In the phase I/II BRUIN trial reported in The New England Journal of Medicine, Anthony R. Mato, MD, and colleagues found that the noncovalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor pirtobrutinib exhibited strong activity in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had received prior treatment with a covalent BTK inhibitor. As noted by the investigators, pirtobrutinib was designed to reestablish BTK inhibition.
Anthony R. Mato, MD
Study Details
In the trial, 317 patients with relapsed or refractory CLL or SLL were enrolled from sites in 10 countries between March 2019 and July 2022, including 247 patients who had previously received at least one covalent BTK inhibitor (efficacy population). Among the 247 patients, including 86 from the phase I portion and 161 from the phase II portion, the median number of previous lines of therapy was three (range = 1–11), and 100 patients (40%) had also received a BCL2 inhibitor (eg, venetoclax).
Patients received pirtobrutinib at 200 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate on independent review.
Responses
Partial response or better was observed in 181 (73.3%, 95% confidence interval [CI] = 67.3%–78.7%) of 247 patients, with complete response in 4 (1.6%). Response was observed in 82.2% (95% CI = 76.8%–86.7%) when an additional 22 patients (8.9%) with partial response with lymphocytosis were included as responders. Among the 100 patients who also received a BCL2 inhibitor, corresponding response rates were 70.0% and 79.0%.
At a median follow-up of 19.4 months, median progression-free survival was 19.6 months (95% CI = 16.9–22.1 months) among the 247 patients, with a 12-month rate of 69.8%. Among patients who also received a BCL2 inhibitor, median progression-free survival was 16.8 months (95% CI = 13.2–18.7 months). At a median follow-up of 22.6 months, overall survival among the 247 patients was 86.0% (95% CI = 81.0%–89.8%) at 12 months and 80.5% (95% CI = 74.8%–85.0%) at 24 months.
Adverse Events
Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events of any grade were infections (71.0%), bleeding (42.6%), and neutropenia (32.5%). The most common grade ≥ 3 adverse events were infections (28.1%) and neutropenia (26.8%). Treatment-related adverse events led to permanent discontinuation of pirtobrutinib in nine patients (2.8%). Death occurred in 16 patients while receiving pirtobrutinib for causes other than disease progression, including COVID-19–related pneumonia (n = 8), pneumonia or fungal pneumonia (n = 2), septic shock or shock (n = 2), and other causes (n = 4).
The investigators stated, “At a median duration of treatment of 16.5 months…, some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%).”
The investigators concluded: “In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia.”
Jennifer A. Woyach, MD, of The Ohio University Comprehensive Cancer Center, Columbus, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by Loxo Oncology. For full disclosures of the study authors, visit nejm.org.
