Waldenström’s macroglobulinemia: outcome optimization via combinations
Final analysis of iNNOVATE
Ibrutinib is the only once-daily BTK inhibitor approved as a single agent or in combination with rituximab for patients with Waldenström’s macroglobulinemia (WM) across all lines of therapy. In the international, double-blind, randomized, phase III iNNOVATE trial, ibrutinib plus rituximab was tested against placebo plus rituximab in patients with rituximab-sensitive WM. Each arm contained 75 individuals. Crossover to single-agent ibrutinib was allowed in the control arm after disease progression. The primary analysis after a median follow-up of 26.5 months yielded improved progression-free survival (PFS) in the experimental arm . At 33.4 months, the combination continued to show superiority regardless of the genomic subtype . Infusion-related reactions and immunoglobulin M flares occurred less frequently with ibrutinib/rituximab than with placebo/rituximab.
The final analysis of the iNNOVATE study for the randomized arms was presented at EHA 2021 after an overall follow-up of 63 months . Here, ibrutinib/rituximab demonstrated ongoing superiority over placebo/rituximab across clinical outcomes. PFS in the ITT population had not been reached in the experimental arm and was 20.3 months in the control arm (HR, 0.250; p < 0.0001). At 54 months, 68 % vs. 25 % of patients were progression-free. The PFS benefit was independent of the genotype, i.e., the presence of MYD88 and/or CXCR4 mutations. Moreover, previously treated and untreated patients derived similar PFS benefits from ibrutinib/rituximab. In contrast, in the control arm, the previously untreated group had better results than the treated group, with both of them showing inferior outcomes compared to the patients in the experimental arm. Ibrutinib/rituximab significantly improved PFS across all prespecified subgroups within the previously treated population and within most of the subgroups in the previously untreated population.
Major responses (i.e., complete, very good partial and partial remissions) deepened and were sustained over time in the experimental arm, with superior results compared to rituximab alone (Figure). The combination induced higher responses irrespective of the genotype or prior treatment status. IgM levels decreased rapidly during the first year and continued to decrease in patients treated with ibrutinib/rituximab, whereas IgM levels in the control arm tended to fluctuate over time and were generally higher. The maximum changes across the two arms amounted to -33.5 g/L vs. -26.9 g/L. Similarly, a significantly greater proportion of patients receiving ibrutinib/rituximab had sustained improvement in hemoglobin levels (77 % vs. 43 %; p < 0.0001). Among those with baseline levels ≤ 110 g/L, 95 % vs. 56 % experienced persistent improvement (p < 0.0001). Median overall survival had not been reached in either arm, with 54-month OS rates of 86 % vs. 84 % (HR, 0.81).
The combination maintained a manageable safety profile. No new safety signals occurred with long-term ibrutinib treatment for over five years. The prevalence of grade ≥ 3 adverse events (AEs) of clinical interest, such as infections, neutropenia, atrial fibrillation and hypertension, generally decreased over time. Eighty-eight percent of AEs that led to ibrutinib dose reductions resolved following dose modification.
Figure: Responses over time observed with ibrutinib/rituximab vs. placebo/rituximab in the iNNOVATE trial. MR, major response
Mavorixafor/ibrutinib in MYD88/CXCR4 co-mutation
The presence of the CXCR4WHIM mutation, which is found in 30–40 % of patients with WM, is associated with higher disease burden and reduced response to BTK inhibitors, as manifested by delayed response, inferior depth of response, and/or shorter PFS [4-6]. Inhibition of CXCR4 has been demonstrated to sensitize CXCR4WHIM-expressing cells to ibrutinib [7, 8], thus providing a rationale for combination therapy. The oral small-molecule CXCR4 antagonist mavorixafor inhibits CXCL12 binding as well as extracellular signal-regulated kinase and protein kinase B (AKT) hyperactivation for many CXCR4 mutations in vitro . Mavorixafor was well tolerated and active in combination with standard-of-care treatment in clinical studies for other solid malignancies [10, 11].
An ongoing, phase Ib, open-label, multicenter, single-arm study is assessing intra-patient dose escalation, safety, pharmacokinetics and pharmacodynamics of mavorixafor plus ibrutinib in patients with both MYD88L265P and CXCR4WHIM mutations after 0–3 prior therapies. Three cohorts (A–C) are initiated on mavorixafor 200 mg and ibrutinib 420 mg daily. In the absence of dose-limiting toxicities (DLTs), mavorixafor is escalated to 400 mg after 28 days and then again to 600 mg if 400 mg is deemed tolerable (< 2/6 DLTs). The cohorts differ with respect to the steps taken if DLTs occur (i.e., withdrawal of the patient, de-escalation). Treon et al. reported preliminary clinical data for eight patients included in Cohorts A and B at EHA 2021 .
Rapid and clinically relevant benefits
At the time of the analysis, all patients had completed the low- and mid-dose levels. Mavorixafor and ibrutinib exposures were shown to be consistent with previous single-agent studies, which suggests no drug-drug interactions. Mavorixafor exposures tracked with increases in key white blood counts in all patients. The combination was well tolerated, with 77 % of AEs rated as grade 1. AEs related to use of mavorixafor only occurred in two patients; these were grade 1 or 2 and included nausea, acid reflux, constipation, elevated white blood cell count, and worsening pain/numbness in the shoulder/hands/wrists.
All patients experienced reductions in IgM levels, and none progressed while on treatment. Median absolute serum IgM levels decreased from pretreatment levels of 23.56 g/L to 9.93 g/L at 6 months. At the same time, patients with decreased baseline hemoglobin levels showed increases toward normal. In those on treatment for six cycles, median hemoglobin increased by > 20 g/L. The authors noted in their conclusions that further follow-up will help define the potential of mavorixafor plus ibrutinib to improve clinical response to BTK inhibition in patients with MYD88 and CXCR4 mutations.
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- García-Sanz R et al., Ibrutinib plus rituximab vs placebo plus rituximab for Waldenström’s macroglobulinemia: final analysis after five years of follow-up from the randomized phase 3 iNNOVATE study. EHA 2021, EP782
- Treon SP et al., Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood 2014; 123(18): 2791-2796
- Treon SP et al., Long-term follow-up of ibrutinib monotherapy in symptomatic, previously treated patients with Waldenström macroglobulinemia. J Clin Oncol 2021; 39(6): 565-575
- Treon SP et al., Ibrutinib monotherapy in symptomatic, treatment-naïve patients with Waldenström macroglobulinemia. J Clin Oncol 2018; 36(27): 2755-2761
- Cao Y et al., CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88(L265P)-directed survival signalling in Waldenström macroglobulinaemia cells. Br J Haematol 2015; 168(5): 701-707
- Cao Y et al., The WHIM-like CXCR4(S338X) somatic mutation activates AKT and ERK and promotes resistance to ibrutinib and other agents used in the treatment of Waldenstrom’s macroglobulinemia. Leukemia 2015; 29(1): 169-176
- X4 Pharmaceuticals. Data on File
- McDermott D et al., 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. Ann Oncol 2019: 30 (suppl_5): v475-v532
- Choueiri TK 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 2021 Jan 28. doi: 10.1007/s10637-020-01058-2. Online ahead of print
- Treon SP et al., Preliminary clinical data from a phase 1b study of mavorixafor and ibrutinib in patients with Waldenström’s macroglobulinemia with MYD88 and CXCR4 mutations. EHA 2021, EP784
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