The Study: You may remember the historic tumor agnostic FDA indication for pembrolizumab in anybody with microsatellite instability-high tumor. Nivolumab is now following suit with CheckMate 227, a big “multi-part” phase III trial of nivo-based regimens in various biomarker-based populations with untreated, non-ALK or EGFR mutated advanced non-small cell lung cancer (NSCLC). Last week’s pub, one of many CheckMate 227 spin-offs to come, reports one of the co-primary endpoints: progression-free survival (PFS) after nivo+ ipi versus platinum-doublet chemo in patients with a high tumor mutational burden (TMB) regardless of PD-L1 expression. High TMB was defined as 10 mutations per megabase, which was obtained from the FoundationOne CDx assay. Close to 45% of patients met this criteria after randomization, and, importantly, TMB did not correlate with PD-L1 expression. Compared to chemo, first-line nivo + ipi improved PFS at one year from 13 → 43% among patients with high TMB across all tumor histologies (squamous and non-squamous) and levels of PD-L1 expression. Patients with low TMB were analyzed separately and showed no benefit with immunotherapy compared to chemo.
Bottom Line: Pembro recently proved it doesn’t rely on PD-L1 expression for efficacy in patients with advanced NSCLC, so nivo upped the ante with a whole new biomarker for response: tumor mutational burden. | Hellmann, N Engl J Med 2018