Venetoclax-based therapy is a standard option for pts with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) previously treated with a covalent BTK inhibitor (cBTKi). Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi designed to overcome the pharmacologic limitations of cBTKi and restore BTK inhibition. Pirtobrutinib has demonstrated marked efficacy and a favorable safety profile. This unanchored MAIC was designed to estimate the treatment effect of pirtobrutinib (BRUIN, NCT03740529) vs venetoclax continuous monotherapy (NCT02141282) in pts with R/R CLL previously treated with a cBTKi.

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 the pirtobrutinib cohort were re-weighted to match the venetoclax cohort using method of moments approach, 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, and reason for prior cBTKi discontinuation). KaplanMeier 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.

The median age in pirtobrutinib and venetoclax cohorts was 66.5 and 66.0 years; all other prognostic factors were well matched in both cohorts. Median follow-up was 21.3 months and 14 months for the pirtobrutinib and venetoclax cohorts, respectively. PFS and OS were comparable with no significant differences noted for pirtobrutinib versus venetoclax (both p > 0.05). ORR was 80% for pirtobrutinib (inclusive of PR-L) vs 65% for venetoclax (p = 0.01). Grade ≥3 TEAEs reported in both trials indicated that febrile neutropenia, neutropenia, anemia, and thrombocytopenia were significantly lower for pirtobrutinib vs venetoclax in adjusted analyses (all p < 0.01). No differences were observed for pneumonia (p = 0.06) or for discontinuation due to TEAEs (3% vs 7%, p = 0.32) in adjusted analyses. Unadjusted results were consistent with the adjusted analyses.

The efficacy of pirtobrutinib was comparable to continuously administered venetoclax monotherapy in pts with R/R CLL previously treated with a cBTKi. Pirtobrutinib was associated with improved ORR and favorable overall safety profile for most TEAEs vs venetoclax. This study raises questions regarding optimal treatment sequencing of pirtobrutinib and venetoclax in cBTKi-treated CLL, but the lack of prospective direct comparisons and limited long-term follow-up preclude definitive conclusions. Randomized Phase 3 studies of pirtobrutinib in pts with CLL are ongoing. Previously presented at EHA 2023.