Palbociclib, a Selective CDK4/6 Inhibitor, Administered Before and After Chemoradiotherapy for Human Papillomavirus–Negative, Locally Advanced Head and Neck Squamous Cell Carcinoma: A Single-Arm, Phase II Trial

PURPOSE The primary aim of this single-arm, phase II trial was to determine the objective response rate (ORR) with palbociclib, a selective CDK4/6 inhibitor, administered before chemoradiotherapy (CRT) in patients with human papillomavirus (HPV)–negative head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS Eligibility required untreated stage III-IVB HPV-negative HNSCC. Palbociclib 125 mg once daily was administered on days 1-21 of each 28-day cycle for two cycles before and six cycles after CRT. Pretreatment tumor samples underwent genome sequencing. The primary end point was tumor response to palbociclib given before CRT, assessed by RECIST1.1. A sample of 24 evaluable patients (those with response assessment) yielded an 80% power at a one-sided significance level of 0.05 if the ORR was ≥38% (null ORR 17%). A key secondary end point was relapse. RESULTS We enrolled 26 patients with HPV-negative, locally advanced HNSCC. Alterations in CDKN2A were identified in 15 patients (58%), and alterations in CCND1 were identified in eight (31%). Twenty-four patients were evaluable for the primary end point, and 25 were evaluable for relapse. The ORR with palbociclib given before CRT was 41.7% (95% CI, 22.1 to 63.4). Response to palbociclib occurred in 10 of 15 patients (66.7%) with versus 0 of 9 (0%) without tumor CDKN2A alterations (P 5 .002) and in one of six patients (16.7%) with versus nine of 18 (50%) without CCND1 alterations (P 5 .34). The median follow-up was 33.9 months (IQR, 31.3-49.2). Relapse occurred in two of 15 patients (13.3%) with versus seven of 10 (70%) without tumor CDKN2A alterations (P 5 .009) and in one of seven patients (14.3%) with versus 8 of 18 (44.4%) without CCND1 alterations (P 5 .36). CONCLUSION Palbociclib is an active drug in previously untreated HPV-negative, locally advanced HNSCC. Alterations in CDKN2A were associated with a higher ORR with palbociclib and a lower relapse risk after CRT.