bintrafusp alfa (M7824)

P1/2, N=51, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

We highlight that TGF-β-driven immune suppression and immune exclusion are often spatially organized within stromal niches, vary across indications, and are not always the dominant barrier even when PD-L1 is expressed. SHR-1701's approval provides proof of principle in a defined context and supports mechanism-aligned development using biomarker-driven selection, rational combinations and sequencing, and pharmacodynamic endpoints that directly test these assumptions.

Although the primary endpoint was not met, BA showed a manageable safety profile and a subset of patients derived clinical benefit with prolonged stable disease, including one patient with a complete metabolic response. This first clinical trial of systemic therapy in R/M ONB serves as proof of clinical trials feasibility in this setting and supports further investigation of combinatorial immunotherapy strategies in this patient population. Trial registration ClinicalTrials.gov Identifier: NCT05012098, https://clinicaltrials.gov/ct2/show/NCT05012098. Registered 18 August 2021.

We conducted a clinical trial of bintrafusp alfa, a bifunctional PD-L1/TGF-β inhibitor, in small cell lung cancer...External validation across cell lines and tumor samples confirmed a tumor-intrinsic TGF-β-high transcriptional state associated with inferior survival. Together, these findings identify a context-dependent, growth-constraining function of TGF-β and support tumor-intrinsic biomarker-guidance while targeting stromal immunosuppressive pathways.

Novel therapeutic approaches are emerging, including PRMT5 inhibitors in MTAP-deficient tumors, TROP-2-directed antibody-drug conjugates (e.g., sacituzumab govitecan), and chimeric antigen receptor (CAR) T-cell therapies targeting mesothelin. Bispecific agents such as bintrafusp alfa and ivonescimab, which co-target various pathways, offer innovative strategies. Despite these advances, TC remains a challenging malignancy with no standardized treatment algorithm. Collaborative efforts across institutions will be essential to accelerate progress and improve outcomes in this rare disease.

P1/2, N=8, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; Insufficient accrual

P2, N=9, Active, not recruiting, National Cancer Institute (NCI) | Recruiting --> Active, not recruiting | N=44 --> 9 | Trial primary completion date: Mar 2026 --> Jul 2026

Our findings provide strong support for the combined targeting of TGF-β and PD-L1 as a promising immunotherapeutic strategy to overcome immunosuppressive barriers in glioblastoma and induce potent antitumor responses.

P3, N=22, Completed, EMD Serono Research & Development Institute, Inc. | N=32 --> 22

Quadruplet therapy produced one objective response in unselected mCRC patients (n = 20). There were no responses with triplet therapy (n = 12). The role of ICB-based combination immunotherapy in pMMR CRC remains unclear. NCT04491955.

89Zr-bintrafusp alfa imaging is safe, feasible and provides relevant tumor targeting information for patient selection and treatment.

P1/2, N=55, Active, not recruiting, National Cancer Institute (NCI) | Trial primary completion date: Dec 2025 --> Nov 2026