FDA Approves Pirtobrutinib for Patients With MCL


Based on findings from the phase 1/2 BRUIN trial, pirtobrutinib has been approved by the FDA for patients with relapsed/refractory mantle cell lymphoma.

The FDA has granted approval to pirtobrutinib (Jaypirca) for the treatment of adult patients with relapsed/refractory mantle cell lymphoma (MCL) who previously received at least 2 lines of systemic therapy, including a Bruton's tyrosine kinase (BTK) inhibitor.1

The basis of the approval comes from findings of the phase 1/2 BRUIN trial. Results showed that covalent BTK inhibitor pre-treated patients with relapsed/refractory MCL reached an overall response rate of 50% when treated with pirtobrutinib. Further, 13% of patients achieved a complete response (CR) at time of analysis.

This approval for pirtobrutinib marks the first BTK inhibitor of any kind to be approved for patients with MCL treated with a prior covalent BTK inhibitor.

"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," said Michael Wang, MD, Puddin Clarke endowed professor of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center, in a press release announcing the approval. "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. [Pirtobrutinib] offers a new approach to targeting the BTK pathway following treatment with a covalent BTK inhibitor and has the potential to meaningfully impact the treatment paradigm for relapsed and refractory [patients with] MCL."

Pirtobrutinib is a highly selective kinase inhibitor. The agent uses a novel binding mechanism and has the potential to reestablish BTK inhibition in patients with MCL previously treated with a covalent BTK inhibitor, including ibrutinib (Imbruvica), acalabrutinib (Calquence), or zanubrutinib (Brukinsa). Moreover, pirtobrutinib may extend the benefit of targeting the BTK pathway.

In the phase 1/2 BRUIN trial, investigators evaluated the efficacy of pirtobrutinib at 200 mg given once daily until disease progression or unacceptable toxicity in 120 patients with MCL.

Among those enrolled in the study, the median prior lines of therapy were 3 (range, 1-9), 93% of patients had 2 or more prior lines, and all patients received 1 or more prior lines of therapy containing a covalent BTK inhibitor. A total of 83% of patients discontinued their last BTK inhibitor because of refractory or progressive disease.

Investigators evaluated efficacy based on overall response rate (ORR) and duration of response (DOR) as assessed by an independent review committee (IRC) using 2014 Lugano criteria.The primary end point of the study was progression-free survival (PFS), and secondary end points included event-free survival, time to treatment failure, time to worsening of MCL-related symptoms, comparative tolerability, ORR, DOR, and overall survival.

Findings showed that among the 120 enrolled patients with MCL, the agent elicited an ORR of 50% (95% CI, 41%-59%) among those given pirtobrutinib at a daily dose of 200 mg. This included a CR rate of 13% and a partial response rate of 38%. Median time to response was 1.8 months (range, 0.8-4.2) and the median duration of response among patients was 8.3 months (95% CI, 5.7-not evaluable).

Regarding safety, 128 patients with MCL were evaluated, 36% of whom were exposed to treatment for 6 months or longer. Another 10% evaluated for safety were exposed for at least 1 year. Adverse events (AEs) which resulted in dose reductions were seen in 4.7% of patients, treatment interruptions were observed in 32%, and permanent discontinuation of the study drug were seen in 9% of patients.

Further, permanent discontinuation of pirtobrutinib was linked with AEs in more than 1% of patients. Serious AEs were observed in 38% of patients, and AEs which occurred in greater than or equal to 2% of patients included pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%).

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. Loxo@Lilly. January 27, 2023. Accessed January 27, 2023. https://prn.to/3RdCyOT
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