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

Bintrafusp alfa (anti-PD-L1/TGF beta RII) is a first-in-class bifunctional agent designed to act both as a checkpoint inhibitor and as a trap for TGF beta 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 TGF beta 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 naive 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 TGF beta 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.

Automated summary

Bintrafusp alfa is a novel bifunctional agent designed to target the immune system and tumor microenvironment, with promising results in HPV-associated malignancies. Clinical studies have shown superior efficacy of bintrafusp alfa in combination with HPV therapeutic vaccine and IL-12 immunocytokine compared to standard-of-care therapies.