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

Andrew J. Armstrong*, Ravit Geva, Hyun Cheol Chung, Charlotte Lemech, Wilson H. Miller, Aaron R. Hansen, Jong Seok Lee, Frank Tsai, Benjamin J. Solomon, Tae Min Kim, Christian Rolfo, Vincent Giranda, Yixin Ren, Fang Liu, Bhargava Kandala, Tomoko Freshwater, Judy S. Wang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

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).

Original languageEnglish
Pages (from-to)145-159
Number of pages15
JournalInvestigational New Drugs
Volume42
Issue number1
DOIs
StatePublished - Feb 2024

Funding

FundersFunder number
Merck Sharp & Dohme LLC
National Institutes of Health1R01CA233585-04
Samuel Waxman Cancer Research Foundation
Merck
Catholic Relief Services
Canadian Cancer Society Research Institute
Canadian Institutes of Health Research
Terry Fox Research Institute

    Keywords

    • C-X-C chemokine
    • Clinical trial
    • Navarixin
    • Pembrolizumab
    • Solid tumors

    Fingerprint

    Dive into the research topics of 'CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial'. Together they form a unique fingerprint.

    Cite this