bintrafusp alfa (M7824) / EMD Serono - LARVOL DELTA

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

Identification of anoikis-related genes in heart failure: bioinformatics and experimental validation. (PubMed, Hereditas) - "These findings suggest that Tln1 and TGFβ2 may play important roles in HF development through the regulation of anoikis and may serve as therapeutic targets for HF."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • TGFB1 • TGFB2 • TLN1

NHS-IL12 Monotherapy and in Combination With M7824 in Advanced Kaposi Sarcoma (clinicaltrials.gov) - P1/2 | N=80 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial primary completion date: Sep 2025 ➔ Dec 2028

Monotherapy • Trial primary completion date • Kaposi Sarcoma • Oncology • Sarcoma • Solid Tumor • CD4 • IL12A

TRUST: Bintrafusp Alfa and Doxorubicin Hydrochloride in Treating Patients With Advanced Sarcoma (clinicaltrials.gov) - P2 | N=80 | Recruiting | Sponsor: Institut Bergonié | Trial completion date: Mar 2025 ➔ Jul 2027 | Trial primary completion date: Sep 2024 ➔ Jan 2027

Trial completion date • Trial primary completion date • Gastrointestinal Cancer • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Bintrafusp alfa and its unsuccessful development journey towards cervical cancer treatment. (PubMed, Expert Opin Biol Ther) - No abstract available

Journal • Cervical Cancer • Oncology • Solid Tumor

Efficacy of bintrafusp alfa (M7824) in patients with gastrointestinal tumors: A meta-analysis. (ASCO 2025) - "Bintrafusp Alfa demonstrated modest efficacy in gastrointestinal tumors and limited survival benefits (PFS: 1.496 months; OS: 8.969 months). The treatment was associated with a significant incidence of Grade 3 or higher adverse events, necessitating careful patient monitoring. Further large-scale trials are required to validate these findings and optimize treatment strategies."

Retrospective data • Gastrointestinal Cancer • Oncology • Solid Tumor

Advances in Combination Therapy for Advanced Hepatocellular Carcinoma (APASL 2025) - "Major guidelines now recognize immune-based regimens as first-line standards, with atezolizumab-bevacizumab (IMbrave150: mOS 19.2 vs. 13.4 months) and durvalumab-tremelimumab (HIMALAYA: mOS 16.4 vs. 13.8 months) demonstrating survival superiority over sorafenib. The CheckMate-9DW trial further showed nivolumab-ipilimumab reduced mortality risk by 21% versus TKIs (HR 0.79), though with increased grade 3–4 immune toxicity (35% vs. 15%)...The LEAP-012 trial reported prolonged PFS in BCLC-B patients receiving TACE with lenvatinib-pembrolizumab versus TACE alone (12.1 vs. 8.2 months), corroborated by China's CHANCE001 cohort (TACE plus immune-targeted therapy mOS 24 vs. 16 months; HR 0.62)...Bispecific antibodies (e.g., PD-L1/TGF-β-targeting M7824) and neoantigen vaccines show early efficacy signals, achieving 21% ORR and isolated complete responses when combined with ICIs...Prioritizing biomarker-driven stratification, rational sequencing, and inclusive trials addressing..."

Combination therapy • IO biomarker • Metastases • Tumor mutational burden • Hepatocellular Cancer • Oncology • Solid Tumor • PD-L1 • TGFB1

M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers (clinicaltrials.gov) - P1/2 | N=37 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Jan 2027 ➔ Mar 2025

Trial completion • Trial completion date • Tumor mutational burden • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Non invasive monitoring of relapsed SCLC using cell free fragmentomes and peripheral blood immunophenotyping (AACR 2025) - P1/2 | "Need for prompt treatment and limited access to biopsies at relapse highlight the demand for noninvasive methods to monitor response. We used sequential blood samples from relapsed/refractory SCLC patients enrolled in 2 clinical trials—durvalumab and olaparib (NCT02484404) or M7824 with/without chemotherapy (NCT03554473). Genome-wide cfDNA fragmentome analysis effectively captures genomic and transcriptomic features of SCLC, offering predictive and prognostic insights into SCLC response to ICB. Consistent with the role of tumor intrinsic features in driving tumor immunity, ctDNA derived features show concordance with peripheral blood immune phenotypes and supporting cfDNA as a non-invasive biomarker for treatment monitoring."

Non-invasive • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • ASCL1

MS200647_0054: Bintrafusp Alfa Program Rollover Study (clinicaltrials.gov) - P3 | N=32 | Completed | Sponsor: EMD Serono Research & Development Institute, Inc. | Active, not recruiting ➔ Completed

Trial completion • Lung Cancer • Oncology • 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

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) | Recruiting ➔ Active, not recruiting | N=107 ➔ 55

Enrollment change • Enrollment closed • 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

Tri-Ad5 vaccine plus bintrafusp alfa for newly diagnosed, advanced-stage head and neck cancer not associated with human papillomavirus infection. (PubMed, Oncologist) - P1/2 | "In this small study, Tri-Ad5 vaccine plus bintrafusp alfa resulted in CPD in 2/6 patients. Participants also had favorable 2-year RFS compared to historical values. Ongoing tissue and peripheral immunome analyses may provide mechanistic insight. (ClincalTrials.gov Identifier: NCT04247282; IRB Approved.)."

Journal • Head and Neck Cancer • Human Papillomavirus Infection • Infectious Disease • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • CEACAM5 • MUC1

PRGN-2009 and bintrafusp alfa for patients with advanced or metastatic human papillomavirus-associated cancer. (PubMed, Cancer Immunol Immunother) - P1/2 | "PRGN-2009 was well tolerated, and immune responses were observed to PRGN-2009. Encouraging anti-tumor activity and OS were noted in the combination with BA arm, consisting mainly of checkpoint-resistant patients. Trial Registration ClinicalTrials.gov Identifier: NCT04432597."

Journal • Cervical Cancer • Gene Therapies • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • CXCL8 • TGFB1

M7824 and Topotecan or Temozolomide in Relapsed Small Cell Lung Cancers (clinicaltrials.gov) - P1/2 | N=37 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Recruiting ➔ Active, not recruiting | N=80 ➔ 37

Enrollment change • Enrollment closed • Tumor mutational burden • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

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

TIGIT inhibitor M6223 as monotherapy or in combination with bintrafusp alfa in patients with advanced solid tumors: a first-in-human, phase 1, dose-escalation trial. (PubMed, J Immunother Cancer) - P1, P2 | "M6223±BA had a manageable safety profile, with RDEs defined for both monotherapy and combination therapy. Further evaluation of M6223 is ongoing in combination with the PD-L1 inhibitor avelumab in patients with advanced urothelial carcinoma (JAVELIN Bladder Medley; NCT05327530)."

Journal • Monotherapy • P1 data • Bladder Cancer • Endocrine Disorders • Hematological Disorders • Nephrology • Oncology • Renal Disease • Solid Tumor • Urothelial Cancer • TGFB1 • TIGIT

21-C-0001: M9241 in Combination With Docetaxel in Adults With Metastatic Castration Sensitive and Castration Resistant Prostate Cancer (clinicaltrials.gov) - P1/2 | N=86 | Recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Dec 2024 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2026

Trial completion date • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor