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. 2021 May 1;7(5):739-743.
doi: 10.1001/jamaoncol.2020.7684.

Response Rates to Anti-PD-1 Immunotherapy in Microsatellite-Stable Solid Tumors With 10 or More Mutations per Megabase

Cristina Valero  1 , Mark Lee  1 , Douglas Hoen  1 , Ahmet Zehir  2   3 , Michael F Berger  2   3 , Venkatraman E Seshan  4 , Timothy A Chan  5   6   7 , Luc G T Morris  1
Affiliations

Response Rates to Anti-PD-1 Immunotherapy in Microsatellite-Stable Solid Tumors With 10 or More Mutations per Megabase

Cristina Valero et al. JAMA Oncol. .

Abstract

Importance: In June 2020, the US Food and Drug Administration approved the anti-programmed cell death 1 drug pembrolizumab for patients with malignant solid tumors of any histologic type with high tumor mutational burden (TMB; ≥10 mutations per megabase). The predictive value of this universal cutoff for high TMB is not well understood.

Objective: To examine the performance of a universal definition of high TMB in an independent cohort of patients with solid tumors treated with immune checkpoint inhibitors.

Design, setting, and participants: This retrospective cohort study included 1678 patients at a single cancer referral center treated with immune checkpoint inhibitors from January 1, 2015, to December 31, 2018. Patients had 16 different cancer types and were treated with anti-programmed cell death 1 or programmed cell death ligand-1 immunotherapy. Tumors underwent next-generation sequencing.

Exposures: At least 1 dose of immune checkpoint inhibitors.

Main outcomes and measures: Best overall response to immune checkpoint inhibitor therapy. The hypothesis tested was formulated after data collection and prior to analysis.

Results: Of 1678 patients, 924 (55%) were male, and the median age was 64 years (interquartile range, 55-71 years). Using the universal cutoff of 10 mutations per megabase, 416 tumors (25%) were categorized as having high TMB. Across cancer types, the proportion of TMB-high tumors ranged from 0% of kidney cancers to 53% of melanomas (113 of 214). Tumors categorized as TMB-high had higher response rates compared with TMB-low tumors in only 11 of 16 cancer types. In the entire cohort, response rates increased with higher cutoffs for TMB-high categorization, reaching 41% (169 of 416) for TMB more than 10 and 56% (90 of 161) for TMB more than 18, the highest TMB decile. Response rates also increased with TMB percentile within cancer type. Using cancer-specific cutoffs, 457 tumors (27%) were categorized as TMB-high. Response rates within cancer type ranged from 4% for pancreatic cancer (1 of 26) to 70% for melanoma (46 of 66). Cancer-specific cutoffs were associated with numerically higher response rates for TMB-high compared with TMB-low tumors in 14 of 16 cancer types.

Conclusions and relevance: 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Hoen reported receiving funding from AstraZeneca outside the submitted work. Dr Zehir reported receiving honoraria from Illumina outside the submitted work. Dr Berger reported receiving personal fees from Roche outside the submitted work. Dr Chan reported receiving grant funding from Bristol Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai; serving as an advisor for Bristol Myers Squibb, Illumina, Eisai, and An2H; holding equity in An2H; receiving royalties from PGDX; and being a cofounder of and holding equity in Gritstone Oncology during the conduct of the study. Dr Morris reported receiving laboratory research funding from AstraZeneca outside the submitted work. Drs Chan and Morris are inventors on a patent held by Memorial Sloan Kettering related to the use of tumor mutational burden in cancer immunotherapy. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Response Rates Based on a Universal Cutoff for High Tumor Mutational Burden (TMB), by Cancer Type
Tumor mutational burden stratified into high and low using 10 mutations per megabase as cutoff for all cancer types. Cancer types with fewer than 5 cases in either the low TMB (TMB-L) or high TMB (TMB-H) group are not shown (see the Table for information on response rates for these cancer types). NSCLC indicates non–small cell lung cancer; SCLC, small cell lung cancer.
Figure 2.
Figure 2.. Response Rates Based on Tumor Mutational Burden (TMB) in the Entire Cohort
A, TMB categorized using universal numerical cutoffs, with increments containing a minimum of 5% of patients in the cohort. B, TMB categorized using cancer type-specific cutoffs, based on the percentile rank of a tumor’s TMB within the corresponding cancer type. OR indicates odds ratio.
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References

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