Addition of idelalisib to SoC for R/R CLL results in improved PFS, but at what risk? Phase III trial results

In January 2017, Andrew D. Zelenetz from the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, and colleagues published in The Lancet Oncology the interim results of an ongoing phase III study into the addition of either idelalisib or placebo to the standard combination of bendamustine and rituximab in the treatment of R/R CLL. The trial was an international, multicenter, double-blind, randomized, placebo-controlled trial enrolling 416 relapsed or refractory CLL patients.

Key Highlights:

  • Treatment: max six-28-day cycles: 375mg/m2 rituximab IV D1 of cycle 1, 500mg/m2 D1 of cycles 2–6, 70mg/m2 bendamustine IV on D1 and D2 of each cycle, plus either placebo or 150mg oral idelalisib two times daily until intolerable toxicity or progressive disease based on iwCLL criteria
  • Idelalisib group = 207pts, placebo group = 209pts, groups were not significantly different in patient characteristics
  • Median follow-up 14 months
  • Median PFS: idelalisib = 20.8 months (95% CI, 16.6­­­–26.4), placebo = 11.1 months (8.9–11.1), HR 0.33 (95% CI, 0.25–0.44, P<0.0001)
  • Idelalisib vs. placebo OR = 70% (95% CI, 63–76) vs. 45% (95% CI, 38–52), CR = 1% vs. 0%, PR = 69% vs. 44%
  • Lymph node size ≥ 50% reduction: idelalisib = 97% (95% CI, 93–99), placebo = 61% (95% CI, 54–68)
  • Adverse Events:
    • Most common treatment-related AEs Grade ≥3 (vs. placebo): neutropenia 60% (vs. 47%), febrile neutropenia 23% (vs. 6%), anemia 13% (vs. 13%), and thrombocytopenia 13% (vs. 13%)
    • Grade ≥3 infections and infestations: idelalisib = 39%, placebo = 25%; resulting in 6 deaths in idelalisib group vs. 3 in placebo group
    • Treatment-related AE ending in death: idelalisib = 11%, placebo = 7% (N.D.)
    • AE leading to dose interruption (or discontinuation): idelalisib = 58% pts (28%), placebo = 24% pts (14%)
    • Serious AEs: idelalisib = 68%, placebo = 44%
  • Death: Idelalisib = 21%, placebo = 28%

In summary, the authors stated that the addition of idelalisib to the standard-of-care (bendamustine with rituximab) resulted in increased median PFS, reduced risk of death, and improved response rates compared with the addition of placebo. However, the addition of idelalisib resulted in higher AE rates and an increase in infection rate, therefore management of these events will need to be considered as part of a risk-benefit assessment for patients.

  1. Zelenetz A.D. et al. Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial. The Lancet Oncology. 2017 Jan 27. DOI: 1016/S1470-2045(16)30671-4. [Epub ahead of print: 2017 Jan 27]


Background. Bendamustine plus rituximab is a standard of care for the management of patients with relapsed or refractory chronic lymphocytic leukaemia. New therapies are needed to improve clinically relevant outcomes in these patients. We assessed the efficacy and safety of adding idelalisib, a first-in-class targeted phosphoinositide-3-kinase δ inhibitor, to bendamustine plus rituximab in this population. Methods. For this international, multicentre, double-blind, placebo-controlled trial, adult patients (≥18 years) with relapsed or refractory chronic lymphocytic leukaemia requiring treatment who had measurable lymphadenopathy by CT or MRI and disease progression within 36 months since their last previous therapy were enrolled. Patients were randomly assigned (1:1) by a central interactive web response system to receive bendamustine plus rituximab for a maximum of six cycles (bendamustine: 70 mg/m2 intravenously on days 1 and 2 for six 28-day cycles; rituximab: 375 mg/m2 on day 1 of cycle 1, and 500 mg/m2 on day 1 of cycles 2–6) in addition to either twice-daily oral idelalisib (150 mg) or placebo until disease progression or intolerable study drug-related toxicity. Randomisation was stratified by high-risk features (IGHV, del[17p], or TP53 mutation) and refractory versus relapsed disease. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat population. This trial is ongoing and is registered with, number NCT01569295. Findings. Between June 26, 2012, and Aug 21, 2014, 416 patients were enrolled and randomly assigned to the idelalisib (n=207) and placebo (n=209) groups. At a median follow-up of 14 months (IQR 7–18), median progression-free survival was 20·8 months (95% CI 16·6–26·4) in the idelalisib group and 11·1 months (8·9–11·1) in the placebo group (hazard ratio [HR] 0·33, 95% CI 0·25–0·44; p<0·0001). The most frequent grade 3 or worse adverse events in the idelalisib group were neutropenia (124 [60%] of 207 patients) and febrile neutropenia (48 [23%]), whereas in the placebo group they were neutropenia (99 [47%] of 209) and thrombocytopenia (27 [13%]). An increased risk of infection was reported in the idelalisib group compared with the placebo group (grade ≥3 infections and infestations: 80 [39%] of 207 vs 52 [25%] of 209). Serious adverse events, including febrile neutropenia, pneumonia, and pyrexia, were more common in the idelalisib group (140 [68%] of 207 patients) than in the placebo group (92 [44%] of 209). Treatment-emergent adverse events leading to death occurred in 23 (11%) patients in the idelalisib group and 15 (7%) in the placebo group, including six deaths from infections in the idelalisib group and three from infections in the placebo group. Interpretation. Idelalisib in combination with bendamustine plus rituximab improved progression-free survival compared with bendamustine plus rituximab alone in patients with relapsed or refractory chronic lymphocytic leukaemia. However, careful attention needs to be paid to management of serious adverse events and infections associated with this regimen during treatment selection. Funding. Gilead Sciences Inc.

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