PRELIMINARY CLINICAL DATA FROM A PHASE 1B STUDY OF MAVORIXAFOR AND IBRUTINIB IN PATIENTS WITH WALDENSTRöM MACROGLOBULINEMIA WITH <i>MYD88</i> AND <i>CXCR4</i> MUTATIONS

Introduction: Waldenström macroglobulinemia (WM) is a rare disorder of clonal proliferation of immunoglobulin M (IgM)-secreting B cells. Most patients with WM (>90%) have somatic mutations in MYD88. Some (≤40%) also have WHIM-like activating mutations in CXCR4 (CXCR4 WHIM ) that impact response to Bruton tyrosine kinase inhibitors (BTKi). C-X-C chemokine receptor type 4 (CXCR4) inhibition has been shown to sensitize CXCR4 WHIM -expressing cells to ibrutinib. This study examines the safety and efficacy of mavorixafor, an oral CXCR4 antagonist, in combination with ibrutinib in patients with WM with MYD88 and CXCR4 mutations. Methods: This phase 1b, open-label, single-arm study (NCT04274738) examines intrapatient dosing, safety, pharmacokinetics (PK), and pharmacodynamics (PD) of mavorixafor in combination with ibrutinib. Adults with clinicopathologic WM diagnosis, consensus criteria indication for treatment, measurable disease, ≤3 prior therapies, and MYD88 L265P and CXCR4 WHIM mutations are eligible. Patients are initiated on mavorixafor 200 mg and ibrutinib 420 mg, both oral and once-daily (QD). Mavorixafor is escalated to 400 mg after 28 days if no dose-limiting toxicities (DLTs) occur and to 600 mg if 400 mg is deemed safe (<2/6 DLTs). Outcomes include adverse events (AEs) and change from baseline in IgM, PK, and PD (peripheral white blood cell [WBC] counts). Results: At data cutoff in January 2021, 7 patients have enrolled and remain on study. All 7 were escalated to 400 mg; 6 remain at 400 mg, and 1 de-escalated to 200 mg (median exposure, 90 days). None have yet escalated to 600 mg. Fifty-six AEs were observed (84% grade 1). Of 50 AEs with complete assessment for causal relationship to study drugs, 4 were deemed related to mavorixafor only, 7 to ibrutinib only, and 18 to the combination. One patient experienced all AEs attributed to mavorixafor only. Only 1 DLT was observed (grade 3 hypertension definitively related to ibrutinib and possibly related to mavorixafor). No AEs led to study discontinuation, and no serious AEs were observed. Six of 7 patients showed IgM decrease after 1 cycle. Four patients received ≥3 cycles; all had IgM decrease, with 2 achieving ≥50% decrease consistent with partial response (median decrease, 51.0%; range, 4.4%–84.5%). Mavorixafor and ibrutinib exposures were consistent with previous single-agent studies, and combination treatment increased WBCs. Conclusions: Our findings to date in patients with WM carrying both MYD88 and CXCR4 mutations show that mavorixafor in combination with ibrutinib is well tolerated at doses ≤400 mg QD. Unaltered mavorixafor and ibrutinib exposures suggest no apparent drug–drug interaction, and mavorixafor exposures tracked with increased WBC counts. Combination of mavorixafor with ibrutinib led to rapid and clinically meaningful decrease in IgM, suggesting mavorixafor may sensitize CXCR4 WHIM -expressing cells to BTKi. EA – previously submitted to EHA 2021. The research was funded by: X4 Pharmaceuticals Keywords: Molecular Targeted Therapies, Combination Therapies, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract S. Treon Consultant or advisory role: PharmaCyclics/Abbvie, Janssen Pharmaceuticals, Beigene Research funding: PharmaCyclics/Abbvie, Janssen Pharmaceuticals, Beigene, BMS, Eli Lilly C. Buske Consultant or advisory role: Roche, Janssen, Bayer, MSD, Celltrion Honoraria: Roche, Janssen, Bayer, MSD, Celltrion Research funding: Roche, Janssen, Bayer, MSD, Celltrion S. Thomas Consultant or advisory role: Beigene, Pharmacyclics, Bristol Myers Squibb, Ascentage Phama, Genetech, X4 Pharmaceuticals, A. Branagan Consultant or advisory role: Beigene, Sanofi-Genzyme, Karyopharm, Pharmacyclics M. Dimopoulos Honoraria: AMGEN, TAKEDA, JANSSEN, BMS, BEIGENE J. J. Castillo Consultant or advisory role: Abbvie, Beigene, Pharmacyclics Research funding: Abbvie, Beigene, Pharmacyclics, TG Therapeutics F. Garzon Consultant or advisory role: X4 Pharmaceuticals W. Tang Employment or leadership position: X4 Pharmaceuticals Stock ownership: X4 Pharmaceuticals R. Ronan Employment or leadership position: X4 Pharmaceuticals S. Seyffert Employment or leadership position: X4 Pharmaceuticals Stock ownership: X4 Pharmaceuticals, PSU, ESPP V. Garg Employment or leadership position: X4 Pharmaceuticals Stock ownership: X4 Pharmaceuticals S. Ali Employment or leadership position: X4 Pharmaceuticals Stock ownership: X4 Pharmaceuticals A. Taveras Employment or leadership position: X4 Pharmaceuticals A. Badarau Employment or leadership position: X4 Pharmaceuticals Stock ownership: X4 Pharmaceuticals K. Zmajkovicova Employment or leadership position: X4 Pharmaceuticals Stock ownership: X4 Pharmaceuticals Research funding: X4 Pharmaceuticals S. Maier Employment or leadership position: X4 Pharmaceuticals Stock ownership: X4 Pharmaceuticals Research funding: X4 Pharmaceuticals B. Maierhofer Employment or leadership position: X4 Pharmaceuticals Stock ownership: X4 Pharmaceuticals Research funding: X4 Pharmaceuticals J. Matous Consultant or advisory role: Janssen Pharmacyclics