Ibrutinib plus Rituximab in Treatment-Naive Patients with Follicular Lymphoma: Results from a Phase 2 Study
Follicular lymphoma (FL) is an indolent type of non-Hodgkin lymphoma that is not cured with standard chemoimmunotherapeutic regimens incorporating the anti-CD20 monoclonal antibody rituximab. Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton’s tyrosine kinase, has shown activity in a phase 1 dose-escalation trial in patients with relapsed/refractory FL, with an overall response rate (ORR) of 38%, including 3 complete responses (CRs).1 Fowler and colleagues reported results of an open-label phase 2 trial (PCYC-1125-CA) that evaluated the efficacy and safety of ibrutinib plus rituximab in treatment-naïve patients with FL.2
In the main arm 1 of this trial, 60 treatment-naïve patients with FL received oral ibrutinib (560 mg once daily) until progressive disease or unacceptable toxicity plus standard rituximab dose (375 mg/m2 IV once weekly for 4 doses) for the first 4 weeks of the study. The exploratory arm 2 of the study evaluated an alternate schedule of ibrutinib plus rituximab in 20 patients, the results of which were not presented. The primary end point was investigator-assessed ORR; secondary end points included duration of response, progression-free survival, overall survival, and safety. At baseline, 80% of patients had stage III/IV disease, and the majority of patients has intermediate- or high-risk Follicular Lymphoma International Prognostic Index risk scores. At a median follow-up of 13.8 months, patients with ibrutinib therapy achieved an investigator-assessed ORR of 82%, including a CR rate of 30% and partial response rate of 52%. Median time to best response was 2.7 months, and a median duration of response was not reached. The 12-month progression-free survival (PFS) rate was 86%, and the 12-month overall survival (OS) rate was 98%; the median PFS and OS were not reached. Common adverse events (AEs) of any grade included fatigue, diarrhea, nausea, constipation, headache, maculopapular rash, myalgia, vomiting, cough, infusion-related reaction, and dry eye. Grade 3/4 AEs were reported in 48% of patients, including fatigue (5%), maculopapular rash (5%), neutropenia (3%), hypertension (3%), and arthritis (3%). Bleeding (any grade) was reported in 32% of patients, and all cases except 1 (grade 2 petechiae) were grade 1 in severity. Serious AEs occurred in 17% of patients regardless of their relationship to ibrutinib; however, these events were deemed uncommon, with no event occurring in ?1 patient. Grade 3/4 atrial fibrillation occurred in 3 patients (5%; 1 each of grade 1, grade 2, and grade 3 severity); 2 patients discontinued as a result of this AE. Secondary malignancies were reported in 4 patients, including Hodgkin’s lymphoma, fallopian tube cancer, melanocytic nevus, and basal-cell carcinoma (1 each). Overall, 35% of patients discontinued ibrutinib in the trial, of which 15% was due to AEs. Based on these results, the authors concluded that ibrutinib plus rituximab combination therapy demonstrated robust clinical activity and was well tolerated in treatment-naïve patients with FL.
- Advani RH, et al. J Clin Oncol. 2013;31:88-94.
- Fowler N, et al. ASH 2015. Abstract 470.