In the randomized phase III BRUIN CLL-322 trial, adding fixed-duration pirtobrutinib, a non-covalent Bruton tyrosine kinase (BTK) inhibitor, to venetoclax-rituximab significantly improved progression-free survival in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma, including those previously treated with covalent BTK inhibitors. The trial, reported in The Lancet by Davids et al, provides the first randomized phase III evidence comparing a novel fixed-duration regimen with the current fixed-duration standard of venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia (including small lymphocytic lymphoma).
Study Details
The open-label, multicenter, randomized trial was conducted at 152 community hospitals and academic centers across 22 countries. Eligible patients were aged 18 years or older and had confirmed chronic lymphocytic leukemia, including small lymphocytic lymphoma, previously treated with at least one line of therapy.
Patients who had previously received a noncovalent BTK inhibitor, a BCL2 inhibitor such as venetoclax, or another BCL2 inhibitor were ineligible for the trial. Patients with known or suspected Richter transformation or central nervous system involvement were also excluded.
A total of 639 patients were randomly assigned 1:1 to receive pirtobrutinib plus venetoclax-rituximab or venetoclax-rituximab alone. Both groups received fixed-duration venetoclax and rituximab; patients in the investigational group also received pirtobrutinib for 28 cycles, with a three-cycle pirtobrutinib-rituximab lead-in before venetoclax initiation.
The primary endpoint was progression-free survival by masked independent review. The key secondary endpoint was overall survival, with other secondary endpoints including investigator-assessed progression-free survival, time to next treatment, event-free survival, overall response rate, patient-reported outcomes, and safety.
Baseline characteristics were generally balanced between groups. The median age was 68 years, and most patients were men. The median number of prior lines of therapy was two. Overall, 80% of patients had previously received a covalent BTK inhibitor, and 71% of those patients had discontinued their most recent covalent BTK inhibitor because of progressive disease.
Key Findings
At a median follow-up of 27.3 months, the pirtobrutinib triplet significantly improved progression-free survival compared with venetoclax-rituximab alone. Median progression-free survival was not reached with the triplet and was 39.7 months with venetoclax-rituximab (hazard ratio [HR] = 0.547, P = .0001). The 24-month progression-free survival rate was 86.9% vs 71.8%, respectively.
This subgroup was a focus of the trial because covalent BTK inhibitors are now commonly used earlier in treatment, and 80% of patients in the trial had previously received one. Among these patients, median progression-free survival was not reached with the triplet and was 36.2 months with venetoclax-rituximab alone (HR = 0.509, P = .0003).
The benefit was also seen among patients whose previous covalent BTK inhibitor had been stopped because of progressive disease. In that subgroup, median progression-free survival was 43.3 months with the triplet and 33.2 months with venetoclax-rituximab (HR = 0.444, P = .0001). The investigators also reported benefit in patients with high-risk genomic features, including TP53 mutation and/or del(17p).
Overall survival data were immature at the interim analysis. Median overall survival was not reached in either group, and further testing of overall survival superiority is planned with additional follow-up.
The overall response rate by independent review was 88.5% with the pirtobrutinib triplet and 83.3% with venetoclax-rituximab. Complete response or complete response with incomplete bone marrow recovery occurred in 32% vs 23% of patients, respectively.
End-of-treatment measurable residual disease data were limited by missing samples and should be interpreted cautiously, according to the investigators. However, among patients with evaluable samples at the end of treatment, undetectable measurable residual disease at a threshold of 10^-4 was more frequent with the pirtobrutinib triplet than with venetoclax-rituximab alone: 86% vs 61%.
Almost all treated patients had adverse events, but rates of grade 3 or higher treatment-emergent adverse events and treatment discontinuation were broadly similar between groups. Treatment-emergent adverse events of any grade occurred in 100% of patients receiving the pirtobrutinib triplet and 98% of those receiving venetoclax-rituximab. Grade 3 or higher events occurred in 79% vs 73%, respectively.
Diarrhea was the most frequent treatment-emergent adverse event in both groups, occurring in 34% of patients receiving the pirtobrutinib triplet and 35% of those receiving venetoclax-rituximab. Rates of atrial fibrillation or flutter were low in both groups, at 3% each. Grade 3 or higher tumor lysis syndrome occurred less often with the triplet than with venetoclax-rituximab alone: 1% vs 4%.
Treatment-related adverse events led to treatment-regimen discontinuation in 5% of patients in each group, and five treatment-related deaths occurred: one in the pirtobrutinib triplet group and four in the venetoclax-rituximab group. The investigators reported no new safety signals.
The researchers concluded that the results support pirtobrutinib plus venetoclax-rituximab as “a potential new standard of care” for relapsed or refractory chronic lymphocytic leukemia, after the regimen showed “a significant and clinically meaningful improvement in progression-free survival, with a manageable safety profile.”
Matthew S. Davids, MD, of the Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, is the corresponding author for The Lancet article.
DISCLOSURE: The study was funded by Eli Lilly and Company. For full disclosures of the study authors, visit thelancet.com.
