[] Preliminary results from a phase 1 trial of M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-beta, in advanced solid tumors. 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-beta (TGF-beta) receptor II, which acts as a TGF-beta trap. We report preliminary data from a phase 1 trial of M7824 in patients with advanced solid tumors. NCT02517398 is a phase 1, open-label, 3+3 dose-escalation study. Eligible patients 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. Sixteen heavily pretreated patients 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-beta1, -beta2, and -beta3 throughout the dosing period in a dose-dependent manner. Grade 3 drug-related treatment-emergent adverse events (TEAEs) occurred in three patients (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 one patient. There was preliminary evidence of efficacy across all dose levels, including one ongoing confirmed complete response (cervical), one durable partial response (pancreatic), a 25% reduction in the sum of diameters of target lesions after two doses of M7824 (cervical), and two cases of prolonged stable disease (pancreatic; carcinoid). Preliminary data from this phase 1 dose-escalation study suggest that M7824 has a manageable safety profile in patients with heavily pretreated advanced solid tumors. Early signs of clinical efficacy warrant further study. As a consequence of these studies, Phase 2 and 3 studies showed evidence of clinical benefit in a range of human cancers. Avelumab has now been approved by the FDA for the therapy of Merkel cell carcinoma and bladder carcinoma. Phase 3 studies are ongoing in other cancer indications.
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