A randomized, double-blind, placebo-controlled phase II study of adjuvant pembrolizumab versus placebo in patients with head and neck squamous cell cancers at high risk for recurrence: The PATHWay study.

6008 Background: Anti-PD1 therapy has become an essential treatment in recurrent and metastatic head/neck squamous cell carcinoma (HNSCC). The optimal use of anti-PD1 therapy in the curative setting is not established. Understanding the benefits of adjuvant anti-PD1 treatment in high risk HNSCC patients treated with curative intent is necessary. Methods: The PATHWay trial (NCT02841748) is a multi-site, randomized, placebo (PL) controlled trial of pembrolizumab (IO) in patients following curative treatment of high recurrence risk HNSCC. Patients with AJCC 7 th edition stage IVa, IVb, and select III HNSCC or multiple primaries were eligible if their cancers had an estimated > 40% chance of recurrence and were not eligible for additional therapy. Patients enrolled into six group criteria: A) high risk nodal disease or interrupted radiation treatment; B) salvage surgery including positive margin; C) Indeterminate distant lesions concerning for metastasis; D) Oligometastatic disease treated definitively; E) Microscopic residual disease after surgery; or F) Multiple prior recurrences or multiple treated primaries who have undergone surgery ≥ 2 times. Patients were randomized with stratification for HPV and EBV status, and received pembrolizumab 200mg IV or placebo for up to 18 cycles. The primary study endpoint was progression-free survival (PFS). The targeted sample size was N=100 patients (50 per arm), which provided >90% power to detect a hazard ratio (HR) of 0.45, based on a stratified logrank test at a one-sided alpha level of 0.10. Results: A total of n=49 IO and n=51 PL patients were enrolled between 2016 and 2023 across 10 US sites. Mean age was 62; 33% female; 45% nonsmoker; 20% HPV+, 2% EBV+. Cancers were stage III (24%), IVa (39%), IVb (8%), with prior surgery in 95% and prior RT in 78%. Median follow-up was 33 months. Compared to PL, IO treated patients had superior PFS with HR 0.61 (80% CI: 0.43-0.86, one-sided p=0.021). PFS rates for IO were 65% and 54% at 1 and 2 years, respectively compared to 48% and 33%, respectively for PL. Overall survival (OS) was not significantly different in IO vs. PL treatment (HR = 1.00, 80% CI: 0.6-1.68, p=0.45). IO improved PFS in 2 sub-groups: In post-salvage surgery patients (group B, n=37), IO had superior PFS vs. PL (HR 0.34, 80% CI: 0.18-0.67, p=0.016); In patients with multiple recurrences/primaries (group F, n=37) IO had superior PFS vs. PL (HR 0.48, 80% CI: 0.27-0.88, p=0.057). Adverse events between treatments were comparable, with 3 (6%) grade 4 adverse events in PL and 1 (2%) grade 5 (2%, unrelated) and 1 grade 4 (2%) in IO. Conclusions: Pembrolizumab treatment for 1 year in patients with high risk of recurrent HNSCC following curative therapy resulted in a statistically significant improvement in PFS compared to placebo, and the benefit was maintained in key subgroups. Clinical trial information: NCT02841748 .