bintrafusp alfa (M7824) / EMD Serono - LARVOL DELTA

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

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

Bintrafusp Alfa (M7824) in Subjects With Thymoma and Thymic Carcinoma (clinicaltrials.gov) - P2 | N=9 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting | N=44 ➔ 9 | Trial primary completion date: Mar 2026 ➔ Jul 2026

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

Potent antitumor activity through dual targeting of PD-L1 and TGF-β pathways in the glioma tumor microenvironment. (PubMed, J Immunother Cancer) - "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."

Biomarker • IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • TGFB1

MS200647_0054: Bintrafusp Alfa Program Rollover Study (clinicaltrials.gov) - P3 | N=22 | Completed | Sponsor: EMD Serono Research & Development Institute, Inc. | N=32 ➔ 22

Enrollment change • Lung Cancer • Oncology • Solid Tumor

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

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

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

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

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

The Quadruple Immunotherapy for Colorectal Cancer (QuICC) Trial for Mismatch Repair-Proficient Metastatic Colorectal Cancer. (PubMed, Oncologist) - P2 | "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."

Journal • Mismatch repair • pMMR • Colorectal Cancer • Oncology • Solid Tumor • IL12A • IL15 • MUC1 • TGFB1

A Bioimaging Study of 89Zr-Bintrafusp Alfa PET Scans in Patients with Advanced or Metastatic NSCLC Receiving Bintrafusp Alfa Alone or in Combination with Chemotherapy. (PubMed, Mol Imaging Biol) - "89Zr-bintrafusp alfa imaging is safe, feasible and provides relevant tumor targeting information for patient selection and treatment."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • 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 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial primary completion date: Dec 2025 ➔ Nov 2026

Trial primary 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

Comparative efficacy and safety of targeted therapeutics or immunotherapy agents combined with chemotherapy as first-line treatment for advanced biliary tract cancer: a systematic review and network meta-analysis. (PubMed, BMC Cancer) - "Our findings directly inform clinical guidelines, address gaps in current therapeutic decision-making. Durvalumab or pembrolizumab combined with GC are optimal first-line regimens for advanced BTC, balancing survival benefits and safety. Sintilimab plus anlotinib combined with GC demonstrates superior PFS but requires further validation. While EGFR inhibitors plus chemotherapy demonstrate potential in KRAS wild-type patients, confirmation in large-scale RCTs is required. PD-L1 expression may represent a promising predictive biomarker for response to PD-1 inhibitor therapy."

IO biomarker • Journal • Retrospective data • Review • Biliary Cancer • Biliary Tract Cancer • Oncology • Solid Tumor • KRAS • PD-L1

M7824 Related Adverse Effects in Adults With Cancer (clinicaltrials.gov) - P=N/A | N=232 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Nov 2025 ➔ Nov 2027 | Trial primary completion date: Nov 2025 ➔ Nov 2027

Adverse events • Trial completion date • Trial primary completion date • Oncology • Skin Cancer • Solid Tumor

HCB301: A Novel Tri-Specific Fc Fusion Protein Targeting PD-L1, CD47, and TGFβ Remodels the Tumor Microenvironment and Enhance Anti-Tumor Immunity (SITC 2025) - "In vivo efficacy was evaluated using NPG™ mice bearing FaDu (HNSCC)/human PBMC co-mixed xenografts, as well as hPD1/hPDL1/hCD47/hSIRPα transgenic BALB/c mice bearing 4T1-hPDL1/hCD47 tumors.Results HCB301 effectively blocked PD-L1 signaling at a level comparable to atezolizumab and suppressed TGF-β1 activity more potently than M7824, a clinically studied bifunctional fusion protein targeting PD-L1 and TGFβ.4 Importantly, HCB301 induced robust phagocytosis of PD-L1-high, CD47-positive cancer cells by human MDMs while showing no off-target phagocytosis of red blood cells. This contrasts with magrolimab analogs and suggests a favorable hematologic safety profile, mitigating concerns observed with some CD47-targeting agents.5 In vivo, HCB301 elicited robust anti-tumor activity, equivalent to a triple-agent combination targeting PD-L1, CD47, and TGF-β individually, in both FaDu and 4T1 tumor models.Conclusions HCB301 represents a novel therapeutic approach that simultaneously..."

Biomarker • IO biomarker • Trispecific • Tumor microenvironment • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • SIRPA • TGFB1

Early changes in serum proteomic profiles predict anti-tumor activity in patients with advanced HPV-associated malignancies treated with novel combination immunotherapy (SITC 2025) - P1/2 | "Background We previously reported on the clinical activity of an HPV16 cancer vaccine (PDS0101), a tumor-targeting IL-12 immunocytokine (NHS-IL12, PDS01ADC), and a bifunctional agent targeting PD-L1 and TGF-β (bintrafusp alfa, BA) for the treatment of advanced HPV-associated malignancies, which demonstrated promising clinical activity (NCT04287868).1 Here, we perform a comprehensive survey of the peripheral immunome from patients treated with this novel immunotherapeutic combination to query systemic immunological changes and build models predicting clinical response.Methods Peripheral blood was serially collected from patients (n=50) for HPV16 circulating tumor DNA (ctDNA) detection, qualitative serum proteome profiling with the Olink ImmunoOncology platform, and immunophenotyping by flow cytometry. These data pave the way for outcome prediction in patients with HPV-associated malignancies using readily quantifiable molecular correlates from peripheral blood and..."

Clinical • Metastases • Oncology • GZMB • HMOX1 • IFNG • IL12A • IL6 • TGFB1

Early kinetics of circulating tumor HPV-16 and HPV-18 DNA are associated with survival in patients with HPV-associated cancers treated with dual blockade of PD-L1 and TGF-β (SITC 2025) - P2 | "Immune checkpoint blockade (ICB) with a dual inhibitor of programmed cell death ligand 1 (PD-L1) and transforming growth factor β (TGFβ), induced clinical responses in 30.5% of patients with HPV-associated malignancies who were ICB-naïve and 10% who were ICB-resistant.1 2 Circulating tumor DNA (ctDNA) is a promising, non-invasive tool for monitoring tumor dynamics and potentially predicting therapeutic outcomes; however, few studies have evaluated ctDNA kinetics in patients with HPV-associated malignancies treated with immunotherapy.3 We evaluated HPV16/18-ctDNA as a predictive biomarker of clinical response and survival in patients with HPV-associated malignancies treated with dual blockade of PD-L1 and TGF-β.Methods Peripheral blood was collected before and after 1 and 3 cycles of administration of a dual inhibitor of PD-L1 and TGF-β, bintrafusp alfa, in 51 patients with HPV16/18-associated cancers (NCT03427411)...These data support the continued..."

Clinical • IO biomarker • Oncology • TGFB1

Interrogation of the peripheral immunome from QuEST1 in men with castration-resistant prostate cancer (SITC 2025) - P1/2 | "The combination phase I/II Quick Efficacy Seeking Trial (QuEST1, NCT03493945) was designed to generate a tumor-directed immune response with BNVax (a vaccine targeting the transcription factor brachyury, involved in invasion and metastasis) and facilitate the resulting anti-tumor activity with ICB (with bintrafusp alfa (BA), a bifunctional agent providing dual inhibition of PD-L1 and TGF-β) and a lymphocyte stimulating immunocytokine (the IL-15 receptor superagonist NAI (N-803), Anktiva®). These data support the continued investigation of easily accessible peripheral biomarkers, including ALC, in patients with CRPC and suggest that evaluation of multiple circulating biomarkers may be beneficial in predicting clinical response.Ethics Approval All subjects gave written informed consent. Study protocol (NCT03493945) was approved by the NIH's IRB, and conducted in accordance with institutional and federal guidelines."

IO biomarker • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD4 • CD8 • IFNG • IL15 • TGFB1

Characterization of memory T cell immunity in patients with recurrent/metastatic nasopharyngeal carcinoma treated with dual PD-L1 and TGFβ inhibition (ESMO 2025) - P2 | "Background Our previous phase II trial (NCT04396886) of bintrafusp alfa (dual PD-L1/TGFβ blocker) in recurrent/metastatic nasopharyngeal carcinoma (R/M NPC) showed clinical activity but high rate of hyperprogression (HP)...The dissociation of CD95+ Temra and plasma TGFβ level among HPNR suggests that dysregulated Temra and TGFβ at baseline may contribute to HP. Legal entity responsible for the study The authors."

Clinical • Metastases • Nasopharyngeal Carcinoma • Oncology • Solid Tumor • FAS • TGFB1

EFFICACY AND SAFETY OF BINTRAFUSP ALFA IN BILIARY TRACT CANCER: A REVIEW OF THE CLINICAL TRIALS (AASLD 2025) - "We reviewed findings from two multinational clinical trials: (1) An open-label, single-arm Phase 2 trial (n=159) assessing BA monotherapy, and (2) A randomized, double-blind, placebo-controlled Phase 2/3 trial (n=297) evaluating BA + Gemcitabine and Cisplatin (GemCis) versus placebo + GemCis. Comparatively, BA monotherapy showed a bit better response than combination therapy, as the latter had more toxicity without clear additional benefits. BA is not effective for unselected patient population, with limited in only certain molecular subgroups."

Clinical • IO biomarker • Review • Tumor mutational burden • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gallbladder Cancer • Oncology • Solid Tumor • IDH1 • TGFB1 • TMB