Ibrutinib, a small-molecule inhibitor of BTK, has shown significant activity in several B-cell malignancies. In a phase 1 dose-escalation study, ibrutinib induced a response in 38% of patients with relapsed/refractory follicular lymphoma (FL) and in 54% of patients who received doses of ?2.5 mg/kg (Advani RH, et al. J Clin Oncol. 2013;31:88-94). On the basis of these results, at ASH 2014, Bartlett and colleagues reported on a Cancer Therapy Evaluation Program–sponsored phase 2 trial of single-agent ibrutinib in patients with relapsed/refractory FL (Blood. 2014;124. Abstract 800).
A total of 40 patients with relapsed/refractory FL (grade 1, 2, or 3a) that had progressed during or after 1 or more previous chemotherapy regimens were treated with ibrutinib 560 mg daily until progression or unacceptable toxicity. The primary end point was ORR and the secondary end points were safety and tolerability, OS, time to response, time to treatment failure, duration of response, and PFS. The planned exploratory correlative studies included C1D8 and C3D1 [18F]-fluorodeoxyglucose positron emission tomography (PET) response evaluation in a subset of 20 patients, and whole-transcriptome sequencing for the correlation of mutations with response and resistance.
At a median follow-up of 6.5 months, the ORR was 30%, with 1 CR and 11 PRs. In addition, 65% of the patients have exhibited tumor size reduction. Only 11% of patients with RTX-refractory disease responded compared with 42% of patients with RTX-sensitive disease (P = .06) and 67% of patients who were RTX-naïve. The median time to response was 2.4 months, and the median PFS was 9.9 months. Grade 3/4 AEs occurred in 30% of the patients, including anemia, neutropenia, and infection, and 3 patients have died (1 of progressive disease, 1 of pneumonia, 1 of gastric hemorrhage).
Of the 20 patients with C1D8 PET scans, 19 also had C3D1 PET scans and were evaluable for response. Of these 19 patients, 6 had objective responses by computed tomography (CT) criteria at week 8 or beyond, with C1D8 PET/CT showing qualitative (visual) improvement in 3 patients, no visual change in 1, and qualitative worsening in 2 patients. On the C3D1 PET/CT, 4 of the 6 patients had qualitative improvement and 2 had no change.
This study shows that single-agent ibrutinib is well-tolerated with a modest ORR in relapsed/refractory FL at this early assessment. Continued follow-up is warranted to capture late responders and to establish response duration, but, overall, ibrutinib appears to be less active in FL than in MCL and chronic lymphocytic leukemia.
