PT - JOURNAL ARTICLE AU - Zucali, Paolo Andrea AU - Lin, Chia-Chi AU - Carthon, Bradley C AU - Bauer, Todd M AU - Tucci, Marcello AU - Italiano, Antoine AU - Iacovelli, Roberto AU - Su, Wu-Chou AU - Massard, Christophe AU - Saleh, Mansoor AU - Daniele, Gennaro AU - Greystoke, Alastair AU - Gutierrez, Martin AU - Pant, Shubham AU - Shen, Ying-Chun AU - Perrino, Matteo AU - Meng, Robin AU - Abbadessa, Giovanni AU - Lee, Helen AU - Dong, Yingwen AU - Chiron, Marielle AU - Wang, Rui AU - Loumagne, Laure AU - Lépine, Lucie AU - de Bono, Johann TI - 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 AID - 10.1136/jitc-2021-003697 DP - 2022 Jan 01 TA - Journal for ImmunoTherapy of Cancer PG - e003697 VI - 10 IP - 1 4099 - http://jitc.bmj.com/content/10/1/e003697.short 4100 - http://jitc.bmj.com/content/10/1/e003697.full SO - J Immunother Cancer2022 Jan 01; 10 AB - 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.Data are available upon reasonable request. Qualified researchers can request access to patient-level data and related study documents including the clinical study report, study protocol with any amendments, blank case report forms, statistical analysis plan, and dataset specifications. Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of trial subjectss. Further details on Sanofi’s data-sharing criteria, eligible studies, and process for requesting access are at https://www.clinicalstudydatarequest.com.