BTK inhibition in Waldenström’s macroglobulinemia: trial updates and biomarker analysis
The open-label, multicenter, randomized phase III ASPEN trial was set up to assess the efficacy and safety of the potent, selective, irreversible next-generation BTK inhibitor zanubrutinib in Waldenström’s macroglobulinemia (WM). Cohort 1 of the study included patients with MYD88-mutated disease (n = 201); here, zanubrutinib was compared to ibrutinib after 1:1 randomization. In Cohort 2, 28 patients with MYD88 wildtype received zanubrutinib in a non-randomized manner. Both treatment-naïve and pretreated patients participated, although no prior BTK inhibition (BTKi) was allowed. Untreated patients were eligible when considered unsuitable for standard chemoimmunotherapy.
With respect to the primary endpoint, which was complete response (CR) plus very good partial response (VGPR) for zanubrutinib vs. ibrutinib, no significant difference resulted at the time of the primary analysis , although the findings indicated clinically meaningful efficacy and improved tolerability of the newer BTK inhibitor.
43-month follow-up of ASPEN
This impression was corroborated by the long-term follow-up reported at iwWM 2022 . In Cohort 1, the CR + VGPR rate was numerically higher at all time points with zanubrutinib vs. ibrutinib. At 44.4 months, this was 36.3 % vs. 25.3 %, with shorter median time to CR + VGPR (6.7 vs. 16.6 months). Zanubrutinib elicited a higher event-free rate for the duration of CR + VGPR at 24 months (90.6 % vs. 79.3 %). Median PFS and OS had not yet been reached, with hazard ratios favoring zanubrutinib (PFS, 0.63; OS, 0.75). At 42 months, 87.5 % vs. 85.2 % of patients were alive, and 78.3 % vs. 69.7 % were progression-free. After almost four years, 66 % vs. 52 % remained on treatment.
Assessments of patients with MYD88MUT by CXCR4 status demonstrated that patients with CXCR4 mutation derived benefits from zanubrutinib compared to ibrutinib regarding VGPR or better (21.2 % vs. 10.0 %), major response (78.8 % vs. 65.0 %), time to major response (3.4 vs. 6.6 months), and PFS (HR, 0.50). Seventy-three percent of these patients treated with zanubrutinib enjoyed freedom from progression at 42 months, while only 49.0 % in the ibrutinib arm did.
In Cohort 2, responses to zanubrutinib treatment continued to deepen over time. At 42.9 months of follow-up, one patient had achieved complete response, and the rate of major responses had risen to 65 %. Event-free rates of PFS and OS at 42 months were 53.8 % and 83.9 %, respectively.
Likewise, the safety advantages of zanubrutinib remained consistent over time, with less off-target activity versus ibrutinib. Zanubrutinib-treated patients showed lower cumulative incidences of atrial fibrillation, diarrhea, hypertension, muscle spasms, and pneumonia, and had fewer AEs leading to death, treatment discontinuation, or dose reductions. Among AEs of special interest observed in Cohort 1, neutropenia was more common with zanubrutinib (any grade, 34.7 % vs. 20.4 %), although infection rates were similar across the arms (any grade, 79.2 % vs. 79.6 %), with grade 3/4 events occurring less frequently in the experimental arm (21.8 % vs. 27.6 %). Interestingly, in Cohort 1, hemorrhage, neutropenia, diarrhea and infection prevalence decreased over time in patients treated with zanubrutinib (Figure 1). Exposure-adjusted incidence rates of atrial fibrillation/flutter and hypertension were lower with zanubrutinib versus ibrutinib (7.9 % vs. 23.5 % and 14.9 % vs. 25.5 %, respectively).
The authors noted that over time, zanubrutinib showed a consistent trend of deeper, earlier, more durable responses and different safety advantages with less off-target activity compared with ibrutinib.
Figure 1: ASPEN trial – prevalence analysis for adverse events of interest (Cohort 1).
BTKi treatment in WM patients with low frequency genetic alterations
With the advent of high-throughput technologies, it is now known that MYD88 L265P and CXCR4 nonsense (NS) and frameshift mutations (FS) are the most common recurrent variations observed in WM patients, with detection rates of 90 % and 40 %, followed by ARID1A with 17 %, respectively . The mutation status of MYD88 and CXCR4 impacts the efficacy of BTKi in patients with WM. Overall response rates (ORR) are highest in MYD88MUT CXCR4WT patients, worse in MYD88MUT CXCR4MUT and lowest in MYD88WT CXCR4WT patients [3-6]. Thus, the biomarker study, presented at iwWM 2022, evaluated low-frequency genetic alterations and their association with efficacy of ibrutinib and zanubrutinib treatment in patients with WM included in the ASPEN phase III trial .
Next-generation sequencing NGS results were evaluable in 190 patients with MYD88MUT (98 treated with zanubrutinib, and 92 treated with ibrutinib, respectively) and 20 patients with MYD88WT. Besides high rates of CXCR4 mutations (25.7 %), TP53 (24.8 %), ARID1A (15.2 %) and TERT (9.1 %) were the most frequently mutated genes identified in the study. TERTMUT was detected in patients with MYD88MUT, only, and ARID1AMUT and TP53MUT were more commonly associated with CXCR4MUT and more often detected in patients with MYD88MUT.
In patients with MYD88MUT WM, those with CXCR4MUT, TP53MUT, and TERTMUT trended toward lower VGPR+CR rate or MPR and longer median time to response than patients with the respective WT alleles (Table), whereas ARID1AMUT showed limited clinical impact.
Moreover, a less favorable PFS was shown in patients with MYD88MUT WM and CXCR4MUT (HR, 1.32; 95% CI, 0.96-2.51; p = 0.390), TP53MUT (HR, 2.15; 95% CI, 1.19-3.90; p = 0.011), or TERTMUT (HR, 1.79; 95% CI, 0.80-4.00; p=0.150), than patients with the respective WT allele (Figure 2).
Patients with MYD88MUT CXCR4NSWM treated with ibrutinib showed reduced VGPR (15.4 % vs. 30.6 %), MRR (53.8 % vs. 84.7 %) and PFS (43.5 % vs. 57.1 %, p = 0.017) than those with CXCR4WT whereas in the zanubrutinib arm only VGPR (14.3 % vs. 44.6%) was reduced and MRR (85.7 % vs. 83.1 %) and PFS (66.7 % vs. 81.3 %, p = 0.598) were comparable. Although there were only a small number of patients in the CXCR4FS cohort treated with either zanubrutinib (n = 19) or ibrutinib (n = 7), zanubrutinib demonstrated a more favorable VGPR+CR rate compared to ibrutinib (26.3 % vs 0 %, p = 0.06).
Patients with TP53MUT had reduced VGPR (13.6 % vs. 30.0 %), MRR (63.6 % vs. 85.7 %) and PFS (57.9 % vs. 72.1 %, p = 0.027) than those with CXCR4WT in the ibrutinib arm. In the zanubrutinib arm no significant differences were reported [VGPR (34.6 % vs. 37.5 %), MRR (80.8 % vs. 81.9 %) and PFS (62.0 % vs. 84.6 %, p = 0.120)]. Of note, the VGPR rate for TP53MUT was significantly higher in the zanubrutinib arm than in the ibrutinib arm (34.6 % vs. 13.6 %, p < 0.05).
Patients with TERTMUT had reduced VGPR (11.1 % vs. 27.7 %) and MRR (44.4 % vs. 84.3 %) but comparable PFS (74.0 % vs. 68.4 %, p = 0.304) than those with TERTWT in the ibrutinib arm. In the zanubrutinib arm reduced VGPR (10.0 % vs. 39.8 %) and significantly reduced PFS (37.5 % vs 83.4 %, p = 0.001) were reported, whereas MRR (70.0 vs 83.0) was comparable between TERTMUT and TERTWT.
Overall, the authors concluded that in the ASPEN trial, CXCR4MUT, TP53MUT, and TERTMUT were correlated with inferior response to BTKi therapy. Consistent with more potent inhibition of BTK, zanubrutinib demonstrated deeper responses in patients with CXCR4MUT or TP53MUT WM.
Figure 2: Progression-free survival (PFS) in patients with MYD88MUT WM by (A) CXCR4, (B) TP53 and (C) TERT mutational status.
- Tam CS et al., A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinema: the ASPEN study. Blood 2020; 136(18): 2038-2050
- Dimopoulos M et al., ASPEN: long-term follow-up results of a phase 3 randomized trial of zanubrutinib versus ibrutinib in patients with Waldenström macroglobulinemia. iwWM 2022, Session 11.
- Tam CS M et al., ASPEN Biomarker Analysis: Response to Bruton Tyrosine Kinase Inhibitor (BTKi) Treatment in Patients with Waldenström Macroglobulinemia (WM) Harboring CXCR4, TP53, and TERT. iwWM 2022, Session 11.
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