A Comprehensive Multiomic Biomarker Evaluation Across Two Single-arm Cohorts to Elucidate Mechanisms of Response and Resistance in Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC)

Exclusion criteria

• . Participants with non-squamous histologies (e.g., adenocarcinoma, salivary gland carcinomas, and sarcomas) or HNSCC arising from the nasopharynx or paranasal sinuses are excluded. Participants with unknown primary tumors (even if squamous histology is confirmed) are also excluded.
• . Has ongoing adverse reaction(s) from prior therapy that have not recovered to ≤Grade 1 or to the baseline status preceding prior therapy (excluding, for example, alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 neuropathy), or that the Investigator, with the agreement of the Study PI, considers to be not clinically relevant for the tolerability of study intervention in the current clinical study.
• . Any participation in another investigational study within 4 weeks prior to screening.
• . Prior treatment with orlotamab, enoblituzumab, I-Dxd, or other B7-H3 targeted agents.
• . Has a history of autoimmune disease that has required systemic treatments in the 2 years prior to screening.
• . Serious arteriovenous thromboembolic events (such as deep vein thrombosis, pulmonary embolism, etc.) within 3 months prior to the first dose (w/exceptions)
• . Evidence of brain metastasis unless all the following criteria are met:
• . History of another primary solid tumor except for the following: