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

• Published in: Journal for immunotherapy of cancer 2022-01, Vol.10 (1), p.e003697
• Main Authors: Zucali, Paolo Andrea, Lin, Chia-Chi, Carthon, Bradley C, Bauer, Todd M, Tucci, Marcello, Italiano, Antoine, Iacovelli, Roberto, Su, Wu-Chou, Massard, Christophe, Saleh, Mansoor, Daniele, Gennaro, Greystoke, Alastair, Gutierrez, Martin, Pant, Shubham, Shen, Ying-Chun, Perrino, Matteo, Meng, Robin, Abbadessa, Giovanni, Lee, Helen, Dong, Yingwen, Chiron, Marielle, Wang, Rui, Loumagne, Laure, Lépine, Lucie, de Bono, Johann
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase 1 - metabolism; Aged; Aged, 80 and over; Antibodies; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Blood; Cancer; Cancer therapies; Cell death; Chemotherapy; clinical trials as topic; Clinical/Translational Cancer Immunotherapy; combination; Drug dosages; drug therapy; FDA approval; Female; Humans; Immunotherapy; Ligands; Lung cancer; lung neoplasms; Male; Metastasis; Middle Aged; Monoclonal antibodies; Multiple myeloma; Mutation; Neoplasm Metastasis; programmed cell death 1 receptor; Programmed Cell Death 1 Receptor - therapeutic use; Prostate cancer; prostatic neoplasms; Radiation therapy; Response rates; Surgery; Targeted cancer therapy; Tumor Microenvironment
• ISSN: 2051-1426; 2051-1426
• DOI: 10.1136/jitc-2021-003697

BackgroundPreclinical 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.MethodsThis 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.ResultsIsa+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.ConclusionsThe 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 N