Initial performance of pirtobrutinib: Real-world outcomes among CLL patients after prior covalent-BTKi and BCL2i use

Abstract Background: Non-covalent Bruton's tyrosine kinase inhibitors (BTKi) are third-generation BTKis that utilize non-covalent bonding to improve efficacy and safety by reducing unintended binding and off-target effects. A medication from this drug class, pirtobrutinib was approved by the FDA for chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL) in December 2023. Since pirtobrutinib was only recently approved, knowledge of its long-term performance in the real-world is limited. This study aims to evaluate the initial real-world performance of pirtobrutinib compared to non-pirtobrutinib utilizers. Methods: The IntegraConnect PrecisionQ Database, which contains electronic health records from 3 million deidentified patients in the United States, was used to create a retrospective cohort of CLL/SLL patients who were eligible for pirtobrutinib. Eligible patients were 18 years or older, had a history of using at least one covalent BTKi and one B-cell lymphoma 2 inhibitor (BCL2i) and had a minimum of two clinic visits. Utilizing data from 12/1/2023 through 2/28/2025, patients were classified into pirtobrutinib utilizers and non-pirtobrutinib utilizers. Time to next treatment (TTNT; a surrogate for progression-free survival) was calculated for each patient group, a Kaplan Meier curve was generated, and a Cox proportional hazards model was fit to describe and compare TTNT between pirtobrutinib and non-pirtobrutinib utilizers. Results: Among the 135 patients who met eligibility criteria, 42 utilized pirtobrutinib (31%) and 93 did not utilize pirtobrutinib (69%). The median follow-up time for pirtobrutinib utilizers was 7.1 months, and the median follow-up time for non-pirtobrutinib utilizers was 11.1 months. The mean age at treatment was similar for the pirtobrutinib and non-pirtobrutinib groups: 71.9 (standard deviation [SD] 8.9) vs. 72.4 (SD 9.6) years. Gender (74% vs. 71% males, respectively) and racial composition (67% vs. 74% White, respectively) were also similar across the two groups. All patients received at least one covalent BTKi and a BCL2i. After identification, the non-pirtobrutinib patients (n=93) utilized a variety of different medications in their next line of therapy including 49 patients (52.7%) who used a covalent BTKi (BTKi-c), 21 patients (22.6%) who used a BCL2i, 12 patients (12.9%) who used chemotherapy, 9 patients (9.7%) who used a monoclonal antibody, and 2 patients (2.2%) who used a PI3K inhibitor. At 3 months, the estimated probability of continuing pirtobrutinib therapy was 100%, and the estimated probability of continuing non-pirtobrutinib therapy was 96%. At 6 months, the probability of continuing pirtobrutinib therapy was 96%, and the probability of continuing non-pirtobrutinib therapy was 77%. Using an adjusted Cox proportional hazards model with a 12-month follow-up period, patients receiving pirtobrutinib were less likely to change treatment compared to non-pirtobrutinib users adjusting for age at treatment, race, and gender [hazard ratio (HR) 0.19 (95% confidence interval (CI) 0.04, 0.79), p=0.02]. Conclusions: In our real-world analysis, we found that pirtobrutinib utilizers were less likely to change therapy compared to non-pirtobrutinib utilizers. Since pirtobrutinib is a relatively new treatment, we were only able to examine a small number of utilizers with limited follow-up. As time progresses, we will re-analyze our data to extend the follow-up period and increase the number of pirtobrutinib utilizers included in our analysis. Although further study is warranted, our initial findings suggest that for patients who have progressed through a covalent BTKi and a BCL2i, pirtobrutinib provided a helpful alternative to potentially delay further progression of CLL/SLL.