Treatment Outcomes of Patients Treated with Venetoclax-Obinutuzumab Therapy Vs Btki Therapies in 1L CLL: An International Real-World Study
Authors: Lamanna Nicole , Brown Jennifer R. , Ujjani Chaitra S. , Eyre Toby A. , Manzoor Beenish , Ghosh Nilanjan , Roeker Lindsey , Davids Matthew S. , Coombs Catherine C , Skarbnik Alan P , Hill Brian T. , Tuncer Hande H. , Leslie Lori A. , Rhodes Joanna M. , Fleury Isabelle , Barr Paul M , Emechebe Nnadozie , Martinez-Calle Nicolas , Jensen Christopher E. , Choi Yun , Jawaid Dureshahwar , Pearson Laurie K , Thompson Meghan C. , Marx Steven E , Sinai Wendy J. , Lansigan Frederick , Fakhri Bita , Stephens Deborah M. , Schuster Stephen J. , Coyle Michael , Pivneva Irina , Watson Talissa , Guerin Annie , Shadman Mazyar 
Published: December 2024

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 &gt;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: &lt;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.