Long-Term Follow-up of Ibrutinib Treatment for Rituximab-Refractory Waldenström's Macroglobulinemia: Final Analysis of the Open-Label Substudy of the Phase 3 iNNOVATE^TM Trial

Background: Ibrutinib is the only once-daily Bruton's tyrosine kinase inhibitor approved in the US and EU either as single-agent therapy or in combination with rituximab for treatment of patients with Waldenström's macroglobulinemia (WM) across all lines of therapy. The open-label substudy of the phase 3 iNNOVATE trial (PCYC-1127; NCT02165397) demonstrated that single-agent ibrutinib was highly efficacious (90% overall response rate [ORR] per investigator) with improved responses over time in heavily pretreated, rituximab-refractory patients with WM (Buske Blood 2018). Here, we present results from the final analysis of the iNNOVATE open-label substudy.

Methods: Patients with WM who failed to achieve at least a minor response (MR) or who relapsed <12 months after their last rituximab-containing therapy received once-daily ibrutinib 420 mg. Endpoints included progression-free survival (PFS) and ORR (≥MR) per Independent Review Committee (IRC), overall survival (OS), hemoglobin (Hgb) improvement, and safety; serum immunoglobulin M (IgM) reduction was also assessed.

Results: Thirty-one patients with rituximab-refractory disease were enrolled; median age was 67 years (range 47-90), and median number of prior therapies was 4 (range 1-7). Median baseline Hgb was 103 g/L (range 64-146). Median baseline IgM was 39 g/L (range 9-107). Median follow-up was 58 months (range 9-61). Median PFS was 39 months (95% CI 25-NE); the PFS rate at 60 months was 40%. Median PFS was not reached (95% CI 27-NE) in patients with the MYD88^L265P/CXCR4^WT genotype and was 18 months (95% CI 3-28) in patients with the MYD88^L265P/CXCR4^WHIM genotype. ORR was 87%, with similar ORR observed across genetic subtypes (MYD88^L265P/CXCR4^WT, 88% [15/17]; MYD88^L265P/CXCR4^WHIM, 86% [6/7]); major response rates (≥PR) among these genotypes were 88% (15/17) and 71% (5/7), respectively (Figure 1A). Median OS was not reached in the full cohort of patients, regardless of number of prior therapies (1-2 vs ≥3). Improvements in IgM and Hgb were generally rapid and sustained (Figure 1B). Twenty-two patients (71%) had sustained improvement in Hgb, including 17/21 (81%) with baseline Hgb ≤110 g/L. Median change in IgM from baseline to nadir (month 54) was -37 g/L (range -75 to -5). Median duration of ibrutinib treatment was 41 months. The most common reason for discontinuing ibrutinib while on study was progressive disease (42%). At time of study closure, 14 patients (45%) remained on treatment; of these, 6 went on to receive ibrutinib in the commercial setting and 8 enrolled in a treatment extension study. Overall, 97% of patients experienced a treatment-emergent adverse event (TEAE), most commonly diarrhea (48%; grade ≥2, 13%) and pyrexia (35%; grade ≥2, 6%). Grade 3/4 TEAEs occurred in 81% of patients; the most common were neutropenia (16%), hypertension (10%), and anemia (10%). No deaths occurred due to AEs, and no patients died while on treatment. Ibrutinib dose was reduced in 5 patients (16%) due to an AE, and 2 patients (6%) discontinued treatment because of an AE. No patients experienced major hemorrhage or atrial fibrillation.

Conclusions: In this final analysis of the open-label substudy of the iNNOVATE trial, single-agent ibrutinib continued to show sustained efficacy in patients who had heavily pretreated, rituximab-refractory WM. Responses to ibrutinib were consistent across genotypes, although subgroup numbers were small. Ibrutinib maintained a manageable safety profile, and no new safety signals were identified with over 5 years of overall follow-up.

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