Janssen has announced that data concerning RESONATE™ will be included in a presentation during the official press programme at the American Society of Clinical Oncology (ASCO) meeting.
It will be simultaneously published in a special edition of The New England Journal of Medicine.[1]
Janssen has announced that data concerning RESONATE™ will be included in a presentation during the official press programme at the American Society of Clinical Oncology (ASCO) meeting.
It will be simultaneously published in a special edition of The New England Journal of Medicine.[1]
Data from the international, multicentre phase III PCYC-1112 (RESONATE™) trial in 391 patients suggest monotherapy ibrutinib administered once-daily significantly lengthened progression-free survival (PFS) (median not reached versus 8.1 months; hazard ratio [HR] 0.215, 95% confidence interval [CI] 0.146 to 0.317; p<0.0001) and overall survival (OS) (HR 0.434; 95% CI, 0.238 to 0.789; p=0.0049) versus ofatumumab administered intravenously in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
Ibrutinib is an investigational compound in the EU within a class of medicines called Bruton’s tyrosine kinase (BTK) inhibitors. Ibrutinib is defined as an investigational compound as it is not yet approved by any regulatory authority in the EU. On October 30, 2013, Janssen submitted a New Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for ibrutinib for the treatment of adult patients with relapsed or refractory CLL/SLL or relapsed or refractory mantle cell lymphoma (MCL). Ibrutinib is marketed as IMBRUVICA® in the US, where it received approval from the US Food and Drug Administration (FDA) for the treatment of patients with MCL who have received at least one prior therapy[2] and for the treatment of patients with CLL who have received at least one prior therapy.[3]
PFS is the primary endpoint of the RESONATE study, with OS, overall response rate (ORR) and safety as key secondary endpoints. These data will be presented in full by Dr John C. Byrd, MD 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-1112).
In 2011, Janssen and Pharmacyclics Inc. entered into an agreement to jointly develop and commercialise ibrutinib.
The results from the RESONATE study showed ibrutinib monotherapy significantly improved PFS, OS and ORR in the difficult-to-treat patient population, regardless of baseline characteristics. The median PFS in the ibrutinib arm was not reached because progression events occurred more slowly than in the ofatumumab arm. The PFS results represent a 79% reduction in the risk of progression or death in patients treated with ibrutinib compared with ofatumumab. The OS median was also not reached in either arm because progression events occurred slowly. The OS results represent a 57% reduction in the risk of death in patients receiving ibrutinib versus those in the ofatumumab arm.
Additionally, the ORR was significantly higher in patients taking ibrutinib monotherapy versus ofatumumab monotherapy, regardless of response criteria or baseline characteristics. Overall, 43% of ibrutinib patients achieved a partial response (PR) compared with only 4% of patients taking ofatumumab (p<0.0001), following the International Workshop on CLL (IWCLL) response criteria requiring response to be confirmed for at least two months. An additional 20% of ibrutinib treated patients also achieved a PR with lymphocytosis. Investigator-assessed response rates were 85% for ibrutinib and 24% for patients receiving ofatumumab. Significantly higher response rates were seen in the ibrutinib arm consistently across all baseline sub-groups, including those with a deletion of the short arm of chromosome 17 (del 17p), a genetic mutation typically associated with poor prognoses, or refractory to a purine analogue.
“The Phase 3 RESONATE study demonstrated significant progression-free and overall survival benefits in relapsed or refractory CLL patients against the current standard of care,” said Professor Ulrich Jäger, Medical University of Vienna, Department of Medicine, Division of Haematology and Hemostaseology. “The survival improvements seen with use of ibrutinib in this study are particularly encouraging as we look toward its potential for use in patients with difficult-to-treat disease and may offer physicians an effective single-agent treatment option.”
RESONATE is a phase III, multicentre, international, open-label, randomised study that examined ibrutinib monotherapy versus ofatumumab monotherapy in relapsed or refractory patients with CLL/SLL who had received at least one prior therapy and were not considered appropriate candidates for treatment with a purine analog (n=391). Patients were administered either 420 mg oral ibrutinib (n=195) once-daily until progression or unacceptable toxicity or intravenous ofatumumab for up to 24 weeks (n=196, initial dose of 300mg followed by 11 doses at 2,000mg, per dose and schedule consistent with local labelling).
The primary endpoint of the study was PFS evaluated by an Independent Review Committee (IRC), and key secondary endpoints were OS, ORR and safety. The median follow-up was 9.4 months.
“These data add to the body of clinical data supporting the use of ibrutinib in previously treated CLL patients,” said Jane Griffiths, Company Group Chairman of Janssen Europe, the Middle East and Africa (EMEA). “These are the first Phase 3 data for ibrutinib. We’re pleased to see the particularly strong hazard ratios for progression-free and overall survival and are encouraged that patients continue to do well on treatment with ibrutinib.”
The most common Grade 3 or 4 adverse events (AEs) in the RESONATE trial (occurring in 5% or more of ibrutinib patients) were neutropenia (decreased amount of neutrophils in the blood; 16% in the ibrutinib arm versus 14% in the ofatumumab arm), pneumonia (7% versus 5%), thrombocytopenia (decrease in platelets in the blood; 6% versus 4%) and anaemia (5% versus 8%). The most commonly occurring side effects (AEs in 20% or more of patients) were diarrhoea (48% versus 18%), fatigue (28% versus 30%), pyrexia ([fever] 24% versus 15%), nausea (26% versus 18%), anaemia (23% versus 17%) and neutropenia (21% versus 15%). Atrial fibrillation of any grade was noted more frequently in patients receiving ibrutinib (n=10 patients) versus with ofatumumab (n=1 patient), leading to discontinuation of ibrutinib in one patient.
Treatment discontinuation due to progressive disease were 5% in the ibrutinib arm and 19% in the ofatumumab arm. Treatment discontinuations due to adverse events were low in both study arms, with 4% of patients in both treatment arms (eight patients in the ibrutinib arm and seven patients in the ofatumumab arm). Treatment discontinuation due to death occurred in 4% of patients in the ibrutinib arm (eight patients) and 5% of patients in the ofatumumab arm (nine patients). These events were most commonly infectious in nature. Total treatment exposure was longer for the ibrutinib arm (approximately 8.6 months versus 5.3 months on ofatumumab).
In January 2014, RESONATE was stopped early at the unanimous recommendation of an Independent Data Monitoring Committee (IDMC) based on a planned interim analysis which concluded that the study showed a significant difference in PFS as compared to the control (the primary endpoint of the study). The IDMC recommended that the sponsor provide access to ibrutinib to patients in the ofatumumab arm. The data served as the basis of the April 2014 supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) in relapsed or refractory CLL patients who have received at least one prior therapy.
CLL is a slow-growing blood cancer of white blood cells called lymphocytes, most commonly B cells.[4] CLL is the most common adult leukemia in the Western world and predominantly a disease of the elderly with a median age of diagnosis of 72.(4,5) This orphan disease often eventually progresses; patients are faced with fewer treatment options and are often prescribed multiple lines of therapy as they relapse or become resistant to treatments.(6) SLL is a slow-growing lymphoma in which too many immature white blood cells cause lymph nodes to become larger than normal.(4)
References
- Byrd, JC. Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia. NEJM. 2014. Available at: http://www.nejm.org/ (accessed May 2014).
- US Food and Drug Administration. Press Announcement: FDA approves Imbruvica for rare blood cancer. Nov 2013. Available at: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm374761.htm (accessed May 2014).
- U.S. Food and Drug Administration. Press Announcement: FDA approves Imbruvica to treat chronic lymphocytic leukemia. Feb 2014. Available at: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm385764.htm (accessed May 2014).
- American Cancer Society. “Leukemia–Chronic Lymphocytic”. Available at: http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf (accessed April 2014).
- Parker, T. Chronic lymphocytic leukemia: prognostic factors and impact on treatment. Discovery Medicine. 2011;57.
- Veliz M, Pinilla-Ibarz J. Treatment of relapsed or refractory chronic lymphocytic leukemia. Cancer Control. 2012;19(1):37–ß53.
