Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients with Esophageal Adenocarcinoma: Results from a Phase 1 Cohort

Tan, Benjamin; Khattak, Adnan; Felip, Enriqueta; Kelly, Karen; Rich, Patricia; Wang, Ding; Helwig, Christoph; Dussault, Isabelle; Ojalvo, Laureen S.; Isambert, Nicolás

doi:10.1007/s11523-021-00809-2

Cited by 32 publications

(17 citation statements)

References 48 publications

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“…The investigator-assessed and independent review-confirmed overall response rate (ORR) was 13.3% and 20%, respectively, with 83% of responses occurring in tumors with an immune-excluded phenotype. 36 Nineteen patients (63%) had TRAEs, with seven having grade 3 events. In a cohort in Asia in patients with esophageal squamous cell carcinoma investigator-assessed confirmed ORR rate and independent review, ORR was 20% and 10%, respectively.…”

Section: Clinical Applications Of Bintrafusp Alfamentioning

confidence: 99%

Preclinical and clinical studies of bintrafusp alfa, a novel bifunctional anti-PD-L1/TGFβRII agent: Current status

Gameiro

Strauss

Gulley

et al. 2022

Exp Biol Med (Maywood)

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Bintrafusp alfa (anti-PD-L1/TGFβRII) is a first-in-class bifunctional agent designed to act both as a checkpoint inhibitor and as a “trap” for TGFβ in the tumor microenvironment (TME). This article is designed to review the preclinical studies interrogating the mode of action of bintrafusp alfa and to present a comprehensive overview of recent bintrafusp alfa clinical studies. Preclinical studies have demonstrated that bintrafusp alfa immune-mediating and antitumor activity can be enhanced by combining it with a human papillomavirus (HPV) therapeutic cancer vaccine, a tumor-targeting interleukin 12 (IL-12) immunocytokine and/or an IL-15 superagonist. The importance of TGFβ in HPV-associated malignancies is also reviewed. The clinical studies reviewed span extended phase I cohorts in patients with a spectrum of malignancies, two randomized phase II studies in lung and one in biliary tract cancers in which bintrafusp alfa did not demonstrate superiority over standard-of-care therapies, and provocative results in patients with HPV-associated malignancies, where as a monotherapy, bintrafusp alfa has shown response rates of 35%, compared to overall response rate (ORR) of 12–24% seen with other Food and Drug Administration (FDA)-approved or standard-of-care agents. This article also reviews preliminary phase II study results of patients with HPV+ malignancies employing bintrafusp alfa in combination with an HPV therapeutic vaccine and a tumor-targeting IL-12 immunocytokine in which the combination therapy outperforms standard-of-care therapies in both checkpoint naïve and checkpoint refractory patients. This review thus provides an example of the importance of conducting clinical studies in an appropriate patient population – in this case, exemplified by the role of TGFβ in HPV-associated malignancies. This review also provides preclinical and preliminary clinical study results of the combined use of multiple immune-modulating agents, each designed to engage different immune components and tumor cells in the TME.

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Section: Clinical Applications Of Bintrafusp Alfamentioning

confidence: 99%

Preclinical and clinical studies of bintrafusp alfa, a novel bifunctional anti-PD-L1/TGFβRII agent: Current status

Gameiro

Strauss

Gulley

et al. 2022

Exp Biol Med (Maywood)

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“…Results from 2 phase 1 studies (NCT02517398 and NCT02699515) of > 670 patients treated with bintrafusp alfa demonstrated promising clinical activity in various expansion cohorts of advanced solid tumors [ 90 , 120 , 123 , 124 , 125 , 126 , 127 , 128 , 129 ]. Durable responses of > 6 months were reported in multiple advanced solid tumor types, and response rates were compared favorably with historical data for anti‐PD‐(L)1 therapies in the same tumor type, although no head‐to‐head studies have been conducted.…”

Section: Treatment Strategies For the Dual Inhibition Of Tgf‐β And Pd‐l1mentioning

confidence: 99%

Dual inhibition of TGF‐β and PD‐L1: a novel approach to cancer treatment

et al. 2022

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Transforming growth factor‐β (TGF‐β) and programmed death ligand 1 (PD‐L1) initiate signaling pathways with complementary, nonredundant immunosuppressive functions in the tumor microenvironment (TME). In the TME, dysregulated TGF‐β signaling suppresses antitumor immunity and promotes cancer fibrosis, epithelial‐to‐mesenchymal transition, and angiogenesis. Meanwhile, PD‐L1 expression inactivates cytotoxic T cells and restricts immunosurveillance in the TME. Anti‐PD‐L1 therapies have been approved for the treatment of various cancers, but TGF‐β signaling in the TME is associated with resistance to these therapies. In this review, we discuss the importance of the TGF‐β and PD‐L1 pathways in cancer, as well as clinical strategies using combination therapies that block these pathways separately or approaches with dual‐targeting agents (bispecific and bifunctional immunotherapies) that may block them simultaneously. Currently, the furthest developed dual‐targeting agent is bintrafusp alfa. This drug is a first‐in‐class bifunctional fusion protein that consists of the extracellular domain of the TGF‐βRII receptor (a TGF‐β ‘trap’) fused to a human immunoglobulin G1 (IgG1) monoclonal antibody blocking PD‐L1. Given the immunosuppressive effects of the TGF‐β and PD‐L1 pathways within the TME, colocalized and simultaneous inhibition of these pathways may potentially improve clinical activity and reduce toxicity.

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“…In patients with advanced esophageal adenocarcinoma and esophageal squamous cell carcinoma, bintrafusp alfa shows clinical antitumor efficacy with a manageable safety profile. In patients with esophageal adenocarcinoma, the confirmed objective response rate is 20.0% (NCT02517398) [ 230 ]. Similarly, the confirmed objective response rate is 10.0% in patients with esophageal squamous cell carcinoma, with a median overall survival of 11.9 months (NCT02699515) [ 231 ].…”

Section: Therapies Based On Tgf-β Signal Transduction In Diseasementioning

confidence: 99%

TGF-beta signal transduction: biology, function and therapy for diseases

et al. 2022

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The transforming growth factor beta (TGF-β) is a crucial cytokine that get increasing concern in recent years to treat human diseases. This signal controls multiple cellular responses during embryonic development and tissue homeostasis through canonical and/or noncanonical signaling pathways. Dysregulated TGF-β signal plays an essential role in contributing to fibrosis via promoting the extracellular matrix deposition, and tumor progression via inducing the epithelial-to-mesenchymal transition, immunosuppression, and neovascularization at the advanced stage of cancer. Besides, the dysregulation of TGF-beta signal also involves in other human diseases including anemia, inflammatory disease, wound healing and cardiovascular disease et al. Therefore, this signal is proposed to be a promising therapeutic target in these diseases. Recently, multiple strategies targeting TGF-β signals including neutralizing antibodies, ligand traps, small-molecule receptor kinase inhibitors targeting ligand–receptor signaling pathways, antisense oligonucleotides to disrupt the production of TGF-β at the transcriptional level, and vaccine are under evaluation of safety and efficacy for the forementioned diseases in clinical trials. Here, in this review, we firstly summarized the biology and function of TGF-β in physiological and pathological conditions, elaborated TGF-β associated signal transduction. And then, we analyzed the current advances in preclinical studies and clinical strategies targeting TGF-β signal transduction to treat diseases.

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Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-β and PD-L1, in Patients with Esophageal Adenocarcinoma: Results from a Phase 1 Cohort

Cited by 32 publications

References 48 publications

Preclinical and clinical studies of bintrafusp alfa, a novel bifunctional anti-PD-L1/TGFβRII agent: Current status

Preclinical and clinical studies of bintrafusp alfa, a novel bifunctional anti-PD-L1/TGFβRII agent: Current status

Dual inhibition of TGF‐β and PD‐L1: a novel approach to cancer treatment

TGF-beta signal transduction: biology, function and therapy for diseases

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