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.
tTMB was evaluated using the FoundationOne CDxTM 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).
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.
| Table. Efficacy outcomes in subgroups based on blood and tissue TMB | ||||||||||||
| TMB cut-off (mut/Mb) | ||||||||||||
| tTMB ≥10 | tTMB <10 | bTMB ≥16 | bTMB <16 | bTMB ≥20 | bTMB <20 | |||||||
| N + I + chemo n = 101 | Chemo n = 82 | N + I + chemo n = 135 | Chemo n = 138 | N + I + chemo n = 113 | Chemo n = 85 | N + I + chemo n = 165 | Chemo n = 156 | N + I + chemo n = 80 | Chemo n = 61 | N + I + chemo n = 196 | Chemo n = 180 | |
| Median OS, mo | 15.0 | 10.8 | 16.8 | 12.4 | 15.4 | 10.4 | 15.0 | 11.2 | 19.4 | 11.4 | 14.1 | 10.8 |
| HR (95% CI) | 0.74 (0.51−1.08) | 0.75 (0.55−1.02) | 0.60 (0.42−0.86) | 0.73 (0.55−0.96) | 0.54 (0.35−0.84) | 0.74 (0.57−0.95) | ||||||
| Median PFS, mo | 8.9 | 4.7 | 5.6 | 5.0 | 7.2 | 5.3 | 5.6 | 4.5 | 9.7 | 5.3 | 5.6 | 4.5 |
| HR (95% CI) | 0.49 (0.34−0.70) | 0.83 (0.63−1.10) | 0.55 (0.39−0.78) | 0.78 (0.60− 1.00) | 0.48 (0.32−0.73) | 0.78 (0.62−0.99) | ||||||
| ORR, % | 46 | 28 | 33 | 27 | 49 | 27 | 33 | 28 | 55 | 31 | 33 | 27 |
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.
NCT03215706
Writing and editorial assistance were provided by Nick Patterson, of Caudex, London, UK, funded by Bristol Myers Squibb.