Phase II randomized trial of radiotherapy with pembrolizumab vs. cisplatin for unfavorable-risk p16+ head and neck squamous cell carcinoma (KEYCHAIN).

6016 Background: Standard chemoradiation (CRT) for unfavorable risk p16+ head and neck squamous cell carcinoma (HNSCC) is associated with high rates of toxicity and treatment failure. We hypothesized that concurrent and adjuvant pembrolizumab (pembro) could achieve superior PFS with acceptable toxicity compared to CRT in this population. Methods: KEYCHAIN was an open-label randomized phase II trial conducted at 6 US academic centers. Eligible patients had newly diagnosed unresected p16+ HNSCC with unfavorable risk (AJCC 8 th edition stage II-III oropharynx or stage III-IVB non-oropharynx HNSCC). Patients were randomized 1:1 to RT (70 Gy in 35 fractions) plus pembro (200 mg, 2 weeks prior to RT then every 3 weeks starting day 1 of RT up to 20 total cycles) or RT plus concurrent cisplatin (cis) (100 mg/m 2 every 3 weeks). Age, ECOG status, and oropharynx site were stratification factors. The primary endpoint was PFS, defined as time from randomization to first progression or death from any cause. Primary analysis was in the modified intent-to-treat population, including all patients having ≥ 1 dose of study medication and ≥ 1 efficacy evaluation after baseline. The study design had 80% power with 1-sided α = 0.15 (log-rank test) and planned sample size of 50 analyzable subjects per arm. The study is registered with clinicaltrials.gov (NCT03383094). Results: Between Feb 2019 and Aug 2025, 108 patients were randomized (53 pembro, 55 cis), with 102 analyzable (50 pembro, 52 cis). Median follow-up was 26.5 months. 79% had minimum follow-up of 2 years. At 2 years, there were 7 PFS events and 1 death in the pembro arm, and 14 PFS events and 7 deaths in the cis arm. Two-year PFS was 84% (95% CI: 74-96%) vs. 70% (95% CI: 58-85%) in the pembro vs cis arm (HR 0.57, 95% CI: 0.25-1.31; 1-sided p = 0.09) (see Table). Two-year OS was 98% (95% CI: 94-100%) vs. 85% (95% CI: 76-96%) for pembro vs. cis (HR 0.33, 95% CI: 0.09-1.28; 1-sided p = 0.048). HRs adjusted for T3-4 and N2-3 category were 0.68 (PFS) and 0.31 (OS). As of the latest follow-up, there were 24 total PFS events and 12 deaths. Grade ≥ 3 adverse events definitely or probably related to treatment were 36% vs. 46% in the pembro vs. cis arm. The median number of cycles received in the pembro arm was 18. In the cis arm, 94% completed ≥ 2 cycles. Results by CPS status will be reported when available. Conclusions: Pembro plus RT met the pre-specified significance criterion for improvement in PFS compared to cisplatin plus RT in this phase II trial. A phase III trial of RT with pembrolizumab for unfavorable risk p16+ HNSCC is warranted. Clinical trial information: NCT03383094 . Pembro Cisplatin N 50 52 Mean age 63.5 62.5 Male 87% 89% White 85% 89% Age > 65 42% 35% ECOG 0 83% 70% Oropharynx 94% 96% T1 8% 10% T2 22% 12% T3 38% 38% T4 32% 40% N0 6% 8% N1 42% 29% N2 46% 54% N3 6% 10% 2-yr PFS 84% 70% 2-yr OS 98% 85% Completed RT w/in 56 days</j