In patients with Richter transformation (RT), pirtobrutinib — a first-in-class, noncovalent reversible BTK inhibitor (BTKi) — showed promising activity and acceptable safety in a phase I/II trial. Many of the patients had received prior RT-directed therapy, including covalent BTKis. The results were published in The Lancet Haematology.
“For a disease with few treatment options, pirtobrutinib offered single-agent activity and, as is often the goal for some patients, a bridge to a potentially curative treatment option,” lead author William G. Wierda, MD, of the University of Texas, MD Anderson Cancer Center in Houston, wrote on behalf of the research team. The cohort “included many heavily pretreated patients who historically have a poor expected overall survival (OS).”
RT often presents as an aggressive diffuse large B-cell lymphoma (DLBCL). Because pirtobrutinib has shown promise in patients with relapsed or refractory B-cell malignancies, the researchers assessed it as a monotherapy in patients with RT — a subgroup of the open-label, phase I/II BRUIN trial. The primary endpoint of phase I was to establish the recommended phase II dose for pirtobrutinib monotherapy. Overall response rate (ORR) was the primary endpoint for phase II. The researchers assessed safety and activity in all patients who received at least one pirtobrutinib dose.
Between December 26, 2019, and July 22, 2022, the study enrolled 82 patients (median age = 67; 67% male; 79% white) with RT and an Eastern Cooperative Oncology Group performance status score of 0-2. Five patients enrolled during phase I and 77 during phase II. Of the 82 patients, 90% had received at least one prior RT-directed therapy, and 74% had received previous covalent BTKi therapy for chronic lymphocytic leukemia (CLL) or RT. During the trial, 81 patients received 200 mg of pirtobrutinib orally once daily in 28-day cycles. The remaining patient received 150 mg of pirtobrutinib once daily.
Across all patients, the ORR was 50.0% (95% CI 38.7-61.3), with a complete response (CR) in 13%, a partial response in 37%, and stable disease in 13%. The median OS stood at 12.5 months (95% CI 6.9-20.5). The 18-month OS was 44.3% (95% CI 32.5-55.4). For patients who received prior BTKi therapy, the ORR was 45.9% (95% CI 33.1-59.2), which the authors suggested highlights the efficacy of pirtobrutinib in patients with high-risk disease.
Discontinuation of pirtobrutinib occurred in 65% of the patients due to progressive disease, in 10% to undergo hematopoietic cell transplantation (HCT) or other consolidative therapy, and in 6% due to adverse events (AEs). Neutropenia was the most common grade 3 or greater AE. Two patients died, with no deaths deemed treatment related.
“Pirtobrutinib was well tolerated with low rates of covalent BTKi-associated adverse events (AEs) and discontinuations due to drug-related toxicity,” the authors wrote.
Limitations to the study include its open-label, single-arm design. A small number of patients had response assessments with PET scans, pathologic data, genetic markers, and clonal relationship analyses, limiting the generalizability of these data. Longer follow-up is needed to assess the durability of response and toxicity over time with pirtobrutinib in patients with RT.
“These results support the continued investigation of pirtobrutinib, alone or in combination with other therapies, in patients with [RT],” the authors concluded.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
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. 2024;11(9):e682-e692.
Perspectives
Over the last 10 years, patients with CLL have greatly benefited from the introduction of targeted kinase inhibitors such as BTKi. These therapies have resulted in prolonged survival over standard chemotherapy drugs and resulted in many new drug approvals for CLL.1,2 Unfortunately, for patients with RT, a devastating complication experienced by approximately 10% of patients when CLL transforms into rapidly growing B-cell lymphoma, survival demonstrated in clinical trials remains abysmal with a general estimated length of less than one year and no drugs approved for this indication.3-8 Attempts to intensify the treatment of RT with combination chemoimmunotherapy regimens have been unsuccessful due to lack of response and the older population with comorbidities that is typically afflicted with RT.7-9
The BRUIN study is a large phase I/II clinical trial administering the oral, non-covalently binding BTKi pirtobrutinib continuously at target doses of 200 mg daily.10 The study included a subgroup of 82 patients with RT, which is the largest prospective clinical trial performed for this population. These patients had heavy pretreatment, including 90% with prior CLL or RT treatment and 74% with prior BTKi therapy. For a single-agent oral therapy, the study demonstrated an impressive ORR and even a 13% CR rate. Even more notable is the favorable toxicity profile with only two grade 3 or higher AEs reported at a rate of more than 15% (neutropenia in 22% and infections in 18%).10
Despite the impressive response rates and tolerability of therapy, the median progression-free survival was estimated at a short 3.7 months. In those who achieved a response, the duration of response (DOR) was a median of 7.4 months. OS was also quite short at 12.5 months. Eight patients who achieved response were able to move on to definitive and potentially curative therapy with allogeneic HCT.10
No clear predictive factors emerged for which patients might have the best or longest response to pirtobrutinib. Clonal relatedness to the underlying CLL clone was only available in 21 of the patients. Although, it was promising that those with related RT and CLL clones (typically the worst clinical outcomes) still had an ORR of 61%. This promising response may be related to the fact that the majority of clonally related RT is of the non-germinal center B-subtype DLBCL, which has better known responses to BTKi.11,12 Most patients had prior therapy, so these data don’t reveal if earlier treatment of RT with pirtobrutinib might improve outcomes.
Overall, these data suggest some activity of pirtobrutinib in RT, but it is definitely not curative therapy and does not result in prolonged DOR. The most appropriate use of pirtobrutinib for patients with RT may be as a bridge to more definitive therapy like HCT or chimeric antigen receptor T-cell therapy. Alternatively, given the favorable tolerability of the treatment, pirtobrutinib may serve as a palliative option. Given its activity, more research should be done with pirtobrutinib in RT, perhaps earlier after transformation or in combination with other active agents.
Deborah M. Stephens, DO
Division of Hematology, Department of Medicine
University of North Carolina
Chapel Hill, North Carolina
Conflict of interest: Dr. Stephens has provided consulting for Abbvie, AstraZeneca, Beigene, BMS, Celegene, Eli Lilly, Genentech, Janssen, and Pharmacyclics. She has received research funding from Abbvie, Genentech, and Beigene, and is supported by NIH NCI R50 CA275929.
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- 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. 2024;11(9):e682-e692.
- El Hussein S, Medeiros LJ, Lyapichev KA, et al. Immunophenotypic and genomic landscape of Richter transformation diffuse large B-cell lymphoma. Pathology. 2023;55(4):514-524.
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