Phase 2/3 Randomized Study of Ordastobart (INBRX-106) Add-on to Pembrolizumab in 1L HPV+ PD-L1+ R/M OPSCC (HexAgon-HN)

This seamless phase 2/3 randomized controlled study will evaluate the efficacy and safety of the hexavalent OX40 agonist antibody ordastobart (INBRX-106) combined with the anti-PD-1 antibody pembrolizumab versus pembrolizumab (+ placebo in phase 3) as first-line treatment for patients with recurrent or metastatic (R/M) HPV-positive Oropharyngeal Squamous Cell Carcinoma (HPV+ OPSCC) expressing PD-L1.

Inclusion Criteria: * Has histologically or cytologically confirmed diagnosis of recurrent/metastatic oropharyngeal squamous cell carcinoma (OPSCC) considered incurable by local therapies. * Has tumor PD-L1 expression with a combined proportion score (CPS) ≥1 by central testing. * HPV-positive tumor status as assessed locally by p16 immunohistochemistry (IHC). * Has measurable disease per RECIST 1.1 guidelines. * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Exclusion Criteria: * Has primary tumor site (any histology) of any other location than oropharynx. * Has received prior systemic therapy (eg, prior chemo-, immune-, or biologic therapy) for R/M 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 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. * Active or high risk of tumor-associated bleeding. * Current or history of immune-related disease that required systemic treatment in past 2 years, except for replacement therapy.