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A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy

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Summary

Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration. Methods Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks. Results Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7–14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit. Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.

Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

Funding was provided by X4 Pharmaceuticals and the Dana-Farber/Harvard Cancer Center Kidney Program and Kidney SPORE.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA

    Toni K. Choueiri

  2. Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA

    Michael B. Atkins

  3. Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Tracy L. Rose

  4. John Theurer Cancer Center Hackensack UMC, Hackensack, NJ, USA

    Robert S. Alter

  5. X4 Pharmaceuticals, Cambridge, MA, USA

    Yawen Ju, Katie Niland, Yan Wang, Robert Arbeit, Sudha Parasuraman & Lu Gan

  6. Beth Israel Deaconess Medical Center, Boston, MA, USA

    David F. McDermott

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  1. Toni K. Choueiri
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Contributions

Each author participated in the writing of and has approved the submitted version of this manuscript.

Corresponding author

Correspondence to Toni K. Choueiri.

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Conflict of interest

TKC reports institutional and personal support from AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, and Takeda. TKC also reports honoraria from AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, and Lilly. TKC has played consulting or advisory roles with AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, and Tempest. TKC reports stock ownership in Pionyr and Tempest. TKC reports the following patents, royalties or other intellectual properties related to biomarkers of checkpoint blockers: International Patent Application No. PCT/US2018/12209, entitled “PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response,” filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017; International Patent Application No. PCT/US2018/058430, entitled “Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy,” filed October 31, 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed November 3, 2017. TKC reports travel, accommodations, and expenses in relation to consulting, advisory roles, or honoraria. Medical writing and editorial assistance support may have been supported by communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others). The institution (Dana-Farber Cancer Institute) may have received additional independent funding from drug companies or/and royalties potentially involved in research around the subject matter. Finally, TKC has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components.

MBA reports grants and personal fees from BMS, Merck, and Roche to the institution; a grant from X4 Pharmaceuticals; consulting fees from Exelixis, Pfizer, Array, and Immunocore; and Advisory Board fees from Eisai, Arrowhead, Pyxis Pharma, Werewolf, Novartis, Leads, and Aveo.

TLR reports no conflicts of interest.

RSA reports Advisory Board membership for Eisai and Bayer.

YJ and LG were X4 Pharmaceuticals employees during the research described herein.

YW and SP were X4 Pharmaceuticals employees and stock owners during the research described herein.

KN reports being an X4 Pharmaceuticals employee at time of the research and still owns X4 stock.

DFM reports consulting fees from BMS, Pfizer, Merck, Alkermes, Inc., EMD Serono, Eli Lilly & Company, and research support from BMS, Merck., Genentech, Pfizer, Exelixis, Novartis, X4 Pharma, Alkermes, Inc., outside the submitted work.

Ethical approval

All patients provided signed informed consent. The protocol was approved by each site’s Institutional Review Board or, and the study was conducted according to local and federal regulations and the Declaration of Helsinki.

Informed consent

All study participants provided written informed consent. 

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Choueiri, T.K., Atkins, M.B., Rose, T.L. et al. A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy. Invest New Drugs 39, 1019–1027 (2021). https://doi.org/10.1007/s10637-020-01058-2

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