The phase 1/2 BRUIN trial has demonstrated that pirtobrutinib (Jaypirca), a novel noncovalent Bruton tyrosine kinase (BTK) inhibitor, provides significant clinical benefit for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) who have previously failed covalent BTK inhibitor therapy.
Results published in the New England Journal of Medicine showed an overall response rate (ORR) of 73.3% (95% CI, 67.3%-78.7%) among 247 patients previously treated with covalent BTK inhibitors. At a median follow-up of 19.4 months, the median progression-free survival (PFS) reached 19.6 months (95% CI, 16.9-22.1).
"Patients with relapsed or refractory CLL or SLL following treatment with a covalent BTK inhibitor represent a population with limited treatment options," said Dr. Jennifer A. Woyach, professor and hematologist-oncologist at The Ohio State University Comprehensive Cancer Center, and co-lead author of the study. "These data support the potential for pirtobrutinib to extend the benefit of BTK inhibition for patients with CLL or SLL with a once-daily oral therapy."
Addressing a Critical Treatment Gap
The BRUIN trial (NCT03740529) enrolled 773 patients with B-cell cancers across 49 sites in 10 countries, including 317 with relapsed or refractory CLL/SLL. Of these, 247 had received prior BTK inhibitor therapy, primarily ibrutinib (87.4%), with others having received acalabrutinib, zanubrutinib, or other BTK inhibitors.
Most patients (76.9%) had discontinued previous BTK inhibitor therapy due to disease progression, while 23.1% stopped due to toxicity. The study population was heavily pretreated, with a median of 3 prior lines of therapy (range 1-11), and many patients exhibited high-risk features including deletion 17p, TP53 mutation, complex karyotype, or unmutated IGHV.
Pirtobrutinib's mechanism of action differentiates it from covalent BTK inhibitors like ibrutinib, acalabrutinib, and zanubrutinib. As a selective, noncovalent BTK inhibitor, pirtobrutinib remains effective against both wild-type and C481-mutant BTK, addressing a key resistance mechanism that limits sequential use of covalent BTK inhibitors.
Efficacy Across Subgroups
The trial demonstrated consistent efficacy across most predefined subgroups. Among the 247 patients previously treated with BTK inhibitors, researchers observed 4 complete responses (1.6%), 1 nodular partial response (0.4%), and 176 partial responses (71.3%). When including partial response with lymphocytosis, the ORR increased to 82.2% (95% CI, 76.8%-86.7%).
In the subset of 100 patients who had received both BTK inhibitor and BCL2 inhibitor therapy (such as venetoclax), the ORR was 70.0%, rising to 79.0% when including partial response with lymphocytosis. These patients achieved a median PFS of 16.8 months (95% CI, 13.2-18.7).
For patients who had received BTK inhibitor therapy but not BCL2 inhibitor therapy, the median PFS was 22.1 months (95% CI, 19.6-27.4). Even in the most heavily pretreated patients who had received all five classes of available CLL/SLL therapy (BTK inhibitors, BCL2 inhibitors, PI3K inhibitors, chemotherapy, and anti-CD20 antibodies), the median PFS was 13.8 months.
Notably, 96.9% of evaluable patients experienced a decrease in target lesion size, regardless of the reason for previous treatment discontinuation.
Safety Profile
The safety analysis included all 317 patients with CLL/SLL who received at least one dose of pirtobrutinib, with 277 receiving the recommended phase 2 dose of 200 mg daily. The median treatment duration was 16.5 months.
The most common adverse events were infection (71.0%), bleeding (42.6%), and neutropenia (32.5%). Grade 3 or higher infections occurred in 28.1% of patients, and grade 3 or higher neutropenia was reported in 26.8%. Treatment-related grade 3 or higher neutropenia occurred in 14.8% of patients.
Despite these adverse events, only 4.7% of patients required dose reductions due to treatment-related adverse events, and just 2.8% discontinued pirtobrutinib treatment. This favorable tolerability profile suggests pirtobrutinib may be suitable for long-term administration in this patient population.
Sixteen patients died for reasons other than disease progression, including eight due to COVID-19, two due to pneumonia or fungal pneumonia, two due to septic shock or shock, and four from other causes.
Survival Outcomes
At a median follow-up of 22.6 months, the 12-month overall survival rate was 86.0% (95% CI, 81.0%-89.8%), and the 18-month overall survival rate was 80.5% (95% CI, 74.8%-85.0%).
"We are pleased to have the detailed safety and efficacy results of pirtobrutinib in adults with CLL or SLL published in NEJM and shared with the broader medical community," said Dr. David Hyman, chief medical officer of Loxo@Lilly, the oncology unit of Eli Lilly and Company. "Treating clinicians have expressed the desire to fully exhaust BTK inhibition prior to switching their patients to another therapy class. These data continue to reinforce pirtobrutinib's ability to help reestablish BTK inhibition following treatment with a covalent BTK inhibitor."
Future Directions
Pirtobrutinib is currently approved for use in mantle cell lymphoma based on its efficacy in those patients in the BRUIN trial. The drug is now under investigation in several ongoing clinical trials, including four phase 3 randomized trials evaluating its use in patients with CLL/SLL.
Dr. Anthony R. Mato, a hematologic oncologist and director of the CLL Program at Memorial Sloan Kettering Cancer Center, and co-investigators concluded, "Pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had had disease progression during previous treatment with a covalent BTK inhibitor. These findings indicate that reestablishing BTK inhibition with pirtobrutinib is a potential therapeutic option regardless of whether previous covalent BTK inhibitor therapy is discontinued owing to disease progression, toxic effects, or other reasons."
The BRUIN trial results suggest that pirtobrutinib represents an important advancement in addressing the unmet need for effective therapies in patients with CLL/SLL who have exhausted covalent BTK inhibitor options.
