Tumor mutational burden (TMB) has been correlated with response to CTLA-4 and PD-(L)1 inhibitors. We explored the association of TMB with outcomes in cohorts A through J of KEYNOTE-158, a phase II basket study of pembrolizumab monotherapy for patients (pts) with select advanced solid tumors (NCT02628067). Key eligibility criteria were progression on or intolerance to ≥ 1 line of standard therapy, ECOG PS 0 or 1, provision of a tumor sample for biomarker analysis, and either anal, biliary, cervical, endometrial, salivary, thyroid, or vulvar carcinoma, mesothelioma, a neuroendocrine tumor, or SCLC. Pts received pembrolizumab 200 mg Q3W for 35 cycles or until PD, intolerable toxicity, or physician or pt decision. TMB was assessed in FFPE tumor samples using the FoundationOne CDx™ assay. TMB-high was defined as 10 Mut/Mb. Primary study endpoint was ORR (RECIST v1.1, central review); DOR, PFS, OS, and safety were secondary endpoints. The relationship between antitumor activity and TMB was an exploratory endpoint. Of the 1032 pts with ≥26 weeks of follow-up as of 06 Dec 2018, 755 (73.2%) had evaluable TMB; of these, 120 (15.9%) were TMB-high, with 15/120 (12.5%) known to be MSI-H. Baseline characteristics were generally similar for TMB-high and low. There was low correlation between TMB and PD-L1 expression (ρ = 0.19). ORR (95% CI) was 28.3% (20.5-37.3) for TMB-high (24.8% [16.9-34.1] non–MSI-H) and 6.5% (4.7-8.7) for TMB-low. Median DOR was not reached for TMB-high or low (range 2.2+ to 28.8+ and 4.1 to 30.6+, respectively). Median (95% CI) PFS for TMB-high and low was 2.1 mo (2.1-3.7) and 2.1 mo (2.1-2.3), respectively; 12-mo rates were 24.3% and 14.0%. Median (95% CI) OS for TMB-high and low was 11.1 mo (8.1-16.1) and 13.3 mo (11.5-14.8), respectively; 12-mo rates were 48.0% and 52.9%. The safety profile was consistent with that previously observed for pembrolizumab. TMB-high was associated with higher ORR in pts with select advanced solid tumors treated with pembrolizumab monotherapy. The tail of the PFS curve favored TMB-high. These data suggest that TMB may be predictive of the efficacy of pembrolizumab monotherapy in pts with the tumor types included in KEYNOTE-158. NCT02628067, December 11, 2015. Melanie Leiby of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. A. Marabelle: Research grant / Funding (institution), principal investigator: Roche/Genentech, BMS, Merck (MSD), Pfizer, Lytix pharma, Eisai, AstraZeneca/MedImmune, Tesaro, Chugai ; Research grant / Funding (institution): MSD; Travel / Accommodation / Expenses: MSD, AstraZeneca, Roche/Genentech, BMS ; Research grant / Funding (institution), rincipal investigator, sponsor Unicancer; ACSE NIVOLUMAB/NCT03012581 : INCa, Ligue contre le Cancer & BMS; Research grant / Funding (institution), principal investigator, sponsor Leon Berard Cancer Center; ISIJX/NCT02977156: Transgene; Research grant / Funding (institution), principal investigator, sponsor Gustave Roussy; NIVIPIT/NCT02857569 : BMS; Research grant / Funding (institution), principal investigator, sponsor Gustave Roussy; PEMBIB/NCT02856425 : Boehringer Ingelheim; Research grant / Funding (institution): Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi ; Non-remunerated activity/ies, drug supply: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche ; Advisory / Consultancy: GSK, AstraZeneca; Advisory / Consultancy: Oncovir, Inc.; Advisory / Consultancy: Innate Pharma, Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, Bayer, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncovir, Pfizer, Seattle Genetics, Flexus Bio, Roche/Genentech, OSE immunotherapeutics, Transgene, Gritstone, ; Speaker Bureau / Expert testimony: Roche/Genentech, BMS, Merck (MSD), Merck Serono, AstraZeneca/MedImmune, Amgen, Sanofi ; Advisory / Consultancy: Roche, Pierre Fabre, Onxeo, EISAI, Bayer, Genticel, Rigontec, Daiichi Sankyo, Imaxio, Sanofi, BioNTech, Corvus, GLG, Deerfield, Guidepoint Global, Edimark, System Analytics, imCheck, Sotio, Bioncotech, Molecular Partners, Pillar Partners, Boehringer Inge; Shareholder / Stockholder / Stock options: Pegascy SAS (Gustave Roussy Spin Off for Drug Repositioning) ; Research grant / Funding (institution): Merus, BMS, Boehringer Ingelheim, Transgene, Fondation MSD Avenir; Officer / Board of Directors, supervisory board member: Gustave Roussy Foundation; Advisory / Consultancy, steering committee of the immuno-oncology task force: Unicancer; Research grant / Funding (institution), sub-investigator of clinical trials: Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, AstraZeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol; Licensing / Royalties, Patent Issued (not licensed yet) : “Humanized and Chimeric Monoclonal Antibodies to CD81”, Stanford Office of Technology Licensing, 3000 El Camino Real, Bldg. 5, Suite 300, Palo Alto, CA 94306-2100. U.S. Application Serial No. 62/351,054. M.G. Fakih: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Amgen; Advisory / Consultancy: Array; Advisory / Consultancy: Bayer; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Novartis; Research grant / Funding (institution): MSD. J. Lopez: Advisory / Consultancy: Genmab; Advisory / Consultancy: Novartis; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Basilea. M. Shah: Research grant / Funding...