As reported by Andrew D. Zelenetz, MD, of Memorial Sloan Kettering Cancer Center, and colleagues in The Lancet Oncology, interim analysis of a phase III trial has shown the superiority of adding the phosphoinositide-3-kinase δ inhibitor idelalisib (Zydelig) to bendamustine/rituximab (Rituxan) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).¹

Study Details

In the double-blind trial, 416 patients from 110 sites in 19 countries including the United States were randomized between June 2012 and August 2014 to receive bendamustine at 70 mg/ m² on days 1 and 2 for six 28-day cycles plus rituximab at 375 mg/m² on day 1 of cycle 1 and 500 mg/m² on day 1 of cycles 2 to 6 with either twice-daily oral idelalisib at 150 mg (n = 207) or placebo (n = 209) until disease progression or intolerable toxicity. Patients had to be 18 years of age or older with measurable lymphadenopathy by computed tomography or magnetic resonance imaging and had to have disease progression within 36 months since the last previous therapy. Randomization was stratified by high-risk features (unmutated IGHV, del[17p], or TP53 mutation) and refractory vs relapsed disease. The primary endpoint was progression-free survival on independent review committee assessment in the intention-to-treat population.

For the idelalisib vs control groups: median age was 62 vs 64 years; 77% vs 75% were men; 90% vs 91% were white; median time since diagnosis was 74 vs 75 months; Rai stage was 0, I, II, III, and IV in 1% vs 2%, 19% vs 20%, 29% vs 34%, 10% vs 8%, and 40% vs 33%; median number of previous regimens was 2 in both (range = 1–4 in both); 16% vs 18% were refractory to fludarabine; ≤ 1% had not received an anti-CD20 antibody; prior treatments included fludarabine-containing regimens in 93% vs 90%; disease status was relapsed in 66% vs 68% and refractory in 34% vs 33%; and genetic risk markers were del(17p) in 18% vs 19%, del(17p) and TP53 mutation in 33% vs 33%, and unmutated IGHV in 84% vs 83%.

Key Efficacy Outcomes

A prespecified interim efficacy analysis performed with data cutoff in June 2015, when the median duration of follow-up was 11 months and 75% of the prespecified 260 progression-free survival events had occurred, resulted in the recommendation by the independent data monitoring committee to halt and unblind the study on the basis of high efficacy of idelalisib.

At updated analysis at median follow-up of 14 months, median progression-free survival was 20.8 months (95% confidence interval [CI] = 16.6–26.4 months) in the idelalisib group vs 11.1 months (95% CI = 8.9–11.1 months) in the placebo group (hazard ratio [HR] = 0.33, P < .0001). Hazard ratios favored idelalisib in all prespecified subgroups and were significant for most. The hazard ratio approached significance among 78 patients with del(17p); 0.62, 95% CI = 0.37–1.04).

The addition of idelalisib to [bendamustine plus rituximab] should be considered if the goal of therapy is to maximise progression-free and overall survival….

— Andrew D. Zelenetz, MD, and colleagues

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Median overall survival was not reached in the idelalisib group (95% CI = not reached to not reached) vs 31.6 months (95% CI = 21.3 months to not reached) in the placebo group (HR = 0.62, P = .031). Hazard ratios favored idelalisib in all prespecified subgroups, although the study was not powered to detect a significant benefit in subgroup analysis. The overall response rates were 70% vs 45%, with median response durations of 22.8 vs 11.2 months. A ≥ 50% reduction in the sum of perpendicular diameters of lymph nodes was observed in 97% vs 61% of patients. Organomegaly response was observed in 85% vs 57% in the spleen and 58% vs 43% in the liver.

Adverse Events

The most common adverse events of any grade were neutropenia (64%) and pyrexia (41%) in the idelalisib group and neutropenia (55%) and nausea (34%) in the placebo group. The most common grade ≥ 3 adverse events were neutropenia (60%) and febrile neutropenia (23% vs 5%) in the idelalisib group and neutropenia (47%) and thrombocytopenia (13%) in the placebo group. Grade ≥ 3 adverse events occurring more frequently in the idelalisib group also included diarrhea (9% vs 2%) and alanine transaminase (21% vs 3%) and aspartate transaminase (15% vs 2%) elevation. Infection of any grade occurred in 69% vs 59% of patients, with 39% vs 25% being grade ≥ 3. 

Serious adverse events occurred in 68% vs 44%, with the most common in the idelalisib group being febrile neutropenia (20% vs 5%) and pneumonia (14% vs 7%). Treatment was discontinued due to adverse events in 27% vs 13%. Adverse events led to death in 11% vs 7% of patients.

The investigators concluded: “This randomised, placebo-controlled, phase III trial is, to our knowledge, the first study to show that the addition of the small molecule targeted agent idelalisib to a standard-of-care regimen of bendamustine plus rituximab leads to an improvement in progression-free survival and overall survival in patients with relapsed or refractory [CLL]. Our findings suggest that although chemoimmunotherapy with bendamustine plus rituximab has a role in the management of these patients, the addition of idelalisib to this standard regimen should be considered if the goal of therapy is to maximise the clinically relevant endpoints of progression-free survival, overall survival, and duration of response…. However, careful attention needs to be paid to management of serious adverse events and infections associated with this regimen during treatment selection.” 

DISCLOSURE: The study was funded by Gilead Sciences Inc. For full disclosures of the study authors, visit www.thelancet.com.

REFERENCE

1. Zelenetz AD, Barrientos JC, Brown JR, et al: Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia. Lancet Oncol 18:297-311, 2017.