Ibrutinib–Obinutuzumab Combination a Promising First-Line Therapy Option for CLL and SLL

San Diego, California—Obinutuzumab plus ibrutinib has demonstrated superiority over obinutuzumab plus chlorambucil, and represents a promising new treatment option for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL), according to results from a recent clinical trial by Carol Moreno, MD, PhD, Hospital de la Santa Creu Sant Pau, Autonomous University of Barcelona, Spain, and colleagues.

Citing efficacy data supporting the superiority of obinutuzumab plus chlorambucil over chlorambucil monotherapy or rituximab plus obinutuzumab, Dr Moreno and colleagues sought to determine whether obinutuzumab plus ibrutinib produced more favorable outcomes than obinutuzumab plus chlorambucil. Thus, they conducted an international, open-label, phase 3 clinical trial, iLLUMINATE, in patients with first-line CLL or SLL.

Dr Moreno presented the findings of iLLUMINATE at the 2018 ASH Annual Meeting.

Treatment-naïve patients with CLL or SLL were eligible for inclusion in the trial if they were aged ≥65 years, or if they were aged <65 years and had coexisting conditions. The primary end point was progression-free survival (PFS).

The secondary end points included PFS in high-risk populations (ie, patients with del17p, TP53 mutation, del11q, and/or unmutated IGHV), rate of undetectable minimal residual disease (MRD), overall response rate (ORR), overall survival (OS), and safety. Patients whose disease progressed with chlorambucil plus obinutuzumab were given the option cross over to next-line therapy with ibrutinib monotherapy.

A total of 229 patients (median age, 71 years) were enrolled and randomized in a 1:1 ratio to receive ibrutinib plus obinutuzumab for 6 cycles (n = 113) or chlorambucil plus obinutuzumab for 6 cycles (n = 116). High-risk genomic features were present in 65% of patients.

Dr Moreno and colleagues observed that, at a median follow-up of 31.3 months, ibrutinib plus obinutuzumab significantly prolonged PFS compared with chlorambucil plus obinutuzumab (median, not reached [NR] vs 19.0 months; hazard ratio [HR], 0.231; 95% confidence interval [CI], 0.145-0.367; P <.0001), with a 77% reduction in risk for progression or death.

At 30 months, the PFS rates for ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab were 79% and 31%, respectively. The PFS benefits seen with ibrutinib plus obinutuzumab were consistent across all subgroups examined.

In addition, PFS with ibrutinib plus obinutuzumab was also superior in the high-risk population (median, NR vs 14.7 months with chlorambucil plus obinutuzumab; HR, 0.154; 95% CI, 0.087-0.270; P <.0001), with an 85% reduction in risk for progression or death in this population.

The ORR was 88% and 73% in the ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab arms, respectively; complete response rates were also higher with ibrutinib plus obinutuzumab (19% vs 8%, respectively). MRD was undetectable in the blood and bone marrow of 35% of patients and 25% of patients in each arm, respectively.

At 30 months, the OS rates were 86% and 85% in the ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab arms, respectively; 40% of patients in the latter arm were receiving single-agent ibrutinib as second-line therapy.

The most common (≥3%) serious adverse events were pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%) with ibrutinib plus obinutuzumab, and infusion-related reactions (7%), febrile neutropenia (6%), pneumonia (4%), tumor lysis syndrome (4%), and pyrexia (3%) with chlorambucil plus obinutuzumab. Of note, infusion-related reactions of any grade were less frequent with ibrutinib plus obinutuzumab than with chlorambucil plus obinutuzumab.

A total of 7 (6%) patients discontinued treatment with chlorambucil plus obinutuzumab because of infusion-related reactions, whereas no patients discontinued ibrutinib plus obinutuzumab for this reason. Adverse events were the cause for discontinuation of ibrutinib and chlorambucil in 18 (16%) and 11 (9%), respectively; 10 (9%) patients discontinued obinutuzumab in the ibrutinib plus obinutuzumab arm, and 15 (13%) discontinued the drug in the chlorambucil plus obinutuzumab arm.

Across approximately 3 years of follow-up, 70% of patients in the ibrutinib plus obinutuzumab arm continued taking ibrutinib monotherapy.

Ultimately, Dr Moreno and colleagues concluded that, when compared with the standard regimen of chlorambucil plus obinutuzumab, ibrutinib plus obinutuzumab leads to superior PFS, regardless of a patient’s high-risk genomic features. They also noted that response rates and depth of remission were higher with ibrutinib plus obinutuzumab than with chlorambucil plus obinutuzumab.

“Combination therapy with ibr-G [ibrutinib plus obinutuzumab] was tolerable with no new safety signals identified and represents an effective chemotherapy-free treatment option for first-line CLL/SLL including the high-risk population,” concluded Dr Moreno and colleagues.—Hina Khaliq

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. Presented at: the 60th ASH Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 691.

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