A Phase I, open-label, dose escalation study of MGA271 in combination with pembrolizumab in patients with B7-H3-expressing melanoma, squamous cell cancer of the head and neck, or squamous cell non-small cell lung cancer

Background MGA271 is an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3 (CD276), a member of the B7 family, currently undergoing Phase I testing. The Fc domain is engineered for enhanced binding to the activating FcgR, CD16A, and decreased binding to the inhibitory FcgR, CD32B. B7-H3 has limited expression in normal tissue and high expression in multiple tumors including melanoma (M), squamous cell cancer of the head and neck (SCCHN) and non-small cell lung cancer (NSCLC). The correlation between B7-H3 overexpression and poor prognosis in certain cancers suggests a role for B7-H3 in tumor escape. Despite the clinical success of agents including anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies, the majority of patients with M, SCCHN or NSCLC progress nonetheless, and substantial unmet need exists for these patients. The underlying hypotheses for combining MGA-271 (anti-B7-H3) with pembrolizumab (antiPD-1) are: 1) combining immune-modulating agents may mediate additive or synergistic antitumor activity (e.g. anti-CTLA-4+anti-PD-1), and can do so where neither single agent has pronounced antitumor activity (e.g. antiPD-1+anti-LAG-3), 2) coordinate engagement of both innate and adaptive immunity, 3) both agents may enhance the immune response against tumors via modulation of T cell immunosuppression, and 4) limited expression of B7-H3 on normal tissues may help focus an immune attack on tumors, limiting the risk of immunerelated adverse events (irAEs) resulting from the disruption of self-tolerance, allowing MGA271 to be combined more readily with other immune-modulating agents, including anti-CTLA-4 and anti-PD-1 antibodies. /PD-1 /PD-L1.