Pirtobrutinib Displays Efficacy in Patients With Richter Transformation

William G. Wierda, MD, PhD

The highly selective, non-covalent BTK inhibitor pirtobrutinib (Jaypirca) demonstrated activity with a tolerable safety profile in patients with Richter transformation, according to findings from a subgroup analysis of the phase 1/2 BRUIN trial (NCT03740529).¹

At the May 5, 2023, data cutoff, patients with Richter transformation in the form of diffuse large B-cell lymphoma (DLBCL; n = 82) who received pirtobrutinib achieved an overall response rate (ORR) of 50.0% (95% CI, 38.7%-61.3%), including a complete response rate of 13.0%. The median duration of response (DOR) was 7.4 months (95% CI, 3.1-19.1) and the 12-month DOR rate was 45.9% (95% CI, 28.3%-61.8%). Patients experienced a median time to response of 1.9 months (IQR, 1.8-1.9).

Additionally, the ORR was 48.6% (95% CI, 36.9%-60.6%) among patients who received previous Richter transformation-directed therapy (n = 74), and was 62.5% (95% CI, 24.5%-91.5) among patients who did not (n = 8).

“Pirtobrutinib [showed] promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors,” William G. Wierda, MD, PhD, and coauthors wrote. “These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor.”

Weirda is deputy department chair and section chief of the Department of Leukemia Center as well as a professor of medicine at The University of Texas MD Anderson Cancer Center in Houston. He is also the Jane and John Justin Distinguished Chair in Leukemia Research in Honor of Dr. Elihu Estey, the executive medical director of Inpatient Medical Services, and the center medical director of the Department of Leukemia Center.

In December 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) following treatment with at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor. Previous data from BRUIN supported the regulatory decision.²

The multicenter, open-label BRUIN study enrolled adult patients with hematologic malignancies, including CLL, SLL, and mantle cell lymphoma. To be eligible for the subgroup analysis, patients with histologically confirmed active Richter transformation in the form of a DLBCL per local pathology review needed to be at least 18 years of age and have an ECOG performance status of 2 or less. Notably, the number of prior lines of treatment was not limited and patients receiving frontline therapy were permitted to enter the study.¹

Patients received 25 mg to 300 mg of oral pirtobrutinib daily in 28-day cycles of phase 1. In phase 2, patients were treated with pirtobrutinib at a dose of 200 mg daily in 28-day cycles. Doses could be held for up to 28 days or reduced due to clinically significant adverse effects (AEs); all patients with Richter transformation received treatment during the dose escalation or expansion phase of the trial.

The primary end point of phase 1 of BRUIN was to establish the recommended phase 2 dose of pirtobrutinib monotherapy and the primary end point of phase 2 was investigator-assessed ORR. Secondary end points included DOR, progression-free survival (PFS), overall survival (OS), and pharmacokinetics.

Patients in the Richter transformation subgroup were a median age of 67 years (IQR, 59-72). Most patients were male (67%), White (79%), received prior therapy for Richter transformation (90%), and had elevated lactate dehydrogenase levels (80%). The median number of lines of prior CLL and Richter transformation therapy was 4 (range, 0-13); previous Richter transformation therapies included an anti-CD20 antibody (78%), chemoimmunotherapy (76%), BCL2 inhibitors (38%), and covalent BTK inhibitors (34%).

Additional findings from the subgroup analysis demonstrated that the median OS was 12.5 months (95% CI, 6.9-20.5); the 6-, 12-, 18- and 24-month OS rates were 68.8%, 50.8%, 44.3%, and 33.5%, respectively. The median PFS was 3.7 months (95% CI, 2.7-4.9); the 6-, 12-, 18- and 24-month PFS rates were 34.9%, 26.3%, 21.1%, and 12.6%, respectively. Among those who received prior Richter transformation-directed therapy, the median OS was 11.8 months (95% CI, 6.9-19.5) and the median PFS was 3.6 months (95% CI, 2.4-4.6).

In terms of safety, most patients experienced any-grade treatment-emergent AEs (TEAEs; 94%) and 60% experienced grade 3 or higher TEAEs. The most common any-grade TEAEs included neutropenia (29%), fatigue (24%), and dyspnea (18%), pyrexia (18%), diarrhea (18%), and contusion (18%). Grade 5 TEAEs of infection were reported in 2 patients; TEAEs leading to dose discontinuation (n = 5) were also reported.

“For a disease with few treatment options, pirtobrutinib offered single-agent activity and….a bridge to a potentially curative treatment option,” Wierda and coauthors wrote in conclusion. “This subgroup with Richter transformation included many heavily pretreated patients who historically have a poor expected OS. These results support the continued investigation of pirtobrutinib, alone or in combination with other therapies, in patients with Richter transformation.”

References

1. Wierda WG, Shah NN, Cheah CY, et al. Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study. Lancet Haematol. Published online July 18, 2024. doi:10.1016/S2352-3026(24)00172-8
2. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed August 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic