Safety and efficacy of the oral CXCR4 inhibitor X4P-001 + axitinib in advanced renal cell carcinoma patients: An analysis of subgroup responses by prior treatment

Abstract

Background: The CXCR4 chemokine receptor modulates immunosuppressive cell trafficking that can inhibit antitumor immune responses. X4P-001 is a selective, oral CXCR4 antagonist currently in clinical development as a novel therapy for solid tumors, including renal cell carcinoma (RCC). In xenograft models, X4P-001 in combination with axitinib, a VEGF receptor tyrosine kinase inhibitor (TKI), reduced myeloid-derived suppressor cell infiltration and proangiogenic signals and demonstrated greater than additive antitumor activity. Methods: Here we report combined Phase I/II study results for 65 patients (Pts) with advanced RCC treated with 400 mg oral X4P-001 (200 mg BID or 400 mg QD) + 5 mg oral BID axitinib. All Pts had failed at least 1 prior treatment with a TKI, immuno-oncology (IO) agent, or other systemic therapy (2+, n = 49 Pts, 75%; 3+, n = 31, 48%) and had an ECOG performance status of ≤ 2. Results: The median age was 64 years (range 42-87), and the median treatment duration was 25 weeks (range 1-148). Of the 65 Pts, 12 (18%) remain on combination therapy. The objective response rate (ORR) among the 62 clinically evaluable Pts was 29% (1 complete response; 17 partial responses) and the interim median progression-free survival (mPFS) was 7.4 months. The ORR for Pts receiving immediate prior TKI therapy was 18% (n = 34) and mPFS was 7.4 months. The ORR for Pts receiving immediate prior IO therapy was 61% (n = 18) and mPFS was 11.6 months. Thirteen Pts (20%) were discontinued from the study due to adverse events (AEs) regardless of attribution. The most common (> 20%) treatment-related (TR)AEs of any grade were diarrhea (35 Pts, 54%), decreased appetite (29 Pts, 45%), fatigue (28 Pts, 43%), hypertension (25 Pts, 38%), nausea (17 Pts, 28%), and dysphonia (14 Pts, 22%). The most common TRAEs ≥ Grade 3 were hypertension (14 Pts, 22%) and diarrhea (7 Pts, 11%). Conclusions: X4P-001 + axitinib is well tolerated in Pts with advanced RCC with a manageable safety profile. In this population, X4P-001 + axitinib demonstrates encouraging mPFS. Therapy is ongoing and updated study results will be presented. Clinical trial identification: X4P-001-RCCA; Release date: 7 April 2015. Editorial acknowledgement: Timothy Henion of Acumen Medical Communications. Legal entity responsible for the study: X4 Pharmaceuticals. Funding: X4 Pharmaceuticals. Disclosure: D.F. McDermott: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Exelixix; Honoraria (self), Advisory / Consultancy: Array BioPharm; Honoraria (self), Advisory / Consultancy: Genentech BioOncology; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: EMD Serono; Research grant / Funding (institution): Prometheus Laboratories; Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Jounce Therapeutics. T. Ho: Advisory / Consultancy: Exelixis; Advisory / Consultancy: Ipsen Bioscience; Advisory / Consultancy: Roche; Advisory / Consultancy: Cardinal Health; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Novartis. B. Keam: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dohme; Advisory / Consultancy: Genexine; Research grant / Funding (self): Ono Pharmaceutical. R. Joseph: Advisory / Consultancy: BMS; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Array. W. Stadler: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Caremark/CVS; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Sotio; Speaker Bureau / Expert testimony: Applied Clinical Education; Speaker Bureau / Expert testimony: Dava Oncology; Speaker Bureau / Expert testimony: Global Academy for Medical Education; Speaker Bureau / Expert testimony: OncLive; Speaker Bureau / Expert testimony: PeerView; Speaker Bureau / Expert testimony: Vindico; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Astellas (Medivation); Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): X4 Pharmaceuticals. J. Picus: Advisory / Consultancy: NovoNordisk; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): BioClin Therapeutics; Research grant / Funding (institution): Agensys; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Innocrin Pharmaceuticals; Research grant / Funding (institution): Rexahn Pharmaceuticals; Research grant / Funding (institution): Endocyte; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Tracon Pharmaceuticals; Research grant / Funding (institution): eFFECTOR Therpeutics. Y. Zakharia: Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche Diagnostics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Janssen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Array BioPharm; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Castle Bioscience; Advisory / Consultancy: Pfizer. L. Gan: Full / Part-time employment: X4 Pharmaceuticals. M.B. Atkins: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy: Arrowhead; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Genentech-Roche; Advisory / Consultancy: Galactone; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Werewolf; Advisory / Consultancy: Fathom; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Aveo; Advisory / Consultancy: Array; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Ideera; Advisory / Consultancy: Amgen; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Alexion; Advisory / Consultancy: Iovance; Advisory / Consultancy: Newlink. All other authors have declared no conflicts of interest.