On May 31, 2014 Pharmacyclics reported trial results of the first Phase III study (RESONATE, PCYC-1112-CA;NCT01578707), a head-to-head comparison of IMBRUVICA (ibrutinib) versus ofatumumab in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) (Press release Pharmacyclics, MAY 31, 2014, View Source [SID:1234500660]). Patients receiving IMBRUVICA realized a significant improvement in progression free survival (PFS), overall survival (OS) and overall response rate (ORR) as compared to patients receiving ofatumumab. The RESONATE data will be discussed today in the official Press Program by lead investigator Dr. John Byrd from The Ohio State University Medical Center at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, IL. This release corresponds to abstract LBA7008. IMBRUVICA is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

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The RESONATE Phase III trial results have been published today in an online first edition of the New England Journal of Medicine. This study was also selected to be presented at the European Hematology Association (EHA) (Free EHA Whitepaper) Annual Meeting in Milan on June 14, 2014 in the Presidential Symposium. This forum is set aside for abstracts of the highest impact and quality.

These Phase III study results show that IMBRUVICA significantly prolonged PFS in patients with relapsed/refractory CLL in comparison to those randomized to receive ofatumumab. Patients treated with IMBRUVICA experienced a 78% reduction in risk of progression or death versus patients receiving ofatumumab (HR 0.215, 95% CI, 0.146 to 0.317, p < 0.0001) per Independent Review Committee (IRC) evaluation. The median PFS for IMBRUVICA was not reached with a median time on study of 9.4 months. The median PFS for ofatumumab was 8.1 months. IMBRUVICA significantly prolonged OS compared with ofatumumab. IMBRUVICA reduced the risk of death by 57% (HR=0.434, 95% CI, 0.238 to 0.789; p < 0.0049) compared to the ofatumumab arm. This was observed despite a total of 57 patients who were initially randomized to ofatumumab crossing over to receive IMBRUVICA prior to the analysis. Patient characteristics were well balanced between arms: patients receiving IMBRUVICA had a median of 3 prior therapies with 32% deletion of the short arm of chromosome 17 (del17p), a mutation typically associated with poor prognosis, and 56% RAI stage III/IV (indicative of high risk CLL patients) versus patients receiving ofatumumab who had a median of 2 prior therapies with 33% del17p and 58% RAI stage III/IV.

ORR was significantly higher in patients receiving IMBRUVICA by both investigator and IRC evaluations. Investigator assessed overall response rate (including complete responses (CR), partial responses (PR) and partial responses with lymphocytosis (PR+L)) was 85 % for IMBRUVICA and 23% for patients receiving ofatumumab, evaluated based on the International Workshop on CLL (IWCLL) response criteria. The RESONATE study also had IRC evaluate sequential CT scans (performed per protocol, approximately 12 weeks apart) to assess and confirm response. With this analysis 63 % of IMBRUVICA patients achieved a partial response (PR or a PRL) compared to only 4 % of patients receiving ofatumumab (p < 0.0001). Significantly higher response rates were observed in the IMBRUVICA arm consistently across all subgroups by baseline disease risk factors, including those patients with del 17p or those whose disease was considered refractory to purine analogue therapy. Only 3% of the patients receiving IMBRUVICA experienced progressive disease as a best response versus 10% receiving ofatumumab as evaluated by IRC.

"In this patient population this is the first study ever, to demonstrate significant progression and overall survival benefits against an approved standard of care in CLL," said Dr. John Byrd*, Director, Division of Hematology, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital & Richard J. Solove Research Institute and lead investigator for RESONATE (PCYC 1102-CA). "As shown by the results presented today, IMBRUVICA is transforming the treatment for patients with CLL. It is an effective, patient friendly therapy that provides a real alternative to chemotherapy."

"The conclusion of IMBRUVICA’s first Phase III study is a major milestone on our company’s mission to achieving meaningful improvements in the quality and duration of life for patients," said Bob Duggan, CEO and Chairman of the Board of Pharmacyclics. "We are at the beginning of a transformational shift which will provide patients a new alternative to chemotherapy. Together, with our partner Janssen, we are proud of the accomplishments achieved to date. Establishing a large clinical program which currently consists of 11 Phase III studies, and a total of 45 ongoing trials in 8 histologies is a manifestation of our extraordinary confidence in IMBRUVICA."

The most commonly occurring adverse events independent of Grade (AEs in 20% or more of patients) were diarrhea (48% vs.18%), fatigue (28% vs. 30%), pyrexia (fever; 24% vs. 15%), nausea (26% vs.18%), anemia (23% vs. 17%) and neutropenia (22% vs. 15%). Hematologic adverse events that were Grade 3 or 4 in the RESONATE trial were neutropenia (decreased amount of white blood cells; 16% in the IMBRUVICA arm vs. 14% in the ofatumumab arm), thrombocytopenia (decrease in platelets in the blood; 6% vs. 4%), and anemia (5% vs. 8%). Atrial fibrillation of any grade was noted more frequently in patients receiving IMBRUVICA (5%versus 0.5% with ofatumumab), these events were manageable and lead to discontinuation for only 1 patient. There was no difference in major bleeding between the IMBRUVICA or ofatumumab arms (reported in 2 patients randomized to IMBRUVICA and 3 patients receiving ofatumumab). The incidence of grade 3 or higher infection was 24% for IMBRUVICA arm and 22% for the ofatumumab arm. Richter’s Transformation occurred in 2 patients in the IMBRUVICA arm and in 2 patients in the ofatumumab arm.

Patients receiving IMBRUVICA showed a discontinuation rate due to progressive disease, adverse events or death of 13%, with 86% of patients continuing on therapy. Patients receiving ofatumumab showed a discontinuation rate due to progressive disease, adverse events or death of 28%.