Background

In CheckMate 9LA (NCT03215706), 1L NIVO + IPI + chemo (2 cycles) significantly improved overall survival (OS) vs chemo (4 cycles) in patients (pts) with aNSCLC regardless of tumor histology or PD-L1 expression. TMB is potentially associated with the clinical efficacy of immune checkpoint inhibitors. We evaluated efficacy by tissue and blood TMB (tTMB/bTMB) in CheckMate 9LA.

Methods

tTMB was evaluated using the FoundationOne CDx^TM assay from tissue samples collected prior to enrollment. Plasma samples collected at baseline were used for isolation of circulating cell-free tumor DNA and evaluation of bTMB using the Guardant OMNI platform. TMB was not a stratification factor for randomization. Analyses of OS, progression-free survival (PFS), and objective response rate (ORR) were based on prespecified TMB thresholds (tTMB, 10 mut/Mb; bTMB, 16 and 20 mut/Mb). Analyses were based on the March 9, 2020 database lock (DBL; minimum OS follow-up, 12.7 mo).

Results

Of 711 randomized pts with available TMB data at DBL, 64% had evaluable tTMB and 73% had evaluable bTMB. Baseline characteristics were generally well balanced between all randomized, TMB-evaluable and non-evaluable, as well as TMB-high and TMB-low subgroups (both bTMB and tTMB). Overall, clinical benefit (OS, PFS, ORR) was observed with NIVO + IPI + chemo vs chemo in both TMB-high and TMB-low subgroups (Table). The OS benefit with NIVO + IPI + chemo vs chemo was similar between tTMB ≥10 and <10 mut/Mb, and between bTMB ≥16 and <16 mut/Mb subgroups; a numerically higher OS benefit was seen in bTMB ≥20 vs <20 mut/Mb subgroups. For PFS and ORR, the magnitude of benefit was higher in TMB-high versus TMB-low subgroups for both tTMB and bTMB.

Conclusions

Higher TMB appeared to be associated with improved PFS and ORR benefits of NIVO + IPI + chemo over chemo. OS benefit was generally similar between high and low TMB.

Clinical trial identification: NCT03215706.

Editorial acknowledgement

Writing and editorial assistance were provided by Nick Patterson, of Caudex, London, UK, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb.

Funding

Bristol Myers Squibb.

Disclosure

L. Paz-Ares: Honoraria (self): Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Servier, Sysmex, Takeda; Speaker Bureau/Expert testimony: Roche, Lilly, AstraZeneca, MSD, BMS; Leadership role: Altum sequencing; Research grant/Funding (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme; Officer/Board of Directors: Genómica; Spouse/Financial dependant: AAA, Advanz Pharma, Bayer, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Servier and Sanofi. T-E. Ciuleanu: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca, Amgen, Astellas, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Janssen, MSD, Novartis/GSK, Pfizer, Roche, Sanofi, Servier. M. Schenker: Research grant/Funding (self), Fees for clinical trial activities : Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Merck, MSD, Mylan, Novartis, Pfizer, Pharma Mar, Regeneron, Roche, Serono. B. Zurawski: Research grant/Funding (self): Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen-Cilag, MSD, Roche. J. Bennouna: Honoraria (self), Advisory/Consultancy: Bristol Myers Squibb, Boehringer Ingelheim, AstraZeneca, MSD, Servier, Bayer, Roche; Research grant/Funding (self): AstraZeneca; Travel/Accommodation/Expenses: AstraZeneca, Roche. E. Felip: Advisory/Consultancy: AbbVie, Amgen, AstraZeneca, Bayer, Blueprint Mediines, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, GSK, Janssen, Merck, MSD, Novartis, Pfizer, Puma Biotechnology, Roche, Sanofi Genzyme, Takeda; Speaker Bureau/Expert testimony: AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Medscape, MSD, Novartis, Peervoice, Pfizer, Prime Oncology, Roche, Springer, Takeda, Touchime, CME OUtfitters; Research grant/Funding (self): Fundacion Merck Salud; Officer/Board of Directors: Orifols. O. Juan-Vidal: Advisory/Consultancy: Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp and Dohme, Roche/Genentech, AstraZeneca, AbbVie, Pfizer, Takeda and Eli Lilly; Speaker Bureau/Expert testimony: Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp and Dohme, Roche/Genentech, AstraZeneca; Travel/Accommodation/Expenses: Roche and Merck Sharp and Dohme. A. Alexandru: Advisory/Consultancy: Roche, Boehringer Ingelheim; Speaker Bureau/Expert testimony: Sandoz, Novartis, Bristol Myers Squibb; Travel/Accommodation/Expenses: Boehringer Ingelheim, Sanofi, Pfizer, Roche, AstraZeneca, Bristol Myers Squibb. H. Sakai: Advisory/Consultancy: Bristol Myers Squibb, Merck KGaA; Speaker Bureau/Expert testimony: Bristol Myers Squibb, Ono Pharmaceutical, Chugai Pharmaceutical, AstraZeneca, Merck & Co, Merck KGaA. A. Scherpereel: Advisory/Consultancy: AstraZeneca, Bristol Myers Squibb, MSD, Roche; Speaker Bureau/Expert testimony: AstraZeneca, Bristol Myers Squibb, MSD; Research grant/Funding (institution): Bristol Myers Squibb; Travel/Accommodation/Expenses: AstraZeneca, Bristol Myers Squibb, MSD, Roche. M. Reck: Advisory/Consultancy: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche, Samsung; Speaker Bureau/Expert testimony: AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Research grant/Funding (self): Bristol Myers Squibb, Boehringer-Ingelheim; Travel/Accommodation/Expenses: AbbVie, Amgen, AstraZeneca, BMS, Boehringer-Ingelheim, Lilly, Merck, MSD, Novartis, Pfizer, Roche. S. Lu: Advisory/Consultancy: AstraZeneca, Boehringer-Ingelheim, Hutchison MediPharma, Simcere, ZaiLab, GenomiCare and Roche; Speaker Bureau/Expert testimony: AstraZeneca, Roche, Hansoh. T. John: Honoraria (self): Bristol Myers Squibb, AstraZeneca, Roche, Merck, MSD, Boehringer Ingelheim, Bayer; Honoraria (institution): Specialised Therapeutics, Pfizer, Novartis; Advisory/Consultancy: MSD, Merck, Roche, AstraZeneca, Bristol Myers Squibb, Takeda, BI, Bayer. S. Meadows-Shropshire: Research grant/Funding (self), Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol Myers Squibb. D. Balli: Shareholder/Stockholder/Stock options, Full/Part-time employment: Bristol Myers Squibb. S. Agrawal: Full/Part-time employment: Bristol Myers Squibb. D.P. Carbone: Honoraria (self): AstraZeneca, Pfizer, Bristol Myers Squibb, Eisai; Advisory/Consultancy: AstraZeneca, EMD Serono/Merck, GI Therapeutics (Intellisphere), Gritstone Oncology, GSK, Inivata, Roche China, Oncocyte, GenePlus, Gloria Biosciences, Roche, BMS, Daiichi Sankyo Inc, Boehringer-Ingelheim, Seattle Genetics, Flame Biosciences, Novocure; Leadership role, Chair of the Lung Biology subcommittee for the Eastern Cooperative Oncology Group and on the Thoracic Core committees for both the Alliance and ECOG/ACRIN. I am also Past-President of the International Association for the Study of Lung Cancer (IASLC).: ECOG, ECOG/ACRIN, IASLC; Research grant/Funding (institution): Bristol Myers Squibb; Travel/Accommodation/Expenses: AbbVie, AstraZeneca, Bristol Myers Squibb, EMD Serono, Inivata, Inovio, Janssen, Loxo Oncology, Merck, MSD, Pfizer, Roche/Genentech, Takeda Oncology, Trinity, Incyte, Kyowa Kirin, Novartis, Gritstone Oncology, GSK, Roche China GenePlus, Daiichi Sankyo Inc; Officer/Board of Directors: IASLC, LCFA, LUNGevity, ALCMI, Joan's Legacy Foundation, Lance Armstrong Foundation, Wendy Wyrick Foundation, Wendy Will Case Foundation, Jack Roth Foundation. All other authors have declared no conflicts of interest.