dc.contributor.author | Zucali, PA | |
dc.contributor.author | Lin, C-C | |
dc.contributor.author | Carthon, BC | |
dc.contributor.author | Bauer, TM | |
dc.contributor.author | Tucci, M | |
dc.contributor.author | Italiano, A | |
dc.contributor.author | Iacovelli, R | |
dc.contributor.author | Su, W-C | |
dc.contributor.author | Massard, C | |
dc.contributor.author | Saleh, M | |
dc.contributor.author | Daniele, G | |
dc.contributor.author | Greystoke, A | |
dc.contributor.author | Gutierrez, M | |
dc.contributor.author | Pant, S | |
dc.contributor.author | Shen, Y-C | |
dc.contributor.author | Perrino, M | |
dc.contributor.author | Meng, R | |
dc.contributor.author | Abbadessa, G | |
dc.contributor.author | Lee, H | |
dc.contributor.author | Dong, Y | |
dc.contributor.author | Chiron, M | |
dc.contributor.author | Wang, R | |
dc.contributor.author | Loumagne, L | |
dc.contributor.author | Lépine, L | |
dc.contributor.author | de Bono, J | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2022-09-06T11:56:59Z | |
dc.date.available | 2022-09-06T11:56:59Z | |
dc.date.issued | 2022-01-01 | |
dc.identifier | ARTN e003697 | |
dc.identifier | jitc-2021-003697 | |
dc.identifier.citation | Journal for ImmunoTherapy of Cancer, 2022, 10 (1), pp. e003697 - | en_US |
dc.identifier.issn | 2051-1426 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5421 | |
dc.identifier.eissn | 2051-1426 | |
dc.identifier.eissn | 2051-1426 | |
dc.identifier.doi | 10.1136/jitc-2021-003697 | |
dc.description.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. | |
dc.format | Print | |
dc.format.extent | e003697 - | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | BMJ PUBLISHING GROUP | en_US |
dc.relation.ispartof | Journal for ImmunoTherapy of Cancer | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc/4.0 | en_US |
dc.subject | clinical trials as topic | |
dc.subject | combination | |
dc.subject | drug therapy | |
dc.subject | lung neoplasms | |
dc.subject | programmed cell death 1 receptor | |
dc.subject | prostatic neoplasms | |
dc.subject | ADP-ribosyl Cyclase 1 | |
dc.subject | Aged | |
dc.subject | Aged, 80 and over | |
dc.subject | Antibodies, Monoclonal, Humanized | |
dc.subject | Antineoplastic Combined Chemotherapy Protocols | |
dc.subject | Female | |
dc.subject | Humans | |
dc.subject | Male | |
dc.subject | Middle Aged | |
dc.subject | Neoplasm Metastasis | |
dc.subject | Programmed Cell Death 1 Receptor | |
dc.subject | Tumor Microenvironment | |
dc.title | 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. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-12-07 | |
dc.date.updated | 2022-09-06T11:55:52Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1136/jitc-2021-003697 | en_US |
rioxxterms.licenseref.startdate | 2022-01-01 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/35058326 | |
pubs.issue | 1 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1136/jitc-2021-003697 | |
pubs.volume | 10 | |
icr.researchteam | PrCa Targeted Therapy | en_US |
dc.contributor.icrauthor | De Bono, Johann | |
icr.provenance | Deposited by Mr Arek Surman on 2022-09-06. Deposit type is initial. No. of files: 1. Files: Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies results from a phase II.pdf | |