Ibrutinib-rituximab demonstrates sustained superiority over rituximab alone in patients with Waldenström’s macroglobulinaemia

Interim results of the phase III iNNOVATE study previously demonstrated superiority of the ibrutinib-rituximab combination over rituximab alone in patients with Waldenström’s macroglobulinaemia (WM). Updated results of this trial, with five years of follow-up, demonstrate ongoing superiority of ibrutinib-rituximab across clinical outcomes in patients with WM regardless of genotype, prior treatment, and key patient characteristics. In addition, ibrutinib-rituximab maintained a manageable safety profile and no new safety signals could be identified with long-term ibrutinib.

Background

The Bruton’s tyrosine kinase inhibitor ibrutinib is approved as either a single-agent or in combination with rituximab for patients with Waldenström’s macroglobulinaemia (WM) across all lines of therapy. In the primary analysis of the phase III iNNOVATE study, with 26.5 months median follow-up, ibrutinib plus rituximab was found to induce a superior progression-free survival (PFS) over placebo plus rituximab in patients with WM. This finding was confirmed in a subsequent analysis of the study with a median follow-up of 33.4 months. At ASH 2020, results from the final analysis of the randomised arms of iNNOVATE were presented, with an overall follow-up of 63 months. In total, 150 patients with confirmed symptomatic WM requiring treatment were randomised (1:1) to once-daily ibrutinib 420 mg or placebo plus rituximab (375 mg/m²/week IV on day 1 of weeks 1–4 and 17–20). Importantly, for patients in the placebo-rituximab arm there was the possibility to cross over to single-agent ibrutinib after disease progression. Patients could be either treatment-naïve or previously treated, although patients with prior rituximab therapy were required to have achieved at least a minor response to their last rituximab-based regimen.

Results

After a median follow-up of 50 months, 45% of patients in the placebo-rituximab arm discontinued treatment due to disease progression, as compared to only 9% in the ibrutinib-rituximab arm. After disease progression, 47% of patients in the placebo-arm crossed over to single-agent ibrutinib. Demographics and clinical characteristics between the two arms were well-balanced at baseline.

In the intent-to-treat population, the median PFS was not reached with five years of ibrutinib-rituximab, as compared to 20.3 months for placebo-rituximab (HR [95%CI]: 0.25 [0.148-0.420], p<0.0001). The 54-month PFS rates were 68% and 25% for the ibrutinib and placebo arms, respectively. Importantly, the PFS benefit obtained from adding ibrutinib to rituximab was observed independent of the genotype (MYD88^L265P/CXCR4^WHIM, MYD88^L265P/CXCR4^WT, MYD88^WT/CXCR4^WT) and the prior treatment status. Furthermore, PFS benefit of ibrutinib over placebo was also observed across all other investigated subgroups, irrespective of age, gender, serum immunoglobulin and haemoglobin level, and IPSS risk status. Moreover, ibrutinib-rituximab was associated with a higher major response rate (76% vs. 31%) and this difference was maintained over time. The median time to overall response was one month for patients treated with ibrutinib with a median time to major response of 3 months. The level of IgM rapidly decreased during the first year of treatment with a maximum decrease of 33.5 g/L with ibrutinib and 26.9 g/L with placebo. Compared to placebo-rituximab, a greater proportion of patients in the ibrutinib-rituximab arm experienced a sustained haemoglobin improvement (77% vs. 43%; p<0.0001). Median OS was not reached in either treatment arm (HR [95%CI]: 0.81 [0.328-1.990], p<0.6430). At the 54-month landmark analysis, the OS rate was 86% with ibrutinib vs. 84% with placebo.

With 63 months of overall follow-up, ibrutinib-rituximab maintained a manageable safety profile with 88% of adverse events (AEs) leading to an ibrutinib dose reduction that resolved following the dose reduction. The most common grade 3–4 AEs with ibrutinib-rituximab were atrial fibrillation (16%), hypertension (15%), neutropenia (13%), and anaemia (12%). Interestingly, there seems to be a tendency that AEs appear to occur less frequently later on in treatment. After study closure, 68 patients (45%) remained on treatment (32 enrolled in a treatment extension study and 36 continued to receive ibrutinib in a non-trial setting).

Conclusions

With 63 months overall follow-up, ibrutinib-rituximab demonstrates ongoing superiority over placebo-rituximab across all clinical outcomes in patients with WM. This superiority was observed regardless of genotype, prior treatment and other patient characteristics. Interestingly, the patterns of response with ibrutinib-rituximab were similar for previously treated and untreated patients. Finally, ibrutinib-rituximab maintained a manageable safety profile without new safety signals during the additional 24 months of follow-up.

Reference

Buske C, Tedeschi A, Trotman J, et al. Five-Year Follow-Up of Ibrutinib Plus Rituximab Vs Placebo Plus Rituximab for Waldenstrom’s Macroglobulinemia: Final Analysis From the Randomized Phase 3 iNNOVATETM Study. Presented at ASH 2020; Abstract 336.