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 7th 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 .