bintrafusp alfa (M7824) / EMD Serono - LARVOL DELTA

Phase II evaluation of combination immunotherapy with CV301, N-803, bintrafusp alfa, and M9241 in patients with advanced small bowel and colorectal cancers. (ASCO-GI 2023) - P2 | "All patients had received prior 5-fluorouracil-based treatment, with 29/30 (96.7%) having received ≥ 2 lines of systemic therapy. Combination therapies with CV301, N-803, bintrafusp alfa, and M9241 had manageable safety profiles. Preliminary clinical activity was observed in patients with advanced MSS/pMMR small bowel or CRC. Median OS was promising as compared to historical median survivals of 6-7 months following receipt of multiple lines of therapy."

Clinical • Metastases • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • IL12A • MUC1 • TGFB1

A Phase I/II Study of Combination Immunotherapy for Advanced Cancers Including HPV-Associated Malignancies, Small Bowel, and Colon Cancers (clinicaltrials.gov) - P1/2 | N=55 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Nov 2026 ➔ Aug 2026

Trial completion • Trial completion date • Anal Carcinoma • Cervical Cancer • Colon Cancer • Colorectal Cancer • Genito-urinary Cancer • Gynecologic Cancers • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Penile Cancer • Small Intestinal Carcinoma • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Vaginal Cancer • Vulvar Cancer • CD4 • PD-L1

Bintrafusp alfa versus pembrolizumab in patients with treatment-naive, PD-L1-high advanced non-small cell lung cancer: a randomized, open-label, phase 3 trial. (PubMed, J Thorac Oncol) - P3 | "First-line treatment with bintrafusp alfa did not demonstrate superior efficacy compared with pembrolizumab in patients with PD-L1-high, advanced NSCLC."

Journal • Metastases • P3 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1 • TGFB1

Final analysis of the BIMES trial, a phase II single arm study assessing efficacy and safety of bintrafusp alfa in previously treated advanced malignant pleural mesothelioma (GECP 20/09). (ASCO 2024) - P2 | "Bintrafusp alfa did not reach the expected efficacy in patients with advanced malignant pleural mesothelioma previously treated with platinum-based chemotherapy."

Clinical • Metastases • P2 data • Acute Kidney Injury • Anemia • Endocrine Disorders • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Immunology • Malignant Pleural Mesothelioma • Mesothelioma • Nephrology • Oncology • Renal Disease • Solid Tumor • TGFB1

Phase I/II Evaluation of the Combination of Entinostat, M9241 and Bintrafusp Alfa in Patients with Advanced HPV Related Malignancies (SITC 2022) - P1/2 | "Background More than 630,000 cases of HPV related cancer (e.g. cervical, oropharyngeal, anal) occur worldwide annually. To date the triple combination appears to have a manageable safety profile along with encouraging clinical activity in patients with advanced checkpoint refractory HPV related cancers including in pts who have previously progressed on PD(L)1 inhibitor then on PDS0101, M9241 and bintrafusp alfa. Trial Registration NCT04708470"

Clinical • P1/2 data • Cervical Cancer • Oncology • Oropharyngeal Cancer • IL12A • STAT3 • TGFB1

Novel Combination Immunotherapy and Clinical Activity in Patients With HPV-Associated Cancers: A Nonrandomized Clinical Trial. (PubMed, JAMA Oncol) - P1/2 | "In this trial, the combination of PDS0101, PDS01ADC, and bintrafusp alfa showed an acceptable safety profile and promising antitumor activity and improved OS in patients with HPV-16-positive cancers, in both ICB-naive and ICB-resistant patients, warranting further evaluation of the combination of PDS0101 and PDS01ADC with simultaneous PD-L1/TGF-β inhibition in these populations."

Clinical • Journal • Oncology • Solid Tumor • IL12A • TGFB1

Efficacy and safety of bintrafusp alfa in two phase 1 expansion cohorts with advanced hepatocellular carcinoma. (PubMed, Hepatology) - P1 | "Bintrafusp alfa showed moderate clinical activity and a safety profile consistent with previous studies of bintrafusp alfa in patients with advanced HCC."

Journal • Metastases • P1 data • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • TGFB1

Potential effects of TGF-β inhibition on immune resistance by targeting immunosuppressive microenvironment in advanced gastric cancer (AGC): Multi-omics post-hoc analysis of the K-Umbrella-06 trial. (ASCO 2026) - P1/2 | "A separate cohort treated with nivolumab + paclitaxel (n=26) served as a control. Integrated AI-WSI, transcriptomic, and longitudinal ctDNA analyses suggest that TGF-β pathway activation and an immune-excluded phenotype are associated with clinical benefit from bintrafusp alfa plus paclitaxel, and may identify a responder subset distinct from conventional PD-1/PD-L1–based therapy. These findings support further evaluation of anti–TGF-β strategies for AGC with an immunosuppressive tumor microenvironment."

IO biomarker • Metastases • Retrospective data • Fibrosis • Gastric Cancer • Immunology • Oncology • Solid Tumor • CD8 • HER-2 • SMAD2 • TGFB1

Trust: a randomized phase ii study of bintrafusp alfa plus doxorubicin versus doxorubicin in advanced soft-tissue sarcoma stratified by tertiary lymphoid structure status (ESMO 2026) - No abstract available

Clinical • Metastases • P2 data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Efficacy and safety of bintrafusp alfa evaluated in a phase II single-arm clinical trial in previously treated advanced pleural mesothelioma. (PubMed, Lung Cancer) - "Bintrafusp alfa did not reach the expected efficacy in patients with advanced PM. We did not identify new safety signals with bintrafusp alfa, and no case of bleeding was reported. Our study suggested that bintrafusp alfa has limited efficacy in PM, as reported in other solid tumours."

Journal • P2 data • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor

Bintrafusp alfa with cCRT followed by bintrafusp alfa versus placebo with cCRT followed by durvalumab in patients with unresectable stage III NSCLC: A phase 2 randomized study. (PubMed, J Thorac Oncol) - P2 | "BA with cCRT followed by BA demonstrated no efficacy benefit over placebo with cCRT followed by durvalumab in patients with stage III unresectable NSCLC."

Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Efficacy and Safety of Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting Transforming Growth Factor-β and Programmed Death-Ligand 1, Plus Chemotherapy in Patients With Stage IV NSCLC. (PubMed, JTO Clin Res Rep) - P1/2 | "On the basis of an interim analysis, the data were considered mature, and no further analysis has been planned. Bintrafusp alfa with chemotherapy was found to have a manageable safety profile and encouraging clinical activity in patients with stage IV NSCLC."

IO biomarker • Journal • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PD-L1

Bintrafusp Alfa: A Bifunctional Fusion Protein Targeting PD-L1 and TGF-β, in Patients with Pretreated Colorectal Cancer: Results from a Phase I Trial. (PubMed, Oncologist) - P1 | "The objective response rate was 3.1% and the disease control rate was 6.3% (1 partial response, 1 stable disease); 2 patients were not evaluable. The safety profile was consistent with previously reported data."

Journal • P1 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • TGFB1

Phase 2 trial of bintrafusp alfa as second-line therapy for patients with locally advanced/metastatic biliary tract cancers. (PubMed, Hepatology) - P2 | "Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile."

Journal • Metastases • P2 data • Biliary Cancer • Biliary Tract Cancer • Dermatology • Gastrointestinal Cancer • Hematological Disorders • Hepatology • Liver Failure • Oncology • Pruritus • Solid Tumor • TGFB1

A phase Ib single-arm trial of bintrafusp alfa (BA) for pretreated, locally advanced/unresectable or metastatic (advanced) urothelial cancer (aUC) (ESMO 2023) - P1 | "Limitations: relatively small sample size and no randomization. Future studies can assess the role of TGF-β pathway inhibition in UC."

Metastases • P1 data • Genito-urinary Cancer • Oncology • Solid Tumor • Urothelial Cancer • TGFB1

20-C-0012: Bintrafusp Alfa (M7824) and PDS01ADC Alone and in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Metastatic Non-Prostate Genitourinary Malignancies (clinicaltrials.gov) - P1 | N=22 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting | N=100 ➔ 22 | Trial completion date: Dec 2027 ➔ Dec 2028 | Trial primary completion date: Dec 2027 ➔ Aug 2026

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Bladder Cancer • Genito-urinary Cancer • Oncology • Solid Tumor • Urology • Urothelial Cancer • CD4

20-C-0104: HPV Vaccine PRGN-2009 Alone or in Combination With Anti-PDL1/TGF-Beta Trap (M7824) in Subjects With HPV Associated Cancers (clinicaltrials.gov) - P1/2 | N=39 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Trial completion • Anal Carcinoma • Cervical Cancer • Colorectal Cancer • Gynecologic Cancers • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Penile Cancer • Rectal Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Vaginal Cancer • Vulvar Cancer • CD4

Bintrafusp Alfa (M7824) in Subjects With Thymoma and Thymic Carcinoma (clinicaltrials.gov) - P2 | N=9 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2026 ➔ Jul 2027 | Trial primary completion date: Jul 2026 ➔ Dec 2026

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • Thymic Carcinoma • Thymic Epithelial Tumor • Thymoma • Thymus Cancer

BLOCKADE OF TUMOR-INTRINSIC TGF-Β SIGNALING DRIVES HYPERPROGRESSION IN SMALL CELL LUNG CANCER. (PubMed, Cancer Discov) - "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."

IO biomarker • Journal • Lung Cancer • Neuroendocrine Carcinoma • Oncology • Small Cell Lung Cancer • Solid Tumor • TGFB1

Durable responses to triplet immunotherapy targeting TGF-β, PD-L1, and tumor antigen, with an IL-15 receptor superagonist in mismatch repair proficient castration-resistant prostate cancer. (PubMed, J Immunother Cancer) - P1/2 | "Analyses of peripheral immune profiles provided evidence of a multifaceted antitumor immune response, including IL-15 receptor superagonist NAI-dependent expansion and activation of natural killer cells and CD8+ T cells, increased effector-to-suppressor immune cell ratios, and induction of cytotoxic immune gene programs."

Journal • Mismatch repair • pMMR • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • IL15 • PD-L1 • TGFB1

Breaking immune exclusion in cold tumors via TGF-β pathway inhibition. (PubMed, Expert Opin Biol Ther) - "It systematically analyzes preclinical and clinical evidence on bifunctional fusion proteins, represented by M7824 and SHR-1701, as well as bispecific antibodies. The success of TGF-β-targeted therapy depends on moving beyond broad pathway inhibition toward biomarker-guided patient selection and context-dependent intervention. Spatially or biologically restricted targeting, multi-parametric biomarker frameworks, and mechanism-driven combination regimens are likely to define the next phase of clinical development in this field."

IO biomarker • Journal • Oncology • TGFB1

TRUST: Bintrafusp Alfa and Doxorubicin Hydrochloride in Treating Patients With Advanced Sarcoma (clinicaltrials.gov) - P2 | N=80 | Active, not recruiting | Sponsor: | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

From M7824 to SHR-1701: lessons for dual PD-L1/TGF-β targeting. (PubMed, J Immunother Cancer) - "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."

IO biomarker • Journal • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Oncology • Solid Tumor • PD-L1 • TGFB1

TGF-ß and PD-L1 inhibition with bintrafusp alfa combined with definitive chemoradiation therapy for esophageal squamous cell carcinoma (Tapestry): A single-arm, phase II, investigator-initiated, multicenter, feasibility study (ESMO-GI 2026) - P=N/A | "Patients received BA (2400 mg, 3-weekly, 3 cycles) during 6 weeks of dCRT (carboplatin AUC=2, paclitaxel 50 mg/m 2 , 50.4 Gy in 28 fractions). Table: 614P Conclusions Adding BA to dCRT is feasible in irresectable/inoperable non-metastatic ESCC, with favorable survival outcomes compared to dCRT only. Follow-up and biomarker analyses are ongoing."

Clinical • IO biomarker • P2 data • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Oncology • TGFB1

Combination Immunotherapy in Subjects With Advanced HPV Associated Malignancies (clinicaltrials.gov) - P1/2 | N=51 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed

Trial completion • Anal Carcinoma • Cervical Cancer • Colorectal Cancer • Gynecologic Cancers • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Penile Cancer • Rectal Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • Vaginal Cancer • Vulvar Cancer • CD4 • CDKN2A • PD-L1