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Ibrutinib demonstrates long-term effectiveness in previously treated CLL
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NEW YORK — Ibrutinib demonstrated long-term efficacy in patients with previously treated chronic lymphocytic leukemia, according to updated results from the phase 3 RESONATE trial presented at Lymphoma & Myeloma 2015.
Even patients with high-risk prognostic features at baseline derived benefit, results showed.
Jennifer R. Brown
Ibrutinib (Imbruvica; Pharmacyclics, Janssen), a Bruton’s tyrosine kinase inhibitor, is approved for the treatment of patients with CLL who received at least one prior therapy, as well as for patients with CLL who have 17p deletion.
In the RESONATE trial, Jennifer R. Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, and colleagues randomly assigned 391 patients to ibrutinib 420 mg once daily (n = 195) or IV ofatumumab (Arzerra, Novartis) for up to 24 weeks.
Interim analysis results showed patients assigned ibrutinib demonstrated improvement in PFS assessed by independent review committee — the study’s primary endpoint — as well as OS and overall response rate. Based on these findings, the data monitoring committee recommended crossover to the ibrutinib arm.
In the current analysis, Brown and colleagues reported long-term investigator-assessed efficacy outcomes, including subgroup analyses that accounted for baseline gene mutations and other high-risk factors.
About 75% of patients (ibrutinib, n = 142; ofatumumab, n = 149) had samples evaluable for gene mutations and chromosomal abnormality analysis at baseline.
Researchers reported comparable rates of 17p deletion (32% vs. 33%), 11q deletion (33% vs. 31%) and unmutated IGHV (73% vs. 63%) in the ibrutinib and ofatumumab arms.
Baseline analyses also showed similar rates of ATM mutations (20% vs. 22%), NOTCH1 mutations (28% vs. 30%) and BIRC3 mutations (15% vs. 10%) in the ibrutinib and ofatumumab groups.
Median follow-up was 19 months.
Patients assigned ibrutinib achieved significantly longer median PFS (not reached vs. 8.1 months; HR = .106; P < .0001). At 18 months, 86% of ibrutinib-treated patients were alive and 76% were progression free.
Researchers reported investigator-assessed overall response rates of 90% in the ibrutinib arm vs. 25% in the ofatumumab arm (P < .0001).
A higher percentage of patients assigned ibrutinib achieved complete response or complete response with incomplete bone marrow recovery (7% vs. < 1%).
Median time to complete response or complete response with incomplete bone marrow recovery in the ibrutinib arm was 11 months. One patient assigned ofatumumab achieved complete response at 8 months.
Results showed ibrutinib was associated with a significantly higher 12-month PFS rate and overall response rate, regardless of patients’ baseline gene mutations or the number of prior therapies (P < .001). However, ibrutinib-treated patients who underwent only one prior therapy achieved significantly better PFS and overall response rates than those who underwent two or more prior therapies.
In the subset of patients with NOTCH1 mutations, ofatumumab appeared associated with significantly shorter PFS than ibrutinib (P = .0064).
The most common grade 3 to grade 4 adverse events reported in the ibrutinib arm were neutropenia (19%), pneumonia (10%), thrombocytopenia (6%), anemia (6%) and hypertension (6%).
Thirteen (7%) patients experienced atrial fibrillation (grade 1, n = 2; grade 2, n = 4; grade 3, n = 7).
During approximately 1 year of follow-up since the interim analysis, researchers reported incident each of grade 3 epistaxis, grade 3 spontaneous hematoma and grade 4 subdural hematoma.
The majority of patients (74%) initially assigned to ibrutinib remained on treatment at the time of analysis.
“Longer-term follow-up demonstrates continued efficacy of ibrutinib in patients with previously treated CLL regardless of high-risk prognostic features at baseline,” Brown and colleagues wrote. “The presence of genetic abnormalities frequently implicated in CLL pathogenesis does not confer inferior outcomes in patients treated with ibrutinib with 19-month follow-up.” – by Mark Leiser
Reference:
Brown JR, et al. Abstract P12. Presented at: Lymphoma & Myeloma 2015: An International Congress on Hematologic Malignancies; Oct. 22-24, 2015; New York.
Disclosure: Brown reports consultant roles with Celgene, Janssen, ProNai, Roche/Genentech and Sun BioPharma.