Jaypirca (pirtobrutinib) received US FDA approval for the treatment of advanced Mantle Cell Lymphoma in 2019 and expanded approval to CLL and SLL in 2023. Preliminary results of a trial evaluating Jaypirca – an investigational Bruton’s tyrosine kinase (BTK) inhibitor were initially released at the December 2019 American Society of Hematology Annual Meeting. At all doses studied, Jaypirca delivered objective responses in patients who had received diverse prior therapies and had exhibited acquired resistance. Approval was based on results from the BRUIN clinical trial.
About Jaypirca (pirtobrutinib)
Jaypirca is a highly selective, non-covalent BTK inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia (CLL), Waldenstrom macroglobulinemia, mantle cell lymphoma and marginal zone lymphoma. Currently available BTK inhibitors irreversibly inhibit BTK however the long-term effectiveness of these therapies has been limited by acquired resistance, most commonly through BTK C481 mutations, and intolerance, due to off target inhibition of other cellular targets. Jaypirca was designed to reversibly bind BTK, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors.
BRUIN Phase 1/2 Trial
The BRUIN clinical trial which began enrolling patients in March 2019 is a dose escalation and expansion clinical trial designed to determine the recommended dose for further clinical study and the safety of Jaypirca in patients with B-cell leukemias and lymphomas.
Results of the initial 28 patients enrolled to five dose escalation groups were released at the 2019 American Society of Hematology annual meeting. There were 16 patients with CLL, eight patients with MCL, two patients with Waldenstrom macroglobulinemia, one patient with diffuse large B-cell lymphoma (DLBCL), and one patient with marginal zone lymphoma (MZL). Seventy-five percent of the CLL and 88% of the MCL patients had received at least one prior BTK inhibitor.
Responses were observed across all dose levels:
- 77% of CLL patients responded to treatment with evidence of deepening response over time. Responses were observed in patients with acquired resistance to prior BTK therapy (those with and without C481S mutations), in patients who were intolerant to prior BTK therapy, and in patients with acquired resistance to prior BCL2 therapy.
- 50% of MCL patients responded to treatment including patients that failed prior BTK therapy.
In the phase II portion of BRUIN, 120 patients with MCL previously treated with a BTK inhibitor were evaluated. Patients had a median of 3 prior lines of therapy, with 93% having 2 or more prior lines. The most common prior BTK inhibitors received were ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%); 83% had discontinued their last BTK inhibitor due to refractory or progressive disease.
Overall 50% of the MCL patients responded to treatment with Jaypirca, 13% with a complete response. The estimated median duration of response was 8.3 months.
Chronic lymphocytic leukemia and small lymphocytic lymphoma
The Food and Drug Administration expanded approval to Jaypirca for adults with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. The median duration of response was 12.2 months.
The most common side effects were fatigue, musculoskeletal pain, diarrhea, edema, shortness of breath, pneumonia, and low blood counts. The prescribing information includes warnings and precautions for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, and second primary malignancies.
Jaypirca is a novel BTK inhibitor with promising clinical activity in patients with lymphoid cancers that is active in patients who have developed resistance to other BTK inhibitors. Additional evaluation is ongoing beyond MCL at the recommended dose to further define safety and effectiveness.
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