Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Feb;42(1):145-159.
doi: 10.1007/s10637-023-01410-2. Epub 2024 Feb 7.

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

Andrew J Armstrong  1 , Ravit Geva  2 , Hyun Cheol Chung  3 , Charlotte Lemech  4 , Wilson H Miller Jr  5 , Aaron R Hansen  6 , Jong-Seok Lee  7 , Frank Tsai  8 , Benjamin J Solomon  9 , Tae Min Kim  10 , Christian Rolfo  11 , Vincent Giranda  12 , Yixin Ren  12 , Fang Liu  12 , Bhargava Kandala  12 , Tomoko Freshwater  12 , Judy S Wang  13
Affiliations
Clinical Trial

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

Andrew J Armstrong et al. Invest New Drugs. 2024 Feb.

Erratum in

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).

Keywords: C-X-C chemokine; Clinical trial; Navarixin; Pembrolizumab; Solid tumors.

PubMed Disclaimer

Conflict of interest statement

Andrew J. Armstrong: Research support (to Duke) from Astellas, Pfizer, Bayer, Janssen, Dendreon, Genentech/Roche, Bristol Myers Squibb, AstraZeneca, Merck, Forma, Celgene, and Amgen. Consulting or advising relationships with Astellas, Epic Sciences, Pfizer, Bayer, Janssen, Dendreon, Bristol Myers Squibb, AstraZeneca, Merck, Forma, Celgene, Clovis, Exact Sciences, Myovant, Exelixis, Point Biopharma, Medscape CME, OncLive, and Research to Practice. Ravit Geva: Options: Pyxis. Medical Lead: Pyxis. Honoraria: Roche, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Merck & Co., Inc., Rahway, NJ, USA, Medison, Janssen, Pfizer, and Bristol Myers Squibb. Consulting and Advisory: Eisai, AstraZeneca, Roche, Ranium, Johnson & Johnson, Bayer, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Oncotest. Travel, Accommodations, Expenses: Takeda and Medison. Hyun Cheol Chung: Grants/Research Support: Lilly, GSK, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Merck-Serono, Bristol Myers Squibb/Ono, Taiho, Amgen, BeiGene, Incyte, and Zymeworks. Honoraria: Merck-Serono and Lilly. Consultation: Taiho, Celltrion, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Lilly, Bristol Myers Squibb, Merck-Serono, Gloria, BeiGene, Amgen, and Zymeworks. Charlotte Lemech: No competing interests to disclose. Wilson H. Miller Jr.: Grants Support: Merck, CIHR, CRS, Terry Fox Research Institute, Samuel Waxman Cancer Research Foundation, and CCSRI. Participated in clinical trials within the past 2 years: Bristol Myers Squibb, Novartis, GSK, Roche, AstraZeneca, Methylgene, MedImmune, Bayer, Amgen, Merck, Incyte, Pfizer, Sanofi, Array, MiMic, Ocellaris Pharma, Astellas, Alkermes, Exelixis, VelosBio, and Genentech. Consulting/Honoraria: Merck, Bristol Myers Squibb, Roche, GSK, Novartis, Amgen, Mylan, EMD Serono, and Sanofi. Aaron R. Hansen: Research: Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, GSK, Bristol Myers Squibb, Novartis, Pfizer, Roche, Genentech, Boehringer Ingelheim, Tyra Biosciences, Neoleukin Therapeutics, Astellas, Point Biopharma, and AstraZeneca. Consulting: Pfizer, Merck, and GSK. Jong-Seok Lee: No competing interests to disclose. Frank Tsai: No competing interests to disclose. Benjamin J. Solomon: Advisory Boards/Honoraria: Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, AstraZeneca, Pfizer, Novartis, Takeda, Bristol Myers Squibb, Eli Lilly, Novartis, Amgen, BeiGene, and Roche. Tae Min Kim: Received honoraria from or played an advisory role with AstraZeneca, Boryung, F. Hoffmann-La Roche Ltd/Genentech, Inc., IMBDx, Inc., Janssen, Novartis, Regeneron, Samsung Bioepis, Sanofi, Takeda, and Yuhan, and has received research funding outside this work from AstraZeneca-Korea Health Industry Development Institute. Christian Rolfo: Consulting fees: Archer, Inivata, Bristol Myers Squibb, Novartis, Boston Pharmaceuticals, EMD Serono, Pfizer, Mirati, Eisai, Daiichi Sankyo, Sanofi Genzyme-Regeneron, Blueprint Medicines, CEA, Bayer U.C. LLC, General Dynamics, MedStar, Diverse HealthHub, Merck, MH Live Events, Janssen Scientific Affairs, EMD, Amgen, LUNGevity, Postgraduate Institute of Medicine, ACC Med, GME, Nadirex, ASCO Plenary Series, Imagene, HMP Education, Medical Educator Consortium, Thermo Fisher Scientific, and AbbVie. Research grant: LCRF-Pfizer. Ownership interest: Novartis. Fees for non-CME/CE services: AstraZeneca, Roche, Guardant Health, Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, COR2ED, Physicians Education Resource, LLC, Intellisphere, LLC, and Boehringer Ingelheim. Participation on a Data Safety Monitoring Board: EMD Serono. President: ISLB. Chair Educational Committee: IASLC. Scientific Board Member: ESO. Faculty Lung Cancer Advanced Editor in Chief: CROH. Associate Editor: ESMO Open. Vincent Giranda: former employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholder in Merck & Co., Inc., Rahway, NJ, USA. Yixin Ren, Fang Liu, Bhargava Kandala, and Tomoko Freshwater: employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and stockholders in Merck & Co., Inc., Rahway, NJ, USA. Judy S. Wang: Consulting/Advisory: Janssen Research & Development, Stemline Therapeutics, Kanaph Therapeutics, and Fusion Pharmaceuticals. Speakers’ Bureau: AstraZeneca and Eisai. Research Funding (to institution): AstraZeneca, Bicycle Therapeutics, BioNTech, Boehringer Ingelheim, Celgene, cyteir, Daiichi Sankyo, Genentech/Roche, GlaxoSmithKline, H3 Biomedicine, Hutchison MediPharma, Jacobio, Janssen Research & Development, Klus Pharma, Kymab, Loxo, LSK BioPharma, Macrogenics, Merck, Moderna Therapeutics, Phoenix Pharmaceuticals, Prelude Therapeutics, QiLu Pharmaceutical, Revolution Medicines, Ribon Therapeutics, Syndax, Taiho Pharmaceutical, Tesaro, TopAlliance BioSciences Inc, Xencor, Artios, Erasca, Inc, Immunogen, Cullinan Oncology, Immune-Onc Therapeutics, Bayer Health, Biosplice, Zymeworks, BioTheryX, TeneoBio, Nurix, IgM Biosciences, PureTech, Forty Seven, Treadwell Therapeutics, MabSpace Biosciences, Novartis, Olema Oncology, Seven and Eight Biopharmaceuticals, ORIC Pharmaceuticals, Relay Therapeutics, Jazz Pharmaceuticals, Adagene, NGM Biopharmaceuticals, Agenus, Metabomed, BeiGene, Astellas Pharma, Blueprint Medicines, and Hotspot Therapeutics.

Figures

Fig. 1
Fig. 1
Maximum percentage change from baseline in target lesions and spider plots of percentage change from baseline for target lesions, based on investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1, in patients with A castration-resistant prostate cancer, B microsatellite-stable colorectal cancer, and C non–small-cell lung cancer. The last assessment before discontinuation of study drug (or within 1 cycle of discontinuation of study drug) is plotted as ‘Patient off study drug’ in the spider plots
Fig. 1
Fig. 1
Maximum percentage change from baseline in target lesions and spider plots of percentage change from baseline for target lesions, based on investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1, in patients with A castration-resistant prostate cancer, B microsatellite-stable colorectal cancer, and C non–small-cell lung cancer. The last assessment before discontinuation of study drug (or within 1 cycle of discontinuation of study drug) is plotted as ‘Patient off study drug’ in the spider plots
Fig. 1
Fig. 1
Maximum percentage change from baseline in target lesions and spider plots of percentage change from baseline for target lesions, based on investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1, in patients with A castration-resistant prostate cancer, B microsatellite-stable colorectal cancer, and C non–small-cell lung cancer. The last assessment before discontinuation of study drug (or within 1 cycle of discontinuation of study drug) is plotted as ‘Patient off study drug’ in the spider plots
See this image and copyright information in PMC

References

    1. Cheng Y, Ma XL, Wei YQ, Wei XW. Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochim Biophys Acta Rev Cancer. 2019;1871:289–312. doi: 10.1016/j.bbcan.2019.01.005. - DOI - PubMed
    1. Korbecki J, Kupnicka P, Chlubek M, Goracy J, Gutowska I, Baranowska-Bosiacka I (2022) CXCR2 receptor: regulation of expression, signal transduction, and involvement in cancer. Int J Mol Sci 23:2168 [Epub]. 10.3390/ijms23042168 - PMC - PubMed
    1. Di Mitri D, Mirenda M, Vasilevska J, Calcinotto A, Delaleu N, Revandkar A, Gil V, Boysen G, Losa M, et al. Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence and tumor inhibition in advanced prostate cancer. Cell Rep. 2019;28(2156–2168):e2155. doi: 10.1016/j.celrep.2019.07.068. - DOI - PMC - PubMed
    1. Zhao J, Ou B, Feng H, Wang P, Yin S, Zhu C, Wang S, Chen C, Zheng M et al (2017) Overexpression of CXCR2 predicts poor prognosis in patients with colorectal cancer. Oncotarget 8:28442–28454. 10.18632/oncotarget.16086 - PMC - PubMed
    1. Wei L, Liu Y, Ma Y, Ding C, Zhang H, Lu Z, Gu Z, Zhu C. C-X-C chemokine receptor 2 correlates with unfavorable prognosis and facilitates malignant cell activities via activating JAK2/STAT3 pathway in non-small cell lung cancer. Cell Cycle. 2019;18:3456–3471. doi: 10.1080/15384101.2019.1689471. - DOI - PMC - PubMed

Publication types

MeSH terms

Associated data