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

Abstract

SummaryC-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).

Immune Cell Migration to Cancer

“…Another avenue with the potential to aid in cancer treatment is the control and trafficking of immune cells to cancer, including MDSCs and Tregs, summarized in this review. Preclinical and clinical attempts to suppress cancer by antagonizing CCR2, CCR4, CCR5, CXCL8, CXCR1/2, CXCR4 combined with or without other therapies [206,222,229,[466][467][468][469][470][471][472][473][474][475][476][477] (clinical trials reported by ClinicalTrials.gov: NCT03177187, NCT03851237), by chemokine modulation regimen via cytokine and TLR agonist/antagonist injection [229] (clinical trials reported by ClinicalTrials.gov: NCT06149481, NCT05570825, NCT03161431), or by targeting non-chemokine/chemokine receptor mechanisms such as eATP metabolism [359,362] (clinical trials reported by ClinicalTrials.gov: NCT05234853, NCT05177770, NCT05431270) or complement [304,478] (clinical trials reported by ClinicalTrials.gov: NCT02257528) are being continued.…”

Identification of ibuprofen targeting CXCR family members to alleviate metabolic disturbance in lipodystrophy based on bioinformatics and in vivo experimental verification

“…A multicenter, randomized, double-blind, placebo-controlled trial on newly diagnosed type 1 diabetes revealed that short-term ladarixin treatment did not significantly preserve residual β-cell function ( 30 ). Navarixin is currently mainly used in the treatment of advanced solid tumors, and there are no experiments investigating the relationship between navarixin and metabolic diseases ( 31 ). Clotrimazole is a broad-spectrum antifungal agent that is mainly used to treat fungal infections such as Candida albicans .…”

DataSheet_1.docx

“…A multicenter, randomized, double-blind, placebo-controlled trial on newly diagnosed type 1 diabetes revealed that short-term ladarixin treatment did not significantly preserve residual b-cell function (30). Navarixin is currently mainly used in the treatment of advanced solid tumors, and there are no experiments investigating the relationship between navarixin and metabolic diseases (31). Clotrimazole is a broad-spectrum antifungal agent that is mainly used to treat fungal infections such as Candida albicans.…”