Richter’s transformation (RT) is a rare blood cancer that occurs in up to 10% of patients with chronic lymphocytic leukemia (CLL) and represents an aggressive lymphoma, usually as large B-cell lymphoma (DLBCL). Because of the rarity of the disease, there are no FDA-approved therapies specific to RT, and these patients are treated using regimens derived from DLBCL treatment paradigms and other small-scale clinical trials. The prognosis of patients with RT is poor, with a median overall survival (mOS) of up to 11 months, highlighting an unmet need. Eli Lilly’s pirtobrutinib is a next-generation reversible BTK inhibitor being investigated for activity in various CLL settings, including RT.
At the 2022 annual conference of the American Society of Hematology 2022 (ASH 2022), which was held between December 10-13, new data from the multi-arm, uncontrolled Phase I/II BRUIN study of pirtobrutinib was presented by Dr. Nirav Shah.associate professor, Medical College of Wisconsin, Milwaukee.
Among the patients enrolled, 68 were previously treated and seven were newly diagnosed. Patients had received a median of two anti-RT therapies and a median of two anti-CLL therapies. Only 75 patients were evaluable for response, of which ten underwent complete response, and 29 partial response, resulting in a 52% overall response rate (ORR). The MOS was 13.1 months, which in the historical context, was an improvement in the natural disease course of this patient. In the pirtobrutinib safety cohort, only 2.6% of patients discontinued treatment due to adverse events. The most common Grade ≥3 treatment-related adverse events were neutropenia in 20%, hypertension in 3%, and hemorrhage.
These results pave the way for new options for RT relapsed/refractory (R/R) patients. Pirtobrutinib has received FDA orphan drug designation for CLL, and given the true orphan status of RT, regulatory approval and specific labeling of RT can be rapidly implemented with these data.
Interestingly, AstraZeneca’s BTK inhibitor Calquence (acalabrutinib) has also shown activity in RT patients, as part of the Phase I/II trial ACE-CL-001, although in a smaller number of patients (n = 29). Given the similar mechanism of action, data from the pirtobrutinib study strongly support the use of its competitor Calquence in RT patients. Calquence already has a broad FDA label for use in all CLL patients, so it can also be used in RT patients, while pirtobrutinib must await marketing authorization before being used outside of clinical trials.
Consensus analysts GlobalData forecast the database projects peak sales of pirtobrutinib to reach $892 million by 2028, and $4.8 billion for Calquence. GlobalData is the parent company of Pharmaceutical Technology.