The iNNOVATE trial: ibrutinib plus rituximab vs Placebo plus rituximab for Waldenström’s macroglobulinemia

Study design

The iNNOVATE trial randomized 150 patients with Waldenström's macroglobulinemia (both treatment-naïve patients and those experiencing disease recurrence) to ibrutinib in combination with rituximab or rituximab alone.
The patients were randomly assigned in a 1:1 ratio to receive either oral ibrutinib (420 mg once daily) or placebo until disease progression or unacceptable toxic effects.
The two groups also received extended intravenous rituximab (375 mg per square meter of body-surface area, with infusions at weeks 1 to 4 and 17 to 20).^1,2

Figure 1: Study design of the iNNOVATE trial. Derived from Dimopoulos, MA et al. N Engl J Med. 2018; 378:2399-2410, Dimopoulos MA et al. 62nd ASH Annual Meeting Exposition abstract 336.^1,2

Results

Progression-free survival (PFS) and overall survival (OS)

The final analysis of iNNOVATE occurred after a median follow-up of 50 months. The results demonstrated a 68% progression-free survival (PFS) in the combination group vs 25% in the rituximab-placebo group at the 54-month time point.
The median PFS was not reached with ibrutinib-rituximab vs 20.3 months with placebo–rituximab.
Patients treated with ibrutinib-rituximab had a PFS benefit that was independent of genotype (HR (95% CI): MYD88^L265P/CXCR4^WT, 0.18 (0.08–0.43); MYD88^L265P/CXCR4^WHIM, 0.27 (0.12–0.62); MYD88^WT/CXCR4^WT, 0.29 (0.07–1.19)) (Figure 2).
The 54-month overall survival rate was 86% with ibrutinib–rituximab and 84% with placebo–rituximab.

Responses

The major response rate at 60 months was 76% in the ibrutinib-rituximab arm vs 31% for placebo-rituximab (p<0.0001) and the overall response rate 92% vs 44% (p<0.0001).
High response rates were observed with combination therapy across genotypes (94% (30/32) in MYD88^L265P/CXCR4^WT; 100% (26/26) in MYD88^L265P/CXCR4^WHIM; 82% (9/11) in MYD88^WT/CXCR4^WT).²

Safety

Overall, the safety profile was consistent with that of the 30-month follow-up. Minimal differences in adverse effect (AE) rates were observed after 24 months of additional follow-up and AEs even decreased over time.
The most common grade 3–4 AEs were atrial fibrillation (16%), hypertension (15%), neutropenia (13%), and anemia (12%).²

Figure 2: Progression free survival per IRC for treatment group and genotype. Derived from Dimopoulos MA et al. 62nd ASH Annual Meeting Exposition abstract 336.²

Summary

With up to 5 years of follow-up, ibrutinib-rituximab showed ongoing superiority in patients with WM irrespective of key clinical features including genotype.
Ibrutinib-rituximab maintained a manageable safety profile, with no new safety signals identified and minimal increases in common AEs after an additional 24 months of follow-up.²

References

1.Dimopoulos MA, Tedeschi A, Trotman J, et al. Phase 3 Trial of Ibrutinib plus Rituximab in Waldenström’s Macroglobulinemia. N Engl J Med. 2018: 378;2399-2410.

2.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. 62nd ASH Annual Meeting Exposition abstract.