First-in-Human Study of Oleclumab, a Potent, Selective Anti-CD73 Monoclonal Antibody, Alone or in Combination With Durvalumab in Patients With Advanced Solid Tumors

Authors

Johanna Bendell
Patricia LoRusso
Michael Overman
Anne M Noonan
Dong-Wan Kim
John H Strickler
Sang-We Kim
Stephen Clarke
Thomas J George
Peter S Grimison
Minal Barve
Manik Amin
Jayesh Desai
Trisha Wise-Draper
Steven Eck
Yu Jiang
Anis A Khan
Yuling Wu
Philip Martin
Zachary A Cooper
Nairouz Elgeioushi
Nancy Mueller
Rakesh Kumar
Sandip Pravin Patel

Publication Date

7-1-2023

Journal

Cancer Immunology, Immunotherapy

Abstract

BACKGROUND: CD73 upregulation in tumors leads to local immunosuppression. This phase I, first-in-human study evaluated oleclumab (MEDI9447), an anti-CD73 human IgG1λ monoclonal antibody, alone or with durvalumab in patients with advanced colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or epidermal growth factor receptor-mutant non-small-cell lung cancer (NSCLC).

METHODS: Patients received oleclumab 5-40 mg/kg (dose-escalation) or 40 mg/kg (dose-expansion) intravenously every 2 weeks (Q2W), alone (escalation only) or with durvalumab 10 mg/kg intravenously Q2W.

RESULTS: 192 patients were enrolled, 66 during escalation and 126 (42 CRC, 42 PDAC, 42 NSCLC) during expansion. No dose-limiting toxicities occurred during escalation. In the monotherapy and combination therapy escalation cohorts, treatment-related adverse events (TRAEs) occurred in 55 and 54%, respectively, the most common being fatigue (17 and 25%). In the CRC, PDAC, and NSCLC expansion cohorts, 60, 57, and 45% of patients had TRAEs, respectively; the most common were fatigue (15%), diarrhea (9%), and rash (7%). Free soluble CD73 and CD73 expression on peripheral T cells and tumor cells showed sustained decreases, accompanied by reduced CD73 enzymatic activity in tumor cells. Objective response rate during escalation was 0%. Response rates in the CRC, PDAC, and NSCLC expansion cohorts were 2.4% (1 complete response [CR]), 4.8% (1 CR, 1 partial response [PR]), and 9.5% (4 PRs), respectively; 6-month progression-free survival rates were 5.4, 13.2, and 16.0%.

CONCLUSIONS: Oleclumab ± durvalumab had a manageable safety profile, with pharmacodynamic activity reflecting oleclumab's mechanism of action. Evidence of antitumor activity was observed in tumor types that are generally immunotherapy resistant.

Clinical trial registration: Clinicaltrials.gov, NCT02503774; date of registration, July 17, 2015.

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Antibodies, Monoclonal, Antineoplastic Agents, Fatigue

Comments

Supplementary Materials

Data Availability Statement

PMID: 37016126