The primary aims of this single-arm, phase 2 trial were to determine the objective response rate (ORR) of human papillomavirus (HPV)-unrelated, locally advanced head and neck squamous-cell carcinoma (LA-HNSCC) to palbociclib monotherapy, and to correlate responses to somatic genomic alterations in CDKN2A. HPV-unrelated disease was defined as 1) SCC of the larynx, hypopharynx or oral cavity, or 2) SCC of the oropharynx with <70% of tumor cells expressing p16 by immunohistochemistry and/or absence of high-risk HPV-RNA by in situ hybridization. Genome sequencing (FoundationOne CDx or Tempus xT) was performed on tumor tissue obtained before treatment. Patients received palbociclib 125 mg/d orally on days 1-21 of each 28-day cycle. Tumor response was assessed using RECIST 1.1 on CT scans performed before and after two cycles of palbociclib. After palbociclib, patients received chemoradiation therapy. A sample size of 24 patients yielded an 80% power if the ORR was >38% (alternative hypothesis), using an exact binomial test of one sample proportion comparison with an upper one-sided nominal significance level of 0.05 and null ORR of <17%. To date, 12 patients have enrolled and completed two cycles of palbociclib: primary site (larynx-7; hypopharynx-2; oropharynx-2, oral cavity-1), stage (III-3; IV-9), and smoking history (yes-11; no-1). The ORR to palbociclib monotherapy was 33%: CR (1 patient), PR (3), SD (7), and PD (1). CDKN2A alterations were identified in 6 patients (50%), and included loss-of-function mutations (4) or deletions (2). Tumor responses to palbociclib occurred in 4 of 6 patients (67%) with CDKN2A alterations versus 0 of 6 patients (0%) without CDKN2A alterations (p=0.06, Fisher's Exact Test). These preliminary results suggest that palbociclib may be an effective treatment for CDKN2A-altered, HPV-unrelated, LA-HNSCC, but not in disease that lacks CDKN2A alterations.

Citation Format: Peter Oppelt, Jessica Ley, Kevin Palka, Randal C. Paniello, Sidharth V. Puram, Jason Rich, Ryan Jackson, Patrik Pipkorn, Hiram Gay, Jingxia Liu, Wade Thorstad, Jose Zevallos, Douglas R. Adkins. Correlation of CDKN2A genomic alterations with tumor response to palbociclib given before chemoradiation therapy to patients with human papillomavirus-unrelated, locally advanced head and neck squamous-cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT153.