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.
Loading...
Embargo End Date
ICR Authors
Authors
Zucali, PA
Lin, C-C
Carthon, BC
Bauer, TM
Tucci, M
Italiano, A
Iacovelli, R
Su, W-C
Massard, C
Saleh, M
Daniele, G
Greystoke, A
Gutierrez, M
Pant, S
Shen, Y-C
Perrino, M
Meng, R
Abbadessa, G
Lee, H
Dong, Y
Chiron, M
Wang, R
Loumagne, L
Lépine, L
de Bono, J
Lin, C-C
Carthon, BC
Bauer, TM
Tucci, M
Italiano, A
Iacovelli, R
Su, W-C
Massard, C
Saleh, M
Daniele, G
Greystoke, A
Gutierrez, M
Pant, S
Shen, Y-C
Perrino, M
Meng, R
Abbadessa, G
Lee, H
Dong, Y
Chiron, M
Wang, R
Loumagne, L
Lépine, L
de Bono, J
Document Type
Journal Article
Date
2022-01-01
Date Accepted
2021-12-07
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.
Citation
Journal for ImmunoTherapy of Cancer, 2022, 10 (1), pp. e003697 -
Source Title
Journal for ImmunoTherapy of Cancer
Publisher
BMJ PUBLISHING GROUP
ISSN
2051-1426
eISSN
2051-1426
2051-1426
2051-1426
Collections
Research Team
PrCa Targeted Therapy