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CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized
Andrew J Armstrong1, Ravit Geva2, Hyun Cheol Chung3
1Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, NC, 27710, USA. andrew.armstrong@duke.edu.
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).
Insights
The CXCR2 antagonist navarixin combined with pembrolizumab showed limited efficacy in advanced cancers. This combination therapy did not meet primary endpoints, indicating a need for alternative treatment strategies in castration-resistant prostate cancer, colorectal cancer, and non-small-cell lung cancer.
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- C-X-C motif chemokine receptor 2 (CXCR2) plays a role in tumor progression and immune evasion.
- Preclinical studies suggested CXCR2 inhibition could benefit patients with solid tumors.
- Navarixin is a CXCR2 antagonist investigated for its potential in cancer treatment.
Purpose of the Study:
- To evaluate the efficacy and safety of navarixin plus pembrolizumab in patients with advanced cancers.
- To assess the objective response rate (ORR) and progression-free survival (PFS) of the combination therapy.
- To explore potential dose-response relationships for navarixin.
Main Methods:
- A Phase 2 randomized study (NCT03473925) involving patients with castration-resistant prostate cancer (CRPC), microsatellite-stable colorectal cancer (MSS CRC), or non-small-cell lung cancer (NSCLC).
- Patients received either 30 mg or 100 mg of navarixin orally once daily plus 200 mg of pembrolizumab intravenously every 3 weeks.
- Primary endpoints included investigator-assessed objective response rate (RECIST v1.1) and safety.
Main Results:
- The overall objective response rates were low: 5% in CRPC, 2.5% in MSS CRC, and 0% in NSCLC.
- Median progression-free survival ranged from 1.8 to 2.4 months, with no clear dose-response observed.
- Treatment-related adverse events occurred in 67% of patients, with manageable safety and tolerability profiles, including neutropenia and liver enzyme elevations.
Conclusions:
- Navarixin plus pembrolizumab did not demonstrate sufficient efficacy in previously treated advanced CRPC, MSS CRC, or NSCLC.
- The study was closed early due to lack of efficacy at a prespecified interim analysis.
- While the combination showed manageable safety, its clinical benefit was not established in these patient populations.
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