5-year survival outcomes after perioperative pembrolizumab (pembro) in patients with human papillomavirus (HPV)-unrelated, locally advanced head and neck squamous cell carcinoma (LA-HNSCC): A multi-center, two-cohort, phase 2 trial.

Abstract

6079 Background: A phase 2 trial (NCT02296684) demonstrated that perioperative pembro added to standard of care (SOC) surgery/adjuvant radiation-based therapy resulted in frequent pathologic tumor responses (pTR) and favorable 2-year survival relative to historical rates in patients with HPV-unrelated, LA-HNSCC (Uppaluri et al., CCR 2020; Oliveira et al., Sci Immunol 2023). The early results of this institutional phase 2 trial provided necessary rationale for the Merck-sponsored, KEYNOTE-689 phase 3 trial that compared perioperative pembro with SOC versus SOC in patients with resectable LA-HNSCC. Here, we report 5-year survival outcomes from the phase 2 trial. We also evaluated the effect of two pembro dosing schedules and the presence or absence of pTR at the primary tumor site on long-term survival outcomes. Methods: Cohort 1 received one dose of neoadjuvant pembro (200 mg IV) and, in patients with high-risk pathology, six doses of adjuvant pembro. Cohort 2 received two doses of neoadjuvant but no adjuvant pembro. pTR primary was defined as the proportion of the resected primary site tumor bed that exhibited pathologic response: 0 (<10%), 1 (10%-49%), and 2 (≥50%). Event-free survival (EFS), defined as the time from surgery to disease progression, recurrence, or death, and overall survival (OS) was analyzed by the Kaplan-Meier method with log-rank testing for significance. Results: Sixty-five patients enrolled (36 in cohort 1 and 29 in cohort 2). The median follow-up was 48.4 months (IQR: 30.1-60.9). The 5-year OS for all patients was 73% (95% CI: 62-85%) and the EFS was 71% (95% CI: 61-83%). A comparison of patients in cohort 2 versus 1 showed no significant differences in OS (HR = 0.39; 95% CI: 0.12-1.20; p = 0.09) or EFS (HR = 0.72; 95% CI: 0.28-1.84; p = 0.48). For all patients, those with pTR primary 1 or 2 versus 0 had significantly better EFS (HR = 0.34; 95% CI: 0.11-1.02; p = 0.04), but not OS (HR = 0.42; 95% CI: 0.14-1.3; p = 0.10). Conclusions: Among patients with HPV-unrelated, LA-HNSCC treated with perioperative pembro and SOC, the 5-year OS and EFS were favorable relative to historical results (~40-50% 5-year OS and EFS) with SOC alone. While OS was numerically better in cohort 2 compared to cohort 1, and among patients with pTR primary 1 or 2 compared pTR primary 0, the differences did not reach statistical significance, possibly due to the small sample size. pTR primary after neoadjuvant pembro was significantly associated with better EFS, suggesting its potential utility as an early surrogate marker for EFS. Clinical trial information: NCT02296684 .