Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab

Abstract

Ibrutinib, a once-daily oral inhibitor of Bruton tyrosine kinase, has greatly improved outcomes for patients with chronic lymphocytic leukemia (CLL). The phase 3 RESONATE trial, which compared single-agent ibrutinib to ofatumumab in high-risk, relapsed patients with CLL, provided support for approval of ibrutinib in the United States and Europe. We describe long-term follow-up of patients treated in RESONATE, where continued superiority of progression-free survival (PFS) (hazard ratio [HR], 0.133; 95% confidence interval [CI], 0.099-0.178) was observed. Overall survival benefit continues (HR, 0.591; 95% CI, 0.378-0.926), although with decreased magnitude relative to that seen before crossover to ibrutinib was implemented for patients on ofatumumab (HR, 0.426; 95% CI, 0.220-0.823). Notably, overall response to ibrutinib increased over time, with 91% of patients attaining a response. The PFS benefit with ibrutinib was independent of baseline risk factors, although patients with ≥2 prior therapies had shorter PFS than those with <2 prior therapies, and the presence of TP53 or SF3B1 mutations showed a trend toward shorter PFS vs without these factors. Median duration of ibrutinib was 41 months, with 46% remaining on treatment at a median follow-up of 44 months. Grade ≥3 adverse events generally decreased over time, causing only a small proportion of patients to cease therapy. Ibrutinib was discontinued due to progressive disease in 27% of patients. This long-term study provides support for sustained efficacy and safety of ibrutinib in relapsed/refractory CLL and consideration of study provisions that allow crossover to investigational therapy when benefit has been clearly demonstrated. This trial was registered at www.clinicaltrials.gov as #NCT01578707.

Conflict of interest statement

Conflict-of-interest disclosure: J. C. Byrd received research funding and/or honoraria for a consultancy/advisory role from Genentech, Acerta, Verastem, Jazz, Pharmacyclics LLC, an AbbVie Company, and Janssen. P.H. received honoraria and research funding from and reports a consultancy/advisory role for AbbVie, Pharmacyclics LLC, an AbbVie Company, and Janssen and travel expenses from AbbVie and Janssen. S.O. received honoraria from and reports a consultancy/advisory role AbbVie, Janssen, and Pharmacyclics LLC, an AbbVie Company and received research funding from Pharmacyclics LLC, an AbbVie Company. J. C. Barrientos reports a consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, AbbVie, Gilead, and Janssen and received research funding from Pharmacyclics LLC, an AbbVie Company, AbbVie, and Gilead. N.M.R. reports a consultancy/advisory role for Celgene, AbbVie, Gilead, and BMS and received research funding from BMS. S.C. reports a consultancy/advisory role for Beigene, Abbvie, and Janssen and received research funding from AbbVie, Gilead, Pharmacyclics LLC, an AbbVie Company, Janssen, and Acerta and honoraria from Pharmacyclics LLC, an AbbVie Company, and Janssen. C.S.T. received honoraria from Janssen and Pharmacyclics LLC, an AbbVie Company, and research funding from Janssen. S.P.M. received honoraria from and reports a consultancy/advisory role for Roche, AbbVie, Janssen, Gilead, and GSK; received research funding from Roche, AbbVie, and Janssen; and is a member of the speakers bureau for Roche, AbbVie, Janssen, and Gilead. U.J. received honoraria and travel expenses from and reports a consultancy/advisory role for Gilead, Novartis, and AbbVie. P.M.B. reports a consultancy/advisory role for AbbVie, Celgene, Novartis, Seattle Genetics, Genentech, Verastem, Gilead, and Merck. R.R.F. reports a consultancy/advisory role for AbbVie, Acerta, Genentech, Gilead, Incyte, Loxo Oncology, Janssen, Pharmacyclics LLC, an AbbVie Company, Sunesis, TG Therapeutics, and Verastem and reports another relationship with Incyte DSMB. T.J.K. reports a consultancy/advisory role for AbbVie, Genentech-Roche, Gilead, Celgene, and Pharmacyclics LLC, an AbbVie Company, and receives and research funding from AbbVie, Genentech-Roche, Oncternal, and Pharmacyclics LLC, an AbbVie Company. P.T. received honoraria and travel expenses from Roche and reports a consultancy/advisory role for Janssen and AbbVie. C.M. reports a consultancy/advisory role for Janssen, AbbVie, and Pharmacyclics LLC, an AbbVie Company. M.M. received honoraria from Roche, Gilead, Janssen, and AbbVie; reports a consultancy/advisory role for AbbVie, Gilead, and Janssen; received travel expenses from Gilead and Janssen; is a member of the speakers bureau for AbbVie, Janssen, Gilead, and Roche; and received research funding from Roche. J.M.P. reports a consultancy/advisory role for Pharmacyclics and Gilead. J.A.B. received honoraria and travel expenses from Janssen; reports a consultancy/advisory role for Gilead, Pharmacyclics LLC, an AbbVie Company, and Janssen; and received research funding for Pharmacyclics LLC, an AbbVie Company. S.D. and R.V. are employees of Pharmacyclics LLC, an AbbVie Company, and have stock or other ownership of AbbVie. D.F.J. is an employee of AbbVie and Pharmacyclics LLC, an AbbVie Company (her husband is an employee of AbbVie) and has stock or other ownership with AbbVie (self and husband) and patents, royalties, and other intellectual property with AbbVie. J.R.B. reports a consultancy/advisory role for Janssen, Gilead, Sun Biopharma, AbbVie, Pfizer, AstraZeneca, Astellas, RedX, Pharmacyclics LLC, an AbbVie Company, and TG Therapeutics and received research funding for Gilead and Sun. J.A.W. declares no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

PFS at a median follow-up of 44 months (intention-to-treat [ITT] population). NE, not evaluated.

Figure 2.

Forest plot of HRs for PFS by baseline subgroups (ITT population). *All 15 patients with mutated BIRC3 in the ofatumumab arm had events.

Figure 3.

PFS by number of prior therapies and cytogenetic subgroups (ITT population randomized to ibrutinib). (A) Analysis by number of prior therapies. (B) Analysis by del(17)(p13.1) and del(11)(q22.3). (C) Analysis by complex karyotype.

Figure 4.

PFS by genomic subgroups (ITT population randomized to ibrutinib). (A) Analysis by IGHV. (B) Analysis by NOTCH1. (C) Analysis by TP53. (D) Analysis by SF3B1. (E) Analysis by BIRC3. (F) Analysis by XPO1.

Figure 5.

OS analysis.

Figure 6.

Cumulative best response over time per investigator assessment (ITT population). CR, complete response; nPR, nodular partial response; PR, partial response; PR-L, partial response with lymphocytosis.

Figure 7.

Prevalence of grade ≥3 AEs of clinical interest over time (ITT population). Prevalence was determined by the proportion of patients with a given AE (which can be an existing event or new onset of an event) during each yearly interval. Multiple onsets of the same AE term within a given yearly interval were counted once, and the same AE term continuing across several yearly intervals were counted in each of the intervals. *Defined as any hemorrhagic event grade ≥3 or in severity or that results in one of the following: intraocular bleeding causing vision loss, need for a transfusion of ≥2 U red blood cells or equivalent, hospitalization, or prolongation of hospitalization.