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Responses to Anti–PD-1/PD-L1 Immunotherapy in Patients With MSS Solid Tumors and High Tumor Mutational Burden


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In a single-institution study reported in JAMA Oncology, Valero et al found that response rates to anti–PD-1 or anti–PD-L1 treatments in patients with microsatellite-stable (MSS) solid tumors were generally higher among those with high tumor mutational burden (TMB) defined as ≥ 10 mutations/megabase. However, the association varied among cancer types, and no clear association with survival outcomes was observed.

Study Details

The study included 1,678 patients with 16 cancer types from Memorial Sloan Kettering Cancer Center who received at least one dose of anti–PD-1/PD-L1 immunotherapy between January 2015 and December 2018. Tumors were analyzed with next-generation sequencing.

The data from this cohort study validate the finding of generally higher response rates following immune checkpoint inhibitor therapy for tumors with TMB of 10 or more mutations per megabase, across multiple cancer types. However, the predictive value of a universal numerical threshold for TMB-high was limited….
— Valero et al

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Key Findings

Using the conventional cutoff of 10 mutations/megabase, 416 tumors (25%) were categorized as having high TMB. Among cancer types, the proportion of TMB-high tumors ranged from 0% of kidney cancers to 53% of melanomas, with intermediate values in, for example, esophageal cancer (9%), colorectal cancer (14%), bladder cancer (32%), and non–small cell lung cancer (31%). 

Among all tumors, objective response was observed in 41% of patients with high TMB vs 21% of those with low TMB, although TMB-high tumors did not have higher response rates in 5 of the 16 cancer types (including gastric, hepatobiliary, and pancreatic cancers and mesothelioma).

In the entire cohort, response rates increased with higher TMB cutoffs (odds ratio [OR] = 1.04 per mutation/megabase, 95% confidence interval [CI] =1.02–1.05), including the 41% response rate for ≥ 10 mutations up to 56% for TMB > 18 mutations (the highest TMB decile). Response rates also increased with TMB percentile rank within cancer types (OR = 1.01 per percentile increase, 95% CI = 1.01–1.02), with the finding suggesting that the association is not due only to higher response rates in tumor types with higher TMB (eg, melanoma and lung cancer).

In an analysis using tissue-specific cutoffs for high TMB defined by the investigators, response rates also increased with TMB percentile within cancer type. Using the cancer-specific cutoffs, 457 tumors (27%) were categorized as high TMB. Response rates within cancer type ranged from 4% for pancreatic cancer to 70% for melanoma. Cancer-specific cutoffs were associated with higher response rates for TMB-high vs TMB-low tumors in 14 of 16 cancer types.

Neither progression-free survival nor overall survival was consistently associated with high TMB defined as ≥ 10 mutations/megabase or using tissue-specific cutpoints across cancer types.  

The investigators concluded, “The data from this cohort study validate the finding of generally higher response rates following immune checkpoint inhibitor therapy for tumors with TMB of 10 or more mutations per megabase, across multiple cancer types. However, the predictive value of a universal numerical threshold for TMB-high was limited, owing to variability across cancer types and unclear associations with survival outcomes. Further investigation will help define cancer type–specific TMB cutoffs to guide decision-making.”

Luc G.T. Morris, MD, MSc, of the Department of Surgery, Memorial Sloan Kettering Cancer Center, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Fundación Alfonso Martín Escudero, National Institutes of Health, Sebastian Nativo Fund, Jayme and Peter Flowers Fund, and National Cancer Institute. For full disclosures of the study authors, visit jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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