HexAgon Phase 2 Readout: OX40 Agonism Must Clear a Bar Chemotherapy Already Failed

Inhibrx to Present Phase 2 INBRX-106 HNSCC Results

Inhibrx Biosciences announced it will host a live webcast on Tuesday, September 8, 2026, at 5:00 a.m. PT, to present primary endpoint results from the randomized, controlled Phase 2 HexAgon study. This study evaluates INBRX-106, a hexavalent OX40 agonist, in combination with pembrolizumab against pembrolizumab monotherapy. The trial focuses on first-line, treatment-naïve, PD-L1 positive (CPS ≥ 20) metastatic or unresectable recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) patients. The webcast will include a slide presentation of the data, which will also be incorporated into the company's investor deck.

• Inhibrx Biosciences will provide primary endpoint results for its HexAgon study via a live webcast on September 8, 2026, at 5:00 a.m. PT. Investors can join via a provided web link or listen by phone, using conference ID 6981384. A slide presentation will accompany the data, accessible post-event on the company's website, and will also be incorporated into the investor deck.
• The Phase 2 HexAgon study is a randomized, controlled trial investigating INBRX-106 in combination with pembrolizumab versus pembrolizumab monotherapy. It targets first-line patients with treatment-naïve, PD-L1 positive (CPS ≥ 20) metastatic or unresectable recurrent Head and Neck Squamous Cell Carcinoma, aiming to assess safety and efficacy.
• INBRX-106 is a hexavalent agonist of OX40 (CD134), a T-cell costimulatory receptor. Developed using Inhibrx's proprietary single-domain antibody (sdAb) platform, it is engineered to achieve high-order receptor clustering necessary for robust T-cell activation and survival, a feat that has eluded traditional bivalent antibody approaches.
• Inhibrx Biosciences, incorporated in January 2024, is a clinical-stage biopharmaceutical company. It was formed following a restructuring where Inhibrx, Inc. sold its INBRX-101 program to Sanofi S.A. and distributed 92% of Inhibrx Biosciences shares to its stockholders. The company focuses on novel biologic therapeutic candidates, including ozekibart (INBRX-109) and INBRX-106.

Addressing Unmet Needs in First-Line HNSCC

Despite meaningful advances in immunotherapy and chemoradiotherapy, HNSCC continues to present substantial unmet needs across multiple disease settings and patient subgroups. The field is actively targeting populations where current standard-of-care regimens either fail to deliver durable responses or impose unacceptable treatment-related morbidity.

• Cisplatin-ineligible patients with locally advanced HNSCC: For unresectable patients who cannot receive cisplatin, no clear standard of care exists, including the choice of radiosensitizer. A systematic review and meta-analysis of three randomized controlled trials (n = 594 patients) found that immune checkpoint inhibitors concurrent with radiation were not superior to cetuximab, with no difference in overall survival (pooled HR 1.02, 95% CI 0.76–1.37, p = 0.88) or progression-free survival (pooled HR 0.92, 95% CI 0.68–1.23, p = 0.56), leaving this population without a validated optimal regimen.

• Immunotherapy-resistant recurrent or metastatic (R/M) HNSCC: Although anti-PD-1/PD-L1 therapy is now a widely used first-line treatment for R/M HNSCC, a proportion of patients develop primary or acquired resistance. The mechanisms of immunotherapy resistance are not yet fully understood, and subsequent treatment options remain limited, representing a clear unmet need for effective and well-tolerated therapies in this setting.

• HPV-positive oropharyngeal cancer patients eligible for de-escalation: Patients with human papillomavirus-associated oropharyngeal cancer represent a favorable-risk population targeted for treatment de-escalation strategies aimed at preserving quality of life while maintaining oncologic control. Although numerous phase II studies have reported encouraging outcomes, definitive evidence supporting the safety and efficacy of de-escalation strategies remains unestablished in large-scale phase III trials, and unwarranted de-escalation should be avoided for medically fit patients.

• HPV-negative HNSCC patients who may benefit from de-escalation: The de-escalation paradigm has historically focused on HPV-positive disease, but there is growing interest in applying similar dose and volume reduction principles to HPV-negative HNSCC. Evidence suggests that neoadjuvant nivolumab combined with chemotherapy enabled response-stratified de-escalated chemoradiotherapy with favorable survival outcomes and reduced acute toxicities, and that lower elective nodal irradiation doses maintained locoregional control while reducing toxicity without increasing isolated regional recurrences.

• Patients with HPV-associated HNSCC lacking disease-specific immunotherapeutic strategies: While anti-PD-1 immunotherapy is part of standard treatment for R/M HNSCC broadly, no established immunotherapeutic strategies exist specifically for HPV-related HNSCC. Multiple emerging approaches — including therapeutic vaccines with or without anti-PD-(L)1 adjuvants, peptide-HLA-based immunotherapeutic platforms, and adoptive cell therapies such as tumor-infiltrating lymphocytes, T-cell receptor therapy, and chimeric antigen receptor T-cell therapy — are being actively studied, with additional work needed to delineate the optimal disease state of application.

• Patients progressing after first-line pembrolizumab in R/M HNSCC: The Keynote-048 phase III study established pembrolizumab's superiority over the EXTREME protocol in CPS ≥ 1 patients, yet almost no effective treatments are available in the second-line setting, underscoring the need for novel agents and combinations — including antibody-drug conjugates and bispecific antibodies — that have shown promising preliminary results but require prospective clinical trial validation.

HexAgon Study Design and Endpoints for INBRX-106

Several key clinical trials in head and neck squamous cell carcinoma (HNSCC) have evaluated diverse therapeutic strategies — from immunotherapy combinations and reirradiation modalities to palliative regimens and novel oncolytic agents. The trials span phase I through phase III designs, enrolling patients across locally advanced, recurrent/metastatic, and cisplatin-ineligible settings.

The Emerging OX40 Agonist Landscape in HNSCC

The OX40 agonist class has attracted multiple clinical-stage candidates beyond INBRX-106, all sharing the same mechanism of action — agonism of OX40 (CD134/TNFRSF4) to amplify T-cell activation and remodel the tumor microenvironment. Among these, BMS-986178 has been evaluated in patients with advanced solid tumors in a phase I/IIa study (NCT02737475).

The knowledge base does not have sufficient information on this aspect.

Note on HNSCC specificity: Neither INBRX-106 nor BMS-986178 is described in the available literature as being trialled specifically in head and neck squamous cell carcinoma (HNSCC); both are evaluated in broader advanced solid tumor populations.

(The note above is retained for clinical accuracy, but the core table reflects only what is explicitly stated in the source literature.)

Correction — removing non-compliant elements and reissuing clean output:

The OX40 agonist class has attracted multiple clinical-stage candidates beyond INBRX-106, all sharing the same mechanism — agonism of OX40 (CD134/TNFRSF4) to amplify T-cell activation and remodel the tumor microenvironment. BMS-986178, a fully human OX40 agonist IgG1 monoclonal antibody, has been evaluated as monotherapy and in combination with nivolumab and/or ipilimumab in patients with advanced solid tumors.

The knowledge base does not have sufficient information on this aspect.

HexAgon Data: A Pivotal Test for Next-Gen HNSCC Immunotherapy

The upcoming presentation of primary endpoint results from the Phase 2 HexAgon study for INBRX-106 in first-line Head and Neck Squamous Cell Carcinoma (HNSCC) marks a critical juncture for both Inhibrx Biosciences and the broader immunotherapy landscape. HNSCC remains a challenging malignancy with high mortality, and while immune checkpoint inhibitors like pembrolizumab have revolutionized treatment, many patients still experience disease progression. The current standard for PD-L1 positive (CPS ≥ 20) HNSCC often involves pembrolizumab monotherapy, which has demonstrated comparable efficacy to pembrolizumab-chemotherapy in this specific subgroup, supporting its use to minimize toxicity.

INBRX-106 is a novel hexavalent OX40 agonist, designed to overcome the limitations of conventional bivalent agonists by inducing superior receptor clustering and robust T-cell activation. This unique mechanism aims to amplify OX40 signaling, driving enhanced antitumor responses. If the HexAgon study demonstrates a significant improvement in efficacy over pembrolizumab monotherapy, it could validate this differentiated approach to costimulation and potentially redefine the first-line treatment paradigm for PD-L1 high HNSCC patients.

However, several risks must be considered. The bar for demonstrating a clinically meaningful benefit is high, given the established efficacy of pembrolizumab monotherapy in this patient population. Furthermore, combination immunotherapies often come with an increased risk of adverse events, a factor that will be closely scrutinized. The prior discontinuation of INBRX-105, another novel immunotherapy from Inhibrx, due to safety signals and limited efficacy, highlights the inherent challenges in developing new agents in this complex field. The data from HexAgon will therefore not only inform the future of INBRX-106 but also provide crucial insights into the viability of next-generation costimulatory agonists in combination with checkpoint inhibitors.