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Background: First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non-small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC., Methods: Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m 2 and investigator's choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m 2 for 4 cycles, then pembrolizumab plus pemetrexed for ≤31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next-generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB., Results: 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2 % (95 % CI 31.2-49.6 %), median PFS was 7.2 months (95 % CI 5.6-9.8) and median OS was 18.1 months (95 % CI 13.5-25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3-5, n = 56 [47.9 %]). Of patients with evaluable bTMB (n = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36-0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively)., Conclusions: AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.B. reports advisory roles with AbbVie, AstraZeneca, Bayer, BMS, Causalis, Merck Serono, MSD, Novartis, Roche, and Takeda and receiving research funding from Immunai, OncoHost, MSD, and AstraZeneca. D.R.A. reports personal fees/honoraria for consultancy or advisory roles and lectures from Roche, Genentech, AstraZeneca, Bristol Myers Squibb, Boehringer Ingleheim, MSD, Merck Serono, Eli Lilly, Gilead, Sanofi, Regeneron, Incyte, Pfizer, Takeda, and Novartis; and travel expenses from Roche, Bristol Myers Squibb, MSD, Sanofi, Regeneron, and Novartis. E.F. reports personal fees or honoraria for advisory roles from Abbvie, Amgen, AstraZeneca, Bayer, Bergen Bio, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffman-La Roche, GSK, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point; speaker’s bureau fees from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, F. Hoffman-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Peervoice, Pfizer, Sanofi, Takeda, and Touch Oncology; and independent board membership with Grifols. M.P. reports lecture fees, honoraria, or other fees from Bristol Myers Squibb, Roche, MSD, AstraZeneca, Takeda, Eli Lilly and Company, F. Hoffman-La Roche, Janssen, and Pfizer; and research funds from MSD, AstraZeneca, Roche, Boehringer Ingleheim, and Bristol Myers Squibb. D.R.C. reports lecture fees, honoraria or other fees from Roche and AstraZeneca. S.M.T, J.K., and E.J.D. report employment with MSD. M.A. reports employment and stock ownership with MSD. N.H. reports advisory or consultancy roles and stock ownership with Curve Biosciences. R.Mc. and B.J. report employment with Grail LLC. R.Ma reports employment with Grail LLC and stock ownership with Illumina. D.B. reports employment with GRAIL LLC and stock ownership with Illumina. E.E., S.P.A., M.G., A.R., A.F., S.B.R., G.S., T.C. have no conflicts of interest to disclose., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier B.V. All rights reserved.)