On December 1, 2023, pirtobrutinib (Jaypirca), a selective, noncovalent  Bruton’s tyrosine kinase (BTK) inhibitor that inhibits both wild-type and C481-mutant BTK with equal low nanomolar potency and is designed to address several of the limitations of covalent BTK inhibitors, was granted accelerated approval for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two prior lines of therapy (including a BTK inhibitor and a B-cell lymphoma 2 inhibitor).¹

Supporting Efficacy Data

Approval was based on the multicohort BRUIN trial (ClinicalTrials.gov identifier NCT03740529), in which 108 evaluable patients received oral pirtobrutinib at 200 mg once daily until disease progression or unacceptable toxicity. Patients had received a median of five prior lines of therapy (range = 2–11). A total of 77% of patients discontinued their last BTK inhibitor for refractory or progressive disease.

Objective responses (all partial) on independent review committee assessment were observed in 78 patients (72%, 95% confidence interval [CI] = 63%–80%). Median response duration was 12.2 months (95% CI = 9.3–14.7 months).

How It Is Used

The recommended pirtobrutinib dose is 200 mg orally once daily until disease progression or unacceptable toxicity. Prescribing information provides instructions on dosage modification, including dose reduction, for adverse reactions. Concomitant use with strong CYP3A inhibitors (eg, clarithromycin, erythromycin, fluconazole) and strong or moderate CYP3A inducers (eg, glucocorticoids, rifampin, phenobarbital) should be avoided.

Safety Profile

Among the patients who received pirtobrutinib in the BRUIN trial cohort, the most common adverse events of any grade included fatigue (36%), bruising (36%), cough (33%), musculoskeletal pain (32%), COVID-19 infection (28%), pneumonia (27%), diarrhea (26%), abdominal pain (25%), dyspnea (22%), hemorrhage (22%), edema  (21%), nausea (21%), pyrexia (20%), and headache (20%).

The most common grade 3 or 4 adverse events included renal insufficiency (6%), supraventricular tachycardia (5%), and peripheral neuropathy (3.6%). Overall, serious infection occurred in 32% of patients. The most common grade 3 or 4 laboratory abnormalities were decreases in neutrophil count (45%), hemoglobin (19%), and platelet count (15%).

Serious adverse events occurred in 56% of patients, most commonly pneumonia (18%), COVID-19 infection (9%), sepsis (7%), and febrile neutropenia (7%). Adverse events led to discontinuation of treatment in 9%, most commonly second primary malignancy, COVID-19 infection, and sepsis. Fatal adverse events occurred in 11% of patients, most commonly infections (10%), including sepsis (5%) and COVID-19 (2.7%).

Pirtobrutinib has warnings/precautions for infections, hemorrhage, cytopenias, cardiac arrhythmia, second primary malignancies, and embryofetal toxicity. Patients should be advised not to breastfeed while receiving pirtobrutinib. 

REFERENCE

1. Jaypirca (pirtobrutinib) tablets, for oral use, prescribing information, Eli Lilly and Company, December 2023. Available at https://www.jaypirca.com. Accessed December 15, 2023.