Richter transformation (RT) is a rare blood cancer that occurs in up to 10% of patients with chronic lymphocytic leukemia (CLL) and presents as an aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). . Due to the rarity of the disease, there is no FDA-approved therapy specifically for RT, and these patients are treated with regimens derived from the DLBCL treatment paradigm and other small-scale clinical trials. The prognosis for RT patients is poor, with a median overall survival (mOS) of up to 11 months, highlighting a huge unmet need. Eli Lilly’s pirtobrutinib is a next-generation reversible BTK inhibitor whose activity is being investigated in various CLL settings, including RT.
At the American Society of Hematology 2022 (ASH 2022) Annual Conference, held December 10-13, Nirav Shah, MD, presented new data from the BRUIN phase I/II uncontrolled multi-stage study. arms on pirtobrutinib.Associate Professor, Medical School of Wisconsin, Milwaukee.
Among the enrolled patients, 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 10 experienced a complete response and 29 a partial response, resulting in an overall response rate (ORR) of 52%. The moS was 13.1 months, which in a historical context is an improvement in the natural course of the disease in these patients. 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 20% neutropenia, 3% hypertension, and hemorrhage.
These results pave the way for a new option for relapsed/refractory (R/R) RT patients. Pirtobrutinib has received Orphan Drug Designation from the FDA for CLL and, given the true orphan status of RT, regulatory approval with a specific label for RT could be rapidly sought with these data.
Interestingly, AstraZeneca’s BTK inhibitor Calquence (acalagrutinib) has also shown activity in RT patients, as part of the Phase I/II trial ACE-CL-001, albeit in a smaller number of patients (n=29). Given its same mechanism of action, data from the pirtobrutinib study actually support the use of its competitor Calquence in RT patients. Calquence already has a broad FDA label for use in all CLL patients and can therefore also be used in RT patients, while pirtobrutinib will have to await marketing authorization before it is used off-label. a clinical trial.
The GlobalData Consensus Analyst Forecasts 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.