Neoadjuvant and adjuvant pembrolizumab (pembro) plus standard of care (SOC) for resectable locally advanced head and neck squamous cell carcinoma (LA HNSCC): Efficacy by surgical outcomes in the phase 3 KEYNOTE-689 trial.

6057 Background: In the phase 3 KEYNOTE-689 trial (NCT03765918), neoadjuvant and adjuvant pembro plus SOC (surgery and postoperative [chemo]radiotherapy) significantly improved EFS versus SOC in participants (pts) with resectable LA HNSCC. We present results from an exploratory analysis of EFS by surgical outcomes in KEYNOTE-689. Methods: Adults with newly diagnosed resectable LA HNSCC were randomly assigned to receive 2 cycles neoadjuvant pembro 200 mg followed by surgery and 15 cycles adjuvant pembro starting concurrently with postoperative (chemo)radiotherapy (pembro arm) versus surgery and postoperative (chemo)radiotherapy only (control arm). This exploratory analysis evaluated EFS in pts with R0 resection (negative [≥5mm] or close [1-5mm] margin) by local assessment, and postoperative presence or absence of extranodal extension (ENE) or positive (<1mm) surgical margins by BIPR in the PD-L1 CPS ≥1 and total populations of the study. Median study follow-up (data cutoff date: July 25, 2024) was 38.3 months (range, 9.0-66.5). Results: Of 714 total pts, 630 underwent surgery (n = 322, pembro arm; n = 308, control arm). Among 630 who underwent surgery, 307 in the pembro arm and 294 in the control arm had tumors with PD-L1 CPS ≥1. EFS in subgroups by surgical outcome is shown in the table. Conclusions: In this exploratory analysis of the KEYNOTE-689 study, EFS benefit with neoadjuvant and adjuvant pembro added to surgery and postoperative (chemo)radiotherapy occurred in all subgroups by surgical outcome, consistent with the primary analysis population. Fewer pts in the pembro arm had ENE or positive margins post-surgery indicating downstaging due to neoadjuvant pembro. ENE presence or positive margins were associated with a poorer EFS prognosis; however, EFS was better in the pembro arm vs control in pts with or without these high-risk pathological features. Results further support the addition of neoadjuvant and adjuvant pembro to SOC for resectable LA HNSCC. Clinical trial information: NCT03765918 . R0 by local assessment ENE present by BIPR ENE absent by BIPR Positive surgical margins by BIPR Negative surgical margins by BIPR All pts Pembron = 287 Controln = 261 Pembron = 82 Controln = 112 Pembron = 228 Controln = 188 Pembron = 64 Control n = 92 Pembron = 249 Control n = 209 Median EFS, mo NR 40.2 25.2 12.6 NR 57.0 50.3 13.8 NR 51.5 HR (95% CI) 0.67 (0.50-0.88) 0.77 (0.52-1.15) 0.74 (0.53-1.05) 0.58 (0.36-0.93) 0.78 (0.57-1.07) 36-mo rate, % 64.0 51.1 41.3 33.8 68.4 58.5 58.0 36.8 63.0 55.6 CPS ≥1 Pembron = 275 Controln = 249 Pembron = 76 Controln = 109 Pembron = 220 Control n = 178 Pembron = 58 Control n = 89 Pembron = 242 Controln = 198 Median EFS, mo NR 35.3 25.2 12.6 NR 57.0 50.3 13.8 NR 50.1 HR (95% CI) 0.62 (0.47-0.83)