Dr Davids on Treatment With Pirtobrutinib in CLL/SLL With/Without Prior BCL-2 Inhibitor Exposure

Matthew S. Davids, MD, MMSc, director, clinical research, Division of Lymphoma, Dana-Farber Cancer Institute, associate professor, medicine, Harvard Medical School, discusses key efficacy results from 2 follow-up analyses of the phase 1/2 BRUIN trial (NCT03740529) evaluating pirtobrutinib (Jaypirca) in patients with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL).

The BRUIN trial was a dose escalation and expansion study that enrolled adult patients with mantle cell lymphoma (n = 166), CLL/SLL ( n = 317), and other histologic subtypes (n = 295), including Richter transformation.

Extended follow-up data from a subgroup analysis of 282 patients with CLL or SLL, had previous exposure to a covalent BTK inhibitor, and were enrolled onto the BRUIN trial were presented at the 2023 ASH Annual Meeting, Davids begins. Notably, patients were stratified based on their exposure to a BCL-2 inhibitor, such as venetoclax (Venclexta), he says. At a median follow-up of 30 months, patients treated with pirtobrutinib experienced a high objective response rate (ORR) with pirtobrutinib regardless of prior BCL-2 inhibitor exposure, Davids reports. The ORR in the total population was 81.6% (95% CI, 76.5%-85.9%). Patients who were naive to BCL2 inhibition (n = 154) achieved an ORR with pirtobrutinib of 83.1% (95% CI, 76.2%-88.7%) and patients who had prior exposure to BCL-2 inhibitors (n = 128) achieved an ORR of 79.7% (95% CI, 71.7%-86.3%) with the agent.

Moreover, the median progression-free survival (PFS) with pirtobrutinib in patients who previously received covalent BTK inhibitors was 19.4 months (95% CI, 16.6-22.1), Davids details. The median PFS in the BCL2 inhibitor–naive group was 23.0 months (95% CI, 19.6-28.4) compared with 15.9 months (95% CI, 13.6-17.5) in the BCL2 inhibitor–exposed group.

These updated data have implications for treatment with pirtobrutinib, shedding light on potential considerations based on prior treatment history, Davids states. The durability of responses with pirtobrutinib also affirms its efficacy in patients with CLL/SLL, he adds.

Updated results with pirtobrutinib in patients with Richter transformation (n = 82) were also presented at the meeting, Davids continues. Patients with Richter transformation are typically underrepresented in clinical trial populations, as it is a relatively rare disease, Davids says, adding that the majority of patients in this cohort had been previously treated for Richter transformation and were thus classified as having high-risk disease.

In this presentation, pirtobrutinib produced an ORR of 50.0% (95% CI, 38.7%-61.3%); this was consistent with early data that were previously reported at the 2022 ASH Annual Meeting, Davids details. Despite eliciting a modest median PFS of 3.7 months (95% CI, 2.7-4.9), the agent led to a median overall survival of 12.5 months (95% CI, 6.9-20.5) in the overall Richter transformation population at a median follow-up of 18.3 months.

This indicates that pirtobrutinib could serve as effective bridging therapy until subsequent therapies like CAR T-cell therapy or allogeneic transplantation can occur, Davids asserts. Additionally, the drug’s favorable ORR positions it as a promising partner for combination therapies targeting Richter transformation, he says, and ongoing studies are exploring such combinations.

The evolving landscape of pirtobrutinib's role in Richter transformation, especially in combination approaches, underscores its potential significance in addressing this challenging malignancy, Davids concludes.