HexAgon-HN: Phase 2/3, randomized study of the hexavalent OX40 agonist INBRX-106 in combination with pembrolizumab vs pembrolizumab alone as first-line treatment for recurrent/metastatic head and neck cancer with a PD-L1 combined positive score of ≥20.
Authors: Jong Chul Park, Lisa F. Licitra, Aditya V. Shreenivas, Yungpo Su, Santosh M. Nair, Andrea S. Teague, Douglas Adkins, Siddharth Sheth, Hye Ryun Kim, Jorge Martinalbo, Yaiza Diaz De Durana, Lane Senne, James Kalabus, Josep Garcia, Dan Paul Zandberg
Journal: Journal of Clinical Oncology (2025)

TPS6109 Background: Pembrolizumab (pembro) ± chemotherapy is a standard-of-care first-line treatment option for recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Pembro monotherapy is commonly used in patients with a PD-L1 combined positive score (CPS) of ≥20, with an objective response rate (ORR) of &lt;25% and median overall survival (OS) of &lt;15 months. 1 Therefore, a high unmet need exists for more effective, non–chemotherapy-based treatment options. INBRX-106 is a novel, hexavalent OX40 agonist designed to promote higher-order clustering of the costimulatory receptor OX40, leading to more potent agonism than the bivalent first generation of OX40 agonists. Combining INBRX-106 with pembro may amplify and prolong the antitumor immune response. In an ongoing phase 1/2 study (NCT04198766), INBRX-106 + pembro has demonstrated robust pharmacodynamics, a favorable safety profile, and promising clinical activity in multiple tumor types, including R/M HNSCC. These findings supported the initiation of HexAgon-HN (NCT06295731), a phase 2/3, randomized study evaluating INBRX-106 + pembro vs pembro alone as first-line treatment for R/M HNSCC with a PD-L1 CPS of ≥20. Methods: Eligible patients must have biopsy-confirmed R/M HNSCC that is considered incurable; a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx; no previous receipt of therapy for R/M disease; a centrally confirmed PD-L1 CPS of ≥20; measurable disease per RECIST 1.1; and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Prior curative-intent treatment for locoregionally advanced HNSCC is allowed if progressive disease occurred ≥6 months (≥12 months if immunotherapy) after completion of treatment. Up to 410 patients will be randomized 1:1 (stratified by locoregional advanced vs distant metastatic disease, HPV status, and ECOG PS) to INBRX-106 + pembro 200 mg every 3 weeks or pembro (alone in the open-label, phase 2 part or in combination with placebo in the double-blind, phase 3 part). If the phase 2 part (N≈60) shows favorable results for the primary efficacy endpoint (ORR) and secondary safety and efficacy endpoints (eg, duration of response [DOR], progression-free survival [PFS] rate at 6 months, and clinical benefit rate [CBR]), the study can seamlessly proceed to the phase 3 part. The phase 3 part (N≈350) has dual primary efficacy endpoints of PFS and OS; secondary endpoints include ORR, DOR, CBR, time to chemotherapy, safety, and patient-reported quality of life. This study is currently enrolling in the US (30 sites), Europe (40 sites), and Asia-Pacific region (15 sites). 1. Burtness B, et al. Lancet . 2019;394:1915-1928. Clinical trial information: NCT06295731 .