Randomized Phase II Study of Concurrent Versus Sequential Pembrolizumab in Combination With Chemoradiation in Locally Advanced Head and Neck Cancer.

Purpose: The optimal timing of pembrolizumab with chemoradiation (CRT) in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) is unknown.

Patients And Methods: Our phase II trial randomly assigned patients 1:1 to concurrent pembrolizumab (200 mg once every 3 weeks × 8) starting 1 week before CRT (cisplatin 40 mg/m once weekly + radiation 70 Gy) versus sequential pembrolizumab starting 2 weeks after CRT. Human papillomavirus (HPV)+ (>10 pack-years or T4 or N3) and HPV(-) LA HNSCC were included, stratified by HPV and N stage. In our pick-the-winner design, if both arms met the trivariate primary end point (1-year locoregional failure <60%, progression-free survival [PFS] ≥60%, and dose limiting toxicity rate ≤20%), the arm with numerically superior 1-year PFS would be selected. Survival end points were compared by a univariate Cox model. Pretreatment and on-treatment tumor biopsies (week 2 of CRT) were evaluated by multispectral imaging and compared using two-sided paired -tests.

Results: Treated patients (41 concurrent and 39 sequential) were 71% oropharynx (53% HPV+), 92.5% stage IV (46% T4, 76% N2), similar by arm. Both arms met the trivariate primary end point, with superior 1-year PFS in the sequential arm (84% 71%) and favorable 4-year outcomes: locoregional control (96% 64%; hazard ratio [HR], 0.11 [95% CI, 0.01 to 0.89]; = .012), PFS (69% 49%; HR, 0.55 [95% CI, 0.25 to 1.22]; = .132), and overall survival (83% 71%; HR, 0.51 [95% CI, 0.19 to 1.37]; = .17). There was a significant increase in macrophages, PD-L1+ macrophages, and PD-L1+ tumor cells with treatment in the concurrent but not the sequential arm.

Conclusion: CRT with sequential pembrolizumab met criteria for further study. Immunosuppressive changes in the TME differed between arms, reflecting the impact of one dose of pembrolizumab in the concurrent arm.