In a phase I/II BRUIN study, the non-covalent (reversible) Bruton’s tyrosine kinase (BTK) inhibitor, pirtobrutinib showed efficacy in patients with heavily pretreated chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) who had had disease progression during previous treatment with a covalent BTK inhibitor.
These findings indicate that re-establishing BTK inhibition with pirtobrutinib is a potential treatment option regardless of whether previous covalent BTK inhibitor is discontinued because of disease progression, adverse events, or other reasons. The results are published by Dr. Jennifer A. Woyach of the Ohio University Comprehensive Cancer Center in Columbus, OH, US, and colleagues on 6 July 2023 in The New England Journal of Medicine.
The authors wrote in the background that although chemoimmunotherapy remains an important option for a subset of patients, the standard of care for most patients with CLL or SLL has gradually moved during the past decade toward targeted therapies such as covalent BTK inhibitors and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax.
However, all covalent BTK inhibitors share common resistance mechanisms. Consequently, once patients have disease progression while receiving any of these agents, the remaining treatment options are limited. Venetoclax can induce a rapid tumour lysis syndrome and duration of disease control is approximately 2 years. A growing number of patients have now received both, a covalent BTK inhibitor and a BCL2 inhibitor, and outcomes in these heavily pretreated patients are extremely poor.
Pirtobrutinib is a selective, non-covalent (reversible) BTK inhibitor that inhibits both wild-type and C481-mutated BTK as the most common mutation associated with resistance to covalent BTK inhibitors with equal low nanomolar potency and is designed to address several of the limitations of covalent BTK inhibitors.
In a phase I/II BRUIN study, patients with relapsed or refractory B-cell malignancies received pirtobrutinib. The study investigators report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor, as well as safety results among all the patients with CLL or SLL. The primary endpoint was an overall response, defined as partial response or better, as assessed by independent review. Secondary endpoints included progression-free survival (PFS) and safety.
A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of treatment was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a BCL2 inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI] 67.3 to 78.7), and the percentage was 82.2% (95% CI 76.8 to 86.7) when partial response with lymphocytosis was included. The median PFS was 19.6 months (95% CI 16.9 to 22.1).
Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (71.0%), bleeding (42.6%), and neutropenia (32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (14.2%), atrial fibrillation or flutter (3.8%), and major haemorrhage (2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event.
The authors commented that these data suggest that CLL and SLL maintain nearly universal dependency on B-cell receptor signalling mediated by BTK, despite previous exposure to a covalent inhibitor. Sequential use of a covalent BTK inhibitor followed by pirtobrutinib may therefore meaningfully extend the total period of clinical benefit of targeting this critical pathway dependency. More data are needed on mechanisms of resistance to pirtobrutinib. Recent data suggest that venetoclax maintains efficacy in patients previously treated with a non-covalent BTK inhibitor.
Several ongoing clinical studies are evaluating pirtobrutinib in the treatment of B-cell malignancies, including four phase III, international, randomised studies evaluating pirtobrutinib in patients with CLL or SLL.
In an accompanied editorial article, Prof. Arnon P. Kater of the Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam in Amsterdam, The Netherlands and Prof. Barbara Eichhorst of the Department I of Internal Medicine and Center for Integrated Oncology Aachen, Bonn, Cologne, Düsseldorf, University of Cologne in Cologne, Germany wrote that other non-covalent BTK inhibitors are under development, but how well they will treat tumours with resistance mutations has yet to be determined.
A new class of drugs, currently in clinical trials, BTK degraders induce proteasomal degradation of BTK proteins and appear to work well against CLL regardless of variant status. Time-limited combination treatment is another approach. The idea is to avoid resistance variants that arise in response to prolonged drug exposure. BTK inhibitors such as pirtobrutinib could also be combined with bispecific T-cell–engaging antibodies, an approach that would be expected to overcome the acquired T-cell dysfunction that occurs in CLL, and hampers T-cell directed therapies.
The BRUIN study was funded by Loxo Oncology, a wholly owned subsidiary of Eli Lilly.
