Sequential Pembrolizumab (PD-1) Tops Concurrent for 4-yr Control in LA-HNSCC

Pembrolizumab—an anti-PD-1 antibody—was tested with definitive chemoradiation (CRT: weekly cisplatin 40 mg/m² + 70 Gy RT) either concurrently (start 1 wk pre-CRT) or sequentially (start 2 wks post-CRT) in a randomized phase 2 “pick-the-winner” study of locally advanced (LA) HNSCC (n=80; 41 concurrent, 39 sequential; 71% oropharynx, 53% HPV+; 92.5% stage IV). Both met the trivariate primary endpoint; the sequential arm showed higher 1-yr PFS (84% vs 71%) and superior 4-yr locoregional control 96% vs 64% (HR 0.11, p=.012); 4-yr PFS 69% vs 49% (HR 0.55, p=.132) and OS 83% vs 71% (HR 0.51, p=.17) favored sequential but were not statistically significant. Dose-limiting toxicity targets (≤20%) were met in both; early on-treatment biopsies showed increased macrophages and PD-L1+ macrophages/tumor cells with concurrent—but not sequential—therapy, suggesting timing-dependent TME effects. While cisplatin-based CRT alone remains US SOC and adding concurrent PD-1 did not improve EFS in the phase 3 KEYNOTE-412 (HR 0.83), these data propose sequencing as the differentiator rather than simple addition (NCT02777385; pembrolizumab not approved with definitive CRT in LA-HNSCC in the US).