PI3K Inhibition in CLL Wows at ASH! Pivotal data for Idelalisib plus Rituxan
| Dec 10, 2013
Co-authored by Greg Wolfe, Ph.D., Senior Consultant
Today, on the final day of the annual meeting of the American Society of Hematology (ASH), Richard Furman presented exciting results from a planned interim analysis of a Phase III, randomized double-blind, placebo-controlled study evaluating efficacy and safety of idelalisib (GS-1101, Gilead Sciences) and Rituxan® (rituximab, Genentech/Roche) for previously-treated patients with chronic lymphocytic leukemia (CLL).1 Patients who have relapsed following prior treatment of their CLL frequently have few therapeutic options, may have co-morbidities or poor renal/bone marrow function that preclude administration of highly toxic chemotherapies, and relapsed CLL is often associated with adverse cytogenetics that renders the disease unresponsive to available therapies. Thus, there remains a great need for novel therapies for relapsed CLL patients who are unable to tolerate chemotherapy. Phase III trials in CLL are ongoing or recently completed for Arzerra® (ofatumumab, GlaxoSmithKline), ibrutinib (BTK inhibitor, Pharmacyclics/Johnson & Johnson), and Gazyva® (obinutuzumab, Genentech/Roche), and several other new agents may be entering Phase III development soon based on encouraging early-stage data reported at ASH 2013. We previously reported on the very promising results of Gazyva and Arzerra in their pivotal trials that were presented at ASH 2013, and the idelalisib results further add to the CLL excitement that permeated the conference this year.
Idelalisib is a first-in-class, oral small molecule that is a highly selective inhibitor of the delta isoform of phosphatidalyinositol-3-kinase (PI3K-δ). Idelalisib inhibits homing and retention of CLL cells in lymphoid tissues, restrains proliferation and induces apoptosis in CLL cells. In the Phase III Study 116 trial, patients with relapsed CLL deemed “unfit” for further chemotherapy, who progressed less than 24 months since their last therapy, and who had received one or more anti-CD20 antibody-containing therapies or two or more cytotoxic therapies were eligible for this trial. Patients were randomized to receive six months of therapy with idelalisib plus Rituxan (n=110) or with Rituxan plus placebo (n=110). Median PFS was not reached for the idelalisib arm and was 5.5 months for the Rituxan/placebo arm; however, PFS at 24 weeks was 93% versus 46% (HR 0.15; p<0001), respectively. Idelalisib also significantly improved overall response rate (81% for the idelalisib arm versus 13% for the placebo arm; p<0.0001), and overall survival (HR=0.28; p=0.018). The combination of idelalisib plus Rituxan had an acceptable adverse event (AE) profile, with Grade ≥3 AEs reported in 56% of patients compared to 48% in the Rituxan/placebo arm. The most common AEs included transaminitis, pyrexia, fatigue, nausea, chills, diarrhea and infusion-related reaction. Based upon a review of interim efficacy and safety data, the data monitoring committee recommended stopping this study early.
These are the first randomized data for idelalisib and follow on the heels of pivotal Phase II data for the drug in of indolent non-Hodgkin's lymphoma (iNHL), and also supported FDA Breakthrough Therapy Status, which was granted in Q4 2013. Gilead Sciences has already filed for regulatory approval in relapsed/refractory iNHL with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Based on the results of Study 116, Gilead has also filed for approved in relapsed/refractory CLL with the EMA, and is in discussions for filing with the FDA.
CLL is poised for major changes in the coming years with the advent of novel targeted therapies. With multiple novel agents rapidly advancing toward approval for treatment of CLL, the stage is set for an epic battle. Perhaps the fiercest advisories in the CLL market will be idelalisib versus the Bruton’s tyrosine kinase inhibitor (BTKi) Imbruvica® (ibrutinib, Pharmacyclics/Janssen). The companies developing these agents have different goals for each of these agents. Janssen hopes that the promising efficacy data with Imbruvica will be repeated in Phase III trials and helps Imbruvica become the natural standard to replace Arzerra in the relapsed setting or to become the key combination partner with chemoimmunotherapy. Gilead instead has chosen to pursue the development of idelalisib as an ideal combination partner with chemoimmunotherapy. Both of these targeted therapies are very well-tolerated compared to chemotherapy making them very lucrative partners or candidates for CLL. But several other challengers are also waiting in the wings, based on promising data reported during the ASH 2013, including ABT-199 (GDC-199, Abbvie/Genentech/Roche), CTL019 (Novartis), and IPI-145 (Infinity Pharmaceuticals). IT’s certainly an exciting time for CLL development! References:
1. Furman et al., Abstract LBA6, ASH 2013