In the phase III HELIOS trial reported in The Lancet Oncology, Asher Chanan-Khan, MD, of the Mayo Clinic Cancer Center, Jacksonville, Florida, and colleagues found that addition of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) to bendamustine (Treanda)/rituximab (Rituxan) increased progression-free survival in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma relapsing after initial therapy.¹

Study Details

In this double-blind trial, 578 patients from 133 sites in 21 countries with measurable lymph node disease (> 1.5 cm), relapsed or refractory disease after at least one previous line of systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomized between September 2012 and January 2014 to receive bendamustine/rituximab with ibrutinib (n = 289) or placebo (n = 289). Treatment consisted of bendamustine at 70 mg/m² intravenously on days 2 to 3 in cycle 1 and days 1 to 2 in cycles 2 to 6 and rituximab at 375 mg/m² on day 1 of cycle 1 and 500 mg/m² on day 1 of cycles 2 to 6, for a maximum of six 28-day cycles, plus either oral ibrutinib at 420 mg daily or placebo until disease progression or unacceptable toxicity. Patients with del(17p), previous treatment with ibrutinib or another BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or hematopoietic stem cell transplant were excluded.

The primary endpoint was progression-free survival assessed by an independent review committee. Crossover from placebo to ibrutinib was permitted after disease progression.

For the ibrutinib and placebo groups: median age was 64 and 63 years; 67% and 65% were male; 89% in both had chronic lymphocytic leukemia; 58% and 54% had bulky disease; 81% and 80% had unmutated IGHV; 26% in both were purine analog refractory; 48% in both had one previous line of therapy, and 27% and 25% had at least three lines of therapy; and previous therapy consisted of a purine analog in 71% and 72%, an alkylating agent in 95% in both, and an anti-CD20 agent in 70% and 69%. More placebo patients had Rai stage III or IV disease (39% and 46%), and more ibrutinib patients had del(11q) (30% and 22%).

Study Outcomes

The primary endpoint was met at a preplanned interim analysis. After a median follow-up of 17 months, median progression-free survival was not reached in the ibrutinib group vs 13.3 months (95% confidence interval [CI] = 11.3–13.9 months) in the placebo group (hazard ratio [HR] = 0.203, P < .0001). Progression-free survival at 18 months was 79% vs 24% (HR = 0.203, P < .0001).

Hazard ratios favored ibrutinib in all subgroups, including in patients with chronic lymphocytic leukemia (0.193, 95% CI = 0.138–0.269), small lymphocytic lymphoma (0.399, 95% CI = 0.187–0.853), Rai stage III or IV disease (0.301, 95% CI = 0.188–0.480, refractoriness to purine analog therapy (0.236, 95% CI = 0.143–0.389), del(11q; 0.083, 95% CI = 0.043–0.163), more than one prior therapy (0.223, 95% CI = 0.151–0.329), and unmutated IGHV (0.157, 95% CI = 0.109–0.226).

The overall response rate was 83% vs 68% (P < .0001). A total of 31% of placebo patients crossed over to ibrutinib.

Median overall survival was not reached in either group (HR = 0.628, P = .0598). In analysis adjusting for crossover, the hazard ratio was 0.577
(P = .033).

Adverse Events

The most common adverse events of any grade were neutropenia (mostly grade ≥ 3) and nausea (grade 1–2 in 36% vs 35%, grade 3 or 4 in < 1% vs < 1%). Grade 1 or 2 diarrhea was more common with ibrutinib (33% vs 20%, grade 3 or 4 in 2% vs 1%). Grade ≥ 3 adverse events occurred in 77% of ibrutinib patients and 74% of placebo patients. The most common adverse event in the ibrutinib group were neutropenia (54% vs 51%), thrombocytopenia (15% vs 15%), febrile neutropenia (12% vs 9%), and pneumonia (8% vs 7%). Bleeding of any grade occurred in 31% vs 15%, with major hemorrhage in 4% vs 2%. Atrial fibrillation occurred in 7% vs 2%. Serious adverse events occurred in 52% vs 44%. Ibrutinib or placebo dose reductions occurred in 15% vs 9%. Treatment-emergent adverse events led to death in 19 patients (6.6%) and 18 patients (6.3%). 

The investigators concluded: “In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile.” ■

Disclosure: The study was funded by Janssen Research & Development. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. Chanan-Khan A, Cramer P, Demirkan F, et al: Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): A randomised, double-blind, phase 3 study. Lancet Oncol 17:200-211, 2016.