IPH5201, an Anti-CD39 mAb, as Monotherapy or in Combination with Durvalumab in Advanced Solid Tumors

Abstract

Monotherapy; Durvalumab; Advanced solid tumors

Monoteràpia; Durvalumab; Tumors sòlids avançats

Monoterapia; Durvalumab; Tumores sólidos avanzados

Purpose: Blocking enzymatic activity of cluster of differentiation 39 (CD39) with IPH5201 may promote antitumor immunity by increasing immunostimulatory ATP and reducing immunosuppressive adenosine levels in the tumor microenvironment. This first-in-human, phase 1 study evaluated IPH5201 as monotherapy or in combination with durvalumab (anti–PD-L1) in patients with advanced solid tumors. Patients and Methods: The study consisted of two consecutive dose-escalation parts: IPH5201 monotherapy (100, 300, 1,000, and 3,000 mg) every 3 weeks and IPH5201 (300, 1,000, and 3,000 mg) + durvalumab 1,500 mg every 3 weeks. The primary endpoint was to evaluate safety and tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, and immunogenicity. Results: Overall, 38 patients received IPH5201 monotherapy and 19 received IPH5201 + durvalumab, with a median duration of follow-up of 7.6 months (range, 1.0–23.7). The most common cancer types were pancreatic (42.1%), non–small cell lung (19.3%), and colorectal (17.5%) cancers. The most common treatment-related adverse events were infusion-related reactions and fatigue. There were no adverse event–related deaths, and the maximum tolerated dose was not reached. Overall, 23/57 patients (40.4%) had stable disease as their best overall response. IPH5201 exhibited a linear pharmacokinetic profile and an estimated terminal half-life of 8 to 9 days at higher doses. On-treatment tumor biopsies revealed decreased CD39 ATPase activity in 5/7 patients, including all evaluable patients receiving the maximum dose of IPH5201 3,000 mg every 3 weeks. Conclusions: IPH5201 as monotherapy, or in combination with durvalumab, was well tolerated at pharmacologically active doses that induced reduction of intratumoral CD39 enzymatic activity and showed preliminary evidence for disease stabilization. Significance: The adenosine pathway is a source of emerging targets in cancer immunotherapy. IPH5201 is a mAb that targets the adenosine pathway by blocking human CD39 enzymatic activity. In this first-in-human, phase 1 study, IPH5201 as monotherapy or in combination with durvalumab was well tolerated with a manageable safety profile in patients with advanced solid tumors. Preliminary evidence for disease stabilization and reduction of tumoral CD39 enzymatic activity were observed.

This study was sponsored by AstraZeneca. The authors would like to thank the patients, their families, and caregivers for their participation in the study. We thank Elena Young, AstraZeneca R&D, Cambridge, United Kingdom, for valuable contributions to the study. Medical writing support for the development of this article, under the direction of the authors, was provided by Taylor Stepien, PhD, of Ashfield MedComms, an Inizio company, in accordance with Good Publication Practice (GPP) guidelines (http://www.ismpp.org/gpp-2022) and funded by AstraZeneca. The authors would like to dedicate this work to the memory of Ray Mager, whose contribution to this study was fundamental and who sadly passed away before his time during the revision of this article.