M7824

Overview

Bintrafusp alfa (M7824) is an investigational, first‑in‑class bifunctional fusion protein that combines an anti–PD‑L1 monoclonal antibody with two extracellular domains of TGF‑β receptor II, functioning as a TGF‑β “trap.” It has been studied across multiple solid tumors. Large randomized trials to date have not shown superiority over standard PD‑1/PD‑L1 monotherapy, and the 2019–2021 Merck KGaA–GSK collaboration was terminated following negative Phase 3 results in NSCLC. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Structure: human IgG1 anti–PD‑L1 antibody with each heavy chain fused to the extracellular domain of TGF‑βRII to sequester all three TGF‑β isoforms. This is intended to co‑localize dual blockade within the tumor microenvironment. (pubmed.ncbi.nlm.nih.gov)
• Rationale and preclinical data: Dual targeting of PD‑L1 and TGF‑β enhanced antitumor activity versus either pathway alone, activating innate and adaptive immunity and improving responses to chemo‑/radiotherapy in murine models. (psychology.as.uky.edu)
• Dose selection: Early clinical pharmacology supported 1200 mg IV every 2 weeks as a recommended Phase 2 dose; a characteristic class effect was TGF‑β–inhibition–related cutaneous lesions (e.g., keratoacanthoma). (ascpt.onlinelibrary.wiley.com)

Efficacy

Non–small cell lung cancer (NSCLC)
- Phase 3, first‑line PD‑L1–high advanced NSCLC: Bintrafusp alfa did not improve PFS or OS versus pembrolizumab (median PFS 7.0 vs 11.1 months; HR 1.23; median OS 21.1 vs 22.1 months). Trial discontinued at interim for futility. (pubmed.ncbi.nlm.nih.gov)
- Phase 1/expansion, second‑line NSCLC: ORR 21.3% overall; at 1200 mg, ORR 25.0% (PD‑L1–high ≥80%: 85.7% in a small subgroup). Longer‑term follow‑up reported sustained activity in a subset. (pubmed.ncbi.nlm.nih.gov)
- Phase 1 bintrafusp alfa + chemotherapy (stage IV NSCLC): exploratory cohorts suggested activity (ORR 48.3% overall; 71.4% if PD‑L1 TPS ≥50%); program not advanced further. (pubmed.ncbi.nlm.nih.gov)

Biliary tract cancer (BTC)
- Phase 2/3 randomized (bintrafusp alfa + gemcitabine/cisplatin vs placebo + chemo, first‑line; N=297): No overall survival benefit; program stopped early (trial terminated August 20, 2021). (pubmed.ncbi.nlm.nih.gov)
- Phase 2 single‑arm (second‑line BTC; N≈159): ORR 10.7% (median DoR 10.0 months), median PFS 1.8 months, OS 7.6 months; primary endpoint not met. (pubmed.ncbi.nlm.nih.gov)
- Phase 1 (pretreated BTC, primarily Asian cohort; N=30): ORR 20% by independent review; some durable responses. (pubmed.ncbi.nlm.nih.gov)

Other tumor types (selected)
- Recurrent glioblastoma (Phase 1 expansion; N=35): Disease control in 22.9% (2 PRs); median PFS 1.4 months, OS 5.3 months. (pubmed.ncbi.nlm.nih.gov)
- Esophageal adenocarcinoma (Phase 1 cohort; N=30): ORR 20% (IRC); responses 1.3–8.3 months. (pubmed.ncbi.nlm.nih.gov)
- Pleural mesothelioma (Phase 2 single‑arm; 2025): ORR 6.5%, median PFS 1.9 months; limited efficacy. (pubmed.ncbi.nlm.nih.gov)
- Hepatocellular carcinoma (Phase 1 dose‑escalation/expansion): ORR below a prespecified 20% benchmark (≈9–11% across cohorts). (journals.lww.com)

Program status
- INTR@PID Lung 037 (Phase 3) was halted in January 2021 for futility; subsequently, the Merck KGaA–GSK global alliance on bintrafusp alfa ended on September 30, 2021. (prnewswire.com)

Safety

• General: Safety broadly resembled PD‑(L)1 inhibitors, with immune‑related AEs; additional TGF‑β–pathway findings included cutaneous lesions (hyperkeratosis/keratoacanthoma/cSCC) in a minority of patients. (ascpt.onlinelibrary.wiley.com)
• Randomized NSCLC Phase 3: higher grade 3–4 treatment‑related AEs with bintrafusp alfa vs pembrolizumab (42.4% vs 13.2%). (pubmed.ncbi.nlm.nih.gov)
• BTC Phase 2/3 (first‑line, with chemo): anemia was the most common grade ≥3 TRAE (26.0% vs 22.8% with placebo+chemo); bleeding AEs were more frequent with bintrafusp alfa (28.8% vs 7.4%). Early deaths within 60 days were 7.5% vs 1.3%. (pubmed.ncbi.nlm.nih.gov)
• Glioblastoma expansion cohort: treatment‑related AEs in 71.4% (grade ≥3 in 17.1%); intracranial bleeding events were observed, often in the context of tumor progression. (academic.oup.com)

Further reading

• Phase 3 NSCLC (bintrafusp alfa vs pembrolizumab), Journal of Thoracic Oncology (2023). https://www.jto.org/article/S1556-0864(23)00738-4/fulltext (jto.org)
• Randomized Phase 2/3 BTC (bintrafusp alfa + gemcitabine/cisplatin), Hepatology (2025). https://journals.lww.com/hep/fulltext/2025/03000/bintrafusp_alfa_and_chemotherapy_as_first_line.14.aspx (journals.lww.com)
• Phase 2 single‑arm BTC (second‑line), Hepatology (2023). https://pubmed.ncbi.nlm.nih.gov/36999533/ (pubmed.ncbi.nlm.nih.gov)
• Phase 1 NSCLC expansion (second‑line), JTO Clinical Research Reports/JVSO (2020) and ASCO abstract (2020 follow‑up). https://pubmed.ncbi.nlm.nih.gov/32173464/; https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.9558 (pubmed.ncbi.nlm.nih.gov)
• Preclinical rationale, Science Translational Medicine (2018). https://doi.org/10.1126/scitranslmed.aan5488 (psychology.as.uky.edu)
• Dose selection and class‑specific safety, Clinical Pharmacology & Therapeutics (2020). https://ascpt.onlinelibrary.wiley.com/doi/full/10.1002/cpt.1776 (ascpt.onlinelibrary.wiley.com)
• Program updates/termination of GSK alliance (press releases). https://www.businesswire.com/news/home/20210930005596/en/ (businesswire.com)

Notes: Results above reflect publications and conference abstracts through October 7, 2025.

Last updated: Oct 2025