Background: Enoblituzumab, an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3 (CD276), a member of the B7 family, is currently in Phase 1 testing. Enoblituzumab is Fc-engineered with 5 amino acid substitutions to enhance binding to the activating FcγR and decrease binding to the inhibitory FcγR. B7-H3 has limited expression in normal tissue but high expression in many cancers including melanoma (M), squamous cell cancer of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC). B7-H3 overexpression correlates with poor prognosis in a broad range of cancers suggesting a potential role in enabling tumor immune escape. The hypotheses for combining enoblituzumab with pembrolizumab are: 1) immune-modulating agent combinations may mediate additive or synergistic antitumor activity and in tumors where neither single agent alone has substantial anti-tumor effect, 2) engagement of both innate and adaptive immunity, 3) targeting both B7-H3 and PD-1 may enhance the immune response against tumors via modulation of T-cell immunosuppression, 4) limited expression of B7-H3 on normal tissues may limit the risk of auto-immune related adverse events; thus enoblituzumab may be combined more readily with immune-modulating agents. Methods: This Phase 1 trial is a dose escalation/cohort expansion study (NCT02475213) enrolling patients with advanced B7-H3 expressinors. The escalation phase uses a 3+3+3 plan to enroll successive cohorts of patients with escalating doses of weekly intravenous (IV) enoblituzumab starting at 3 mg/kg, and 2 mg/kg IV pembrolizumab administered every 3 weeks. Response is first determined at 6 weeks and followed by irRECIST; based on response, both drugs will be given up to 1 year. A 3-cohort expansion phase will open at the established maximum tolerated dose (16 patients each) with M, SCCHN, and NSCLC. Progression on previous checkpoint inhibitor is allowed. Study objectives are the characterization of safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the combination. This is the first clinical trial evaluating combined targeting of B7-H3 and PD-1 in patients with advanced cancer. Enrollment is ongoing. Clinical trial information: NCT02475213