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4615 Treatment with First-Line Ibrutinib Improves Overall Survival in Patients with Chronic Lymphocytic Leukemia (CLL) and High-Risk Genomic Features to Rates Approximating an Age-Matched US Population: Pooled Analysis of Phase 3 Trials with 10 Years of Follow-up

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Lymphoid Leukemias, CLL, Clinical Research, Diseases, Treatment Considerations, Lymphoid Malignancies, Non-Biological therapies
Monday, December 9, 2024, 6:00 PM-8:00 PM

Jan A. Burger, MD, PhD 1, Neil E. Kay, MD2, John N. Allan, MD3, Paul M Barr, MD4, Jacqueline C. Barrientos, MD, MS5*, Carolyn Owen, MD6, Victoria Wang7*, Hsin-Hui Huang, PhD8*, Lynne Neumayr, MD8*, Christopher Abbazio, PharmD8*, Gabriel S. Krigsfeld, PhD8*, Sneh Mody, MBA, PharmD8*, Paolo Ghia, MD, PhD9,10 and Tait D. Shanafelt, MD11*

1MD Anderson Cancer Center, Houston, TX
2Department of Immunology, Mayo Clinic, Rochester, MN
3Division of Hematology and Oncology, Weill Cornell Medicine, Long Island City, NY
4University of Rochester, Rochester, NY
5Mount Sinai Comprehensive Cancer Center, Miami Beach, FL
6Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada
7Dana-Farber Cancer Institute, Boston
8AbbVie, North Chicago, IL
9Università Vita-Salute San Raffaele, Milano, Italy
10IRCCS Ospedale San Raffaele, Milan, Italy
11School of Medicine, Stanford University, Stanford, CA

Introduction: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), changed the treatment landscape by demonstrating improved overall survival (OS) compared with chemotherapy/chemoimmunotherapy across multiple phase 3 trials in patients (pts) with CLL, including those with high-risk genomic features. Recently, data were reported for pts treated with ibrutinib in the phase 3 RESONATE-2 trial with up to 10 years of follow-up, representing the longest follow-up of any BTKi used in first-line treatment of CLL. With the most robust long-term follow-up data among BTKis, ibrutinib therapy trials are uniquely positioned to assess the long-term OS benefit of first-line BTKi treatment in pts with CLL across pt subgroups. We previously demonstrated that first-line ibrutinib is associated with OS rates that are similar to those in the age-matched general population, with a median follow-up of 5.9 years since initial diagnosis (Ghia P et al. HemaSphere 2024), but it remains unclear whether this holds true for pts with high-risk genomic features. This updated analysis evaluated long-term OS outcomes with a median follow-up of 8 years since randomization and 10 years since initial diagnosis in a pooled population of pts with previously untreated CLL, including those with high-risk features, who received first-line ibrutinib treatment in 2 phase 3 trials with comparison of survival estimates to the US age-matched general population.

Methods: Data were pooled for pts who received first-line treatment with single-agent ibrutinib or ibrutinib + rituximab in the RESONATE-2 (NCT01722487) and ECOG-ACRIN E1912 (NCT02048813) trials, respectively. OS probabilities from the time of randomization and from the time of initial diagnosis for ibrutinib-treated pts were compared with an age-matched general population using 2021 life tables for the total US population published by the Centers for Disease Control and Prevention using the Kaplan-Meier method. Subgroup analyses were performed for high-risk pts, defined as those with del(11q), del(17p), mutated TP53, and/or unmutated IGHV (uIGHV).

Results: A total of 490 pts were pooled across the 2 studies: 352 pts (71.8%) were treated with ibrutinib + rituximab, and 135 pts (27.6%) were treated with single-agent ibrutinib; 3 pts did not receive study treatment. The median age at time of randomization was 61 years; 36.5% (179/490) were aged ≥65 years, 21.8% had del(11q), 7.8% had del(17p) and/or mutated TP53, and 54.7% had uIGHV. The median time from initial CLL diagnosis to randomization was 20.9 months (range, 0.0–341.8); the median follow-up was 123.5 months (10.3 years) from initial diagnosis and 99.2 months (8.3 years) from the time of randomization.

From the time of randomization, estimated 9-year OS rates were 81.2% (95% CI, 76.8–84.9) in all ibrutinib-treated pts versus 82.0% (95% CI, 78.3–85.2) in the age-matched population (hazard ratio [HR] 1.17; 95% CI, 0.86–1.58). In high-risk pts, estimated 9-year OS rates were 79.5% (95% CI, 73.5–84.3) for ibrutinib-treated pts versus 83.2% (95% CI, 78.5–86.9) in the age-matched general population (HR 1.24; 95% CI, 0.84–1.84). In pts aged ≥65 years, estimated 9-year OS rates were 68.7% (95% CI, 60.5–75.6) for ibrutinib-treated pts and 68.7% (95% CI, 61.4–75.0) in the age-matched general population (HR 1.12; 95% CI, 0.77–1.63). In pts aged <65 years, estimated 9-year OS rates were 89.3% (95% CI, 84.6–92.7) for ibrutinib-treated pts and 90.0% (95% CI, 86.1–92.9) in the age-matched general population (HR 1.15; 95% CI, 0.68–1.94). From the time of initial diagnosis, estimated 15-year OS rates were 78.4% (95% CI, 72.8–83.0) in all ibrutinib-treated pts versus 72.0% (95% CI, 67.8–75.7) in the age-matched general population (HR 0.83; 95% CI, 0.62–1.11). Study treatment had been discontinued in 59.8% (293/490) of pooled ibrutinib-treated pts; the most frequent reasons for discontinuation were adverse events (43.0%; 126/293) and progressive disease (20.5%; 60/293). Study treatment was ongoing in 31.8% of pooled pts (156/490).

Conclusions: With the longest follow-up time for any commercially available targeted therapy, this pooled analysis demonstrates that, regardless of evaluation from randomization or initial diagnosis, and irrespective of age or high-risk features, first-line treatment with ibrutinib provides long-term OS benefit with survival estimates that appear similar to those of a US age-matched cohort.

Disclosures: Burger: Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Novartis: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; BeiGene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy. Kay: Agios Pharma: Other: data safety monitoring committee; Boehringer Ingelheim Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squibb: Research Funding; Celgene: Research Funding; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: data safety monitoring committee and advisory board; Acerta Pharma: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: data safety monitoring committee and advisory board; Behring: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Other: data safety monitoring committee; BeiGene: Membership on an entity's Board of Directors or advisory committees; BMS –Celgene: Other: data safety monitoring committee; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Vincerx: Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Allan: TG Therapeutics: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy, Speakers Bureau; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Epizyme: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Barr: Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Gilead: Consultancy; MEI Pharma: Consultancy; Janssen: Consultancy; Merck: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy; MorphoSys: Consultancy; Seagen: Consultancy; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy. Barrientos: Janssen: Honoraria; BeiGene: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy; MEI: Consultancy; Oncternal: Research Funding; Velosbio/Merck: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Owen: Janssen: Honoraria; Incyte: Honoraria; Gilead: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Merck: Honoraria; Roche: Honoraria. Huang: AbbVie: Consultancy, Current Employment, Research Funding; Everest Clinical Research: Consultancy, Current Employment, Research Funding. Neumayr: Pfizer: Research Funding; Forma Therapeutics: Other: travel, accomodations, expenses; ApoPharma: Consultancy; Novartis: Honoraria; AbbVie: Current Employment, Current holder of stock options in a privately-held company; Sancilio: Research Funding. Abbazio: AbbVie: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb: Current holder of stock options in a privately-held company. Krigsfeld: AbbVie: Current Employment, Current holder of stock options in a privately-held company, Other: travel, accommodations, expenses; BMS: Current Employment, Current holder of stock options in a privately-held company, Other: travel, accommodations, expenses; Pharmacyclics LLC, an AbbVie Company: Current Employment, Other: travel, accommodations, expenses; Moderna: Current holder of stock options in a privately-held company; Dynavax: Current holder of stock options in a privately-held company; Inovio: Current holder of stock options in a privately-held company. Mody: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Ghia: BeiGen: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Johnson&Johnson: Consultancy, Research Funding; Galapagos: Consultancy; Loxo@Lilly: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbvVie: Consultancy, Research Funding; MSD: Consultancy; Galapagos: Consultancy; Roche: Consultancy. Shanafelt: Genentech: Research Funding; Pharmacyclics LLC, an AbbVie company: Research Funding; AbbVie: Research Funding.

*signifies non-member of ASH