BTK Inhibitor Ibrutinib Produces High Response Rate in Relapsed/Refractory Mantle Cell Lymphoma
Ibrutinib is a first-in-class oral covalent inhibitor of Bruton’s tyrosine kinase (BTK), a mediator of the B-cell receptor signaling pathway implicated in the pathogenesis of B-cell cancers. As reported in The New England Journal of Medicine, Michael L. Wang, MD, of The University of Texas MD Anderson Cancer Center, and colleagues found that single-agent ibrutinib resulted in a high response rate and prolonged responses with a favorable toxicity profile in patients with relapsed or refractory mantle cell lymphoma.
Study Details
In a phase II study, 111 patients with relapsed or refractory mantle cell lymphoma received ibrutinib 560 mg/d. Patients were enrolled in two groups consisting of those who had previously received at least two cycles of bortezomib (Velcade) therapy (n = 48) and those who had received less than two complete cycles of bortezomib or no prior bortezomib (n = 63). Patients had a median age of 68 years, 76% were male, and 86% had intermediate- or high-risk disease based on clinical prognostic factors. Patients had received a median of three prior therapies.
High Response Rate, Durable Responses
Response was observed in 75 patients (68%), with complete response in 21% of patients and partial response in 47%. Response rates did not differ between patients with no prior bortezomib therapy (68%, including complete response in 19%) and those with prior bortezomib therapy (67%, including complete response in 23%) and also did not vary according to other baseline characteristics or risk factors associated with chemotherapy treatment failure. The overall response rate and complete response rate were found to improve over time with continued therapy.
After an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI] = 15.8 months to not reached), estimated median progression-free survival was 13.9 months (95% CI = 7.0 months to not reached), and median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months. At the estimated follow-up duration of 15.3 months, 46 patients (41%) were still receiving treatment.
Favorable Toxicity Profile
The majority of adverse events observed were grade 1 or 2. The most common nonhematologic treatment-related adverse events of any grade were diarrhea (50%), fatigue (41%), and nausea (31%), with grade 3 or higher nonhematologic adverse events being infrequent. Grade 3 or higher hematologic adverse events were also infrequent and included neutropenia in 16% of patents, thrombocytopenia in 11%, and anemia in 10%. Grade 3 bleeding events occurred in 5 patients (4.5%). Adverse events led to discontinuation of therapy in 8 patients (7%). A total of 16 patients (14%) died during the trial, 12 from disease progression and four due to an adverse event (2 from pneumonia, 1 from sepsis, and 1 from a cardiac arrest that was not considered drug-related).
The investigators concluded: “[T]he BTK inhibitor ibrutinib is a highly active new agent showing durable single-agent activity in relapsed and refractory mantle cell lymphoma. The favorable toxicity profile suggests that ibrutinib provides the opportunity for treatment with less intensive and more effective regimens than those currently available.”
The study was supported by Pharmacyclics, Janssen Biotech, and others. For full disclosures of the study authors, visit www.nejm.org.
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