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

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.

Keywords: clinical trials as topic; combination; drug therapy; lung neoplasms; programmed cell death 1 receptor; prostatic neoplasms.

Conflict of interest statement

Competing interests: PAZ: Pfizer, Novartis, Sanofi, BMS, MSD, Roche, Amgen, AstraZeneca, Astellas, Janssen, Ipsen, and Bayer. C-CL: Abbvie, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Novartis, PharmaEngine, and Roche. BCC, MT, W-CS, GD, MS, AG, SP, Y-CS, MP: nothing to disclose. TMB: AstraZeneca, Lilly, Bristol Myers Squibb, Foundation Medicine, Pfizer, Loxo, Bayer, Guardant Health, Exelixis, Blueprint Medicines, and Sanofi. AI: Epizyme, Lilly, Merck Sharp & Dohme, Novartis, Pharmamar, Roche, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Pfizer. RI: Ipsen, Pfizer, Janssen, Sanofi, Merck, Astellas, and MSD. CM: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, and Orion. MG: Bristol Myers Squibb, Merck, Eli Lilly, Esanex, Foundation Medicine, AstraZeneca, and Guardant 360. RM, GA, HL, YD, MC, RW, and LLo are employed by Sanofi and may hold stock and/or stock options in the company. LLe is employed by Excelya on behalf of Sanofi and may hold stock and/or stock options in the company. JdB: AstraZeneca, GlaxoSmithKline, Pfizer, Taiho, Daiichi Sankyo, Bayer, Orion Pharma, Roche/Genentech, Merck Serono, Sierra Oncology, MSD, Terumo, Menarini/Silicon Biosystems, Astellas, BioexcelTherapeutics, Cellcentric, Merck Sharp & Dohme, Qiagen, Sanofi Aventis, and Vertex Pharmaceuticals.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

mCRPC, metastatic castration-resistant prostate cancer; NSCLC, non-small cell lung cancer; PD-L1, programmed death ligand 1; TPS, tumor-positive score.