The U.S. Food and Drug Administration (FDA) has approved an expansion to the IMBRUVICA® (ibrutinib) U.S. Prescribing Information (PI) based on data supporting its use in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Janssen announced. The approved label now includes overall survival (OS) data from the Phase 3 RESONATE™-2 (PCYC-1115) trial in treatment-naïve CLL/SLL patients 65 years or older. The updated label also contains clinical data from the Phase 3 HELIOS (CLL3001) trial investigating the use of IMBRUVICA in combination with bendamustine and rituximab (BR) versus placebo plus BR in patients with relapsed or refractory CLL/SLL.
About the IMBRUVICA Label Update
Updated data from the RESONATE-2 trial reflect a statistically significant 56 percent reduction in the risk of death with IMBRUVICA compared to chlorambucil after a median follow-up of 28.1 months (HR=0.44 [95 percent CI, 0.21, 0.92]). The RESONATE-2 trial served as the basis for the March 2016 FDA approval of IMBRUVICA as a first-line treatment for patients with CLL.
Additionally, the first data from the HELIOS study on the use of IMBRUVICA in combination with other therapies were added to the label, highlighting the improvement in progression-free survival (PFS) and overall response rate (ORR) when using IMBRUVICA plus BR versus placebo plus BR in patients with relapsed/refractory CLL/SLL. Following a review of the November 2015 supplemental New Drug Application, the FDA has expanded the indication to include the use of IMBRUVICA for SLL patients with or without deletion of the chromosome 17p (del 17p). SLL is a slow-growing lymphoma that is similar to CLL.1,2
"The clinical development plan for IMBRUVICA is very robust and includes many Phase 2 and 3 clinical trials across various indications and combinations," said Peter F. Lebowitz, M.D., Ph.D., Global Oncology Head, Janssen Research & Development, LLC. "In partnership with Pharmacyclics, an AbbVie company, we continue to explore the clinical utility of IMBRUVICA and potential benefit it offers to patients with CLL/SLL and other hematologic malignancies."
"The update helps to affirm the established efficacy, safety and tolerability of this therapy for the treatment of patients with CLL/SLL, both as a monotherapy or in combination with other agents," said Jan Burger, M.D., Ph.D., Associate Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX and RESONATE-2 study lead investigator. "It reflects the growing body of clinical evidence supporting this therapy as a potential treatment option for people living with CLL/SLL."
About the RESONATE-2 Study
Building on existing positive PFS results from the RESONATE-2 trial, the updated labeling includes information from an additional analysis of the OS data. IMBRUVICA demonstrated a statistically significant 56 percent reduction in the risk of death after a median follow-up of 28.1 months (HR=0.44 [95 percent CI, 0.21, 0.92]). This analysis included 41 percent of patients in the chlorambucil arm who crossed over to receive IMBRUVICA therapy after progressing.
RESONATE-2 is a Pharmacyclics-sponsored, randomized, open-label, international, multi-center Phase 3 study which evaluated the safety and efficacy of IMBRUVICA versus chlorambucil in 269 treatment-naïve patients with CLL/SLL aged 65 years or older. Patients were randomized to receive either IMBRUVICA 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil 0.5 to 0.8 mg/kg on days 1 and 15 of each 28-day cycle for up to 12 cycles, with an allowance for intrapatient dose increases up to 0.8 mg/kg based on tolerability. The primary endpoint of the study was PFS as assessed by an Independent Review Committee (IRC) according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis. OS was a key secondary endpoint assessed in the study.
Results from RESONATE-2 were presented in an oral session at the American Society of Hematology (ASH) meeting in Orlando, FL in December 2015 and simultaneously published in The New England Journal of Medicine. The results were also part of the official press program at ASH 2015.
About the HELIOS Study
Results showed the combination of IMBRUVICA plus BR was associated with an 80 percent reduction in the risk of progression or death (HR=0.20 [95 percent CI, 0.15, 0.28, P<0.0001]) versus placebo plus BR; the median PFS was not reached in the IMBRUVICA plus BR arm, compared to 13.3 months in the placebo plus BR arm (95 percent CI, 11.3, 13.9).
HELIOS is a Janssen-sponsored, randomized, double-blind, placebo-controlled, international, multi-center, Phase 3 study conducted in 21 countries, which evaluated the safety and efficacy of IMBRUVICA in combination with BR in 578 patients with relapsed/refractory CLL/SLL who had received at least one prior therapy. Patients were randomized to receive either the combination of 420 mg IMBRUVICA orally once daily and six cycles of BR, or matching regimen of placebo orally once daily and six cycles of BR, with IMBRUVICA or placebo continued until disease progression or unacceptable toxicity. The primary endpoint was IRC-assessed PFS using the iWCLL 2008 criteria with modification for treatment-related lymphocytosis. Secondary endpoints included IRC-assessed ORR and safety.
Data from an interim analysis of HELIOS were presented during the official press program at the American Society of Clinical Oncology (ASCO) meeting in Chicago, IL in May 2015. The results were also published in The Lancet Oncology in December 2015.