Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort

Cho, Byoung Chul; Daste, Amaury; Ravaud, Alain; Salas, Sébastien; Isambert, Nicolás; McClay, Edward F.; Awada, Ahmad; Borel, Christian; Ojalvo, Laureen S.; Helwig, Christoph; Rolfe, P. Alexander; Gulley, James L.; Penel, Nicolas

doi:10.1136/jitc-2020-000664

Cited by 65 publications

(64 citation statements)

References 38 publications

(29 reference statements)

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“…The results for the overall SCCHN cohort are reported in a separate manuscript. 26 HPV status for all patients was determined post hoc and not required for enrollment. Thirty-six patients were enrolled in the phase 2 study from February 27, 2018, to July 16, 2019, including 20 patients with checkpoint inhibitor-refractory disease.…”

Section: Resultsmentioning

confidence: 99%

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

Strauss

Gatti‐Mays

Cho

et al. 2020

J Immunother Cancer

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110

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BackgroundBintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor (TGF)-βRII (a TGF-β ‘trap’) fused to a human IgG1 mAb blocking programmed cell death ligand 1. This is the largest analysis of patients with advanced, pretreated human papillomavirus (HPV)-associated malignancies treated with bintrafusp alfa.MethodsIn these phase 1 (NCT02517398) and phase 2 trials (NCT03427411), 59 patients with advanced, pretreated, checkpoint inhibitor-naive HPV-associated cancers received bintrafusp alfa intravenously every 2 weeks until progressive disease, unacceptable toxicity, or withdrawal. Primary endpoint was best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1; other endpoints included safety.ResultsAs of April 17, 2019 (phase 1), and October 4, 2019 (phase 2), the confirmed objective response rate per RECIST V.1.1 in the checkpoint inhibitor-naive, full-analysis population was 30.5% (95% CI, 19.2% to 43.9%; five complete responses); eight patients had stable disease (disease control rate, 44.1% (95% CI, 31.2% to 57.6%)). In addition, three patients experienced a delayed partial response after initial disease progression, for a total clinical response rate of 35.6% (95% CI, 23.6% to 49.1%). An additional patient with vulvar cancer had an unconfirmed response. Forty-nine patients (83.1%) experienced treatment-related adverse events, which were grade 3/4 in 16 patients (27.1%). No treatment-related deaths occurred.ConclusionBintrafusp alfa showed clinical activity and manageable safety and is a promising treatment in HPV-associated cancers. These findings support further investigation of bintrafusp alfa in patients with advanced, pretreated HPV-associated cancers.

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Section: Resultsmentioning

confidence: 99%

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

Strauss

Gatti‐Mays

Cho

et al. 2020

J Immunother Cancer

Self Cite

110

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“…289 M7824 showed a manageable safety profile and encouraging clinical efficacy in phase 1 clinical trials, including patients with advanced solid tumors, NSCLCs, recurrent glioblastoma, cervical cancer, metastatic TNBC, heavily pretreated CRC, or human papillomavirus (HPV)-associated cancers. [290][291][292][293][294][295][296] M7824 is now being evaluated in a phase 2 clinical trial for patients with advanced/metastatic biliary tract cancer, gallbladder cancer, recurrent respiratory papillomatosis, thymoma, CRC, head and neck squamous cell cancer, advanced pancreas cancer, or recurrent prostate cancer. 297 Moreover, the evaluation of M7824 for patients with advanced NSCLC or biliary tract cancer is now under investigation in phase 3 clinical trials.…”

Section: Targeting Tgfβ In Cancer Therapy: Challenges and Opportunitiesmentioning

confidence: 99%

Targeting TGFβ signal transduction for cancer therapy

Liu

Ren

Dijke

2021

Sig Transduct Target Ther

250

173

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Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial–mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.

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“…These promising findings resulted in the advancement of bintrafusp alfa to clinical trials. Dose escalation studies (phase I) showed manageable safety profiles while some clinical efficacy seemed to be present at the administered dosage [148][149][150][151][152][153][154]. Currently, a number of phase I and phase I/II trials are ongoing that investigate combinatorial effects of bintrafusp alfa with radiotherapy and chemotherapeutics, among other treatments.…”

Section: Clinical Exploitation Of the Synergistic Potential Of Tgf-β mentioning

confidence: 99%

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

2021

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Cancers may escape elimination by the host immune system by rewiring the tumour microenvironment towards an immune suppressive state. Transforming growth factor-β (TGF-β) is a secreted multifunctional cytokine that strongly regulates the activity of immune cells while, in parallel, can promote malignant features such as cancer cell invasion and migration, angiogenesis, and the emergence of cancer-associated fibroblasts. TGF-β is abundantly expressed in cancers and, most often, its abundance associated with poor clinical outcomes. Immunotherapeutic strategies, particularly T cell checkpoint blockade therapies, so far, only produce clinical benefit in a minority of cancer patients. The inhibition of TGF-β activity is a promising approach to increase the efficacy of T cell checkpoint blockade therapies. In this review, we briefly outline the immunoregulatory functions of TGF-β in physiological and malignant contexts. We then deliberate on how the therapeutic targeting of TGF-β may lead to a broadened applicability and success of state-of-the-art immunotherapies.

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Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort

Cited by 65 publications

References 38 publications

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies

Targeting TGFβ signal transduction for cancer therapy

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

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