Anas Younes, MD
Adding ibrutinib to standard rituximab (R)-CHOP chemotherapy for non-Hodgkin lymphoma (NHL) resulted in an objective response rate of 100%, according to the results of a small preliminary clinical trial. The research was presented at the 2013 ASCO Annual Meeting.
In the study, first-line treatment with ibrutinib and chemotherapy led to complete responses in 10 of 15 patients, and the remaining five patients had partial responses. Complete responses occurred in all three ibrutinib dosages evaluated. The maximum tolerated dose of ibrutinib was not reached, and no pharmacokinetic interaction occurred between ibrutinib and the individual drugs that constitute R-CHOP.
â€œAn expansion cohort using 560 mg of ibrutinib is under way to further explore the safety and efficacy of the combination in patients with newly diagnosed, untreated diffuse large B-cell lymphoma [DLBCL],â€ said Anas Younes, MD, chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center in New York City. â€œBased on these data, a phase III study is planned to compare R-CHOP versus R-CHOP plus ibrutinib in patients with DLBCL.â€
Despite a long history of use, R-CHOP remains the therapeutic standard for most common B-cell malignancies. The regimen achieves a high initial response rate, but the disease does not respond or relapses in a substantial proportion of patients.
Ibrutinib is the first member of the Brutonâ€™s tyrosine kinase inhibitor drug class and has demonstrated single- agent activity in several types of relapsed/refractory B-cell malignancies and has been well tolerated, said Younes. The promising activity in previously treated patients provided a rationale to combine the agent with R-CHOP as first-line therapy for NHL.
Younes reported findings from a phase Ib study that had a primary objective of determining the dose for phase II evaluation and identifying dose-limiting toxicities with ibrutinib when used in combination with R-CHOP in patients with previously untreated NHL. Secondarily, investigators wanted to assess the adverse-event profile of the combination, evaluate ibrutinib pharmacokinetics in combination with R-CHOP, and determine overall response rate with the combination.
The study comprised two stages of clinical evaluation. During the first stage, investigators evaluated dose escalation of ibrutinib in combination with R-CHOP, beginning with 280 mg and increasing to 420 mg and 560 mg in separate cohorts. The stage included patients with mantle cell lymphoma, follicular lymphoma, and DLBCL. The second stage is ongoing and will evaluate the 560-mg dose with R-CHOP in an additional 15 patients, all of whom have DLBCL.
Investigators entered 17 patients into the first stage, and 15 completed the planned six cycles of therapy. One patient discontinued prematurely because of nonadherence and one because of grade 2 gastritis.
Three patients developed dose-limiting toxicity, two in the 280-mg cohort. One patient had a brief episode of syncope and another developed periorbital cellulitis. The third patient was in the 560-mg cohort and discontinued treatment because of gastritis.
The most common adverse events (all grades) were neutropenia (14 patients), thrombocytopenia, (14), nausea (13), vomiting (11), anemia (8), headache (7), diarrhea (6), constipation (4), fatigue (7), and infusion-related reaction (6).
â€œKeep in mind that R-CHOP is associated with most of these toxicities,â€ said Younes.
The most frequent grade 3/4 adverse events were neutropenia (15), thrombocytopenia (7), anemia (5), and syncope (3). Two patients (both in the 280-mg cohort) developed febrile neutropenia during a cumulative total of 91 cycles of therapy among the 17 patients entered into the dose-finding stage.
Ibrutinib pharmacokinetics were consistent with data from single-agent studies, demonstrating that R-CHOP did not affect the targeted agentâ€™s pharmacokinetic profile. Specifically, ibrutinib did not alter pharmacokinetics of vincristine, the only CYP3A4 agent in R-CHOP, Younes noted.
Responses (including complete responses) occurred at all ibrutinib doses and in all of the lymphoma subtypes included in the first stage of the evaluation. Three patients who achieved partial responses in the 560-mg cohort have not completed six cycles of therapy, and their response status could change.
Younes A, Flinn I, Berdeja JG, et al. Phase Ib study combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with CD20-positive B-cell non-Hodgkin lymphoma (NHL). J Clin Oncol. 2013;31(suppl; abstr 8502).