FDA Approves Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma


The FDA has approved pirtobrutinib (Jaypirca) for the treatment of adult patients with relapsed or refractory mantle cell lymphoma following at least 2 lines of systemic therapy, including a BTK inhibitor.



The FDA has approved pirtobrutinib (Jaypirca) for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) following at least 2 lines of systemic therapy, including a BTK inhibitor.1,2

The agent was greenlit under the regulatory agency's Accelerated Approval pathway, with the decision supported by findings from a subset of patients enrolled to the open-label, single-arm phase 1/2 BRUIN trial (NCT03740529).

Pirtobrutinib elicited an overall response rate of 50% (95% CI, 41%-59%) in those who received the agent at a daily dose of 200 mg (n = 120); this included a complete response rate of 13% and a partial response rate of 38%.

The median time to response was 1.8 months (range, 0.8-4.2) and the median duration of response (DOR) was 8.3 months (95% CI, 5.7-not evaluable). The Kaplan-Meier estimate for the 6-month DOR rate was 65.3% (95% CI, 49.8%-77.1%).

"We are pleased to bring a meaningful new therapeutic option to patients with MCL that can reestablish the benefit of targeting the BTK pathway after receiving multiple prior therapies, including a covalent BTK inhibitor," Jacob Van Naarden, chief executive officer of Loxo@Lilly, stated in a press release. "We are grateful to the patients, investigators, and other members of the clinical care teams for their contributions. Our team has been committed to rapidly advancing the development of Jaypirca for patients with MCL, and we look forward to building on this milestone by continuing to bring forward important new treatments for people with hematologic malignancies."

Pirtobrutinib is a highly potent and selective noncovalent BTK inhibitor that has nanomolar potency against wild-type and C481-mutant BTK in cell and enzyme assays. Additionally, favorable pharmacologic properties allow sustained BTK inhibition throughout dosing intervals.

BRUIN consisted of a phase 1 dose-escalation and -expansion portion, which evaluated between 25 mg and 300 mg of pirtobrutinib daily and a phase 2 portion, which evaluated 200 mg of pirtobrutinib daily, both as part of 28-day cycles.

Eligible patients were at least 18 years of age and had an ECOG performance status between 0 and 2, and active disease requiring treatment. Patients were excluded if they had active central nervous system lymphoma or who received allogeneic hematopoietic stem cell transplantation or CAR T-cell therapy within 60 days.

The efficacy assessment was based on the 120 patients with MCL. The median age of these patients was 71 years (range, 46-88). Most patients were male (79%) and White (78%). Moreover, 78% of patients had the classic/leukemic variant of the disease, 12% had pleomorphic MCL, and 11% had blastoid MCL. The simplified Mantle Cell Lymphoma International Prognostic Index score was low, intermediate, and high in 15%, 59%, and 26% of patients, respectively.

Additionally, patients had received a median of 3 previous lines of therapy, with a range of 1 to 9 lines of treatment. Notably, 93% of patients had received at least 2 prior lines of treatment. All participants received 1 or more prior lines of therapy that contained a BTK inhibitor. Other previous therapies included chemoimmunotherapy (88%), hematopoietic stem cell transplant (20%), lenalidomide (Revlimid; 18%), and CAR-T therapy (9%).

The most common prior BTK inhibitors received included ibrutinib (67%), followed by acalabrutinib (30%), and zanubrutinib (8%). Eighty-three percent of patients discontinued their last BTK inhibitor because of refractory or progressive disease, 10% did so due to toxicity, and 5% discontinued for other unspecified reasons.

Data from the pooled safety analysis of the full study population (n = 583) indicated that the most common toxicities experienced with pirtobrutinib were decreased neutrophil count, decreased hemoglobin, decreased platelet count, fatigue, musculoskeletal pain, decreased lymphocyte count, bruising, and diarrhea.

Of the 128 patients with MCL, 36% received the agent for at least 6 months and 10% received it for 1 year or longer. The most common AEs to occur in 10% or more of patients with MCL who received pirtobrutinib included fatigue (all-grade, 29; grade 3/4, 1.6%), edema (18%; 0.8%), fever (13%; 0%), musculoskeletal pain (27%; 3.9%), arthritis or arthralgia (12%; 0.8%), diarrhea (19%; 0%), constipation (13%; 0%), abdominal pain (11%; 0.8%), nausea (11%; 0%), dyspnea (17%; 2.3%), cough (14%; 0%), bruising (16%; 0%), pneumonia (16%; 14%), upper respiratory tract infections (10%; 0.8%), peripheral neuropathy (14%; 0.8%), dizziness (10%; 0%), rash (14%; 0%), and hemorrhage (11%; 3.1%).

Dose reductions and treatment interruptions due to AEs were required in 4.7% and 32% of patients, respectively. Moreover, 9% of patients experienced AEs that led to permanent discontinuation of pirtobrutinib.

Thirty-eight percent of patients experienced serious AEs. Serious toxicities that occurred in 2% or more of patients included pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%).

Continued approval for the indication may be contingent upon verification of clinical benefit in a confirmatory trial. To this end, The phase 3 BRUIN MCL-321 trial (NCT04662255) is currently enrolling participants.


  1. US 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://investor.lilly.com
  2. Pirtobrutinib (Jaypirca) prescribing information. Eli Lilly and Company; Accessed January 2023. https://pi.lilly.com/us/jaypirca-uspi.pdf?s=pi

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