Bintrafusp Alfa (M7824): A Comprehensive Review of a First-in-Class Bifunctional Immunotherapy from Bench to Bedside and Beyond

Executive Summary

Bintrafusp alfa, also known as M7824, represents a landmark case study in modern immuno-oncology drug development. As a pioneering, first-in-class bifunctional fusion protein, it was engineered with a compelling scientific rationale: to simultaneously inhibit two key, non-redundant immunosuppressive pathways within the tumor microenvironment (TME). The molecule combines a Programmed Death-Ligand 1 (PD-L1) targeting antibody with a "trap" for Transforming Growth Factor-β (TGF-β), aiming to achieve a synergistic anti-tumor effect superior to that of single-pathway agents. This innovative approach was supported by a robust preclinical data package demonstrating enhanced tumor control, favorable immune modulation, and reversal of tumor cell plasticity.

This early promise led to the ambitious, multi-tumor INTR@PID global clinical trial program and a landmark strategic alliance between its discoverer, Merck KGaA, Darmstadt, Germany, and GlaxoSmithKline (GSK), valued at up to $4.2 billion. However, the trajectory of bintrafusp alfa serves as a cautionary tale. The program faced high-profile, definitive failures in two pivotal trials. The INTR@PID Lung 037 study, a head-to-head comparison against the standard-of-care pembrolizumab in first-line non-small cell lung cancer (NSCLC), was discontinued for futility, with bintrafusp alfa showing no superior efficacy and a significantly less favorable safety profile. Subsequently, the INTR@PID BTC 047 study in second-line biliary tract cancer (BTC) failed to meet its primary endpoint for regulatory submission, despite showing some activity in this difficult-to-treat disease.