Date: 2015-05-30
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the American Society of Clinical Oncology (ASCO) annual meeting, in Chicago
Company: Pharmacyclics (USA - CA), now Abbvie (USA - IL) - Janssen-Cilag International, a J&J company (USA - NJ)
Product: Imbruvica® (ibrutinib)
Action
mechanism: Bruton tyrosine kinase inhibitor. Ibrutinib is a novel Bruton’s tyrosine kinase (BTK) inhibitor being jointly developed by Janssen and Pharmacyclics, Inc. for the treatment of B-cell malignancies. Ibrutinib is jointly developed and commercialized in the United States by Pharmacyclics and Janssen Biotech, Inc. In Europe, Janssen-Cilag International NV (Janssen) holds the marketing authorization and its affiliates market Imbruvica® in EMEA (Europe, Middle East, Africa), as well as the rest of the world. Imbruvica® is already approved in Europe to treat adult patients with relapsed or refractory mantle cell lymphoma (MCL) and adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy or in first line use in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. In March 2015, Abbvie and Pharmacyclics announced a definitive agreement under which AbbVie will acquire Pharmacyclics, and its flagship asset Imbruvica® (ibrutinib).
Disease: relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
Therapeutic area: Cancer - Oncology
Country: Argentina, Belgium, Brazil, Canada, Colombia, Czech Republic, France, Germany, Greece, Israel, Republic of Korea, Mexico, Poland, Portugal, Russian Federation, Spain, Sweden, Turkey, Ukraine, UK, USA
Trial
details: HELIOS is a Janssen-sponsored, randomized, double-blind, placebo-controlled, international, multicenter Phase 3 study conducted in 21 countries, which evaluated the safety and efficacy of ibrutinib in combination with BR in 578 patients with relapsed or refractory CLL/SLL who had received at least one prior therapy. Patients were randomized to receive either the combination of 420 mg ibrutinib orally once daily and six cycles of BR, or a matching regimen of placebo orally once daily and six cycles of BR, with ibrutinib or placebo continued until disease progression or unacceptable toxicity. The primary endpoint was IRC-assessed PFS and key secondary endpoints included ORR per IRC, overall survival (OS), rate of minimal residual disease negative remissions (MRD- remissions) and safety. (NCT01611090)
Latest
news: * On May 30, 2015, Janssen Research & Development announced the presentation of data from the Phase 3 CLL3001 (HELIOS) at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL. This trial demonstrated that the combination of ibrutinib (Imbruvica®) plus bendamustine and rituximab (BR) reduced the risk of progression or death by 80% and also significantly improved overall response rate (ORR) versus placebo plus BR in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).
At a pre-planned interim analysis earlier this year, the addition of ibrutinib to BR was shown to significantly improve progression-free survival (PFS; the primary endpoint) and ORR (a key secondary endpoint) compared with the combination of BR and placebo. An independent review committee (IRC) recommended HELIOS be unblinded at that point and patients receiving placebo plus BR be offered the option to receive ibrutinib as their next treatment.
HELIOS is a Janssen-sponsored, randomized, double-blind, placebo-controlled, international, multicenter Phase 3 study conducted in 21 countries, which evaluated the safety and efficacy of ibrutinib in combination with BR in 578 patients with relapsed or refractory CLL/SLL who had received at least one prior therapy. At a median follow-up of 17 months, IRC-assessed PFS was significantly longer with ibrutinib+BR, compared to placebo+BR (median not reached vs. 13.3 months; HR: 0.203, 95% CI: 0.150-0.276, P<0.0001). This difference in PFS rates between study arms was consistent across all subgroups, including high-risk subgroups. IRC-assessed PFS rates at 18 months were 79% for patients in the ibrutinib+BR arm, as compared with 24% for patients in the placebo+BR arm. The IRC-assessed ORR and complete response/complete response with incomplete marrow recovery (CR/CRi) rates were 82.7% and 10.4%, respectively, for patients taking ibrutinib+BR versus 67.8% and 2.8% for people in the placebo+BR arm. The median OS has not yet been reached at a median follow-up of 17 months. Overall, ibrutinib reduced the risk of death by 37% (P=0.06). The OS results are, however, confounded as 90 patients (31%) in the placebo+BR arm with confirmed progressive disease had crossed over to receive ibrutinib and no longer received placebo for the remainder of the trial. The safety profile of ibrutinib+BR was consistent with the known individual safety profiles for ibrutinib and BR therapies, respectively. In addition, ibrutinib had no impact on the ability of BR to be administered, with a similar number of BR cycles administered in both study arms.
The most common all-grade adverse events (AEs ?20%) in the HELIOS trial were neutropenia (58.2% in the ibrutinib+BR arm vs. 54.7% in the placebo+BR arm), nausea (36.9% vs. 35.2%), diarrhea (35.5% vs. 23.7%), thrombocytopenia (30.7% vs. 24.4%), pyrexia (24.7% vs. 22%), anemia (22.6% vs. 28.9%) and fatigue (21.6% vs. 22.6%). The most common Grade 3/4 AEs (?15%) were neutropenia (53.7% vs. 50.5%) and thrombocytopenia (15% in both arms). Higher rates of Grade 1/2 bleeding such as hematoma (8% vs. 1%), contusion (7.7% vs. 3.1%), epistaxis (5.9% vs. 3.1%), ecchymosis (3.1% vs. 0.7%) and petechiae (2.8% vs. 0.3%) were observed in patients taking ibrutinib+BR versus those in the placebo+ BR arm. Rates of major hemorrhage (defined as serious or Grade 3 or greater events) were 3.8% (11 cases) and 1.7% (5 cases), respectively. Few patients had Grade 3/4 atrial fibrillation (8 cases or 2.8% and 2 cases or 0.7%), with most patients having a history of prior atrial fibrillation or cardiac risk factors. Overall, 14.2% of patients in the ibrutinib arm discontinued due to AEs, as compared to 11.8% of patients in the placebo arm. The rates of other malignancies reported during treatment and follow-up were similar in each arm (8.4% in patients taking ibrutinib+BR vs. 8% in patients taking placebo+BR)
A full study report for HELIOS is being prepared and planned to be submitted to health authorities for future labeling considerations. A manuscript is also planned for submission for potential publication in a peer-reviewed journal.
