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).
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Acknowledgements
Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. We thank the patients and their families and caregivers for participating in this study, along with all investigators, the co-investigators Katherine Scilla, MD, and Ranee Mehra, MD, and site personnel. Medical writing assistance was provided by Autumn Kelly, MA, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Dr. Armstrong reports funding from the NIH through 1R01CA233585-04.
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Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
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Conceptualization: Andrew J. Armstrong, Vincent Giranda, Fang Liu, and Bhargava Kandala. Methodology: Andrew J. Armstrong, Vincent Giranda, Fang Liu, and Bhargava Kandala. Formal analysis and investigation: Andrew J. Armstrong, Ravit Geva, Hyun Cheol Chung, Charlotte Lemech, Wilson H. Miller Jr., 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, and Judy S. Wang. Writing – original draft preparation: Andrew J. Armstrong, Hyun Cheol Chung, Frank Tsai, and Vincent Giranda. Writing – review and editing: Andrew J. Armstrong, Ravit Geva, Hyun Cheol Chung, Charlotte Lemech, Wilson H. Miller Jr., Aaron R. Hansen, Jong-Seok Lee, Benjamin J. Solomon, Tae Min Kim, Christian Rolfo, Vincent Giranda, Yixin Ren, Fang Liu, Bhargava Kandala, Tomoko Freshwater, and Judy S. Wang. Resources: Andrew J. Armstrong, Hyun Cheol Chung, Wilson H. Miller Jr., and Aaron R. Hansen.
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All procedures performed in this study were in accordance with local and/or national regulations and with the Declaration of Helsinki. The study protocol was approved by the institutional review board or independent ethics committee at each site.
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Informed consent was obtained from all patients included in the study.
Competing interests
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.
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Vincent Giranda is now retired.
Christian Rolfo affiliation at time of study: Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
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Armstrong, A.J., Geva, R., Chung, H.C. et al. CXCR2 antagonist navarixin in combination with pembrolizumab in select advanced solid tumors: a phase 2 randomized trial. Invest New Drugs 42, 145–159 (2024). https://doi.org/10.1007/s10637-023-01410-2
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DOI: https://doi.org/10.1007/s10637-023-01410-2