2012 - Matching-Adjusted Indirect Comparison of Pirtobrutinib vs Venetoclax Continuous Monotherapy in Patients with Relapsed/Refractory CLL Previously Treated with a Covalent BTK Inhibitor

Background:
Venetoclax-based therapy is a standard option for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) previously treated with a covalent BTK inhibitor (cBTKi). However, nearly all prospective data on venetoclax efficacy in the post-cBTKi setting were generated from a subgroup analysis within a single-arm study of venetoclax administered as continuous monotherapy. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and restore BTK inhibition. Pirtobrutinib has demonstrated marked efficacy and a favorable safety profile in patients with CLL previously treated with a cBTKi.

Aims:
This unanchored MAIC was designed to estimate the treatment effect of pirtobrutinib (BRUIN, NCT03740529) versus venetoclax continuous monotherapy (NCT02141282) in patients with R/R CLL previously treated with a cBTKi.

Methods:
Data from patients with R/R CLL previously treated with at least one cBTKi and without prior venetoclax exposure who received pirtobrutinib were analyzed (n=146). Only one prospective trial of venetoclax (administered as a continuous monotherapy) for patients previously treated with a cBTKi (n=91) was identified (Jones et al., 2018). 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. Patient 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). 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
After adjustment, the median age in the pirtobrutinib and venetoclax cohorts was 66.5 and 66.0 years, respectively; all other prognostic factors were similarly 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; Figure). 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.

Summary/Conclusions
The efficacy of pirtobrutinib was comparable to continuously administered venetoclax monotherapy in patients with R/R CLL previously treated with a cBTKi. Pirtobrutinib was associated with improved ORR and favorable overall safety profile for most TEAEs compared to 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.
Multiple randomized Phase 3 studies of pirtobrutinib in patients with CLL remain ongoing.