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

Paolo Andrea Zucali, Chia Chi Lin, Bradley C. Carthon, Todd M. Bauer, Marcello Tucci, Antoine Italiano, Roberto Iacovelli, Wu Chou Su, Christophe Massard, Mansoor Saleh, Gennaro Daniele, Alastair Greystoke, Martin Gutierrez, Shubham Pant, Ying Chun Shen, Matteo Perrino, Robin Meng, Giovanni Abbadessa, Helen Lee, Yingwen DongMarielle Chiron, Rui Wang, Laure Loumagne, Lucie Lépine, Johann De Bono

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25 Citations (Scopus)


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.

Original languageEnglish
Article numbere003697
JournalJournal for ImmunoTherapy of Cancer
Issue number1
Publication statusPublished - 20 Jan 2022
Externally publishedYes


  • clinical trials as topic
  • combination
  • drug therapy
  • lung neoplasms
  • programmed cell death 1 receptor
  • prostatic neoplasms


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