INBRX-106 Plus Pembrolizumab Improves Responses and PFS in First-Line PD-L1–Positive HNSCC

The addition of the hexavalent OX40 agonist INBRX-106 to pembrolizumab (Keytruda) improved confirmed objective response rate (cORR) and progression-free survival (PFS) vs pembrolizumab alone as first-line treatment for patients with treatment-naive, PD-L1–positive (combined positive score [CPS] ≥20) metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC), according to updated data from the randomized phase 2 portion of the phase 2/3 HexAgon-HN trial (NCT06295731).¹ The benefit was most pronounced among patients with HPV-positive disease.

As of an August 19, 2026, data cutoff, 63 of the 68 patients enrolled in the randomized phase 2 portion were evaluable for efficacy. The cORR was 48.3% in the INBRX-106 arm (n = 29) vs 26.5% in the pembrolizumab monotherapy arm (n = 34). The complete response (CR) rate was 13.8% (n = 4) with the combination vs 0% in the control arm. At an interim analysis, median PFS was 9.6 months vs 4.9 months, respectively, and the 6-month PFS rates were 72.4% vs 42.8%.

Among patients with HPV-positive disease, the cORR was 80.0% with INBRX-106 plus pembrolizumab (n = 10) vs 33.3% with pembrolizumab alone (n = 9). In this subgroup, 30.0% of patients in the combination arm achieved a CR compared with none in the control arm. The 6-month PFS rate was 90.0% vs 33.0%, and median PFS was not yet reached vs 4.6 months, respectively.

Earlier interim data from the phase 2 portion, reported in May 2026, showed a cORR of 44.0% with the combination (n = 25) vs 21.4% with pembrolizumab alone (n = 28).²

How was HexAgon-HN designed?

HexAgon-HN is a seamless, randomized phase 2/3 study evaluating INBRX-106 plus pembrolizumab vs pembrolizumab (plus placebo in the phase 3 portion) in patients with recurrent or metastatic HNSCC that is incurable by local therapies and expresses PD-L1 at a CPS of at least 20.³ In the phase 2 portion, patients received intravenous INBRX-106 plus intravenous pembrolizumab at 200 mg (n = 33) or pembrolizumab alone (n = 35) every 3 weeks.² The phase 2 portion is open label, and the phase 3 portion is planned to be double blind.³

Eligible patients were at least 18 years of age; had histologically or cytologically confirmed HNSCC with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx; had measurable disease per RECIST 1.1 criteria and an ECOG performance status of 0 or 1; and had p16 immunohistochemistry–based HPV testing results for oropharyngeal tumors. Prior systemic therapy given with curative intent for locoregionally advanced disease was permitted if it was completed more than 6 months before consent and recurrence did not occur within 6 months of completion; prior anti–PD-(L)1 therapy in this setting was permitted if recurrence occurred at least 12 months after completion.³

Key exclusion criteria included a nasopharyngeal, salivary gland, or occult primary tumor; prior systemic therapy for locally advanced unresectable or metastatic disease; clinically active central nervous system metastases or carcinomatous meningitis; immunodeficiency or systemic immunosuppressive therapy within 7 days of the first dose; rapidly progressing disease; and immune-related disease requiring systemic treatment within the past 2 years.³

ORR per RECIST 1.1 serves as the primary end point of the phase 2 portion, and PFS and overall survival are the primary end points of the phase 3 portion. Secondary end points include duration of response, clinical benefit rate, time to chemotherapy, time to confirmed deterioration in patient-reported pain and functioning, ORR in the phase 3 portion, and safety. The trial has a planned enrollment of 410 patients, with an estimated completion date of May 2029.³

What did the safety analysis show?

The most common treatment-related adverse effects (TRAEs) with the combination were rash, fatigue, and diarrhea, which were predominantly low grade.¹ Rates of grade 3 or higher TRAEs and treatment discontinuations were not reported.

What are the next steps for INBRX-106?

Inhibrx plans to expand the randomized phase 2 portion of HexAgon-HN by approximately 50 additional patients with HPV-positive oropharyngeal squamous cell carcinoma with a CPS of at least 1 to support a potential accelerated approval pathway. Following the expansion, the company plans to align with the FDA and initiate the phase 3 portion of the trial as a confirmatory study.¹ The company is also evaluating INBRX-106 in a phase 1/2 perioperative study in non–small cell lung cancer, with results expected by mid-2027, and exploring combinations with therapeutic cancer vaccines.

“What is most exciting to us is the depth and durability of the responses we are seeing with INBRX-106, particularly in HPV[-positive] disease,” Mark Lappe, cofounder and chief executive officer of Inhibrx, said in the news release. “These results strengthen our conviction in OX40-mediated T-cell costimulation and give us a strong rationale to expand the program, not only into HPV[-positive] disease, but also to explore the potential of INBRX-106 in other highly immunogenic tumors and in combination with cancer vaccines.”

References

1. Inhibrx’s INBRX-106 nearly doubles response rate and achieves interim median PFS of 9.6 months in phase 2 HNSCC study. News release. Inhibrx Biosciences, Inc. September 8, 2026. Accessed October 2, 2026. https://inhibrxbiosciences.investorroom.com/2026-09-08-Inhibrxs-INBRX-106-Nearly-Doubles-Response-Rate-and-Achieves-Interim-Median-PFS-of-9-6-months-in-Phase-2-HNSCC-Study
2. INBRX-106 Plus Pembrolizumab Yields Efficacy Benefit vs Pembrolizumab Alone in First-Line HNSCC. OncLive. Published May 11, 2026. Accessed October 2, 2026. https://www.onclive.com/view/inbrx-106-plus-pembrolizumab-yields-efficacy-benefit-vs-pembrolizumab-alone-in-first-line-hnscc
3. INBRX-106 in combination with pembrolizumab in first-line PD-L1 CPS≥20 HNSCC (HexAgon-HN). ClinicalTrials.gov. Updated May 8, 2026. Accessed October 4, 2026. https://clinicaltrials.gov/study/NCT06295731