Palbociclib + cetuximab versus cetuximab in patients with CDKN2A-altered, anti-PD-1 resistant, HPV-negative head and neck squamous cell carcinoma (HNSCC): A phase 3 trial.
Authors: Ley Jessica C. , Cohen Jared , Liu Jingxia , Thomeczek Brianne , Oppelt Peter John , Adkins Douglas 
Published: June 2023

TPS6103 Background: Cell cycle deregulation is ubiquitous in HNSCC. In HPV-negative HNSCC, the most common genomic cell-cycling alteration involves CDKN2A, which results in loss of p16 expression, hyper-activation of CDK4/6-cyclin D1, unrestrained cell cycling and tumor progression. The modest antitumor activity of cetuximab in HPV-negative HNSCC may be due to unregulated cell-cycling events downstream of EGFR. In cell-line, xenograft, and PDX models of HPV-negative HNSCC, selective CDK4/6 inhibition arrested cell cycling and inhibited tumor growth. CDKN2A alterations were predictive of efficacy. Palbociclib, a selective CDK4/6 inhibitor, in combination with an EGFR inhibitor synergistically reduced the viability of HPV-negative HNSCC cell lines. An exploratory analysis of a double-blind, randomized, phase 2 trial (PALATINUS) showed that overall survival (OS) was numerically superior in patients with CDKN2A altered, HPV-negative recurrent/metastatic (RM) HNSCC treated with palbociclib + cetuximab vs those treated with placebo + cetuximab (median 9.7 vs 4.6 months, HR 0.38); however, OS was similar between the two treatment arms in patients without CDKN2A-altered disease. Also, the TAPUR trial showed that palbociclib decreased target lesions in 25% of patients with CDKN2A-altered HN cancers. These data provide justification for a randomized trial of palbociclib + cetuximab vs cetuximab in patients with CDKN2A-altered, HPV-negative RM-HNSCC. Enrollment was limited to patients with anti-PD-1 resistant disease, since current treatments fail to improve OS in these patients. Methods: The primary aim of this open-label, phase 3 trial is to determine the OS of patients with CDKN2A-altered (mutation or deletion), anti-PD-1 resistant, HPV-negative HNSCC treated with palbociclib + cetuximab (Arm 1) vs cetuximab (Arm 2). Eligibility also requires 1-3 lines of prior therapy and no cetuximab for RM disease. Patients are randomized (2:1) to Arms 1 or 2, stratified by prior platinum or cetuximab (if given with curative-intent therapy). Patients receive 28-day cycles of palbociclib 125 mg/d orally on days 1-21 + cetuximab 400 mg/m2 IV cycle 1 day 1, then 250 mg/m2 weekly (Arm 1) or cetuximab (Arm 2). Tumor response is assessed using RECIST 1.1. A two-stage sequential design, including one interim and a final analysis, was planned. We hypothesized that the median OS of Arm 1 will be 9.7 months and of Arm 2 4.6 months. O'Brien-Fleming method was used to calculate the sample size at each stage and derive the boundaries of two-sided hypothesis with early stopping to reject or accept H0 (HR = 1). Assuming 22 months enrollment and 12 months follow-up, 66 patients (Arm 1: 44; Arm 2: 22) will be enrolled in the first stage. If the study continues, an additional 15 patients will be enrolled (total Arm 1: 54; Arm 2: 27) which achieves 80% power at a two-sided α 0.05. Clinical trial information: NCT04966481 .