Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial

Abstract

Most patients with follicular lymphoma (FL) experience multiple relapses necessitating subsequent lines of therapy. Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor approved for the treatment of several B-cell malignancies, showed promising activity in FL in a phase 1 study. We report the results of a phase 2 trial evaluating ibrutinib in recurrent FL. Forty patients with recurrent FL were treated with ibrutinib 560 mg/d until progression or intolerance. The primary end point was overall response rate (ORR). Exploratory analyses included correlations of outcome with recurrent mutations identified in a cancer gene panel that used next-generation sequencing in pretreatment biopsies from 31 patients and results of early interim positron emission tomography/computed tomography scans in 20 patients. ORR was 37.5% with a complete response rate of 12.5%, median progression-free survival (PFS) of 14 months, and 2-year PFS of 20.4%. Response rates were significantly higher among patients whose disease was sensitive to rituximab (52.6%) compared with those who were rituximab refractory (16.7%) (P = .04). CARD11 mutations were present in 16% of patients (5 of 31) and predicted resistance to ibrutinib with only wild-type patients responding (P = .002). Maximum standardized uptake value at cycle 1 day 8 correlated with response and PFS. Ibrutinib was well-tolerated with a toxicity profile similar to labeled indications. Ibrutinib is a well-tolerated treatment with modest activity in relapsed FL. Evaluation of BTK inhibitors in earlier lines of therapy may be warranted on the basis of improved response rates in rituximab-sensitive disease. Somatic mutations such as CARD11 may have an impact on response to ibrutinib, may inform clinical decisions, and should be evaluated in larger data sets. This trial was registered at www.clinicaltrials.gov as #NCT01849263.

Conflict of interest statement

Conflict-of-interest disclosure: N.L.B. obtained research funding from Janssen Pharmaceuticals, Inc. and Pharmacyclics LLC. S.M.A. received an honorarium from WebMD and Research to Practice, research funding from Bristol-Myers Squibb, Celldex Therapeutics, Inc, Seattle Genetics, Merck, Affimed Therapeutics, and Trillium Therapeutics Inc. S.T.L. served as a consultant for Takeda Pharmaceuticals, Roche Holding AG, GlaxoSmithKline, Servier Laboratories, and Gilead Sciences and received research funding from Bayer. The remaining authors declare no competing financial interests.

© 2018 by The American Society of Hematology.

Figures

Figure 1.

Maximum reduction in sum of perpendicular diameters (SPDs). Shown are the 37 patients who had follow-up scans available for bidimensional measurements. Two additional patients had no follow-up scans because of early withdrawal for pneumonia and refusal after hip fracture and were considered to be nonresponders for response rate determination. One patient had progressive disease but bidimensional measurements were not available for the new lesions. PD, progressive disease; SD, stable disease.

Figure 2.

Kaplan-Meier PFS and OS estimates. Survival analysis included 40 patients with evaluable disease completing at least 1 dose of ibrutinib. Median PFS was 14.0 months (95% CI, 7.4-16.3 months). Median OS was not reached. NA, not achieved.

Figure 3.

Mutations in CARD11 are associated with inferior clinical outcomes after ibrutinib therapy in relapsed or refractory FL patients. (A) The distribution of best response stratified by CARD11 mutation status for patients with available pre-ibrutinib lymph node samples (n = 31). (B) PFS was significantly shorter in patients with CARD11 mutations (n = 5) compared with wild-type patients. (C) Observed CARD11 mutations (n = 8; top) and CARD11 mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC; bottom) found in lymphoid neoplasms (n = 195). Amino acid positions are indicated by numbers within peptide representations. Exon boundaries are indicated by vertical dashed lines. Patients with mutations in the coiled-coil domain had an event in <12 months. Several mutations observed in relapsed or refractory FL patients examined in this study were previously cataloged in COSMIC (eg, G126D and D230N). The protein mutation diagram was created with ProteinPaint. HR, hazard ratio.

Figure 4.

Progression-free survival by SUVmaxfrom cycle 1 day 8 PET/CT (n = 20). Patients were categorized above and below the cutpoint for SUVmax of 13.78 on day 8.