iLLUMINATE: Superior PFS With Ibrutinib–Obinutuzumab Even in High-Risk, Untreated CLL/SLL

Surabhi Dangi-Garimella, PhD

Ibrutinib combined with obinutuzumab had better progression-free survival (PFS) at 30 months than the standard chemoimmunotherapy regimen, chlorambucil plus obinutuzumab, regardless of high-risk genomic features in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who had never been treated. These results from the iLLUMINATE study were presented at the 60th American Society of Hematology Annual Meeting & Exposition, being held December 1-4, in San Diego, California.

Ibrutinib is a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase and was approved in 2016 in the United States as a single-agent, chemotherapy-free regimen for patients with CLL. The iLLUMINATE trial is a phase 3, open-label, multicenter trial that was designed to test the efficacy of ibrutinib with obinutuzumab versus chlorambucil with obinutuzumab in treatment-naïve patients with CLL/SLL.

Eligibility criteria included treatment-naïve CLL/SLL, ≥65 years or <65 years with coexisting conditions (Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del(17p) or TP53 mutation).

One set of patients received 6 cycles of 420 mg ibrutinib once daily, combined with obinutuzumab 1000 mg on days 1/2, 8, and 15 of cycle 1, and day 1 of subsequent 28-day cycles. The other set of patients was treated with 6 cycles of chlorambucil (0.5 mg/kg on days 1 and 15 of each 28-day cycle) combined with obinutuzumab, in the same dose and frequency as above. PFS was the primary endpoint and secondary endpoints included PFS in a high-risk population—del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV—rate of undetectable minimal residual disease, overall response rate (ORR), overall survival (OS), and safety.

The trial allowed crossover of patients with confirmed progression in the chlorambucil–obinutuzumab arm to single-agent ibrutinib.

The trial enrolled 229 patients, 113 of whom were randomized to the ibrutinib-obinutuzumab arm and 116 to the chlorambucil-obinutuzumab arm. Median age was 71 years (range, 40-87) and 65% of patients had the above listed high-risk genomic features.

With a median follow-up of 31.3 months, patients who were treated with ibrutinib–obinutuzumab had a significantly better PFS compared with the comparator arm (median not reached [NR] vs 19.0 months; hazard ratio [HR], 0.231; 95% CI, 0.145-0.367; P <.0001). At 30 months, the PFS rates were 79% with ibrutinib–obinutuzumab and 31% with chlorambucil–obinutuzumab. These were PFS results as assessed by an independent review committee (IRC), the authors reported.

Investigator (INV)-assessed PFS showed a similar trend for ibrutinib–obinutuzumab versus chlorambucil–obinutuzumab (median PFS NR vs 21.9 months; HR, 0.260; 95% CI, 0.163 to 0.415; P <.0001). Further, the improvements in PFS seen among patients receiving ibrutinib–obinutuzumab were independent of their genomic status compared with the comparator arm (median NR vs 14.7 months; HR, 0.154; 95% CI, 0.087-0.270; P <.0001).

Both IRC- and INV-assessed ORR were better for the ibrutinib-obinutuzumab arm. IRC-assessed ORR was 88% with ibrutinib–obinutuzumab vs 73% with the comparator, while INV-assessed ORRs were 91% and 81%, respectively. Similar trends were observed with the IRC-assessed complete response (CR) rate, which was higher with ibrutinib-obinutuzumab (19% vs 8%). INV-assessed CR rates were 41% and 16%, respectively.

The authors report similar 30-month OS rates: 86% in the ibrutinib–obinutuzumab arm and 85% in the chlorambucil-obinutuzumab arm, with 40% of patients randomized to chlorambucil–obinutuzumab receiving single-agent ibrutinib as second-line therapy. Over a median follow-up of 31.3 months, 4% of patients in the ibrutinib–obinutuzumab arm and 44% in the chlorambucil–obinutuzumab arm initiated subsequent therapy.

Adverse events
The most frequent (≥3%) serious adverse events (AEs) among patients in the ibrutinib–obinutuzumab arm were pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%). The more common serious AEs in the chlorambucil–obinutuzumab were infusion-related reactions (IRRs; 7%), febrile neutropenia (6%), pneumonia (4%), tumor lysis syndrome (4%), and pyrexia (3%). While no patients discontinued obinutuzumab due to IRRs with in the ibrutinib–obinutuzumab arm, 7 patients in the comparator stopped obinutuzumab.

AEs leading to discontinuation of ibrutinib or chlorambucil occurred in 18 (16%) and 11 patients (9%), respectively, and AEs leading to discontinuation of obinutuzumab occurred in 10 patients (9%) in the ibrutinib–obinutuzumab arm and 15 (13%) in the chlorambucil–obinutuzumab arm.

At about the 3-year follow-up mark, 70% of patients in the ibrutinib–obinutuzumab arm are on single-agent ibrutinib.

Based on their findings, the authors conclude that the ibrutinib–obinutuzumab combination therapy was tolerable among treatment-naïve patients with CLL/SLL with no new safety signals identified and that it represents an effective chemotherapy-free treatment option for first-line CLL/SLL including among the high-risk population.

Moreno C, Greil R, Demirkan F, et al. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE. In: Proceedings from the American Society of Hematology; December 1-4, 2018; San Diego, CA. Abstract 691.
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