First-line treatment with the hexavalent OX40 agonist INBRX-106 in combination with pembrolizumab (Keytruda) generated higher rates of confirmed responses vs pembrolizumab monotherapy in patients with PD-L1–positive metastatic or unresectable head and neck squamous cell carcinoma (HNSCC), according to findings from an interim analysis of the phase 2 portion of the phase 2/3 HexAgon-HN trial (NCT06295731).1
Among preliminarily confirmed response–evaluable patients (n = 53), the confirmed overall response rate was 44.0% with INBRX-106 plus pembrolizumab (n = 25) vs 21.4% with pembrolizumab monotherapy (n = 28; absolute increase, 22.6%), at a data cutoff of May 7, 2026. Additionally, patients who received the combination achieved deeper overall tumor reductions; most of these patients achieved target lesion shrinkage of more than 50%, and 3 patients experienced complete radiographic response. Investigators did not observe any complete responses (CRs) in the control arm.
Peripheral blood analysis demonstrated up to a 15-fold increase in CD8- and CD4-positive T-cell proliferation in patients treated with the combination, as well as up to a 4-fold increase in T-cell activation. These increases were 2.5-fold and 1.5-fold, respectively, among patients who received pembrolizumab alone. These findings have been deemed consistent with the expected mechanism of action of INBRX-106.
The preliminary safety profile of the combination was also reported to be manageable and consistent with the safety profile of an immunotherapy combination consisting of an active immunostimulatory agent and a checkpoint inhibitor. The most common treatment-related adverse effects included diarrhea, fatigue, rash, and infusion-related reactions, which were mostly low grade. No treatment-related deaths have been reported in either group.
Baseline prognostic factors have been reported to be balanced between the 2 arms.
“The interim data from the phase 2 portion of the study evaluating INBRX-106 plus pembrolizumab appear encouraging, demonstrating higher response rates vs the pembrolizumab monotherapy control arm, including 3 CRs, supported by evidence of immune-cell expansion, although the data are still maturing and the final analysis of the phase 2 cohort remains pending,” Jong Chul Park, MD, of Massachusetts General Hospital in Boston, said to OncLive®. “Importantly, the CPS of at least 20 population more closely reflects real-world pembrolizumab monotherapy use than many competing first-line studies.”
What is the design of the HexAgon-HN study?
The phase 2 portion of this randomized study enrolled 68 patients with treatment-naive, metastatic or unresectable HNSCC with a PD-L1 combined positive score of at least 20. Patients needed to have a known human papillomavirus status for oropharyngeal cancer by p16 immunohistochemistry testing; measurable disease per RECIST 1.1 criteria; a primary tumor location in the oral cavity, oropharynx, hypopharynx, or larynx; and an ECOG performance status of 0 or 1.2
HexAgon-HN Trial Highlights
- The combination of the OX40 agonist INBRX-106 and pembrolizumab generated a higher ORR and a higher increase in CD8- and CD4-positive T-cell proliferation and activation compared with pembrolizumab monotherapy in patients with treatment-naive, PD-L1–positive HNSCC.
- Preliminary data show a manageable safety profile for the combination regimen, with no treatment-related deaths and common adverse effects being mostly low-grade.
- Progression-free survival data and the initiation of the phase 3 portion of the trial are expected in late 2026.
Patients received intravenous (IV) INBRX-106 plus IV pembrolizumab (n = 33) or pembrolizumab alone (n = 35) every 3 weeks. Pembrolizumab was administered at 200 mg.
ORR served as the primary end point of the phase 2 portion. The trial is also investigating duration of response, clinical benefit rate, quality of life, and safety.
What are the next steps for INBRX-106 development in HNSCC?
Notably, additional patients across both arms of HexAgon-HN have active unconfirmed responses and ongoing tumor reductions or increases.1 These patient outcomes are expected to be included in the final efficacy dataset, to be presented at a later date.
Progression-free survival findings from the phase 2 portion of HexAgon-HN are planned to be presented in the fourth quarter of 2026. Additionally, the initiation of the phase 3 portion of the trial is expected during the third quarter of 2026.
“We are greatly encouraged by these early clinical results,” Mark Lappe, chief executive officer of Inhibrx, the developer of INBRX-106, stated in a news release. “These data, coupled with the clear evidence of T-cell expansion and superior depth of response, give us confidence that INBRX-106 could be the first costimulatory agent to fundamentally shift the efficacy ceiling of immunotherapy, and open the door to combinations with new modalities that could be enhanced by OX40 agonism.”
References
- Inhibrx reports interim phase 2 data for INBRX-106 in first-line HNSCC; initial results demonstrate potential costimulatory benefit over PD-1 monotherapy. News release. Inhibrx Biosciences, Inc. May 11, 2026. Accessed May 11, 2026. https://inhibrxbiosciences.investorroom.com/2026-05-11-Inhibrx-Reports-Interim-Phase-2-Data-for-INBRX-106-in-First-Line-HNSCC-Initial-Results-Demonstrate-Potential-Costimulatory-Benefit-Over-PD-1-Monotherapy
- INBRX-106 in combination with pembrolizumab in first-line PD-L1 CPS≥20 HNSCC (HexAgon-HN). ClinicalTrials.gov. Updated May 8, 2026. Accessed May 11, 2026. https://clinicaltrials.gov/study/NCT06295731
