Puma presents findings from Phase I/II study of alisertib, pembrolizumab

Puma Biotechnology announced the poster presentation of a Phase I/II trial of alisertib plus pembrolizumab for the treatment of patients with Rb-deficient head and neck squamous cell carcinoma at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in Boston, Massachusetts. Alisertib is an adenosine triphosphate-competitive, reversible inhibitor of Aurora Kinase A that results in disruption of mitosis. Human papillomavirus is a common cause of HNSCC, and infection leads to Retinoblastoma protein degradation. A synthetic lethal relationship between AURKA and Rb1 has been implicated preclinically, and alisertib has been shown to induce immunogenic cell death in HPV+ cancer cells. The investigator-sponsored clinical trial was conducted sequentially in two parts: A Phase I study to determine the recommended dose for alisertib in combination with pembroluzimab in patients with advanced solid tumors, and a Phase II study to evaluate efficacy of alisertib and pembroluzimab in patients with recurrent or metastatic, Rb-deficient HNSCC who had progressed on prior anti-PD1 therapy. Biomarkers of response were also evaluated. The Phase I portion of the study enrolled ten patients with advanced solid tumors. There was no requirement for Rb deficiency in the Phase I portion of the trial. Alisertib was dosed twice daily for seven days every twenty-one days at either 30 mg, 40 mg, or 50 mg, and pembrolizumab was dosed at 200 mg intravenously every three weeks. The observed dose-limiting toxicities were predominantly hematologic in nature and congruent with the expected safety profile. Based on these findings, the 40 mg dose level was selected for the Phase II portion of the study. The Phase I portion of the trial enrolled patients with several different solid tumors including small cell lung cancer, thyroid carcinoma showing thymic-like differentiation, oropharynx cancer, salivary cancer and head and neck squamous cell carcinoma. One patient with small cell lung cancer experienced stable disease lasting for 245 days, one patient with HPV-positive orpharynx cancer experienced stable disease lasting for 209 days, and one patient with thyroid carcinoma showing thymic-like differentiation experienced stable disease lasting 811+ days. Fourteen patients with immunotherapy- and platinum-resistant HPV+ HNSCC were enrolled in the Phase II portion of the study. Two of the fourteen patients had confirmed Rb1 loss by next generation sequencing. No objective responses were observed, though seven patients, including three with progression-free survival exceeding 8 months, experienced stable disease. The remaining seven experienced progressive disease. The median PFS was 1.4 months, and the median overall survival was 13.5 months. No new safety signals were observed.