Palbociclib and cetuximab in cetuximab-resistant human papillomavirus-related oropharynx squamous-cell carcinoma: A multicenter phase 2 trial

•The ORR to palbociclib + cetuximab in cetuximab-resistant HPV-related OPSCC was 4%.•Stable disease with ≥ 10% decrease in target lesions occurred in 8%.•The median PFS was 1.9 months and the median OS was 17.1 months.•Grade 3–4 palbociclib-related AEs, mostly non-febrile leukopenia, occurred in 46%.•Palbociclib dose reduction or discontinuation occurred in 12%. We previously reported that palbociclib, a selective CDK4/6 inhibitor, given with cetuximab, resulted in an objective response rate (ORR) of 19% in cetuximab-resistant human papillomavirus (HPV)-unrelated head and neck squamous-cell carcinoma (HNSCC). In this study, we aimed to determine the proportion of patients with cetuximab-resistant HPV-related oropharynx (OP)SCC who achieved an objective response to palbociclib and cetuximab. We performed a multicenter phase 2 trial. Key eligibility requirements included measurable HPV-related OPSCC that progressed on a cetuximab-containing regimen. Palbociclib 125 mg po was administered on Days 1–21 of 28 day cycles, with weekly cetuximab. The primary endpoint was objective response (RECIST1.1). The study design had a probability of 0.70 of accepting the alternative hypothesis (ORR ≥ 20%) and rejecting the null hypothesis (ORR ≤ 5%). Two or more tumor responses among 24 patients were needed to accept the alternative hypothesis. Twenty-four patients enrolled. The median interval from prior cetuximab to study enrollment was 0.7 months (IQR 0.2–6.1). Disease progression on a platinum agent occurred in 23 patients (96%). An objective response occurred in one patient (ORR 4%). The duration of response was 4 months. Stable disease with ≥ 10% decrease in target lesions occurred in 2 patients (8%). Median follow-up was 8.9 (IQR 3.7–16.8) months. The median progression-free survival was 1.9 months (95% CI 1.8–2.1) and the median overall survival was 17.1 months (95%CI: 5.8–21.5). The trial did not meet its primary endpoint. Further investigation of palbociclib and cetuximab in cetuximab-resistant HPV-related OPSCC is not warranted.