Moreno C, et al. - Given that superior efficacy of both single-agent ibrutinib and chlorambucil plus obinutuzumab vs chlorambucil monotherapy has been already reported in chronic lymphocytic leukaemia, researchers tested the efficacy of two treatment combinations in first-line treatment of chronic lymphocytic leukaemia or small lymphocytic lymphoma: ibrutinib plus obinutuzumab vs chlorambucil plus obinutuzumab. In previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma, ibrutinib plus obinutuzumab was found to be an efficacious and safe chemotherapy-free combination treatment, independent of high-risk features. Ibrutinib plus obinutuzumab affords an alternative first-line treatment option for these patients.

Methods

• Researchers performed a multicentre, randomised, open-label, phase 3 trial, named iLLUMINATE, at 74 academic and community hospitals in Australia, Canada, Israel, New Zealand, Russia, Turkey, the EU, and the USA.
• Participants were patients with previously untreated chronic lymphocytic leukaemia or small lymphocytic lymphoma, either aged 65 years or older or younger than 65 years with coexisting conditions.
• They used a blocked randomisation schedule, stratified by Eastern Cooperative Oncology Group performance status and cytogenetics, and randomly assigned (1:1) participants to ibrutinib plus obinutuzumab (oral ibrutinib [420 mg once daily continuously] combined with intravenous obinutuzumab [100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 1 and on day 1 of subsequent 28-day cycles, for a total of six cycles]) or chlorambucil plus obinutuzumab (oral chlorambucil [0·5 mg/kg bodyweight on days 1 and 15 of each 28-day cycle for six cycles] combined with the same obinutuzumab regimen).
• They used an interactive web response system to ensure allocation concealment, however, patients and investigators were not masked to treatment assignment.
• In the intention-to-treat population, progression-free survival (primary endpoint) was evaluated by a masked independent review committee.
• For safety analysis, all patients who received at least one dose of study treatment were evaluated.

Results

• In this study, a total of 229 patients were enrolled and randomly assigned to receive ibrutinib plus obinutuzumab (n=113) or chlorambucil plus obinutuzumab (n=116) between Oct 6, 2014, and Oct 12, 2015.
• A median follow-up of 31·3 months (IQR 29·4–33·2) revealed significantly longer median progression-free survival in the ibrutinib plus obinutuzumab group (median not reached [95% CI 33·6–non-estimable]) vs in the chlorambucil plus obinutuzumab group (19·0 months [15·1–22·1]; hazard ratio 0·23; 95% CI 0·15–0·37; p<0·0001).
• In the ibrutinib plus obinutuzumab group and in the chlorambucil plus obinutuzumab group, the estimated 30-month progression-free survival was 79% (95% CI 70–85) and 31% (23–40), respectively.
• Neutropenia and thrombocytopenia were most commonly experienced as grade 3 or 4 adverse events in both groups.
• Among 113 patients treated with ibrutinib plus obinutuzumab and 115 patients treated with chlorambucil plus obinutuzumab, the occurrence of serious adverse events was reported in 65 (58%) and 40 (35%), respectively.
• In the ibrutinib plus obinutuzumab group and in the chlorambucil plus obinutuzumab group, deaths attributed to ibrutinib or chlorambucil treatment were reported in one (1%) of 113 patients (sudden death) and in one (1%) of 115 patients (neuroendocrine carcinoma of the skin), respectively.