Preliminary results from a phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in advanced solid tumors.

<jats:p> 3006 </jats:p><jats:p> Background: M7824 (MSB0011359C) is a novel bifunctional fusion protein comprised of a fully human IgG1 monoclonal antibody against programmed death ligand 1 (PD-L1) fused to the soluble extracellular domain of transforming growth factor-β (TGF-β) receptor II, which acts as a TGF-β trap. We report preliminary data from a phase 1 trial of M7824 in patients (pts) with advanced solid tumors. Methods: NCT02517398 is a phase 1, open-label, 3+3 dose-escalation study. Eligible pts receive M7824 at 1, 3, 10, or 20 mg/kg Q2W until confirmed progressive disease, unacceptable toxicity, or trial withdrawal; treatment beyond progression is generally allowable. The primary objective is to determine the safety and maximum tolerated dose of M7824; secondary objectives include pharmacokinetics (PK), immunogenicity, and best overall response per RECIST v1.1. Results: 16 heavily pretreated pts with ECOG performance status 0-1 have received M7824. Our PK data show a dose-linear increase in exposure starting at a dose of 3 mg/kg; furthermore, M7824 saturates peripheral PD-L1 and sequesters any released plasma TGF-β1, -β2, and -β3 throughout the dosing period in a dose-dependent manner. Grade 3 drug-related treatment-emergent adverse events (TEAEs) occurred in 3 pts (skin infection secondary to grade 2 bullous pemphigoid [BP], lipase increased, and colitis with associated anemia); there were no grade 4-5 drug-related TEAEs. BP and colitis responded well to steroids. Colitis and its secondary events of anemia and rectal hemorrhage (in a previously radiated area) were considered dose limiting in 1 pt. There was preliminary evidence of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical), 1 durable partial response (pancreatic), a 25% reduction in the sum of diameters of target lesions after 2 doses of M7824 (cervical), and 2 cases of prolonged stable disease (pancreatic; carcinoid). Conclusions: Preliminary data from this phase 1 dose-escalation study suggest that M7824 has a manageable safety profile in pts with heavily pretreated advanced solid tumors. Early signs of clinical efficacy warrant further study. Clinical trial information: NCT02517398. </jats:p>