The noncovalent Bruton's tyrosine kinase (BTK) inhibitor pirtobrutinib achieved noninferiority to the covalent BTK inhibitor ibrutinib in terms of overall response rate in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to findings from a randomized phase III trial presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 683).
This study is the first head-to-head comparison of a noncovalent BTK inhibitor with a covalent BTK inhibitor.
“Pirtobrutinib was clearly noninferior to ibrutinib, and the response rate actually favors pirtobrutinib in the total cohort,” said lead study author Jennifer Woyach, MD, Bertha Bouroncle, MD, and Andrew Pereny Chair of Medicine at The Ohio State University College of Medicine. “This shows that pirtobrutinib is a reasonable choice in both the treatment-naive and relapsed/refractory settings.”
Study Methods and Patient Population
The phase III trial enrolled a total 662 patients with CLL or SLL who were randomly assigned to receive either 200-mg daily pirtobrutinib or 420-mg daily ibrutinib. The intention-to-treat population included 225 patients who were treatment naive and 437 patients with relapsed or refractory disease who were never exposed to a covalent BTK inhibitor before. Patients were stratified by del(17p) status and the number of prior lines of therapy received (0 vs 1 vs ≥ 2). Treatment continued in both arms until disease progression or the development of unacceptable toxicity.
The primary endpoint was noninferiority of overall response rate in both the intent-to-treat and relapsed/refractory populations. To achieve noninferiority, the overall response rate ratio noninferiority margins had to be 0.88 in the intent-to-treat population and 0.86 in the relapsed/refractory population. Progression-free survival was a secondary endpoint to assess superiority.
Key Findings
In the intent-to-treat population, the overall response rate was 87% (95% confidence interval [CI] = 82.9%–90.4%) with pirtobrutinib and 78.6% (95% CI = 73.7%–82.9%) with ibrutinib (overall response rate ratio = 1.11; 95% CI = 1.03–1.19; 2-sided P < .0001). In the relapsed/refractory population, the overall response rate with the noncovalent BTK inhibitor was 84.0% (95% CI = 78.5%–88.6) and 74.8% (95% CI = 68.5%–80.4%) with the covalent BTK inhibitor (overall response rate ratio = 1.12; 95% CI = 1.02–1.24; 2-sided P < .0001). Among treatment-naive patients, the overall response rate was 92.9% (95% CI = 86.4%–96.9%) with pirtobrutinib as compared with 85.8% (95% CI = 78.0%–91.7%) with ibrutinib.
Across subgroups, overall response rates consistently favored pirtobrutinib over ibrutinib in both the intent-to-treat and relapsed/refractory populations.
“While the efficacy and safety of pirtobrutinib have been very clearly established when given after a covalent BTK inhibitor, there are likely going to be subgroups of patients where pirtobrutinib is a more attractive option instead of the covalent BTK inhibitors,” said Dr. Woyach.
Progression-free survival data were not yet mature, but showed signs for favoring pirtobrutinib over ibrutinib in all populations: intent-to-treat (hazard ratio [HR] = 0.57; 95% CI = 0.39–0.83), relapsed/refractory (HR = 0.73; 95% CI = 0.47–1.13), and treatment naive (HR = 0.24; 95% CI = 0.10–0.59). At 18 months, the progression-free survival rates with pirtobrutinib vs ibrutinib were 86.9% (95% CI = 82.4%–90.3%) vs 82.3% (95% CI = 77.3%–86.3%) in the intent-to-treat population, 81.7% (95% CI = 75.1%–86.7%) vs 79.2% (95% CI = 72.3%–84.6%) in the relapsed/refractory patients, and 95.3% (95% CI = 89.1%–98.0%) vs 87.6% (95% CI = 79.7%–92.6%) in the treatment-naive patients, respectively.
“The [progression-free survival] is still a little bit immature at this point, but trends toward favoring pirtobrutinib in all of the groups—in the total cohort, in the relapsed/refractory group, and, importantly, in the treatment-naive cohort,” said Dr. Woyach. “That’s really important, because given the safety of pirtobrutinib, it suggests that this might be a good option in the future for some patients with front-line CLL/SLL.”
No detriment was observed in overall survival in the intent-to-treat population (HR = 0.961; 95% CI = 0.55–1.69).
The most common treatment-emergent adverse events were similar across the treatment arms. Atrial fibrillation/flutter was observed in 2.4% of patients in the pirtobrutinib arm and in 13.5% of patients in the ibrutinib arm, and hypertension was observed in 10.6% and 15.1% of patients, respectively.
Adverse event–related dose reductions were required in 7.9% of patients receiving the noncovalent BTK inhibitor and in 18.2% of patients receiving the covalent BTK inhibitor, and treatment discontinuation due to progressive disease was reported in 4.5% and 10.9% of patients, respectively. Rates of treatment discontinuation due to adverse events were similar between the two arms (7.9% with pirtobrutinib vs 7.3% with ibrutinib).
Treatment is ongoing in 81.3% of patients in the pirtobrutinib arm and in 69.5% of patients in the ibrutinib arm.
Disclosure: This study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit hematology.org.
