Matching-adjusted indirect comparison of pirtobrutinib vs. venetoclax continuous monotherapy in patients with relapsed/refractory CLL previously treated with a covalent BTK inhibitor

Introduction: Venetoclax-based therapy is standard for pts with relapsed/refractory (R/R) CLL previously treated with a covalent BTK inhibitor (cBTKi). Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi designed to overcome pharmacologic limitations of cBTKi and restore BTK inhibition and has demonstrated marked efficacy and a favorable safety profile. This unanchored MAIC estimates the treatment effect of pirtobrutinib (BRUIN) vs venetoclax continuous monotherapy in pts with R/R CLL treated with a cBTKi. Methods: Data from pts with R/R CLL previously treated with at least 1 cBTKi and without prior venetoclax exposure who received pirtobrutinib were analyzed (n = 146). Only 1 prospective trial of venetoclax (administered as a continuous monotherapy) for pts previously treated with a cBTKi (n = 91) was identified. Progression-free survival (PFS), overall survival (OS), investigator-assessed overall response rate (ORR), and grade ≥3 treatment-emergent adverse events (TEAEs) regardless of attribution were evaluated. Pt-level data from pirtobrutinib cohort were re-weighted to match the venetoclax cohort using method of moments, adjusting for well-established prognostic factors reported in both studies (age, IGHV mutation status, TP53 aberrancy, del(17p), del(11q); number of prior lines of therapy, reason for cBTKi discontinuation). Kaplan-Meier PFS and OS curves from the venetoclax trial were digitized (using WebPlotDigitizer) for time-to-event analyses. Fishers exact test was used to compare proportional outcomes (ORR, TEAEs); time-to-event outcomes (PFS, OS) were compared using Cox regression model and log-rank test. Results: The median age in pirtobrutinib and venetoclax cohorts was 66.5 and 66.0 years; all other prognostic factors were well matched; median follow-up was 21.3 months and 14 months. PFS and OS were comparable with no significant differences noted for pirtobrutinib versus venetoclax (p > .05; Figure). ORR was 80% for pirtobrutinib (inclusive of PR-L) versus 65% for venetoclax (p = .01). Grade ≥3 TEAEs indicated febrile neutropenia, neutropenia, anemia, and thrombocytopenia were significantly lower for pirtobrutinib vs venetoclax in adjusted analyses (all p < .01). No differences were observed for pneumonia (p=.06) or discontinuation due to TEAEs (3% vs 7%, p = .32). Unadjusted results were consistent with the adjusted analyses. Conclusions: Pirtobrutinib efficacy was comparable to venetoclax in pts with R/R CLL previously treated with cBTKi. Pirtobrutinib was associated with improved ORR and favorable overall safety profile for TEAEs vs venetoclax, raising questions on optimal treatment sequencing of pirtobrutinib and venetoclax in cBTKi-treated CLL, but lack of prospective direct comparisons and limited long-term follow-up preclude definitive conclusions. Encore Abstract—previously submitted to EHA 2023 The research was funded by: Eli Lilly and Company Keyword: chronic lymphocytic leukemia (CLL) Conflicts of interests pertinent to the abstract T. A. Eyre Consultant or advisory role Roche, AstraZeneca, KITE Gilead, Loxo Oncology, Beigene, Incyte, Abbvie, Janssen, Secura Bio Honoraria: Roche, AstraZeneca, KITE Gilead, Loxo Oncology, Beigene, Incyte, Abbvie, Janssen Research funding: Astrazeneca, Beigene Other remuneration: Roche, AstraZeneca, Janssen, Abbive O. Al-Sawaf Consultant or advisory role AbbVie, Ascentage, AstraZeneca, BeiGene, Gilead, Janssen, Roche Honoraria: AbbVie, Adaptive, AstraZeneca, BeiGene, Gilead, Janssen, Lilly, Roche Other remuneration: AbbVie, BeiGene, Janssen, Roche, AstraZeneca, Gilead M. Jen Employment or leadership position: Eli Lilly and Company Stock ownership: Eli Lilly and Company L. M. Hess Employment or leadership position: Eli Lilly and Company Stock ownership: Eli Lilly and Company B. Goebel Employment or leadership position: Eli Lilly and Company Stock ownership: Eli Lilly and Company J. M. Pagel Employment or leadership position: [email protected] Stock ownership: [email protected]