Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors

Abstract

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.

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…Additionally, an extremely promising strategy to target TGF‐β involves using a bispecific antibody against PD‐L1 or CTLA‐4 with a TGF‐β trap . Dramatic responses were observed with this drug in cervical cancers and pancreatic cancers, with an ongoing study including multiple expansion cohorts . In sarcomas, the role of TGF‐β is largely unexplored, though importance of stromal impact and crosstalk has been theorized preclinically in synovial sarcomas and osteosarcomas, where TGF‐β could play an important role in metastasis …”

“…As a result of the broad impacts of TGF-β, increasing efforts to- with an ongoing study including multiple expansion cohorts. 98 In sarcomas, the role of TGF-β is largely unexplored, though importance of stromal impact and crosstalk has been theorized preclinically in synovial sarcomas and osteosarcomas, where TGF-β could play an important role in metastasis. 99,100…”

Combination systemic therapies with immune checkpoint inhibitors in pancreatic cancer: overcoming resistance to single‐agent checkpoint blockade

“…Combination durvalumab and tremelimumab, however, had higher grade ≥ 3 AEs (22%) than durvalumab alone (6%) leading to more treatment discontinuations (9.4% vs. 3.1%) [57]. Although limited by a small sample size of 5 patients with pretreated advanced pancreatic cancer, treatment with a bifunctional anti-PD-L1 and TGFβ receptor II fusion protein was efficacious and well-tolerated with a MTD not reached at the highest dose, altogether highlighting the feasibility of multitargeted fusion constructs involving checkpoint blockade [58].…”

“…A pilot phase I study demonstrated a PR in 1 patient with mismatch repair (MMR) deficiency out of 5 patients with pretreated advanced pancreatic cancer using a bifunctional fusion protein of anti-PD-L1 antibody fused to the extracellular domain of TGFβ receptor II (TGFβ trap) [58]. A maximum-tolerated dose (MTD) was not reached at the highest dose level of 20 mg/kg every 2 weeks ( Table 2).…”

Vaccines as an Integral Component of Cancer Immunotherapy

“…Vaccines directed against molecules driving this and other important tumor-promoting biological processes are now in clinical trials, including vaccines targeting brachyury, 6 Her2, 7 and oncogenes such as MUC1-C. 8 Agents targeting TGF-β and IL-8 to reverse tumor mesenchymalization are also being employed with vaccines to render tumor cells more susceptible to T-cell‒mediated lysis, one example is a bifunctional anti-PD-L1/TGFβR2 agent. 9 Several checkpoint inhibitor MAbs have now been designed with the ability to also mediate antibody-dependent cell-mediated cytotoxicity (ADCC), thus engaging the patient’s innate immune system via effector NK cells to further enhancing vaccine-induced adaptive immunity (Figure 1). 10 Precisely how and when cancer vaccines will be employed in regimens of immuno-oncology involving multiple agents will be the subject of ongoing and future preclinical and clinical investigations.…”