FDA Grants Pirtobrutinib Accelerated Approval for Relapsed/Refractory MCL

The FDA has approved pirtobrutinib (Jaypirca) for patients with relapsed or refractory mantle cell lymphoma (MCL) who have already undergone treatment with at least 2 lines of systemic therapy, including a BTK inhibitor. The prescribing label comes with warnings for infections, hemorrhage, cytopenias, atrial fibrillation and flutter, second primary malignant tumors, and embryo-fetal toxicity.^1,2

The approval is supported by data from the phase 1/2 BRUIN trial (NCT03740529), which assessed previously treated patients with MCL (n=120). Following 200 mg of daily pirtobrutinib, the overall response rate (ORR) was 50% (95% CI, 41%-59%). This included a complete response rate of 13% (n=15) and a partial response rate of 38% (n=45).¹

Moreover, the median time to response was 1.8 months (range, 0.8-4.2). The median duration of response (DOR) was 8.3 months (95% CI, 5.7-not estimable). At 6 months, response was maintained in 65.3% (95% CI, 49.8%-77.1%) of patients.¹

The treatment should be swallowed whole with water, with or without food. It should not be cut, crushed, or chewed. For patients with severe renal impairment, a reduced dose is advised.²

“The approval of [pirtobrutinib] represents an important advance for patients with relapsed or refractory MCL who currently have limited options and historically have had a poor prognosis following discontinuation of treatment with a covalent BTK inhibitor,” Michael Wang, MD, stated in a press release.¹ Wang is Puddin Clarke Endowed Professor in the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center in Houston.

“These data indicate that [pirtobrutinib] can provide efficacy in patients previously treated with a covalent BTK inhibitor, potentially extending the time patients may benefit from BTK inhibition therapy,” Wang said. “[Pirtobrutinib] offers a new approach to targeting the BTK pathway following treatment with a covalent BTK inhibitor and has the potential to meaningfully [affect] the treatment paradigm for [patients with] relapsed and refractory MCL.”

The trial included a phase 1 dose-escalation phase, a phase 1b combination arm, and a phase 2 dose-expansion phase. Maximum-tolerated dose represented the primary end point for phase 1 of the study. Secondary end points included safety, pharmacokinetics (PK), and preliminary efficacy measured by ORR for monotherapy. In the phase 1b setting, drug combination safety represented the primary end point, and the secondary end points were PK and preliminary efficacy measured by ORR for the drug combinations.³

The median number of prior lines of therapy was 3 lines (range, 1-9), and 93% of patients had undergone at least 2 prior lines. A total of 83% of patients needed to discontinue their previous BTK inhibitor because of refractory or progressive disease.²

The safety analysis for pirtobrutinib included 583 patients with hematologic malignancies who received the treatment daily as a single agent. In this cohort, the most common adverse events (AEs) included decreased neutrophil count, decreased hemoglobin level, decreased platelet count, fatigue, musculoskeletal pain, decreased lymphocyte count, bruising, and diarrhea.

Of the patients with MCL who received pirtobrutinib (n=128), 36% remained on treatment for at least 6 months and 10% remained on treatment for at least 1 year. Dose reductions were necessary in 4.7% of patients, treatment interruptions were required in 32%, and permanent discontinuation occurred in 9% of patients. Pneumonia necessitated permanent discontinuation in more than 1% of patients. Other serious AEs included COVID-19 infection (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%). Pneumonia occurred in 14% of patients.^1,2

Patients receiving pirtobrutinib should be monitored for signs and symptoms of infection, bleeding, and symptoms of arrythmias. The prescribing label comes with warnings for infections, hemorrhage, and cytopenia. Complete blood counts should be monitored for potential cytopenia, and patients should be advised that the treatment comes with a potential risk of secondary primary malignant tumors. In addition, because pirtobrutinib can cause fetal harm, effective contraception is advised.²

The label advises against concomitant use with strong CYP3A inhibitors and strong to moderate CYP3A inducers. If concomitant use with a CYP3A inhibitor is unavoidable, pirtobrutinib dose should be reduced. If concomitant use with a CYP3A inducer is unavoidable, pirtobrutinib dose should be increased. The treatment is also sensitive to CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP substrates; the label provides specific coadministration recommendations for these substrates.²

Pirtobrutinib should be taken at approximately the same time each day. If a dose is missed by more than 12 hours, it should not be made up; rather, the patient should take the next dose as scheduled.²

References

1. U.S. FDA approves Jaypirca (pirtobrutinib), the first and only non-covalent (reversible) BTK inhibitor, for adult patients with relapsed or refractory mantle cell lymphoma after at least two lines of systemic therapy, including a BTK inhibitor. News release. Eli Lilly & Co. January 27, 2023. Accessed January 27, 2023. https://bit.ly/3DnePpM
2. Jaypirca. Prescribing information. Eli Lilly & Co; 2023. Accessed January 27, 2023. https://bit.ly/3mU7ngG
3. Mato AR, Woyach JA, Brown JR, et al. Efficacy of pirtobrutinib in covalent BTK-inhibitor pretreated relapsed / refractory mantle cell lymphoma: additional patients and extended follow-up from the phase 1/2 BRUIN study. Blood. 2022;140(suppl 1):2316-2320. doi:10.1182/blood-2022-159497