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.
| Original language | English |
|---|---|
| Pages (from-to) | 2031-2042 |
| Number of pages | 12 |
| Journal | Blood |
| Volume | 133 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - 9 May 2019 |
| Externally published | Yes |
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In: Blood, Vol. 133, No. 19, 09.05.2019, p. 2031-2042.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab
AU - Byrd, John C.
AU - Hillmen, Peter
AU - O'Brien, Susan
AU - Barrientos, Jacqueline C.
AU - Reddy, Nishitha M.
AU - Coutre, Steven
AU - Tam, Constantine S.
AU - Mulligan, Stephen P.
AU - Jaeger, Ulrich
AU - Barr, Paul M.
AU - Furman, Richard R.
AU - Kipps, Thomas J.
AU - Thornton, Patrick
AU - Moreno, Carol
AU - Montillo, Marco
AU - Pagel, John M.
AU - Burger, Jan A.
AU - Woyach, Jennifer A.
AU - Dai, Sandra
AU - Vezan, Remus
AU - James, Danelle F.
AU - Brown, Jennifer R.
N1 - Funding Information: The authors thank the patients who participated in this study and their supportive families, as well as the investigators, subinvestigators, and coordinators at each of the study sites. The authors thank Joris Diels of Janssen and Suzy Van Sanden of HEMAR, Janssen-Cilag Ltd (Beerse, Belgium) for their work in generating the crossover-adjusted OS analysis using the rank-preserving structural failure time method. Editorial support was provided by Melanie Sweetlove and was funded by Pharmacyclics LLC, an AbbVie Company. Funding Information: 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. Funding Information: 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, Pharma-cyclics LLC, an AbbVie Company, Sunesis, TG Therapeutics, and Vera-stem 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, Pharma-cyclics 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. Funding Information: This study was sponsored by Pharmacyclics LLC, an AbbVie Company, and Janssen Pharmaceuticals. J. C. Byrd is supported by the Four Winds Foundation, D. Warren Brown Foundation, Judy and Michael Thomas, the Sullivan CLL Research Foundation, and the National Institutes of Health, National Cancer Institute (grants R35 CA197734 and R01 CA177292). Publisher Copyright: © 2019 by The American Society of Hematology.
PY - 2019/5/9
Y1 - 2019/5/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065394135&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-08-870238
DO - 10.1182/blood-2018-08-870238
M3 - Article
C2 - 30842083
AN - SCOPUS:85065394135
SN - 0006-4971
VL - 133
SP - 2031
EP - 2042
JO - Blood
JF - Blood
IS - 19
ER -