Ipatasertib Plus Pembrolizumab Improves ORR in Recurrent/Metastatic HNSCC

Ipatasertib, an oral pan-AKT inhibitor, resulted in improved overall response rate (ORR) when added to pembrolizumab (Keytruda) vs pembrolizumab alone in patients with first-line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), according to findings presented at the 2026 ASCO Annual Meeting.

In the randomized phase 2 trial (NCT05172258), the combination resulted in an ORR of 41% compared with 17% with pembrolizumab alone, with an acceptable safety profile. The combination also demonstrated a numerically longer median progression-free survival (PFS) and a substantially higher disease control rate, supporting further investigation of AKT pathway inhibition as a strategy to overcome immunosuppression in this difficult-to-treat malignancy.

“The hypothesis of our study is that by treating with ipatasertib, an AKT inhibitor, we can selectively inhibit regulatory T cells when treating with pembrolizumab,” Jacob Stephen Thomas, MD, of USC Norris Comprehensive Cancer Center, explained in his presentation of the data.

Targeting Treg-Mediated Immunosuppression via AKT

In the landmark KEYNOTE-048 study (NCT02358031), single-agent pembrolizumab yielded an ORR of approximately 19% with a median overall survival (OS) of 13.6 months in R/M HNSCC with PD-L1 combined positive score (CPS) of at least 1, reflecting meaningful but limited activity and substantial room for improvement.

The immunosuppressive tumor microenvironment (TME) of HNSCC is characterized by abundant regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), both of which may contribute to primary and secondary resistance to PD-1 blockade. Preclinical evidence indicates that anti–PD-1 antibodies paradoxically induce Treg activation through the AKT pathway, whereas AKT blockade selectively inhibits Treg proliferation relative to conventional T cells and limits MDSC infiltration and differentiation while boosting effector T-cell function within tumors.

Ipatasertib is an orally administered, highly selective small-molecule inhibitor of all 3 AKT isoforms, providing mechanistic rationale for its combination with pembrolizumab in this setting.

Trial Design and Patient Population

In the randomized phase 2 multicenter trial conducted through the California Cancer Consortium and Experimental Therapeutics Clinical Trials Network, and funded by the National Cancer Institute, 52 patients with R/M HNSCC who had received no prior systemic treatment for recurrent or metastatic disease were randomly assigned 1:1 to ipatasertib plus pembrolizumab or pembrolizumab alone.

A PD-L1 CPS score of 1 or higher was required for enrollment, with stratification by CPS (1 to 19 vs 20 or higher). Arm 1 (n = 27) received ipatasertib 400 mg orally once daily on days 1 to 14 plus pembrolizumab 200 mg intravenously on day 1 of 21-day cycles. Arm 2 (n = 25, with 1 patient withdrawing consent before starting treatment; n = 24 treated) received pembrolizumab monotherapy. Mandatory on-treatment biopsies were required during cycle 2 for all patients to support translational objectives including tumor microenvironment immunophenotyping and assessment of AKT, ERK, and MEK signaling changes. The primary end point was PFS; secondary end points included safety, ORR, and duration of response per RECIST 1.1.

The population was predominantly male (77%) with a median age of 67 years (range, 45-85). Primary tumor sites were oral cavity (46%), oropharynx (38%), and larynx (15%). Among oropharynx primary tumors, 75% were p16-positive. Sixty percent of patients had a PD-L1 CPS of 20 or higher and 56% had an ECOG performance status of 1. Demographics were well balanced across arms.

Efficacy Results

As of the January 21, 2026 data cutoff, ORR in the ipatasertib/pembrolizumab arm was 41% (11/27) vs 17% (4/24) in the pembrolizumab arm. Complete response (CR) rates were 15% in the combination arm vs 4.2% in Arm 2. However, as of May 6, 2026, 3 additional patients in the combination arm had converted from partial response to complete response, bringing the CR rate to 26% and the total number of CRs to 7. Disease control rate was 70% in the combination arm vs 42% with pembrolizumab alone.

“We see durable responses both in patients with PD-L1–high and PD-L1–low disease, as well as p16-positive and p16-negative disease,” Thomas said.

With a median follow-up of 7.0 months overall (9 months in the combination arm and 4.4 months in the comparator arm), median PFS was 8.1 months (95% CI, 4-NA) for the combination vs 6.2 months (95% CI, 1.9-13.5) for pembrolizumab monotherapy; the PFS data were not yet mature at this timepoint. The 6-month PFS rate was 62.7% (95% CI, 40.5%-78.6%) vs 52.3% (95% CI, 30.1%-71.8%), respectively. Thomas noted that in KEYNOTE-048, the median PFS was 3.2 months.

Four patients in the combination arm and 2 in the pembrolizumab arm remained on treatment at the data cutoff; 3 completed 24 months of therapy and came off treatment.

Safety and Tolerability

The combination demonstrated an acceptable toxicity profile. Treatment-related adverse events (TRAEs) occurring in at least 10% of patients included diarrhea (70.4%), fatigue (44.4%), and nausea (40.7%), Importantly, only 1 patient experienced grade 3 diarrhea in the combination arm, and generally patients did not need steroids to manage diarrhea. The most common TRAEs in the comparator arm were fatigue in 37.5%, maculo-papular rash in 29.2%, and aspartate aminotransferase elevation in 16.7%. There were no grade 4 or grade 5 TRAEs in either arm.

Four patients required ipatasertib dose reductions, primarily for diarrhea. Ten patients in the combination arm and 6 in the comparator arm required drug interruptions, and 1 patient in each arm discontinued treatment due to adverse events.

Conclusions and Implications

“Pembrolizumab-based therapy remains a standard of care for [R/M HNSCC]. Combination ipatasertib plus pembrolizumab has an acceptable safety profile and in this randomized phase 2 study, combination ipatasertib and pembrolizumab shows promising efficacy with an [ORR] of 41% compared [with] 17% in the pembrolizumab monotherapy arm with a 26% [CR] rate,” Thomas concluded.

Longer follow-up is needed to evaluate durability of the combination, and translational analyses from mandatory on-treatment biopsies, including TME immunophenotyping and AKT pathway signaling data, could identify biomarkers of response to guide patient selection in future studies.

REFERENCE

1. Thomas JS, Bruce JY, Lorch JH, et al. 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. J Clin Oncol. 2026;44(suppl 16):6006. doi:10.1200/JCO.2026.44.16_suppl.6006

2. Harrington KJ, Burtness B, Greil R, et al. Pembrolizumab with or without chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma: updated results of the phase III KEYNOTE-048 study. J Clin Oncol. 2023;41(4):790-802. doi:10.1200/JCO.21.02508