Dr Leslie on the Significance of the FDA Approval of Pirtobrutinib in Pretreated CLL and SLL

Lori A. Leslie, MD, director, Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs, John Theurer Cancer Center, assistant professor, Hackensack Meridian School of Medicine, discusses the significance of the FDA approval of pirtobrutinib (Jaypirca) for patients with pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

BTK inhibitors have transformed the CLL and SLL treatment paradigms, Leslie begins. These agents play a crucial role in mediating B-cell receptor signaling. Three covalent BTK inhibitors are approved for patients with CLL/SLL: ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), Leslie recounts. Although patients are presently able to switch from 1 covalent BTK inhibitor to another following agent intolerance, this strategy should not be employed for those who have progressed on or been exposed to a covalent BTK inhibitor, Leslie notes, because these 3 agents share similar mechanisms of resistance.

The emergence of the reversible, noncovalent BTK inhibitor pirtobrutinib introduces a novel approach to CLL management following initial treatment progression, addressing the need for more treatment options after progression on prior covalent BTK inhibitors or BCL2 inhibitors, Leslie states. Unlike covalent BTK inhibitors, which bind directly to the active site of BTK, pirtobrutinib continues to bind to and inhibit BTK regardless of the presence of mutations at the active site, such as C481. This mechanism of action allows pirtobrutinib to potentially overcome resistance to covalent BTK inhibitors, Leslie explains.

On December 1, 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with CLL or SLL who had prior exposure to 2 or more lines of therapy, including a BTK inhibitor and a BCL2 inhibitor. This regulatory decision was supported by data from the phase 1/2 BRUIN trial (NCT03740529), in which pirtobrutinib elicited an overall response rate of 72% in the cohort of patients with CLL/SLL (n = 108). The median time to response in this cohort was 3.7 months (range, 1.7-27.9), and the median duration of response was 12.2 months (95% CI, 9.3-14.7).

Overall, pirtobrutinib's mechanism of action positions this agent as a valuable addition to the third-line setting for patients with pretreated CLL and SLL, Leslie emphasizes. The clinical benefit of pirtobrutinib in this population will be confirmed in the ongoing phase 3 BRUIN CLL-321 trial (NCT04666038).