On January 27, 2023, pirtobrutinib was granted accelerated approval for treatment of relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a Bruton’s tyrosine kinase (BTK) inhibitor.1 Pirtobrutinib is a noncovalent inhibitor of BTK.
Supporting Efficacy Data
Approval was based on findings in the BRUIN trial (ClinicalTrials.gov identifier NCT03740529), in which 120 patients with prior BTK inhibitor treatment received oral pirtobrutinib at 200 mg once daily until disease progression or unacceptable toxicity. Patients had a median of three prior lines of therapy, with 93% having at least two prior lines. The most common prior BTK inhibitors received were ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%); 83% of patients discontinued their last BTK inhibitor because of refractory or progressive disease.
An objective response on independent review committee assessment using Lugano criteria was observed in 60 patients (50%, 95% confidence interval [CI] = 41%–59%), with a complete response rate in 15 (13%). The estimated median response duration was 8.3 months (95% CI = 5.7 months to not estimable), with an estimated 65.3% of responses persisting at 6 months.
How It Is Used
The recommended dosage is 200 mg once daily until disease progression or unacceptable toxicity. Prescribing information provides instructions on dosage modification, including dose reduction for hematologic adverse reactions, severe renal impairment, and concomitant use with strong CYP3A inhibitors (clarithromycin, erythromycin, diltiazem) and strong or moderate CYP3A inducers (phenobarbital, phenytoin, rifampicin), if such use cannot be avoided.
Among 128 patients in the BRUIN safety population, the most common adverse events of any grade were fatigue (29%), musculoskeletal pain (27%), diarrhea (19%), edema (18%), dyspnea (17%), pneumonia (16%), and bruising (16%). The most common grade 3 or 4 adverse events included pneumonia (14%), musculoskeletal pain (3.9%), and hemorrhage (3.1%). Atrial fibrillation or flutter occurred in 2.7% of patients and was grade 3 or 4 in 1.0%. Second primary malignancies occurred in 6% of patients, including nonmelanoma skin cancer (3.8%), melanoma, and genitourinary and breast cancers. The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (16%), lymphocytes (15%), and platelets (14%).
Serious adverse events occurred in 38% of patients, most commonly pneumonia (14%), COVID-19 infection (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%). Adverse events, most commonly pneumonia, led to treatment discontinuation in 9%. Fatal adverse events occurred in 7% of patients, most commonly infections (4.7%), including COVID-19 infection (3.1%).
Pirtobrutinib has warnings/precautions for infections, hemorrhage, cytopenias, atrial fibrillation and atrial flutter, second primary malignancies, and embryofetal toxicity. Patients should be advised not to breastfeed while receiving pirtobrutinib.
1. Jaypirca (pirtobrutinib) tablets, for oral use, prescribing information, Eli Lilly and Company, January 2023. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216059s000lbl.pdf. Accessed February 6, 2023.