Tumor mutational load predicts survival after immunotherapy across multiple cancer types

Abstract

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

Conflict of interest statement

Competing Interests Statement

RMS, TAC and LGTM are inventors on a provisional patent application (62/569,053) filed by MSK, relating to the use of TMB in cancer immunotherapy.MDH, NAR and TAC are inventors on a PCT patent application (PCT/US2015/062208) filed by MSK, relating to the use of TMB in lung cancer immunotherapy.MSK and the inventors may receive a share of commercialization revenue from license agreements relating to these patent applications. CHL received research funding from Eisai, BMS, Exelixis, Pfizer, Calithera and consulting fees from Exelixis and Eisai. ANS has received research support from Bristol Myers Squibb, Immunocore, Astra-Zeneca, Xcovery and serves on the advisory board for Bristol Myers Squibb, Immunocore, Castle Biosciences; he also receives royalties from UpToDate. MDH receives research funding from Bristol-Myers Squibb; is paid consultant to Merck, Bristol-Myers Squibb, AztraZeneca, Genentech/Roche, Janssen, Nektar, Syndax, Mirati, and Shattuck Labs. YYJ received research funding from Boehringer Ingelheim, Bayer, Genentech/Roche, Bristol-Myers Squibb, Eli Lilly, Merck and served on advisory boards for Merck Serono, Bristol-Myers Squibb, Eli Lilly, Pfizer, Bayer, Imugene, Merck. SB currently works for Flatiron Health which is a for-profit company. RJM received research support from Pfizer, Genentech/Roche, Bristol Myers Squibb and Eisai and consulting fees from Pfizer, Genentech/Roche, Merck, Incyte, Novartis, Eisai and Exelixis. MHV received commercial research grants from Bristol-Myers Squibb andGenentech/Roche; honoraria from Novartis; travel/accommodation from Eisai, Novartis and Takeda; consultant/advisory board member for- Alexion Pharmaceuticals, Bayer, Calithera Biosciences, Corvus Pharmaceuticals, Exelixis, Eisai,GlaxoSmithKline, Natera; Novartis and Pfizer.

JR receives consulting fees from Merck, AstraZeneca, BMS, EMD-Serono, Roche/Genentech, Sanofi, Seattle Genetics, Agensys, Bayer, Inovio, Lilly, Adicet Bio, Sensei, Chugai, and Inovio. BHB receives consulting fees from Genentech. GJR received research funding from Novartis, Roche/Genentech, Millennium, GlaxoSmithKline, Pfizer, Infinity Pharmaceuticals, Takeda and received travel expense compensation from Merck. ALH receives research funding from Eisai, BMS, Kura Oncology, AstraZeneca, Genentech Roche, Celldex, Pfizer, Lilly, Bayer; consulting fees from BMS, Merck, Novartis, AstraZeneca, Regeneron, Sanofi Aventis, Sun Pharmaceuticals, Eisai, Genentech/Roche, Genzyme, Ayala Pharmaceuticals; and travel fees from Ignyta, and Kura Oncology. CAB receives research funding from Merck, Amgen, Bristol Myers Squibb. JDW was a consultant for Adaptive Biotech, Amgen, Apricity, Array BioPharma, Ascentage Pharma, Beigene, Bristol Myers Squibb, Celgene, Chugai, Elucida, Eli Lilly, F Star, Genentech, Imvaq, Kleo Pharma, MedImmune, Merck, Neon Therapuetics, Ono, Polaris Pharma, Polynoma, Psioxus, Puretech, Recepta, Trienza, Sellas Life Sciences, Serametri,; Surface Oncology, and Syndax; Research support from Bristol Myers Squibb, Medimmune, Merck Pharmaceutical, and Genentech; and Equity in Potenza Therapeutics, Tizona Pharmaceuticals, Adaptive Biotechnologies, Elucida, Imvaq, Beigene, and Trienza.JB is on the Board of Directors for Varian Medical Systems, Bristol-Myers Squibb and Foghorn, and is a past board member of Grail, Aura Biosciences and Infinity Pharmaceuticals.He has performed consulting and/or advisory work for Grail, PMV Pharma, ApoGen, Juno, Roche, Lilly, Novartis and Northern Biologics.He has stock or other ownership interests in PMV Pharma, Grail, Juno, Varian, Foghorn, Aura, Infinity, ApoGen, as well Tango and Venthera, for which is a co-founder.He has previously received Honoraria and/or Travel Expenses from Roche, Novartis, and Lilly.GYK received research funding and consulting fee from AstraZeneca, Bristol-Myers Squibb, and Merck. IKM reports research funding from GE and consulting/speaker fees from Agios Pharmaceuticals, Debiopharm Group, Roche, Merck, Puma Biotechnology, and Deciphera Pharmaceuticals. WDT reports personal fees from Eli Lilly, personal fees from EMD Serono, personal fees from Novartis, personal fees from Eisai, personal fees from Janssen, personal fees from Immune Design, personal fees from Adaptimmune, personal fees from Daiichi Sankyo, personal fees from Blueprint, personal fees from Loxo, personal fees from GlaxoSmithKline, personal fees from Agios Pharmaceuticals,from Plexxikon Pharmaceuticals,outside the submitted work;In addition, WDT has a patent Companion Diagnostic for CDK4 inhibitors - 14/854,329 pending to MSKCC/SKI, and a patent Methods of Treating Metastatic Sarcoma Using Talimogene Laherparepvec (T-Vec) and Pembrolizumab Combination Therapy- 62/671,625 pending to MSKCC/SKI and Scientific Advisory Board - Certis Oncology Solutions, Stock OwnershipÐcientific Advisory Board - Atropos Therapeutics, Stock Ownership. CMR has consulted on oncology drug development with AbbVie, Amgen, Ascentage, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Harpoon, Loxo, Pharmamar, and Seattle Genetics. AZ, DAB, RS, SMK, GI, DFB, RJW, PR, NL, PHG, TJK, LMD, PR, AAH, HIS, CEA, CAK, JEC, SD, RPD, NHS, ZKS, MMT,HAA,RY, LS have no conflicts of interest to report. VT is a co-founder and consultant for BluRock Therapeutics. NAR received consulting fees from Merck, AstraZeneca, Roche, Bristol-Myers Squibb, Novartis, Pfizer, Lilly, Abbvie, Merck KGaA, Regeneron, Janssen; is a cofounder and shareholder in Gritstone Oncology and serves on the advisory board or Neogenomics, OncoMed, and Bellcum.ML has received ad hoc advisory board compensation from AstraZeneca, Bristol-Myers Squibb, Takeda, and Bayer, and research support from LOXO Oncology and Helsinn Healthcare. MFB received research support from Illumina and consulting fees from Roche. DBS received funding from Pfizer, Loxo Oncology, Illumina, Intezyne, Vivideon Therapuetics.NR receives research support from Bristol-Myers Squibb and Pfizer and speakers fees from Illumina. TAC is a co-founder of Gritstone Oncology and holds equity.TAC holds equity in An2H.TAC acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H, and Eisai. TAC has served as an advisor for Bristol-Myers Squibb, Illumina, Eisai, and An2H. LGTM received consulting fees from Rakuten Aspyrian and speaker fees from Physician Educational Resources.

Figures

Figure 1:. Effect of Mutational Load on Overall Survival after ICI Treatment.

A. Kaplan-Meier curves for patients with tumors falling into the depicted deciles of TMB within each histology. Overall survival is from the first dose of ICI. Two-sided log-rank p value indicated for all patients, with univariate Cox regression hazard ratio of 0.76 (95% CI 0.62–0.94) and 0.52 (95% CI 0.42–0.64) for the 10–20% and Top10% groups, respectively, compared to Bottom80% group. m, monthsB. Cox regression hazard ratios for overall survival on 1662 patients, at depicted cutoffs of TMB across all cancer subtypes. Solid black circles represent hazard ratios with p-values <.05 log rank p value>

Figure 2:. Effect of Non-synonymous Mutational Load on Overall Survival after ICI Treatment by Cancer Subtype and Drug Class.

Forest plot for all patients in the identified cohort or individual cancer subtypes.Indicated are the number of patients and hazard ratio comparing overall survival after ICI in patients in the highest 20th percentile TMB within each histology. Horizontal lines represent the 95% confidence interval. The cutoff defining top 20% of normalized mutational burden from MSK-IMPACT for each cancer type is shown, as well as the two-sided log-rank p value for the comparison of high and low mutational burden survival curves. All cancer types in analysis are displayed.