Researchers have found that the noncovalent Bruton's tyrosine kinase inhibitor (BTK) pirtobrutinib may offer superior progression-free survival in adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to recent findings presented by Sharman et al at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 886).
Background
Pirtobrutinib is approved under the U.S. Food and Drug Administration's Accelerated Approval pathway for the treatment of adults with CLL or SLL who have received at least two prior lines of therapy—including a BTK inhibitor and a BCL2 inhibitor—and adults with relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a BTK inhibitor. These indications are approved under accelerated approval based on response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Study Methods and Results
In the recent phase III BRUIN CLL-321 trial, the researchers assigned 238 patients with CLL or SLL who were previously treated with a covalent BTK inhibitor to receive either pirtobrutinib monotherapy (n = 119) or investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab (n = 119).
The patients in all three groups received a median of three prior lines of therapy, and all of them received at least one prior covalent BTK inhibitor. Approximately 50% of the patients had also received a venetoclax-containing regimen. Reflective of the poor prognosis of patients enrolled in this study, a high proportion of them presented with high-risk features indicative of aggressive disease—including a TP53 mutation and/or 17p deletion, unmutated IGHV status, and complex karyotype. Crossover to the pirtobrutinib group was permitted following independent review committee–confirmed disease progression.
The study’s primary endpoint of progression-free survival was met at primary analysis. Based on independent review committee assessment, pirtobrutinib was found to be superior to investigator’s choice. The researchers demonstrated consistent improvement in progression-free survival in patients who received pirtobrutinib—with a 46% reduction in the risk of relapse, disease, or mortality compared with idelalisib plus rituximab or bendamustine plus rituximab.
After a median follow-up of approximately 19 months, median progression-free survival was 14 months among the patients in the pirtobrutinib group compared with 8.7 months among those in the control group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.39–0.75). Progression-free survival results were consistent across key subgroups associated with a poor prognosis, including patients who received prior venetoclax and those with TP53 mutations and/or 17p deletions, unmutated IGHV status, and complex karyotype.
Pirtobrutinib also demonstrated clinically meaningful improvements in other secondary endpoints such as investigator-assessed progression-free survival (median progression-free survival = 15.3 vs 9.2 months, HR = 0.48, 95% CI = 0.34–0.67), event-free survival (median event-free survival = 14.1 vs 7.6 months, HR = 0.39, 95% CI = 0.28–0.53), and time to next treatment or death (median time to next treatment = 23.9 vs 10.9 months, HR = 0.37, 95% CI = 0.25–0.52). Specifically, among patients in the control group who were eligible for crossover, 76% (n = 50/66) crossed over to receive pirtobrutinib. Multiple analyses adjusting for the effect of crossover demonstrated trends in favor of pirtobrutinib (inverse probability censored weighting methodology: HR = 0.89, 95% CI = 0.52–1.53; two-stage accelerated failure time methodology: HR = 0.77, 95% CI = 0.45–1.26).
The overall safety profile among patients treated with pirtobrutinib was consistent with safety data from the phase I/II BRUIN study, including adverse events of special interest. In the phase III study, pirtobrutinib treatment was associated with fewer grade 3 or higher treatment-emergent adverse events and fewer treatment discontinuations caused by adverse events compared with idelalisib plus rituximab or bendamustine plus rituximab. When the investigators adjusted for exposure, the incidence rate of treatment-emergent adverse events was overall lower in patients receiving pirtobrutinib compared with those who received idelalisib plus rituximab or bendamustine plus rituximab.
Conclusions
“These results demonstrate the ability of pirtobrutinib to deliver clinically meaningful outcomes in a postcovalent BTK inhibitor setting, which is especially remarkable given the poor prognosis for the patient population enrolled in BRUIN CLL-321,” emphasized lead study author Jeff Sharman, MD, Disease Chair of the Lymphoma Research Executive Committee at the Sarah Cannon Research Institute at the Willamette Valley Cancer Institute and Research Center. “These data also show that pirtobrutinib can significantly prolong the time to next treatment, with a median of approximately 2 years. Coupled with the safety results, the BRUIN CLL-321 data are important as we consider treatment sequencing for this setting,” he continued.
Disclosure: For full disclosures of the study authors, visit ash.confex.com.
