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Clinical Trial
. 2023 Aug 24;142(8):687-699.
doi: 10.1182/blood.2022018818.

Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial

John F Seymour  1 , John C Byrd  2 , Paolo Ghia  3 , Arnon P Kater  4 , Asher Chanan-Khan  5 , Richard R Furman  6 , Susan O'Brien  7 , Jennifer R Brown  8 , Talha Munir  9 , Anthony Mato  10 , Stephan Stilgenbauer  11 , Naghmana Bajwa  12 , Paulo Miranda  12 , Kara Higgins  13 , Ellie John  14 , Marianne de Borja  15 , Wojciech Jurczak  16 , Jennifer A Woyach  17
Affiliations
Clinical Trial

Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial

John F Seymour et al. Blood. .

Abstract

ELEVATE-RR demonstrated noninferior progression-free survival and lower incidence of key adverse events (AEs) with acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia. We further characterize AEs of acalabrutinib and ibrutinib via post hoc analysis. Overall and exposure-adjusted incidence rate was assessed for common Bruton tyrosine kinase inhibitor-associated AEs and for selected events of clinical interest (ECIs). AE burden scores based on previously published methodology were calculated for AEs overall and selected ECIs. Safety analyses included 529 patients (acalabrutinib, n = 266; ibrutinib, n = 263). Among common AEs, incidences of any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib, with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. Incidences of headache and cough were higher with acalabrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rate, respectively. Among ECIs, incidences of any-grade atrial fibrillation/flutter, hypertension, and bleeding were higher with ibrutinib, as were exposure-adjusted incidence rates (2.0-, 2.8-, and 1.6-fold, respectively); incidences of cardiac events overall (the Medical Dictionary for Regulatory Activities system organ class) and infections were similar between arms. Rate of discontinuation because of AEs was lower for acalabrutinib (hazard ratio, 0.62; 95% confidence interval, 0.41-0.93). AE burden score was higher for ibrutinib vs acalabrutinib overall and for the ECIs atrial fibrillation/flutter, hypertension, and bleeding. A limitation of this analysis is its open-label study design, which may influence the reporting of more subjective AEs. Overall, event-based analyses and AE burden scores demonstrated higher AE burden overall and specifically for atrial fibrillation, hypertension, and hemorrhage with ibrutinib vs acalabrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02477696.

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Conflict of interest statement

Conflict-of-interest disclosure: J.F.S. serves on the advisory board of AbbVie, AstraZeneca, Celgene, Genentech, Genor Bio, Gilead, Janssen, MorphoSys, Roche, and Sunesis; is a speaker for AbbVie, Celgene, and Roche; reports research funding from AbbVie, Celgene, Janssen, and Roche; provides expert testimony to Celgene, Roche, and TG Therapeutics; and reports consultancy for TG Therapeutics. J.C.B. serves as a consultant for Syndax, Trillium, AstraZeneca, Novartis, Newave, and Kronos; and serves as the scientific advisory board chair of, and is a major stockholder with, Vincerx Pharma. T.M. declares honoraria from AstraZeneca, AbbVie, Janssen, Alexion, Gilead, Roche, and Novartis. P.G. serves as a consultant for AbbVie, AstraZeneca, BeiGene, BMS, Janssen, Lilly/Loxo, MSD, and Roche; and reports research funding from AbbVie, AstraZeneca, BMS, and Janssen. A.P.K. serves as a consultant for AbbVie, AstraZeneca, BeiGene, BMS, Janssen, and Roche/Genentech; and reports research funding from AbbVie, AstraZeneca, BMS, Janssen, and Roche/Genentech. A.C.-K. reports advisory board honoraria, research support, board of director, and trial participation with Ascentage, BeiGene, Cellectar, Starton, Janssen, and Pharmacyclics. R.R.F. serves as a consultant for AbbVie, AstraZeneca, BeiGene, Genentech, Incyte, Janssen, Loxo, MEI Pharma, Pharmacyclics, Sanofi, TG Therapeutics, and X4 Pharmaceuticals. S.O. serves as a consultant for AbbVie, Alexion, Amgen, Aptose Biosciences, Astellas, AstraZeneca, Autolus, BMS, Celgene, DynaMed, Eli Lilly and Company, Gilead, GlaxoSmithKline, Janssen Oncology, Johnson & Johnson, Juno Therapeutics, MEI Pharma Inc, Merck, and NOVA Research; and declares research funding from Acerta, Alliance, BeiGene, Caribou Biosciences, Gilead, Kite, Loxo Oncology, Mustang, Nurix, Pfizer, Pharmacyclics, Regeneron, Sunesis, and TG Therapeutics. J.R.B. serves as a consultant for AbbVie, Acerta/AstraZeneca, BeiGene, Bristol Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, MEI Pharma, Pfizer, and Pharmacyclics; and declares research funding from BeiGene, Gilead, Loxo/Lilly, MEI Pharma, SecuraBio, Sun, and TG Therapeutics. A.M. serves as a consultant/advisor for AbbVie, Acerta, Adaptive, AstraZeneca, BeiGene, DTRM Biopharma, Genentech, Curio, Dava, Octopharma, Janssen, Johnson & Johnson, Loxo, Nurix, Genmab, BMS, Pharmacyclics, Sunesis, and TG Therapeutics; reports research funding from AbbVie, Octopharma, Acerta, Adaptive, BeiGene, DTRM Biopharma, Genentech, Genmab, Nurix, Janssen, Johnson & Johnson, Loxo, Pharmacyclics, Sunesis, and TG Therapeutics; and reports other relationship(s) with TG Therapeutics (DSMB). S.S. reports receiving advisory board honoraria, research support, travel support, and speaker fees from, and trial participation with AbbVie, AstraZeneca, BeiGene, BMS, Gilead, GSK, Hoffman-La Roche, Janssen, Novartis, Pharmacyclics, and Sunesis. N.B., P.M., K.H., E.J., and M.d.B. reports employment and stock ownership with AstraZeneca. W.J. received research funding from AstraZeneca, Janssen, BeiGene, and Lilly. J.A.W. received research funding from AbbVie, Janssen, Karyopharm, MorphoSys, Pharmacyclics, and Schrodinger; and serves as a consultant for AbbVie, AstraZeneca, BeiGene, Genentech, Janssen, Loxo, Newave, Pharmacyclics, and Schrodinger.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Time to treatment discontinuation. Kaplan-Meier plot for time to treatment discontinuation overall (A) and because of AEs (B).
Figure 2.
Figure 2.
Incidence of atrial fibrillation/flutter and hypertension in patient subgroups.
Figure 3.
Figure 3.
Cumulative incidence of atrial fibrillation/flutter and hypertension by prior history. Cumulative incidence of atrial fibrillation/flutter (A) and hypertension (B) in patients with and without prior history.
Figure 4.
Figure 4.
Summary of AE burden score by treatment arm and subgroup. AE burden score by treatment arm and subgroup for grade 1 to 4 (A) and grade 1 to 5 (B) AEs. P values based on a 2-sided Wilcoxon rank-sum test without adjustment for multiplicity. Lower figures in each panel show a magnification of the 0 to 20 portion of the scale. Acala, acalabrutinib; Ibr, ibrutinib; pts, patients.
Figure 5.
Figure 5.
Overall AE burden score by time interval. ∗P < .05 based on a 2-sided Wilcoxon rank-sum test without adjustment for multiplicity.
See this image and copyright information in PMC

Comment in

References

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