and a high tumor mutation burden had a near doubling in response rate and 1-year overall survival when ipilimumab (Yervoy) was combined with nivolumab (Opdivo), vs nivolumab alone, new findings from CheckMate 032 have shown. Regardless of the treatment arm, a high tumor mutation burden predicted better outcomes, as compared with a medium or low tumor mutation burden, Naiyer -Rizvi, MD, of Columbia University Medical Center, New York, reported at the 2017 International Association for the Study of Lung Cancer (IASLC) 18th World Conference on Lung Cancer in Yokohama, Japan.1

The results from CheckMate 032 provide clear evidence supporting the power of tumor mutation burden as a biomarker, not only for nivolumab response but even more so for the combination of nivolumab and ipilimumab.
— Naiyer Rizvi, MD

In contrast to non–small cell lung cancer (NSCLC), programmed cell death ligand 1 (PD‑L1) tumor expression has not been a useful biomarker for SCLC, with most SCLC tumors being PD-L1–negative. Emerging data in NSCLC have suggested tumor mutation burden may be an important parameter of treatment response; this was further explored in SCLC. 

“The results from CheckMate 032 provide clear evidence supporting the power of tumor mutation burden as a biomarker, not only for nivolumab response, but even more so for the combination of nivolumab and ipilimumab,” Dr. Rizvi said. “This may begin to impact prescribing practice in SCLC, where a tumor mutation burden biomarker can be used to select patients for combination immunotherapy with nivolumab and ipilimumab.”

Exploratory Analysis of CheckMate 032

CheckMate 032 was a pooled analysis of nivolumab plus ipilimumab in nonrandomized and randomized cohorts of patients with solid tumors. Whole-exome sequencing was performed in tumor and matched blood samples. Tumor mutation burden was defined by the total number of nonsynonymous somatic mutations, stratified into three tertiles: low (0 to < 143), medium (143 to 247), and high (> 248).

Among the 401 patients in the intent-to-treat population, 211 (53%) had sufficient tumor for this exploratory analysis. Included in this group were 133 patients receiving nivolumab alone and 78 patients receiving nivolumab plus ipilimumab. Baseline characteristics were similar between the arms.

Doubling of Benefit With High Tumor Mutation Burden

Among patients treated with nivolumab alone, the objective response, 1-year progression-free survival, and 1-year overall survival rates were highest for the subset of patients with a high tumor mutation burden. Additionally, the researchers found that nivolumab plus ipilimumab outperformed nivolumab treatment alone in the high–tumor mutation burden subgroup.

Tumor Mutation Burden in SCLC

  • In an exploratory analysis of CheckMate 032, tumor mutation burden was evaluated as a biomarker of response to nivolumab and nivolumab plus ipilimumab.
  • In the study, 211 patients were divided into low, medium, and high tumor mutation burden tertiles.
  • Patients in the high tumor mutation burden tertile had improved response rates, 1-year progression-free survival, and overall survival.

“Optimization of the tumor mutation burden cutoff and prospective investigation of tumor mutation burden are warranted,” Dr. Rizvi added. He predicted that tumor mutation burden may be a relevant predictive biomarker not only for combination programmed cell death protein 1/cytotoxic T-lymphocyte–associated protein 4 treatment of SCLC but also for combination therapy in NSCLC as well. ■

DISCLOSURE: Dr. Rizvi is a consultant for Bristol-Myers Squib, cofounder of Gritstone Oncology, and is the co-inventor of a pending patent application related to tumor mutation burden and response to cancer immunotherapy.

REFERENCE

1. Rizvi N, Antonia S, Callahan MK, et al: Impact of tumor mutation burden on the efficacy of nivolumab or nivolumab plus ipilimumab in small cell lung cancer: An exploratory analysis of CheckMate 032. 2017 World Conference on Lung Cancer. Abstract OA 07.03a. Presented October 16, 2017.


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