Treatment with the investigational Bruton’s tyrosine kinase (BTK) inhibitor pirtobrutinib was associated with encouraging rates of response and preliminary efficacy in heavily pretreated patients with Richter transformation (RT), according to a study presented at the 64th ASH Annual Meeting and Exposition. During his presentation, Nirav N. Shah, MD, of the Medical College of Wisconsin in Brookfield, stated that RT is a complication of chronic lymphocytic leukemia (CLL) that has a considerably poor prognosis.
“There haven’t been any drugs specifically approved for RT,” he explained, “and we use conventional chemotherapy and other agents that are used for both diffuse large B-cell lymphoma [DLBCL] and CLL.”
While covalent BTK inhibitors show some response in RT, Dr. Shah noted that most of these responses are limited.
Pirtobrutinib is a “noncovalent reversible BTK inhibitor,” Dr. Shah commented. “It is highly selective for the BTK enzyme and will specifically limit some of the off-target toxicities we can see with other drugs.”
The uncontrolled, phase I/II BRUIN study included patients with previously treated B-cell malignancies, including patients with CLL and histologically confirmed RT (all DLBCL). These patients were eligible to receive single agent pirtobrutinib in either the study’s dose escalation or expansion phase.
In the 57 patients with RT, the researchers assessed overall response rate (ORR) and duration of response (DOR) per Lugano 2014 criteria, in addition to safety.
The response-evaluable cohort comprised all patients with RT who were enrolled in phase I or II of the study and who had undergone their first response assessment or discontinued therapy. In contrast, the safety cohort consisted of patients with B-cell malignancies who received at least one pirtobrutinib dose (n=773).
The median age of the RT cohort was 67 years, and nearly all patients (91%) received at least one previous RT-directed treatment (median = 2). Prior to developing RT, patients received a median of two CLL-directed therapies. Most patients (98%) received the recommended phase II pirtobrutinib dose of once-daily 200 mg as the initial dose.
Among the 75 response-evaluable patients with RT, the ORR was 52%, which included 10 complete responses and 29 partial responses. At the median response follow-up of 5.5 months, the median DOR was 8.6 months. Approximately 63% of responses were censored at the data cutoff.
The median overall survival was 13.1. A total of six patients in ongoing response decided to discontinue pirtobrutinib to switch to curative-intent therapy.
In the group of patients with B-cell malignancies in the safety cohort who received pirtobrutinib, the most common treatment-emergent adverse events (TEAEs) were fatigue (26%), diarrhea (22%), and contusion (19%). Additionally, the most frequent grade 3 or greater TEAE was neutropenia (20%).
The researchers also observed low rates of grade 3 or higher TEAEs of hypertension (3%), hemorrhage (2%), and atrial fibrillation/flutter (1%). Only 2% of patients discontinued the investigational therapy because of a TEAE.
Limitations of the study included the small sample size and lack of a placebo arm or active treatment control group.
Some of the data reported here were updated at the time of presentation and differ from that reported in the abstract. Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Wierda WG, Lewis DJ, Ghia P, et al. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: results from the phase 1/2 BRUIN study. Abstract #347. Presented at the 2022 American Society of Hematology Annual Meeting and Exposition; December 10, 2022; New Orleans, Louisiana.
