Abstract CT047: A phase 2 study of ipatasertib in combination with pembrolizumab for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck
Authors: Thomas Jacob S. , Hsu Robert , Villaflor Victoria , Riess Jonathan , Nieva Jorge , Krailo Mark , Gutkind Silvio , Colevas Dimitri 
Published: April 2023

Abstract
Background: Single agent pembrolizumab in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an ORR of 19% and mOS of 13.6 months. There are many factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment (TME). Low Tregs in the TME have been correlated with clinical efficacy with PD-1 blockade in various solid tumors. Tregs play an active role in HNSCC. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. In the Ice-CAP phase I solid tumor trial, combination PD-L1 antibody and Ipatasertib demonstrated reduction of Tregs and increased CD8+ effector T cells in paired biopsy specimens. This trial is designed to compare the efficacy of combination ipatasertib plus pembrolizumab compared to pembrolizumab monotherapy in R/M HNSCC.
Methods: In this prospective, two-arm, phase II, multicenter trial, patients with R/M HNSCC will be treated with pembrolizumab 200mg on day 1 with or without ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ≥ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with Ipatasertib plus pembrolizumab compared to pembrolizumab using the Cox Model where randomized treatment assignment is the only variable in the model. A total of 48 patients will be enrolled, with 24 patients in each cohort. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Accrual is ongoing (NCT05172258).
Citation Format: Jacob S. Thomas, Robert Hsu, Victoria Villaflor, Jonathan Riess, Jorge Nieva, Mark Krailo, Silvio Gutkind, Dimitri Colevas. A phase 2 study of ipatasertib in combination with pembrolizumab for first line treatment of recurrent or metastatic squamous cell cancer of the head and neck [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT047.