CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial

Summary C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with...

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Published in:	Investigational new drugs 2024-02, Vol.42 (1), p.145-159
Main Authors:	Armstrong, Andrew J., Geva, Ravit, Chung, Hyun Cheol, Lemech, Charlotte, Miller Jr, Wilson H., Hansen, Aaron R., Lee, Jong-Seok, Tsai, Frank, Solomon, Benjamin J., Kim, Tae Min, Rolfo, Christian, Giranda, Vincent, Ren, Yixin, Liu, Fang, Kandala, Bhargava, Freshwater, Tomoko, Wang, Judy S.
Format:	Article
Language:	eng
Subjects:	Adult Antibodies, Monoclonal, Humanized - adverse effects Antineoplastic Combined Chemotherapy Protocols - adverse effects Cancer Carcinoma, Non-Small-Cell Lung - drug therapy Castration Chemokine receptors Colorectal carcinoma CXCR2 protein Effectiveness Hepatitis Humans Immune checkpoint inhibitors Immunologic Factors - therapeutic use Leukocytes (neutrophilic) Lung cancer Lung diseases Lung Neoplasms - drug therapy Male Medicine Medicine & Public Health Metastases Microsatellites Neoplasms Neutropenia Non-small cell lung carcinoma Oncology Pembrolizumab Pharmacology/Toxicology Pneumonitis Prostate cancer Prostatic Neoplasms, Castration-Resistant - drug therapy Safety Small cell lung carcinoma Solid tumors Transaminase Tumors
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Summary:	Summary C-X-C motif chemokine receptor 2 (CXCR2) has a role in tumor progression, lineage plasticity, and reduction of immune checkpoint inhibitor efficacy. Preclinical evidence suggests potential benefit of CXCR2 inhibition in multiple solid tumors. In this phase 2 study (NCT03473925), adults with previously treated advanced or metastatic castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non–small-cell lung cancer (NSCLC) were randomized 1:1 to the CXCR2 antagonist navarixin 30 or 100 mg orally once daily plus pembrolizumab 200 mg intravenously every 3 weeks up to 35 cycles. Primary endpoints were investigator-assessed objective response rate (RECIST v1.1) and safety. Of 105 patients (CRPC, n=40; MSS CRC, n=40; NSCLC, n=25), 3 had a partial response (2 CRPC, 1 MSS CRC) for ORRs of 5%, 2.5%, and 0%, respectively. Median progression-free survival was 1.8–2.4 months without evidence of a dose-response relationship, and the study was closed at a prespecified interim analysis for lack of efficacy. Dose-limiting toxicities occurred in 2/48 patients (4%) receiving navarixin 30 mg and 3/48 (6%) receiving navarixin 100 mg; events included grade 4 neutropenia and grade 3 transaminase elevation, hepatitis, and pneumonitis. Treatment-related adverse events occurred in 70/105 patients (67%) and led to treatment discontinuation in 7/105 (7%). Maximal reductions from baseline in absolute neutrophil count were 44.5%−48.2% (cycle 1) and 37.5%−44.2% (cycle 2) and occurred within 6−12 hours postdose in both groups. Navarixin plus pembrolizumab did not demonstrate sufficient efficacy in this study. Safety and tolerability of the combination were manageable. ( Trial registration : ClinicalTrials.gov , NCT03473925).
ISSN:	0167-6997 1573-0646