National Cancer Institute and Merck KGaA.

Purpose: M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against programmed death ligand 1 (PD-L1) fused to a transforming growth factor-β (TGF-β) "trap."Experimental Design: In the 3+3 dose-escalation component of this phase 1 study (NCT02517398), eligible patients with advanced solid tumors received M7824 at 1, 3, 10, or 20 mg/kg once-every-2-weeks until confirmed progression, unacceptable toxicity, or trial withdrawal; additionally, a cohort received an initial 0.3 mg/kg dose to evaluate pharmacokinetics/pharmacodynamics (PK/PD), followed by 10 mg/kg dosing. The primary objective is to determine the safety and maximum tolerated dose (MTD); secondary objectives include PK, immunogenicity, and best overall response. Results:Nineteen heavily pretreated patients with ECOG 0-1 have received M7824. Grade ≥3 treatment-related adverse events occurred in 4 patients (skin infection secondary to localized bullous pemphigoid, asymptomatic lipase increase, colitis with associated anemia, and gastroparesis with hypokalemia). The MTD was not reached. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-β1, -β2, and -β3 throughout the dosing period at >1 mg/kg. There were signs of efficacy across all dose levels, including 1 ongoing confirmed complete response (cervical cancer), 2 durable confirmed partial responses (PRs; pancreatic cancer; anal cancer), 1 near-PR (cervical cancer), and 2 cases of prolonged stable disease in patients with growing disease at study entry (pancreatic cancer; carcinoid). Conclusions STATEMENT OF TRANSLATIONAL RELEVANCEExcitement surrounding the durable benefits associated with PD-1/PD-L1-targeted therapy has been tempered somewhat by responses being confined to only a subset of patients.To increase the rate of response, many ongoing trials are evaluating anti-PD-1/PD-L1 agents in combination with other immunotherapies; however, these combination strategies have limitations and novel approaches are required. M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused to a TGF-β "trap." We report the first clinical data for M7824 -including pharmacokinetics, safety, and efficacy findings -which derive from a phase 1 dose-escalation study in patients with advanced solid tumors. M7824 saturated peripheral PD-L1 and sequestered any released plasma TGF-β throughout the dosing period at a dose >1 mg/kg. M7824 appeared to have a manageable safety profile and early evidence of clinical efficacy -including 1 ongoing confirmed complete response and 2 durable confirmed partial responses -was demonstrated.

The nuclear transcription factor brachyury has previously been shown to be a strong mediator of the epithelial-to-mesenchymal transition (EMT) in human carcinoma cells and a strong negative prognostic factor in several tumor types. Brachyury is overexpressed in a range of human carcinoma as well as in chordoma, a rare tumor for which there is no standard systemic therapy. Preclinical studies have shown a recombinant Saccharomyces cerevisiae (yeast) vaccine encoding brachyury (GI-6301) can activate human T cells in vitro. A Phase I dose escalation (3+3 design) trial enrolled 34 patients at 4 dose levels (3, 3, 16, and 11 patients, respectively, at 4, 16, 40, and 80 yeast units (YU)). Expansion cohorts were enrolled at 40 and 80 YU dose levels for analysis of immune response and clinical activity. We observed brachyury-specific T-cell immune responses in the majority of evaluable patients despite most having been heavily pretreated. No evidence of autoimmunity or other serious adverse events were observed. Two chordoma patients showed evidence of disease control (one mixed response and one partial response). A patient with colorectal carcinoma, who enrolled on study with a large progressing pelvic mass and rising CEA, remains on study for greater than 1 year with stable disease, evidence of decreased tumor density and decreased serum CEA. This study is the first-in-human to demonstrate the safety and immunogenicity of this therapeutic cancer vaccine and provides rationale for exploration in Phase II studies. A randomized Phase II chordoma study is enrolling.