The FINANCIAL — On December 6, AbbVie announced the results of RESONATE-2 (PCYC-1115), a Phase 3 clinical trial in which ibrutinib (IMBRUVICA) significantly decreased the risk of progression or death (progression-free survival, PFS; the primary endpoint) and significantly decreased the risk of death (overall survival, OS; a key secondary endpoint) versus chemotherapy (chlorambucil) in treatment-naive patients 65 years and older with chronic lymphocytic leukemia (CLL).
This is the first Phase 3 head-to-head trial in the clinical program to evaluate the safety and efficacy of ibrutinib versus traditional chemotherapy in this patient population, according to AbbVie.
The prevalence of CLL/SLL is approximately 115,000 patients in the United States,1 with approximately 16,000 newly diagnosed patients every year.
The results were presented today during the official American Society of Hematology (ASH) press program and simultaneously published online in The New England Journal of Medicine. IMBRUVICA is jointly developed and commercialized in the U.S. by Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc.
These data will be presented in full by Dr. Alessandra Tedeschi, M.D., Azienda Ospedaliera Niguarda Ca Granda, Milan, Italy during the oral abstract session at ASH on Monday, December 7 in the CLL: Therapy, Excluding Transplantation: Upfront CLL Therapy Excluding Transplantation track at 7:30 a.m. ET.
“The data may signal a paradigm shift and demonstrate the value of ibrutinib in the treatment-naive setting,” 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 study lead investigator. “These powerful clinical results show superiority over a traditional, standard-of-care chemotherapy and have the potential to alter how we treat patients with CLL.”
Ibrutinib significantly prolonged PFS as determined by an Independent Review Committee (IRC), reducing the risk of progression or death by 84% versus chlorambucil (median not reached vs. 18.9 months; hazard ratio [HR] 0.16; 95% CI, 0.09-0.28; P<0.001), with a median of 18.4 months of follow-up. The 18-month PFS rate was 90% versus 52%, respectively. Additionally, ibrutinib significantly prolonged OS (HR, 0.16; 95% CI, 0.05, 0.56; P=0.001) with an estimated survival rate of 98% at 24 months, compared to 85% with chlorambucil. Ibrutinib was also associated with a significantly higher overall response rate (ORR; 86% vs. 35%; P<0.001), with a trend toward increased complete response rates. Of note, ibrutinib also significantly improved hematologic function as measured by sustained improvements in hemoglobin and platelets.
“Ongoing studies have continued to show the efficacy of ibrutinib in patients with CLL, however, RESONATE-2 represents the first comparative look at the degree of benefit it can offer to treatment-naive patients compared to a standard chemotherapy agent,” said Danelle James, M.D., M.S., Head of Oncology at Pharmacyclics. “The effectiveness of ibrutinib observed in this trial is extremely encouraging when you consider the magnitude of benefit observed in both progression-free survival and overall survival compared to chemotherapy. When you combine the efficacy of ibrutinib with a tolerable safety profile, collectively, the data suggest that ibrutinib may be an earlier option for some patients, rather than once a relapse occurs.”
“The results from RESONATE-2 continue to reaffirm the clinical benefit of ibrutinib and signal its potential to treat CLL patients in earlier lines of therapy, serving as an alternative to the current standard of care,” said Michael Severino, M.D., Executive Vice President of Research and Development and Chief Scientific Officer, AbbVie. “Ultimately, our goal is to continue advancing care for people affected by CLL and a host of other cancers, transforming these difficult-to-treat diseases that are prone to relapse into manageable, chronic and potentially curable conditions.”
The most common adverse events (AEs >20%) of all Grades in the RESONATE-2 trial for ibrutinib were diarrhea (42%), fatigue (30%), cough (22%) and nausea (22%); AEs for chlorambucil included nausea (39%), fatigue (38%), neutropenia (23%) and vomiting (20%). Hypertension occurred at a higher rate with ibrutinib (14%; including Grade 3 in 4%; with no Grade 4 or 5 events). All six patients with Grade 3 hypertension were managed with hypertensive medication and did not require ibrutinib dose reduction or discontinuation. Atrial fibrillation occurred in eight patients (6%) in the ibrutinib arm and was primarily Grade 2 in six patients and Grade 3 in two patients. It was managed with discontinuation in two patients and without a dose modification in remaining patients.
Overall, AEs leading to treatment discontinuation were less frequent with ibrutinib than with chlorambucil (9% vs. 23%). There were three deaths in the ibrutinib arm and 17 deaths in the chlorambucil arm over the median follow-up of 18.4 months. None of the patients who progressed on ibrutinib died during the subsequent follow-up period.
The safety of ibrutinib in this patient population was consistent with previously reported studies. It is worth noting that exposure to treatment and AE follow-up was nearly 2.5 times longer for ibrutinib compared with chlorambucil, with 87% of patients continuing on single-agent ibrutinib treatment.
A supplemental New Drug Application has been submitted to the U.S. Food and Drug Administration based on these data seeking an expanded indication for the use of IMBRUVICA in patients with treatment-naive CLL.
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