Idelalisib/Ofatumumab Combo Effective in Phase III CLL Trial

June 24, 2015

Treatment with the combination of idelalisib and ofatumumab demonstrated an improvement in objective response rates, progression-free survival, and lymph node response compared with ofatumumab alone in patients with previously treated chronic lymphocytic leukemia.

Jeffrey A. Jones, MD, MPH

Treatment with the combination of idelalisib (Zydelig) and ofatumumab (Arzerra) demonstrated an improvement in objective response rates (ORR), progression-free survival (PFS), and lymph node response (LNR) compared with ofatumumab alone in patients with previously treated chronic lymphocytic leukemia (CLL), according to data from a phase III study.

Jeffrey A. Jones, MD, MPH, presented findings from the trial, labeled Study 119, at the 2015 ASCO Annual Meeting. Based on findings from the study, Gilead, the manufacturer of idelalisib, has filed an application with the FDA to expand the indication of the PI3K delta inhibitor to include use in combination with ofatumumab in patients with relapsed CLL.

“The data reported reinforce prior results showing that idelalisib, here in combination with the anti-CD20 monoclonal antibody ofatumumab, not only significantly improved overall and lymph node response rates, but more importantly progression-free survival in patients with previously treated CLL,” lead investigator Jeffrey A. Jones, MD, MPH, Associate Professor of Medicine, Division of Hematology, The Ohio State University Comprehensive Cancer Center, said in a statement. “Importantly, these improvements were also observed in patients with genetic features typically associated with poor prognosis.”

The phase III trial randomized 261 patients with CLL who progressed within 24 months from their last therapy to idelalisib plus ofatumumab (n = 174) or single-agent ofatumumab (n = 87). Patients were stratified based on relapsed versus refractory status, 17p deletion (del17p) and/or TP53 mutation status, and whether they harbored an IGHV mutation.

The combination reduced the risk of disease progression by 73% versus single-agent ofatumumab, with a medium PFS of 16.3 versus 8.0 months, respectively (HR = 0.27;P<.0001). In patients with del17p or TP53 mutations, the median PFS was 13.7 versus 5.8 months, respectively (HR = 0.33;P<.0001).

The overall response rate was 75.3% in the combination arm versus 18.4% in the ofatumumab alone arm (OR = 15.9;P<.0001). In the ofatumumab arm, the LNR rate was 93.3% versus 4.9% in the ofatumumab arm (OR = 487;P<.00014).

However, at the time of the analysis, improvements in ORR, PFS, and LNR had not yet translated into extensions in overall survival (OS). Medium OS was 20.9 months in the idelalisib/ofatumumab arm compared with 19.4 months in the ofatumumab arm (HR = 0.74;P= .27).

The safety profile seen with the combination was similar to prior studies that explored idelalisib as a treatment for patients with previously-treated CLL. The most commonly seen grade ≥3 adverse events with the combination were diarrhea/colitis (20.2%), pneumonia (12.7%), and febrile neutropenia (11.6%).

“Zydelig has now demonstrated strong efficacy in two randomized phase III studies among previously treated CLL patients,” Norbert Bischofberger, PhD, executive vice president of Research and Development and Chief Scientific Officer at Gilead, said in a statement. “We continue to explore the clinical profile of Zydelig in combination with both standard and novel treatment regimens, including seven ongoing or completed phase III clinical trials for B-cell malignancies.”

In July 2014, the FDA has approved idelalisib in combination with the rituximab (Rituxan) for patients with high-risk relapsed or refractory CLL and as a single-agent for patients with follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). In the supporting CLL study, the addition of idelalisib to rituximab improved OS by 72% and PFS by 82% versus placebo and rituximab.

Idelalisib is approved with a Boxed Warning regarding fatal and serious liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation associated with first-in-class PI3K-delta inhibitor. Additionally, the FDA required a Risk Evaluation and Mitigation Strategy (REMS) for idelalisib.

Jones JA, Wach M, Robak T, et al. Results of a phase III randomized, controlled study evaluating the efficacy and safety of idelalisib (IDELA) in combination with ofatumumab (OFA) for previously treated chronic lymphocytic leukemia (CLL).J Clin Oncol. 2015;33 (suppl; abstr 7023).