Pirtobrutinib Monotherapy for First-Line Chronic Lymphocytic Leukemia: A Non-Anchored Indirect Comparison Using Reconstructed Patient-Level Data

Background: Pirtobrutinib has recently emerged as a promising first-line treatment option for chronic lymphocytic leukemia (CLL). Unlike currently established regimens, which are generally based on doublet combinations, pirtobrutinib can be administered as monotherapy. No head-to-head trials comparing pirtobrutinib with contemporary first-line combinations are currently available; hence, indirect comparative evidence may help define its potential role. Methods: A non-anchored indirect comparison based on reconstructed individual patient data (IPD) was conducted using published Kaplan–Meier curves from randomized controlled trials evaluating first-line treatments for CLL. Progression-free survival (PFS) was the endpoint of interest. Reconstructed IPD were generated using WebPlotDigitizer and the IPDfromKM algorithm. Then, Kaplan–Meier curves were plotted based on these patients, and the values of the restricted mean survival time (RMST) at 36 months were determined. Regarding PFS, pirtobrutinib monotherapy was compared indirectly with acalabrutinib plus obinutuzumab, venetoclax plus obinutuzumab, and venetoclax plus ibrutinib. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using univariate Cox models. The non-inferiority of pirtobrutinib monotherapy versus doublet regimens was assessed according to a non-inferiority margin set at HR = 1.15. Finally, the value-based prices of the new treatments were estimated based on a willingness-to-pay threshold of euro 30,000 per disease-free year gained and compared with the corresponding real prices in the Italian market. Results: The analysis included four randomized trials. Compared with pirtobrutinib monotherapy, HRs for PFS were 0.5544 (95%CI, 0.2696–1.1397) versus venetoclax plus obinutuzumab, 0.4583 (95%CI, 0.2066–1.0200) versus venetoclax plus ibrutinib, and 1.4453 (95%CI, 0.6684–3.1240) versus acalabrutinib plus obinutuzumab. Pirtobrutinib met the non-inferiority criterion compared with venetoclax plus obinutuzumab and venetoclax plus ibrutinib, but not with acalabrutinib plus obinutuzumab; however, these results were negatively affected by the small number of events in the pirtobrutinib arm, which generated wide CIs. In the preliminary pharmacoeconomic analysis, venetoclax plus obinutuzumab showed the most favorable profile in the comparison of value-based price vs. real price. Conclusions: This exploratory non-anchored analysis suggests that pirtobrutinib monotherapy may provide PFS outcomes broadly comparable to current first-line combination regimens for CLL. Given the methodological limitations inherent to indirect comparisons, prospective head-to-head studies are needed to clarify the optimal positioning of pirtobrutinib in treatment-naïve CLL.