This seamless phase 2/3 randomized controlled study will evaluate the efficacy and safety of the hexavalent OX40 agonist antibody INBRX-106 combined with the anti-PD-1 antibody pembrolizumab versus pembrolizumab (+ placebo in phase 3) as first-line treatment for patients with locally advanced recurrent or metastatic head and neck squamous cell carcinoma (R/M HSNSCC) incurable by local therapies, expressing PD-L1 with a combined proportion score (CPS) ≥20.

Inclusion Criteria:

• Has histologically or cytologically confirmed diagnosis of metastatic, recurrent head and neck squamous cell carcinoma (HNSCC) that is considered incurable by local therapies.
• Has tumor PD-L1 expression of CPS ≥20. Tumor tissue must be provided for PD-L1 biomarker analysis.
• Has human papilloma virus (HPV) testing results for oropharyngeal cancer by p16 immunohistochemistry (IHC) testing.
• Has measurable disease per RECIST 1.1 guidelines.
• Has the primary tumor location of the oral cavity, oropharynx, hypopharynx, or larynx.
• Has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
• Female patients of childbearing potential must have a negative highly sensitive pregnancy test within 72 hours prior to randomization and must not be breastfeeding.
• Male and female patients of childbearing potential must be willing to completely abstain from heterosexual sex or agree to use a highly effective method of contraception.

Exclusion Criteria:

• Has primary tumor site (any histology) of nasopharynx or salivary glands or occult primary site.

• Has received prior systemic therapy (eg, prior chemo-, immune-, or biologic therapy) for locally advanced unresectable or metastatic HNSCC.

  • Prior systemic therapy completed >6 months prior to signing informed consent is allowed if given as part of multimodal treatment for locoregionally advanced disease with curative intent, and no PD/recurrence occurred within 6 months of its completion. Prior systemic immunotherapy in the locoregionally advanced disease with curative intent, including but not limited to anti-PD-(L)1 agents, is allowed if PD/recurrence occurred ≥12 months after its completion.

• Has clinically active central nervous system metastases and/or carcinomatous meningitis.

• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.

• Rapidly progressing disease or with features that may confer a high risk of tumor-associated hemorrhage or uncontrolled tumor pain.

• Current or history of immune-related disease that required systemic treatment in past 2 years, except for replacement therapy.

Phase 2: open label; Phase 3: double-blind