In a statement Pfizer confirmed that it has discontinued the development of felmetatug vedotin (also known as PF-08046048 or SGN-B7H4V; see Drugmap).
The investigational drug is an antibody-drug conjugate (ADC) comprising a monoclonal antibody directed to B7-H4, a microtubule-disrupting agent MMAE (monomethyl auristatin E), and a protease-cleavable mc-vc (maleimidocaproyl-valine-citrulline) linker that covalently attaches MMAE to the antibody, which enables preferential release of MMAE within target cells.[1]
B7-H4, a member of the B7 family of immune checkpoint ligands, is a transmembrane protein that binds to an unknown receptor on activated T cells, and has been shown to negatively regulate T-cell function. It is highly expressed by a wide variety of tumors including cholangiocarcinoma (CCA) and breast, ovarian and endometrial cancers, and is associated with poor prognosis.[2]
A growing number of studies, including and immunohistochemistry analyses hace confirmed that B7-H4 expression, seen across multiple solid tumors, is a potential therapeutic target for the treatment of cancer, including breast, endometrial, and ovarian tumors.
In an immunocompetent murine B7-H4-expressing tumor model, felmetatug vedotin demonstrated robust anti-tumor activity as a monotherapy that was enhanced when combined with an anti-PD-1 agent.
Felmetatug vedotin further demonstrated robust anti-tumor activity in preclinical studies through multiple potential mechanisms. In vitro, felmetatug vedotin killed B7-H4-expressing tumor cells by MMAE-mediated direct cytotoxicity and antibody-mediated effector functions including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.[1]
In vivo, felmetatug vedotin demonstrated strong anti-tumor activity in multiple xenograft models of breast and ovarian cancer, including xenograft tumors with heterogeneous B7-H4 expression, consistent with the ability of vedotin ADCs to elicit a bystander effect. [1]
Based on preclinical data, researchers at Seagen (now Pfizer) concluded that the immune checkpoint ligand B7-H4 is a promising molecular target expressed by multiple solid tumors, supporting the evaluation of felmetatug vedotin as a monotherapy in phase 1 study of felmetatug vedotin in advanced solid tumors (NCT05194072) and potential future clinical combinations with immunotherapies.
Initial recruitment for the study started in 2022, was temporarily halted in September 2023, resumed again in October that year. The latest updated showed that enrollment stopped in December 2024.
No meaningful improvement
In early February 2025, as part of the presentation of the financial reports of the forth quarter and full-years 2024, Pfizer confirmed that the company had discontinued the development of felmetatug vedotin, because, according to the company’s statement, “that altough there have no new safety signals observed in patients being treated with the investigational drug, the clinical data generated to date indicated that felmetatug vedotin is unlikely to achieve a meaningful improvement over standard-of-care (SOC) chemotherapy in patients with advanced solid tumors, including triple-negative breast cancer.”
The development field for novel treatment targeting B7-H4 is crowded, with emiltatug ledadotin (XMT-1660; Mersana, see Drugmap),[3] AstraZeneca (AZD8205), GSK/Hansoh (HS20089/GSK5733584) have rival ADCs in the clinic. Now both Pfizer and Genmab (GEN1047/DuoBody-CD3xB7H4) have terminated B7-H4 focused development programs.
Clinical trials
A Study of SGN-B7H4V in Advanced Solid Tumors – ClinicalTrials.gov ID NCT05194072
A Phase I/IIa Study of AZD8205 Given Alone or in Combination With Anticancer Drugs, in Participants With Advanced or Metastatic Solid Malignancies – ClinicalTrials.gov ID NCT05123482
A Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Clinical Activity of GSK5733584 for Injection in Participants With Advanced Solid Tumors (BEHOLD-1) – ClinicalTrials.gov ID NCT06431594
Reference
[1] Gray E, Epp AD, Ulrich M, Sahetya D, Hensley KM, Hahn J, Allred S, Haass J, Snead K, Lucas S, Gosink J, Boyce R, Trueblood E, Treuting P, Frantz C, Smith AJ, Schrum J, Nazarenko N, Gardai SJ. SGN-B7H4V, a novel, investigational vedotin antibody-drug conjugate directed to the T cell checkpoint ligand B7-H4, shows promising activity in preclinical models; Poster Presentation presented during the SITC Annual Meeting (Society for Immunotherapy of Cancer; SITC 2021: EP854)
[2] Podojil JR, Miller SD. Potential targeting of B7-H4 for the treatment of cancer. Immunol Rev. 2017 Mar;276(1):40-51. doi: 10.1111/imr.12530. PMID: 28258701; PMCID: PMC5630270.
[3] Garcia D. Emiltatug Ledadotin (XMT-1660) Encouraging Data in mTNBC; Receives Fast Track Designation. ADC Review | J. Antibody-drug Conjugates, January 10, 2025. DOI: 10.14229/jadc.2025.01.10.001
