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Inhibrx's OX40 agonist nearly doubles response rate versus Keytruda alone in head and neck cancer

Edited by Robert McTiernan··3 min read
Inhibrx's OX40 agonist nearly doubles response rate versus Keytruda alone in head and neck cancer

A hexavalent OX40 agonist that has struggled to find clinical traction across the broader class has now produced the first randomized efficacy signal for an OX40 agonist in a head and neck cancer study, according to primary endpoint results from Inhibrx Biosciences (Nasdaq: INBX). INBRX-106, combined with Merck's Keytruda (pembrolizumab), delivered a 48.3% confirmed objective response rate (cORR) versus 26.5% for pembrolizumab alone in first-line, PD-L1-high (CPS ≥ 20) metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).

The data come from the randomized Phase II portion of the HexAgon study, which enrolled 68 patients across more than 80 sites globally, with 63 evaluable for the primary endpoint analysis. Four patients (13.8%) in the combination arm achieved a complete response; none did in the pembrolizumab monotherapy arm. Interim median progression-free survival (PFS) was 9.6 months for the combination versus 4.9 months for pembrolizumab alone, with six-month PFS rates of 72.4% and 42.8%, respectively. PFS data continue to mature. The most common treatment-related adverse events — rash, fatigue, and diarrhea — were predominantly low grade.

The HPV-positive subgroup showed the most pronounced separation. Among 10 HPV+ patients in the combination arm and 9 in the control arm, the cORR was 80.0% versus 33.3%, the complete response rate 30.0% versus 0%, and the six-month PFS rate 90.0% versus 33.0%. Median PFS in HPV+ patients on the combination had not been reached at the data cutoff of August 19, 2026, compared with 4.6 months for pembrolizumab alone. These are small patient numbers and should be interpreted accordingly, but the magnitude of the difference has prompted Inhibrx to expand the Phase II study by approximately 50 additional HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) patients (CPS ≥ 1) to support a potential accelerated approval pathway.

INBRX-106 targets OX40 (CD134), a costimulatory receptor on T cells. Inhibrx's single-domain antibody platform enables a hexavalent format designed to achieve the high-order receptor clustering required for robust T-cell activation — a configuration that prior bivalent OX40 agonists have not reproducibly delivered in clinical settings. Where checkpoint inhibitors release a brake on T-cell activity, OX40 agonism presses the accelerator, and the two approaches are mechanistically complementary.

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These results build on earlier interim data reported in May 2026 showing a 44.0% cORR versus 21.4% for pembrolizumab alone in a smaller evaluable population. The updated primary endpoint analysis, with more patients and longer follow-up, reinforces that signal. Earlier OX40 agonists have generally failed to show convincing clinical efficacy, with most using conventional bivalent antibody formats.

Pembrolizumab monotherapy is the established standard of care for first-line PD-L1-high HNSCC, based on the KEYNOTE-048 trial, where it demonstrated meaningful survival benefits over chemotherapy in this enriched subgroup. No approved IO-IO or IO-costimulatory agonist combination exists in this setting. Genmab/Merus's petosemtamab, an EGFR×LGR5 bispecific antibody, has received FDA Breakthrough Therapy Designation in combination with pembrolizumab for PD-L1-positive HNSCC and is in Phase III, representing the most clinically advanced competing program.

Inhibrx said it plans to align with the FDA on an accelerated approval framework following the Phase II expansion, then initiate the Phase III portion of HexAgon as a confirmatory study. The company is also running a Phase I/II study of INBRX-106 in perioperative non-small cell lung cancer, with initial results targeted for mid-2027, and plans to explore combinations with therapeutic cancer vaccines. The company's separate pipeline asset, ozekibart (INBRX-109), a tetravalent DR5 agonist, has a BLA under FDA review for conventional chondrosarcoma with a PDUFA date of April 14, 2027.

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