Ibrutinib (Ibr) for treatment of relapsed‐refractory (R/R) chronic lymphocytic leukemia (CLL): a matching‐adjusted indirect comparison of 3 randomized phase 3 trials

Abstract

Introduction: Ibr is a standard therapy for CLL with demonstrated efficacy in first-line and R/R settings. Within R/R CLL, single-agent Ibr was evaluated in 3 randomized phase 3 trials: RESONATE (vs. ofatumumab), ALPINE (vs. zanubrutinib), and ELEVATE-RR (vs acalabrutinib in pts with del(11q) or del(17p)). This analysis evaluated outcomes of Bruton’s tyrosine kinase inhibitor (BTKi) treatment in pts with R/R CLL by comparing the efficacy of Ibr in RESONATE to ALPINE and ELEVATE-RR using a matching-adjusted indirect comparison analysis. Methods: Individual patient data (IPD) of Ibr-treated pts from RESONATE (NCT01578707) were separately match-adjusted to Ibr-treated arms of 1) ALPINE (NCT03734016) and 2) ELEVATE-RR (NCT02477696) for key baseline characteristics: age ≥75 y, bulky disease, ≥3 or ≥4 prior treatments, b2 microglobulin >3.5 mg/L, and del(11q) or del(17p). For comparison with ELEVATE-RR, only pts with del(17p) or del(11q) from RESONATE were included. After matching, adjusted ORR (CR + CRi + nPR + PR) and PFS from RESONATE were compared with published outcomes from ALPINE and ELEVATE-RR; for PFS, IPD for ALPINE and ELEVATE-RR were extracted from published Kaplan-Meier curves. Hazard ratios (HRs) were calculated using a weighted Cox model. Results: The analysis comprised 785 Ibr-treated pts across RESONATE (n = 195), ALPINE (n = 325), and ELEVATE-RR (n = 265). After omission of pts with missing values and the adjustment procedure, the effective RESONATE sample size was 95 pts (vs ALPINE) and 69 pts (vs ELEVATE-RR). Median follow-up was 36.0 versus 29.6 mo (RESONATE adjusted vs. ALPINE published) and 36.1 versus 40.9 mo (RESONATE adjusted vs. ELEVATE-RR published). 2-y PFS (95% CI) for Ibr-treated pts in RESONATE adjusted sample and ALPINE was 81% (74–90) and 66% (60–71), respectively; median PFS was 40.7 and 34.2 mo, with an HR (95% CI) of 0.57 (0.39–0.84) favoring RESONATE, P = 0.0048 (Figure). ORR (95% CI) was 90% (86–94) and 74% (69–79), respectively (P < 0.0001). Compared with the ELEVATE-RR Ibr arm, which included more pts with high-risk genetic features than ALPINE, the RESONATE adjusted sample had greater 2-y PFS (79% [69–89] vs. 69% [64–75], not statistically significant). Median PFS was 41.2 vs. 44.1 mo (HR [95% CI] 0.85 [0.55–1.31], P = 0.46), respectively; ORR was 89% (83–95) and 80% (75–85) (P = 0.0381). Encore Abstract - previously submitted to EHA 2023 The research was funded by: The research was funded by Pharmacyclics LLC, an AbbVie Company. Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract. P. Ghia Consultant or advisory role: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Honoraria: AbbVie, AstraZeneca, BeiGene, Merck Sharp & Dohme, Bristol Myers Squibb, Janssen, Eli Lilly/Loxo Oncology, and Roche Research funding: AbbVie, AstraZeneca, and Janssen T. Munir Consultant or advisory role: Morphosys and Sunesis Honoraria: AbbVie, AstraZeneca, Gilead, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AbbVie, Gilead, or Janssen J. Burger Consultant or advisory role: BeiGene, Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Honoraria: Gilead, Janssen, Novartis, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics Other remuneration: travel/accommodation expenses from Gilead, Janssen, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics J. F. Seymour Research funding: AbbVie, Celgene, Janssen, and F. Hoffmann-La Roche Ltd. Other remuneration: speakers’ bureau with AbbVie, Celgene, and F. Hoffmann-La Roche Ltd.; patents, royalties, or other intellectual property with AbbVie; and expert testimony for F. Hoffmann-La Roche Ltd. K. Rogers Consultant or advisory role: Acerta Pharma, AstraZeneca, Beigene, Genentech, Innate Pharma, and Pharmacyclics, LLC, an AbbVie company Research funding: AbbVie, Genentech, Janssen, and Novartis Other remuneration: travel/accommodation expenses from AstraZeneca H. Huang Employment or leadership position: Everest Clinical Research and AbbVie Consultant or advisory role: Everest Clinical Research and AbbVie Research funding: Everest Clinical Research and AbbVie C. Moreno Consultant or advisory role: AbbVie, Ascentage, AstraZeneca, and Janssen Research funding: AbbVie and Janssen Other remuneration: speakers’ bureau for Janssen L. Neumayr Employment or leadership position: AbbVie Consultant or advisory role: ApoPharma Stock ownership: AbbVie Honoraria: Novartis Research funding: Pfizer and Sancilio Other remuneration: travel accommodations from Forma Therapeutics C. Abbazio Employment or leadership position: AbbVie Stock ownership: AbbVie and Bristol Myers Squibb J. Sharman Consultant or advisory role: AbbVie, AstraZeneca, and BeiGene Honoraria: AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, Genentech, Lilly, Pharmacyclics, LLC, an AbbVie company, and TG Therapeutics