Treatment Outcomes of Patients Treated with Venetoclax-Obinutuzumab Therapy Vs Btki Therapies in 1L CLL: An International Real-World Study

Introduction: Venetoclax + obinutuzumab (VO) and Bruton tyrosine kinase inhibitor (BTKi) therapies used in the first line (1L) setting are highly effective for patients (pts) with chronic/small lymphocytic leukemia (CLL/SLL) but there are no reported comparative studies. This study compared real-world clinical outcomes of pts treated with VO vs BTKi therapy in 1L.

Methods: Data from the CLL Collaborative Study of Real-World Evidence (CORE), an international, retrospective, multi-center chart review study (25 centers) were used. Adult pts who initiated approved 1L treatments of VO (VO cohort) or covalent BTKi (cBTKi cohort) therapy in 1L between 2019-2024 were included. Cohorts were balanced using entropy balancing on sex, age at 1L, year of 1L start, ECOG performance status, Rai stage, del(17p)/TP53 mutation, and comorbidities. Among pts with known mutation status, proportion of pts with unmutated IGHV was similar across cohorts; hence it was not included (VO: 54.8%; cBTKi: 57.6%). Weighted outcomes included overall response rate (ORR: proportion of pts with physician-reported clinical complete/partial response [CR/PR] out of pts with available response data), progression-free-survival (PFS: time from initiation of therapy to disease progression/death [event] or last follow-up [censor]), and time to next treatment or death (TTNT-D: time from initiation of therapy to the change of therapy (including cBTKi to cBTKi)/death [event] or last follow-up [censor]). Time-to-event data were assessed using Kaplan-Meier methods and Cox proportional hazards model at 12 and 18 months (mos). Given >20% of pts were still at risk 18-mos after 1L initiation, results for 18-mos rates were reported.

Results: Of 2,309 total pts, 110 initiated VO and 242 a cBTKi (ibrutinib: 111 [45.9%], acalabrutinib: 102 [42.1%], zanubrutinib: 15 [6.2%], cBTKi+anti-CD20: 14 [5.8%]) in 1L. Before weighting, the VO cohort was younger at 1L initiation (median years VO: 64.5; cBTKi: 67.9) and median time to 1L start post-diagnosis was longer (39.1 vs 25.1 mos). The VO cohort had higher proportion of pts with ECOG 0-2 (among those with known ECOG: 99.0% vs 98.9%), lower proportion with del(17p)/TP53 mutation (6.7% vs 17.1%), and lower median number of comorbidities (1 vs 2). Common comorbidities for both cohorts included cardiovascular (43.6% vs 52.1%) and endocrine/metabolic conditions (20.9% vs 36.8%). Pt and treatment characteristics were well-matched between cohorts after weighting.

After weighting, with a median follow-up of 10.2 mos (IQR: 5.6, 17.9) for the VO cohort and 10.7 mos (IQR: 4.9, 25.5) for the cBTKi cohort, median duration of treatment was 9.5 [IQR: 5.4, 17.3] vs 12.1 [IQR: 4.9, 18.3] mos, respectively; majority of pts were still on therapy at the time of analyses (63.6% vs 74.7%) but fewer pts in the VO cohort initiated a subsequent line of therapy (2.7% vs 18.8%). Among the 58 pts in the cBTKi cohort who sequenced to another therapy, largely due to intolerance (66.7%), 41.9% switched to another cBTKi (36.2% to acalabrutinib) and 58.1% to a different regimen (i.e., venetoclax-based: 45.7%; other: 12.4%). Only 3 pts in the VO cohort started another therapy (2 due to intolerance).

The ORR was descriptively higher for the VO cohort (ORR: 89.2% [CR: 58.1%; PR: 31.1%], available response data for 67.3%) relative to the cBTKi cohort (ORR: 80.7% [CR: 8.8%; PR: 71.9%], available response data for 63.0%).

The median PFS was not reached, however the 18-mos rate was trending higher for the VO cohort (92.2% vs 84.3%). Based on the Cox model, there was no statistically significant difference in PFS at 18-mos for the cBTKi cohort compared to the VO cohort (hazard ratio [HR]: 2.37 (confidence interval [CI]: 0.76, 7.44; p-value: 0.14).

The median TTNT-D was not reached, however the 18-mos rate was higher for the VO cohort (89.4% vs 70.2%). Based on the Cox model, the cBTKi cohort had a statistically significant greater risk of sequencing to the next treatment/death at 18-mos compared to the VO-based cohort (HR: 3.27 (CI: 1.35, 7.94; p-value: <0.01).

Conclusions: This study is one of the first to demonstrate advantages in clinical outcomes of pts using VO vs cBTKi therapy in 1L for TTNT-D. Considering that 19% of BTKi pts switched therapy, largely due to intolerance, this highlights the need for future studies to assess VO vs 2nd-generation BTKis in the 1L setting with longer follow-up time and larger cohorts.

Lamanna:Abbvie, BeiGene, EliLilly/Loxo, Genmab, Janssen, Pharmacyclics, Gilead, AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, AstraZeneca, Eli Lilly/Loxo, Genentech, Genmab, Bei-Gene, MingSight, Oncternal, Octapharma: Research Funding. Brown:Acerta/AstraZeneca: Consultancy; Alloplex Biotherapeutics: Consultancy; Gilead: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Numab Therapeutics: Consultancy; MEI Pharma: Consultancy, Research Funding; Loxo/Lilly: Consultancy, Research Funding; Kite: Consultancy; Janssen: Consultancy; iOnctura: Consultancy, Research Funding; Hutchmed: Consultancy; Grifols Worldwide Operations: Consultancy; Genentech/Roche: Consultancy; BeiGene: Consultancy, Research Funding; Galapagos NV: Consultancy; InnoCare Pharma Inc: Consultancy; Merck: Consultancy. Ujjani:AbbVie, Astrazeneca, Lilly, PCYC: Research Funding; Abbvie, Astrazeneca, Beigene, Genentech, Jansen, Lilly, Pharmacyclics: Honoraria. Eyre:Roche, Gilead, KITE, Takeda, Janssen, Abbvie, AstraZeneca, Loxo Oncology, Beigene, Incyte, Autolus, Galapagos, Medscape, PeerView, Clinical Care Options, The Limbic: Honoraria; Roche, Gilead, KITE, Janssen, Abbvie, AstraZeneca, Loxo Oncology, Beigene: Speakers Bureau; AbbVie: Honoraria, Other: Travel to scientific conferences; AstraZeneca: Honoraria, Research Funding; KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene, AstraZeneca: Research Funding; Loxo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Trial steering committee; Janssen: Honoraria; Roche, Gilead, KITE, Janssen, Abbvie, AstraZeneca, Loxo Oncology, Beigene, Incyte, Autolus, Galapagos: Consultancy; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Other: Travel to scientific conferences, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Secura Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees. Manzoor:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Ghosh:TG Therapeutics, Genentech/Roche, Bristol Myers Squibb, Gilead, Morphosys, AbbVie: Research Funding; Seagen, TG Therapeutics, AstraZeneca, Pharmacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Beigene, Incyte, Karyopharm, Roche/Genentech, Novartis, Loxo Oncology, Genmab, Adaptive Biotech, ADC Therapeutics and Syncopation: Consultancy; Roche/Genentech, AbbVie, BMS: Research Funding; AstraZeneca, Pharmacyclics, Janssen, BMS, Kite Pharma, BeiGene, Incyte, Lava Therapeutics, Roche/Genentech, Novartis, Loxo Oncology, AbbVie, Genmab, Prepromene, and ADC Therapeutics, Ascentage and Ipsen.: Honoraria; AstraZeneca, Pharmacyclics, Janssen, BMS, Gilead Sciences, Kite Pharma, BeiGene, Incyte, Lava Therapeutics, Roche/Genentech, Novartis, Loxo Oncology, AbbVie, Genmab, Adaptive Biotech, Prepromene, Ascentage and Ipsen: Consultancy. Roeker:Ascentage: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Dava Oncology: Honoraria, Speakers Bureau; Dren Bio: Research Funding; Genentech: Research Funding; Janssen: Consultancy; Loxo Oncology: Consultancy, Other: Travel support, Research Funding; Medscape: Honoraria, Speakers Bureau; PeerView: Honoraria, Speakers Bureau; Pfizer: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Qilu Puget Sound Biotherapeutics: Research Funding; Curio: Honoraria, Speakers Bureau; TG Therapeutics: Consultancy; Aptose Biosciences: Research Funding; Adaptive Biotechnologies: Research Funding; AbbVie: Consultancy, Research Funding; Abbott Laboratories: Current equity holder in publicly-traded company. Davids:Ascentage Pharma: Consultancy, Research Funding; Novartis: Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biosciences: Consultancy; Genmab: Consultancy; MEI Pharma: Research Funding; BeiGene: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy, Research Funding; Surface Technology: Research Funding; Eli Lilly: Consultancy; BMS: Consultancy; Merck: Consultancy; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Coombs:AbbVie, Allogene, AstraZeneca, Beigene, Genentech, Janssen, LOXO/Lilly, MEI Pharma, Mingsight, Octapharma, TG Therapeutics, have served on speaker's bureaus for AbbVie, AstraZeneca, Beigene, Genentech, Lilly: Consultancy, Honoraria; Bluebird Bio, Geron, Pfizer: Current equity holder in publicly-traded company; AbbVie, AstraZeneca, Beigene, Genentech, Lilly: Speakers Bureau; AbbVie, AstraZeneca, CarnaBio, LOXO/Lilly: Research Funding. Skarbnik:Beigene: Honoraria, Speakers Bureau; Lilly: Consultancy, Honoraria, Speakers Bureau; Kite: Consultancy, Honoraria, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; SeaGen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Verastem: Honoraria, Research Funding; Acerta Pharma: Research Funding; Novartis: Honoraria; Gilead Sciences: Honoraria. Hill:AstraZeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tuncer:AbbVie: Consultancy; Eli Lilly/LOXO: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Leslie:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Lily: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Consultancy, Speakers Bureau; Astrazeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche/Genenetech: Consultancy, Speakers Bureau; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Evolveimmune: Consultancy; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seagen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy; Karyopharm: Consultancy. Rhodes:ADC Therapeutics: Consultancy; AbbVie: Consultancy, Research Funding; VelosBio: Research Funding; Johnson and Johnson: Consultancy; Oncternal Therapeutics: Research Funding; Loxo Oncology: Research Funding; Janssen: Research Funding; Epizyme: Consultancy; Beigene: Consultancy; MorphoSys: Consultancy; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy; Verastem: Consultancy; Acerta: Research Funding; Seagen: Consultancy; Genentech: Consultancy. Fleury:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Barr:Merck: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; MorphoSys: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Seagen: Consultancy. Emechebe:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Martinez-Calle:Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Travel support, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau. Jensen:Abbvie: Consultancy, Research Funding. Jawaid:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Thompson:Loxo Oncology at Lilly: Consultancy; AbbVie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Clinical Care Options: Honoraria; Genentech: Research Funding; AstraZeneca: Consultancy, Research Funding; Pharmacyclics/Janssen Pharmaceuticals: Consultancy; Mashup Media LLC: Honoraria, Other: Reimbursed Travel; Genmab: Other: Reimbursed travel, Research Funding; Nurix Therapeutics: Other: Reimbursed travel, Research Funding; Dava Oncology: Honoraria, Other: Reimbursed travel; Peerview Institute for Medical Education: Honoraria. Marx:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Sinai:AbbVie: Current Employment, Current equity holder in publicly-traded company. Fakhri:Loxo/Lilly: Research Funding; AbbVie/Genmab, Loxo-Lilly, BMS, Angiocrine: Research Funding; AbbVie, ADC therapeutics, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Genmab, Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stephens:AstraZeneca, Beigene, Novartis: Research Funding; Abbvie, AstraZeneca, Beigene, BMS, Celegene, Eli Lilly, Genentech, Janssen, Pharmacyclics: Consultancy. Schuster:Caribou Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; BeiGene: Consultancy, Honoraria; viTToria biotherapeutics: Consultancy; Nordic Nanovector: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genmab: Consultancy; Kite Pharmaceuticals: Consultancy; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Legend Biotech: Consultancy, Honoraria; Celgene/Juno Therapeutics: Consultancy, Honoraria, Research Funding; BioNTech: Consultancy; Genentech/Roche: Consultancy, Honoraria, Research Funding. Pivneva:Analysis Group, Inc.: Current Employment, Other: Analysis Group, Inc., has received consultancy fees from AbbVie. Watson:Analysis Group, Inc.: Current Employment, Other: Analysis Group, Inc., has received consultancy fees from AbbVie. Guerin:Analysis Group: Other: Annie Guerin is an employee of Analysis Group, Inc. (AG), an economic consulting firm. AG receives consulting fees from pharmaceutical companies and other ineligible companies, including Novartis. Shadman:AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeiGene, BMS, MorphoSys/Incyte, Kite, Eli Lilly, Genmab, Mustang Bio, Regeneron, ADC therapeutics, Fate Therapeutics, Janssen and MEI Pharma: Consultancy; Mustang Bio, BMS, Pharmacyclics, Genentech, AbbVie, TG Therapeutics, BeiGene, AstraZeneca, Genmab, MorphoSys/Incyte, Vincerx: Research Funding.