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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.

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Fig. 1: Effect of mutational load on overall survival after ICI treatment.
Fig. 2: Effect of nonsynonymous mutational load on overall survival after ICI treatment, by cancer subtype and drug class.

Data availability

Data necessary to reproduce the figures are provided in Supplementary Data. All data are publicly available at http://www.cbioportal.org/study?id=tmb_mskcc_2018.

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Acknowledgements

We gratefully acknowledge the patients in this study and their families. We thank M. Gonen for statistical advice. We thank members of the Molecular Diagnostics Service in the Department of Pathology and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology. We acknowledge funding sources, including the AACR-AstraZeneca Immunotherapy Fellowship (R.M.S.), Pershing Square Sohn Cancer Research grant (T.A.C.), the PaineWebber Chair (T.A.C.), Stand Up To Cancer (T.A.C.), NIH R01 CA205426, the STARR Cancer Consortium (T.A.C.), NCI R35 CA232097 (T.A.C.), Precision Immunotherapy Kidney Cancer Fund (T.A.C., R.J.M.), The Frederick Adler Fund, Cycle for Survival, NIH K08 DE024774 and R01 DE027738 (L.G.T.M.), and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748).

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Authors

Contributions

R.M.S., R.S., T.A.C., N.R. and L.G.T.M. performed the analyses. C.-H.L., A.N.S., M.D.H., Y.Y.J., D.A.B., S.M.K. and E.J.J. provided clinical annotations. A.Z., M.F.B., D.B.S., M.L. and J.B. established the assays and coordinated data collection. C.-H.L., A.N.S., M.D.H., Y.Y.J., R.J.M., G.J.R., C.A.B., S.B., P.R., A.O., H.A.A., J.R., D.F.B., A.A.H., B.H.B., M.H.V., C.M.R., H.I.S., A.L.H., D.G.P., N.L., R.J.W., V.T., P.H.G., C.W.B., L.M.D., I.K.M., J.E.C., R.Y., N.H.S., R.P.D., L.S., J.D.W., C.E.A., Z.K.S., W.D.T., M.M.G., N.A.R., S.P.D., J.B., P.R., G.Y.K., T.J.K., C.A.K., G.I. and D.B.S. contributed to sample acquisition and patient recruitment. L.G.T.M., D.B.S., N.R. and T.A.C. supervised the study. L.G.T.M., T.A.C., C.-H.L., A.N.S., M.D.H. and R.M.S. wrote the manuscript with contributions from all authors.

Corresponding authors

Correspondence to David B. Solit or Timothy A. Chan or Luc G. T. Morris.

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Competing interests

R.M.S., T.A.C. and L.G.T.M. are inventors on a provisional patent application (62/569,053) filed by Memorial Sloan Kettering (MSK) relating to the use of TMB in cancer immunotherapy. M.D.H., N.A.R. and T.A.C. 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. C.-H.L. received research funding from Eisai, BMS, Exelixis, Pfizer and Calithera, and consulting fees from Exelixis and Eisai. A.N.S. has received research support from Bristol Myers Squibb, Immunocore, Astra-Zeneca and Xcovery and serves on the advisory board for Bristol Myers Squibb, Immunocore and Castle Biosciences; he also receives royalties from UpToDate. M.D.H. receives research funding from Bristol-Myers Squibb and is a paid consultant to Merck, Bristol-Myers Squibb, AztraZeneca, Genentech/Roche, Janssen, Nektar, Syndax, Mirati and Shattuck Labs. Y.Y.J. received research funding from Boehringer Ingelheim, Bayer, Genentech/Roche, Bristol-Myers Squibb, Eli Lilly and Merck, and served on advisory boards for Merck Serono, Bristol-Myers Squibb, Eli Lilly, Pfizer, Bayer, Imugene and Merck. S.B. currently works for Flatiron Health, which is a for-profit company. R.J.M. 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. M.H.V. received commercial research grants from Bristol-Myers Squibb and Genentech/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. J.R. receives consulting fees from Merck, AstraZeneca, Bristol-Myers Squibb, EMD-Serono, Roche/Genentech, Sanofi, Seattle Genetics, Agensys, Bayer, Inovio, Lilly, Adicet Bio, Sensei, Chugai and Inovio. B.H.B. receives consulting fees from Genentech. G.J.R. received research funding from Novartis, Roche/Genentech, Millennium, GlaxoSmithKline, Pfizer, Infinity Pharmaceuticals and Takeda, and received travel expense compensation from Merck. A.L.H. receives research funding from Eisai, Bristol-Myers Squibb, Kura Oncology, AstraZeneca, Genentech Roche, Celldex, Pfizer, Lilly and Bayer; consulting fees from Bristol-Myers Squibb, Merck, Novartis, AstraZeneca, Regeneron, Sanofi Aventis, Sun Pharmaceuticals, Eisai, Genentech/Roche, Genzyme and Ayala Pharmaceuticals; and travel fees from Ignyta and Kura Oncology. C.A.B. receives research funding from Merck, Amgen and Bristol-Myers Squibb. J.D.W. 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; received research support from Bristol-Myers Squibb, Medimmune, Merck Pharmaceutical, and Genentech; and holds equity in Potenza Therapeutics, Tizona Pharmaceuticals, Adaptive Biotechnologies, Elucida, Imvaq, Beigene and Trienza. J.B. 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 and ApoGen, as well Tango and Venthera, for which he is a cofounder. He has previously received honoraria and/or travel expenses from Roche, Novartis and Lilly. G.Y.K. received research funding and consulting fees from AstraZeneca, Bristol-Myers Squibb and Merck. I.K.M. reports research funding from GE and consulting/speaker fees from Agios Pharmaceuticals, Debiopharm Group, Roche, Merck, Puma Biotechnology and Deciphera Pharmaceuticals. W.D.T. 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 and personal fees from Agios Pharmaceuticals and from Plexxikon Pharmaceuticals, outside the submitted work. In addition, W.D.T. 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 ownership; Scientific Advisory Board—Atropos Therapeutics, stock ownership. C.M.R. has consulted on oncology drug development with AbbVie, Amgen, Ascentage, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Genentech/Roche, Harpoon, Loxo, Pharmamar and Seattle Genetics. V.T. is a cofounder and consultant for BluRock Therapeutics. N.A.R. received consulting fees from Merck, AstraZeneca, Roche, Bristol-Myers Squibb, Novartis, Pfizer, Lilly, Abbvie, Merck KGaA, Regeneron and Janssen; is a cofounder and shareholder in Gritstone Oncology; and serves on the advisory board or Neogenomics, OncoMed and Bellcum. M.L. has received ad hoc advisory board compensation from AstraZeneca, Bristol-Myers Squibb, Takeda and Bayer, and research support from LOXO Oncology and Helsinn Healthcare. M.F.B. received research support from Illumina and consulting fees from Roche. D.B.S. received honoraria/consulted for Pfizer, Loxo Oncology, Illumina, Intezyne and Vivideon Therapuetics. N.R. receives research support from Bristol-Myers Squibb and Pfizer and speakers fees from Illumina. T.A.C. is a cofounder of Gritstone Oncology and holds equity. T.A.C. holds equity in An2H. T.A.C. acknowledges grant funding from Bristol-Myers Squibb, AstraZeneca, Illumina, Pfizer, An2H and Eisai. T.A.C. has served as an advisor for Bristol-Myers Squibb, Illumina, Eisai and An2H. MSK has licensed the use of TMB for the identification of patients that benefit from immune checkpoint therapy to PGDx. MSK and T.A.C. receive royalties as part of this licensing agreement. L.G.T.M. received consulting fees from Rakuten Aspyrian and speaker fees from Physician Educational Resources.

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Supplementary Figures 1–11 and Supplementary Tables 1 and 2

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Supplementary Data

Data file containing patient-level data for ICI- and non-ICI-treated patients

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Samstein, R.M., Lee, CH., Shoushtari, A.N. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet 51, 202–206 (2019). https://doi.org/10.1038/s41588-018-0312-8

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