The international, double-blind, placebo-controlled, phase 3 HELIOS study evaluated ibrutinib plus bendamustine and rituximab (iBR) versus placebo plus bendamustine and rituximab (BR) in patients with previously treated standard-risk chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). At first analysis (median follow-up, 17 months), progression-free survival (PFS) was significantly improved for iBR versus BR (hazard ratio [HR], 0.20; 95% confidence interval [CI], 0.15-0.28; P <0.0001). Because prior studies have shown deepening responses with continued once-daily ibrutinib treatment, long-term assessments of durability and depth of response, as well as safety and tolerability, are important.
Two-year data are now available from the HELIOS study, including additional safety follow-up.1 Because minimal residual disease (MRD) negativity represents a lower disease burden and can potentially affect patient outcomes, researchers focused on these data to better understand the benefit of ibrutinib over time.
In the HELIOS study, 578 patients received BR (up to 6 cycles) and were randomized 1:1 to ibrutinib (420 mg/day) or placebo (N = 289 per arm). Patients with del17p (≥20% of cells) were excluded. The primary end point was independent review committee (IRC)-assessed PFS. Key secondary end points were investigator (INV)-assessed PFS, overall survival (OS), overall response rate (ORR; IRC and INV), and rate of MRD-negative response.
After median follow-up of 25.4 months, iBR continues to show improvement in PFS versus BR (INV-assessed median, not reached vs 14.2 months; HR, 0.20; 95% CI, 0.15-0.26; P <0.0001; 2-year rate, 75% vs 21%). Median OS is still unreached for both arms (HR, 0.67; 95% CI, 0.44-1.02; P = 0.058). Two-year OS rates are 86% for iBR versus 82% for BR. Of note, 49% of patients in the BR arm with confirmed progressive disease crossed over to receive ibrutinib.
The updated INV-assessed best ORR (at any time point) is 87% for iBR versus 66% for BR (P <0.0001). Rates of complete response (CR) and CR with incomplete bone marrow recovery (CR/CRi) are 34% versus 7% (first analysis, 21% vs 6%). Rates of MRD-negative response in the intent-to-treat population are 18% for iBR versus 5% for BR (P <0.0001) (first analysis, 13% vs 5%). As of March 2016, 21% of patients who received iBR demonstrated an MRD-negative response. Patients in the iBR arm who achieved MRD negativity had longer PFS than those who did not. There were no new or unexpected safety signals reported in this update.
Researchers concluded that iBR continues to demonstrate superiority versus BR, with significantly longer PFS and higher ORR. Responses continue to deepen with continuous ibrutinib therapy. Safety remains consistent with the original analysis of the HELIOS study. These data further confirm the importance of ibrutinib in standard-risk patients with previously treated CLL.
1. Fraser G, et al. EHA 2016. Abstract S430.