SUMMARY: The FDA on December 1, 2023, granted accelerated approval to Pirtobrutinib (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 American Cancer Society estimates that for 2023, about 18,740 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4490 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitor, time limited therapy with BCL2 inhibitor Venetoclax given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.
Brutons 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 promote 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 CLL/SLL include IMBRUVICA® (Ibrutinib), CALQUENCE® (Acalabrutinib), and BRUKINSA® (Zanubrutinib). Although covalent BTK inhibitors have dramatically improved outcomes for patients with CLL or SLL, they are not curative. Despite the efficacy of covalent BTK inhibitors, treatment failure often occurs through development of resistance or intolerance.
Pirtobrutinib (JAYPIRCA®) is a highly selective, reversible (non-covalent) 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. Pirtobrutinib is 300 times more selective in BTK inhibition versus 98% of other kinases tested in preclinical studies, and inhibits both wild type and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology. Pirtobrutinib 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 present FDA approval was based on BRUIN trial, which is an open-label, international, single-arm, multicohort, Phase I-II trial, conducted to evaluate the efficacy of Pirtobrutinib in patients with Relapsed or Refractory B-cell cancers. The trial involved patients receiving Pirtobrutinib monotherapy in either the Phase I or Phase II portion. In the Phase I portion, patients received Pirtobrutinib at doses ranging from 25 to 300 mg once daily in 28-day cycles. In the Phase II portion, patients received the recommended dose of 200 mg once daily. Majority of patients (85%) received the recommended dose of 200 mg once daily. Treatment was continued until disease progression or unacceptable toxicities. This analysis included 247 patients (N=247) with CLL or SLL, who had previously received a BTK inhibitor, among who the median number of previous lines of therapy was 3, and 100 patients (40.5%) had also received a B-Cell Lymphoma 2 (BCL2) inhibitor such as Venetoclax. This efficacy cohort (N=247) consisted of 86 patients from the Phase I portion and 161 patients from the Phase II portion. The median age was 69 years and in addition to previous BTK inhibitor therapy and BCL2 inhibitors, patients had also received anti-CD20 antibody (87.9%), chemotherapy (78.9%), PI3K inhibitors (18.2%), Chimeric Antigen Receptor (CAR) T-cell therapy (5.7%), and Allogeneic Stem-Cell Transplantation (2.4%). In those who received previous BTK inhibitor therapy, treatment was discontinued due to disease progression in 77% of patients and 23% discontinued due to toxicities or other reasons. High-risk molecular features were common in this patient group, and when present included the presence of a del(17p) or TP53 mutation or both (46.6%), complex karyotype (42%), and unmutated IGHV (84.8%). The Primary endpoint was Overall Response Rate (ORR), and Secondary endpoints included Progression Free Survival and Safety.
Among the patients who had previously received a BTK inhibitor, the ORR with Pirtobrutinib was 73.3% which were mostly Partial Responses. In the subset of patients who had previously received both a BTK inhibitor and a BCL2 inhibitor, the ORR was 70%. In the overall efficacy cohort, the median Progression Free Survival (PFS) at a median follow up of 19.4 months was 19.6 months. The median PFS was 22.1 months among patients who had received a BTK inhibitor but not a BCL2 inhibitor, and the median PFS was 16.8 months in the subset of patients who had previously received both a BTK inhibitor and a BCL2 inhibitor. The most common adverse events were infections, bleeding and neutropenia, and some adverse events that are typically associated with BTK inhibitors such as hypertension, atrial fibrillation or flutter and major hemorrhage occurred less frequently, and only 2.8% discontinued Pirtobrutinib due to a treatment-related adverse event.
It was concluded that Pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL and these data continue to reinforce the ability of Pirtobrutinib to extend the benefit of BTK inhibition for patients with CLL or SLL, following treatment with a covalent BTK inhibitor.
Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. Mato AR, Woyach JA, Brown JR, et al. N Engl J Med 2023;389:33-44.
