Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial
| Autor: | Charu Aggarwal, Amy Prawira, Scott Antonia, Osama Rahma, Anthony Tolcher, Roger B Cohen, Yanyan Lou, Ralph Hauke, Nicholas Vogelzang, Dan P Zandberg, Arash Rezazadeh Kalebasty, Victoria Atkinson, Alex A Adjei, Mahesh Seetharam, Ariel Birnbaum, Andrew Weickhardt, Vinod Ganju, Anthony M Joshua, Rosetta Cavallo, Linda Peng, Xiaoyu Zhang, Sanjeev Kaul, Jan Baughman, Ezio Bonvini, Paul A Moore, Stacie M Goldberg, Fernanda I Arnaldez, Robert L Ferris, Nehal J Lakhani |
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| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Cancer Research B7 Antigens Lung Neoplasms Squamous Cell Carcinoma of Head and Neck Immunology Programmed Cell Death 1 Receptor Antibodies Monoclonal Antineoplastic Agents Antibodies Monoclonal Humanized Antineoplastic Agents Immunological Oncology Head and Neck Neoplasms Carcinoma Non-Small-Cell Lung Molecular Medicine Immunology and Allergy Humans |
| Zdroj: | Journal for immunotherapy of cancer. 10(4) |
| ISSN: | 2051-1426 |
| Popis: | BackgroundAvailability of checkpoint inhibitors has created a paradigm shift in the management of patients with solid tumors. Despite this, most patients do not respond to immunotherapy, and there is considerable interest in developing combination therapies to improve response rates and outcomes. B7-H3 (CD276) is a member of the B7 family of cell surface molecules and provides an alternative immune checkpoint molecule to therapeutically target alone or in combination with programmed cell death-1 (PD-1)–targeted therapies. Enoblituzumab, an investigational anti-B7-H3 humanized monoclonal antibody, incorporates an immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement of innate and adaptive immunity by targeting distinct members of the B7 family (B7-H3 and PD-1) is hypothesized to provide greater antitumor activity than either agent alone.MethodsIn this phase I/II study, patients received intravenous enoblituzumab (3–15 mg/kg) weekly plus intravenous pembrolizumab (2 mg/kg) every 3 weeks during dose-escalation and cohort expansion. Expansion cohorts included non–small cell lung cancer (NSCLC; checkpoint inhibitor [CPI]–naïve and post-CPI, programmed death-ligand 1 [PD-L1] ResultsOverall, 133 patients were enrolled and received ≥1 dose of study treatment. The maximum tolerated dose of enoblituzumab with pembrolizumab at 2 mg/kg was not reached. Intravenous enoblituzumab (15 mg/kg) every 3 weeks plus pembrolizumab (2 mg/kg) every 3 weeks was recommended for phase II evaluation. Treatment-related adverse events occurred in 116 patients (87.2%) and were grade ≥3 in 28.6%. One treatment-related death occurred (pneumonitis). Objective responses occurred in 6 of 18 (33.3% [95% CI 13.3 to 59.0]) patients with CPI-naïve HNSCC and in 5 of 14 (35.7% [95% CI 12.8 to 64.9]) patients with CPI-naïve NSCLC.ConclusionsCheckpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC.Trial registration numberNCT02475213. |
| Databáze: | OpenAIRE |
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