Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies: results from a phase I/II open-label, multicenter study

• Type of Material: Article
• Authors: Paolo Andrea Zucali, IRCCS Istituto Clinico Humanitas; Chia-Chi Lin, National Taiwan University Hospital; Bradley Carthon, Emory University; Todd M. Bauer, Sarah Cannon Research Institute; Marcello Tucci, Cardinal Massaia Hospital of Asti; Antoine Italiano, Gustave Roussy; Roberto Iacovelli, Fondazione Policlinico Universitario Agostino Gemelli IRCCS; Wu-Chou Su, National Cheng Kung University; Christophe Massard, Universite Paris Saclay; Mansoor Saleh, University of Alabama Birmingham; Gennaro Daniele, Istituto Nazionale Tumori IRCCS Fondazione Pascale; Alastair Greystoke, Newcastle University; Martin Gutierrez, Hackensack University; Shubham Pant, University of Texas MD Anderson Cancer Center; Ying-Chun Shen, National Taiwan University Hospital; Matteo Perrino, IRCCS Istituto Clinico Humanitas; Robin Meng, Sanofi Genzyme; Giovanni Abbadessa, Sanofi Genzyme; Helen Lee, Sanofi Genzyme; Yingwen Dong, Sanofi-Aventis; Marielle Chiron, Sanofi Aventis; Rui Wang, Sanofi Genzyme; Laure Loumagne, Sanofi Aventis; Lucie Lepine, Sanofi-Aventis; Johann de Bono, Institute of Cancer Research London
• Language: English
• Date: 2022-01-01
• Publisher: BMJ PUBLISHING GROUP
• Publication Version: Final Published Version
• Copyright Statement: © Author(s) (or their employer(s)) 2022
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/jitc-2021-003697
• Title of Journal or Parent Work: JOURNAL FOR IMMUNOTHERAPY OF CANCER
• Volume: 10
• Issue: 1
• Grant/Funding Information: This study was sponsored by Sanofi.
• Keywords: prostatic neoplasms; Immunology; lung neoplasms; drug therapy; Oncology; Science & Technology; combination; clinical trials as topic; programmed cell death 1 receptor; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Oncology; Health Sciences, Immunology; Health Sciences, Pharmacology

Abstract

BACKGROUND: Preclinical data suggest that concurrent treatment of anti-CD38 and antiprogrammed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies substantially reduce primary tumor growth by reversing T-cell exhaustion and thus enhancing anti-PD-1/PD-L1 efficacy. METHODS: This phase I/II study enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of phase I were to investigate the safety and tolerability of isatuximab (anti-CD38 monoclonal antibody)+cemiplimab (anti-PD-1 monoclonal antibody, Isa+Cemi) in patients with mCRPC (naïve to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase II used Simon's two-stage design with response rate as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) patients receiving Isa+Cemi were enrolled in phase II. Safety, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, and tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping. RESULTS: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All patients experienced ≥1 treatment-emergent adverse event. Grade≥3 events occurred in 13 (54.2%) patients with mCRPC and 12 (60.0%) patients with NSCLC. Based on PCWG3 criteria, assessment of best overall response with Isa+Cemi in mCRPC revealed no complete responses (CRs), one (4.2%) unconfirmed partial response (PR), and five (20.8%) patients with stable disease (SD). Per RECIST V.1.1, patients with NSCLC receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. In post-therapy biopsies obtained from patients with mCRPC or NSCLC, Isa+Cemi treatment resulted in a reduction in median CD38+ tumor-infiltrating immune cells from 40% to 3%, with no consistent modulation of PD-L1 on tumor cells or T regulatory cells in the TME. The combination triggered a significant increase in peripheral activated and cytolytic T cells but, interestingly, decreased natural killer cells. CONCLUSIONS: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, such CD38 inhibition was not associated with significant antitumor activity. A lack of efficacy was observed in these small cohorts of patients with mCRPC or NSCLC. TRIAL REGISTRATION NUMBERS: NCT03367819.