Pirtobrutinib Shows Promising Efficacy in Previously Treated CLL/SLL

Take-aways:

• Pirtobrutinib is a selective, non-covalent Bruton tyrosine kinase inhibitor for the treatment of patients with B-cell malignancies.
• With no dose-limiting toxicities observed, the recommended phase II dose is once-daily pirtobrutinib 200 mg.
• The overall response rate in patients with CLL/SLL was 63% and was not affected by previous BTK inhibitor experience.

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In patients with previously treated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), treatment with the non-covalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib was safe and associated with high rates of response and efficacy, according to results from the phase I/II BRUIN study. Study investigator Catherine C. Coombs, MD, of the University of North Carolina at Chapel Hill, shared these findings in a presentation at the 2021 Society of Hematologic Oncology Annual Meeting.

The ongoing, multicenter BRUIN trial was conducted across several community hospitals and academic medical centers. At time of data cutoff (September 2020), a total of 323 previously treated patients with B-cell malignancies had been enrolled. Patients included those with CLL/SLL (n = 170), mantle cell lymphoma (MCL, n = 61), Waldenström macroglobulinemia (WM, n = 26), and “other” B-cell lymphomas (n = 66). All patients received once-daily oral pirtobrutinib in 28-day cycles. Treatment was administered in seven dose-escalation levels ranging between 25 mg and 300 mg.

At baseline, the median age of the CLL/SLL population was 69 years. Most patients were male (64%) and had an Eastern Cooperative Oncology Group performance status of 0 (51%) or 1 (41%). Patients had received a median of three prior lines of systemic therapy, but some patients had received up to 11 previous treatments. Prior therapies included BTK inhibitor (86%), chemotherapy (82%), anti-CD20 antibody (90%), BCL2 inhibitor (34%), PI3K inhibitor (21%), lenalidomide (8%), allogenic stem cell transplantation (2%), and chimeric antigen receptor (CAR) T-cell therapy (6%).

The study’s primary objectives were to determine the maximum tolerated dose/recommended phase II dose of pirtobrutinib, the drug’s safety profile, and the agent’s efficacy.

There were no dose-limiting toxicities during the exposure period. Treatment-emergent adverse events observed in 10% or more of patients included fatigue (20%), diarrhea (17%), and contusion (13%).

The researchers selected once-daily pirtobrutinib 200 mg as the recommended phase II dose for future investigations. The overall response rate (ORR), as assessed per the International Workshop on CLL 2018 criteria, was 63%. Outcomes included 69 partial responses, 45 patients with stable disease, and one patient with progressive disease. A total of five patients discontinued treatment prior to the first response assessment.

Responses to therapy reportedly deepened over time in the group of 29 patients who were followed for 10 or more months. The ORR in this cohort was 86%. In contrast, the ORR was 68% in patients who had follow-up of at least 6 months, and 71% in those with follow-up of at least 8 months.

Reasons for prior BTK inhibitor discontinuation or other classes of previously received therapy did not affect the response outcomes, the authors reported. Dr. Coombs and colleagues also noted that, while the responding patient with the longest follow-up has continued on treatment for more than 17.8 months, there is a need for longer-term follow-up “to better understand the pirtobrutinib safety profile associated with chronic administration.”

Disclosures: This research was supported by Loxo Oncology. Study authors report financial relationships with Loxo Oncology, the manufacturer of pirtobrutinib.

Reference

Coombs CC, Pagel JM, Shah NN, et al. Pirtobrutinib (LOXO-305), a next-generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study. Abstract #CLL-039. Presented at the 2021 Society of Hematologic Oncology Annual Meeting, September 8-11, 2021.