Results from the Phase 3 iLLUMINATE Study: Ibrutinib + Obinutuzumab as First-Line Treatment in Patients with CLL/SLL

In iLLUMINATE, researchers investigated the potential for improved efficacy with the addition of obinutuzumab to single-agent ibrutinib versus chlorambucil-obinutuzumab. iLLUMINATE is the first study to prospectively evaluate a chemotherapy-free regimen versus chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) patients. Eligible CLL patients required treatment and were at least 65 years of age or less than 65 years of age with ≥1 of the following: cumulative illness rating score >6, creatinine clearance <70 mL/min, and/or del(17p) or TP53 mutation. Patients were randomized 1:1 to receive ibrutinib (420 mg once daily continuously) combined with obinutuzumab (1000 mg for 6 cycles), or chlorambucil (0.5 mg/kg for 6 cycles) combined with obinutuzumab. The primary study end point was progression-free survival (PFS) and secondary end points included PFS in high-risk patients, rate of undetectable minimal residual disease (MRD), overall response rate (ORR), overall survival (OS), and safety. Patients with confirmed progression were permitted to cross over to next-line therapy with ibrutinib. A total of 229 patients were randomized to ibrutinib-obinutuzumab (n = 113) or chlorambucil-obinutuzumab (n = 116). The median age was 71 years and about two-thirds (65%) of patients had high-risk genomic features.

At a median follow-up of 31.3 months, the median PFS by independent review committee assessment was not reached for ibrutinib-obinutuzumab compared with 19.0 months for chlorambucil-obinutuzumab (P <.0001). This finding translates to a 74% reduction in risk for progression or death. PFS rates at 30 months were 79% and 31% with ibrutinib-obinutuzumab and chlorambucil-obinutuzumab, respectively. Furthermore, PFS benefit with ibrutinib-obinutuzumab was consistent across the high-risk subgroups examined, which included patients with del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV. Similarly, ORRs and complete response rates were higher with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab. MRD was undetectable in blood and/or bone marrow for 35% of patients with ibrutinib-obinutuzumab versus 25% with chlorambucil-obinutuzumab. OS rates with median follow-up of 31 months were statistically similar for the 2 groups; however, it should be noted that 40% of patients randomized to chlorambucil-obinutuzumab crossed over to single-agent ibrutinib as second-line therapy.

In the ibrutinib-obinutuzumab arm, grade ≥3 adverse events included neutropenia (28%) and thrombocytopenia (18%), whereas in the chlorambucil-obinutuzumab arm, grade ≥3 neutropenia and thrombocytopenia rates were 46% and 10%, respectively. Grade ≥3 atrial fibrillation occurred in 3% of ibrutinib-obinutuzumab patients; no grade ≥3 atrial fibrillation was reported in the chlorambucil-obinutuzumab arm. Infusion-related reactions occurred more frequently in the chlorambucil-obinutuzumab arm (8% vs 2%). These adverse event rates were seen despite the fact that median duration of treatment was 29.3 months for patients treated with ibrutinib-obinutuzumab versus 5.1 months for chlorambucil-obinutuzumab.

Ibrutinib-obinutuzumab resulted in superior PFS regardless of high-risk genomic features compared with chlorambucil-obinutuzumab. Furthermore, response rates and depth of remission (complete response and undetectable MRD) were higher with ibrutinib-obinutuzumab. No new safety signals emerged. Researchers concluded that ibrutinib-obinutuzumab represents an effective chemotherapy-free treatment option for first-line CLL/SLL, including the high-risk population.

Moreno C, et al. ASH 2018. Abstract 691.