SUMMARY: The FDA on January 27, 2023, granted accelerated approval to JAYPIRCA® (Pirtobrutinib) for Relapsed or Refractory Mantle Cell Lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.
The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. In the US, approximately 3,300 new cases of MCL are diagnosed each year. Mantle Cell Lymphoma is an aggressive B-cell lymphoma and accounts for approximately 6% of all Non Hodgkin Lymphomas in adults, and is associated with a high relapse rate, following dose-intensive therapies. Early and late relapses in patients with MCL have been attributed to persistence of residual disease. Majority of patients with MCL are elderly and are not candidates for aggressive treatment or Autologous Stem Cell Transplantation.
Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor, and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. BTK inhibitors inhibit cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), and Waldenstrom Macroglobulinemia (WM). The 3 covalent BTK inhibitors presently approved by the FDA for MCL include IMBRUVICA® (Ibrutinib) approved in 2013, CALQUENCE® (Acalabrutinib) approved in 2017, and BRUKINSA® (Zanubrutinib) approved in 2019. Covalent BTK inhibitors have transformed the treatment landscape of Mantle Cell Lymphoma. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.
JAYPIRCA® is a highly selective, reversible (non-covalent) Bruton’s Tyrosine Kinase (BTK) inhibitor, developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. JAYPIRCA® is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies and inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. JAYPIRCA® is well tolerated and demonstrated promising efficacy in patients with poor-prognosis B-cell malignancies following prior therapy, including prior covalent BTK inhibitors (Mato et al. Lancet, 2021).
The BRUIN Phase I/II clinical trial is the ongoing first-in-human, global, open-label, multicenter single armstudy, which evaluated the efficacy of JAYPIRCA® in previously treated patients with Mantle Cell Lymphoma (MCL), Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), or other Non-Hodgkin Lymphomas (NHL). The trial included a Phase I dose-escalation component in which the daily dosing of JAYPIRCA® between 25 mg and 300 mg was evaluated, a Phase Ib drug combination safety arm, and a Phase II dose-expansion component, in which JAYPIRCA® 200 mg daily, as a part of 28-day cycles, is being evaluated.
The present FDA approval is based on data from a subset of patients with Mantle Cell Lymphoma (N=120) in the BRUIN Phase I/II trial, treated with JAYPIRCA® 200 mg once daily until disease progression or unacceptable toxicity. Patients had received a median of three prior lines of therapy with 93% having two or more prior lines, and all patients received one or more prior lines of therapy containing a covalent BTK inhibitor. The most common prior BTK inhibitors received were Ibrutinib (67%), Acalabrutinib (30%), and Zanubrutinib (8%), and 83% had discontinued their last BTK inhibitor due to refractory or progressive disease. Patients with active Central Nervous System Lymphoma or allogeneic Hematopoietic Stem Cell Transplantation or CAR T-cell therapy within 60 days were excluded. The main efficacy measures were Overall Response Rate (ORR) and Duration of Response (DOR), as assessed by an Independent Review Committee, using 2014 Lugano criteria.
The ORR was 50%, with a Complete Response rate of 13%, and the Partial Response rate was 38%. The Time to Response was 1.8 months. The estimated median Duration of Response was 8.3 months, and the estimated Duration of Response rate at 6 months was 65.3%. The most common adverse reactions in 15% or more of MCL patients were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Grade 3 or 4 laboratory abnormalities in 10% or more of patients were cytopenias.
It was concluded that JAYPIRCA® offers a new approach to targeting the BTK pathway for Relapsed and Refractory Mantle Cell Lymphoma patients, previously treated with a covalent BTK inhibitor. The researchers added that this approval of JAYPIRCA® represents an important advance for this group of patients who currently have limited treatment options and have a poor prognosis.
Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory Mantle Cell Lymphoma: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study. Wang ML, Shah NN, Jurczak W. Presented at the 64th ASH Annual Meeting and Exposition, December 10-13, 2022, New Orleans, Louisiana. Abstract # 4218.
