An indirect comparison of pirtobrutinib with second-generation covalent Bruton tyrosine kinase inhibitors in BTKi naive, and relapsed-refractory chronic lymphocytic leukemia: results of a network meta-analysis.

While pirtobrutinib is established in Bruton tyrosine kinase inhibitor (BTKi)-refractory disease, its role in BTKi-naïve relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) remains unclear because of the absence of direct comparative trials with second-generation covalent BTKis. We conducted a systematic literature review and Bayesian network meta-analysis of randomized controlled trials (ELEVATE-RR, ALPINE, BRUIN-CLL-314) linked by a common comparator (ibrutinib). Across 814 patients, pirtobrutinib demonstrated efficacy comparable to acalabrutinib and zanubrutinib, with no significant differences in progression-free survival (PFS) (vs acalabrutinib: HR 0.73, 95% CrI 0.44-1.20 vs zanubrutinib: HR 1.12, 95% CrI 0.67-1.89), overall survival (OS), or overall response rate (ORR). Subgroup analyses by genomic risk were inconclusive. Safety profiles were broadly similar; however, pirtobrutinib was associated with a lower risk of cardiovascular adverse events compared with zanubrutinib (OR 0.52, 95% CrI 0.31-0.88) and similar risk relative to acalabrutinib (OR 1.09, 95% CrI 0.62-1.92). In conclusion, pirtobrutinib demonstrated efficacy and tolerability comparable to those of second-generation covalent BTKis, with a potential cardiovascular safety advantage over zanubrutinib in patients with R/R BTKi-naive CLL. However, given the indirect nature of the comparison, the limited evidence base, and between-study heterogeneity, these findings should be considered exploratory.