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

6006 Background: Single agent pembrolizumab in relapsed/metastatic head and neck squamous cell carcinoma (R/M HNSCC) has limited activity. The immunosuppressive tumor microenvironment (TME) includes regulatory T cells (Treg)s and myeloid-derived suppressor cells (MDSC)s, which may contribute to the low responses to anti-PD-1 therapy. Preclinical studies demonstrate that anti-PD-1 antibodies induce Treg activation through the AKT pathway. AKT blockade selectively inhibits the proliferation of human Tregs compared to conventional T cells. Furthermore, inhibiting the AKT pathway limits MDSC infiltration and differentiation while boosting effector T cell function within tumors. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. This phase II trial compares the efficacy of combination ipatasertib plus pembrolizumab (I+P) versus pembrolizumab (P) monotherapy in R/M HNSCC. Methods: This is a prospective, two-arm, phase II, multicenter trial for 1 st line treatment of R/M HNSCC. Patients were randomized 1:1 to either Arm 1 - P 200mg on day 1 with I 400mg daily on days 1-14 of 21-day cycles, or Arm 2 – P monotherapy. PD-L1 CPS score ≥1 was required. The primary objective is to compare the PFS between the two arms. Secondary objectives included safety and ORR per RECIST 1.1. Results: As of 1/21/2026, 52 patients were randomized, with 27 enrolled in the I+P arm. The median age was 67 and 77% were male. The primary tumor sites were 46% oral cavity, 38% oropharynx, and 15% larynx. Among pts with oropharynx primary, 75% were p16 positive. PD-L1 CPS score was ≥20 in 60%. In the I+P arm the most common G1-3 treatment-related adverse events (TRAEs) occurring in ≥10% were diarrhea (70.4%), fatigue (44.4%), Nausea (40.7%), AST increase (18.5%), ALT increase (14.8%), and maculopapular rash (14.8%). Only 1 pt had grade 3 diarrhea. In P arm the most common G3 TRAEs were maculopapular rash (29.2%), AST increase (16.7%), and diarrhea (12.5%). There were no G4 or G5 TRAEs. Four patients required dose reduction of ipatasertib, primarily for diarrhea. Ten pts in the I+P arm and 6 pts in P arm required dose interruptions. One patient in each arm discontinued due to adverse events. At the data cutoff 4 pts remain on treatment in I+P arm and 2 remain on P arm. The ORR in I+P arm and P arm was 41% and 17% respectively. The CR rate was 15% in I+P arm and 4.2% in P arm. The DCR (CR+PR+SD) was 70% in I+P arm and 42% in P arm. With a median follow up of 7.0 months, the PFS in I+P arm is 8.1 months (95% CI: 4 – NA) and in P arm is 6.2 months (95% CI 1.9 – 13.5). Conclusions: I+P demonstrated an acceptable safety profile and shows promising clinical activity in R/M HNSCC. Clinical trial information: NCT05172258 .