1.1 Mantle Cell Lymphoma

JAYPIRCA is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor.

This indication is approved under accelerated approval based on response rate [see Clinical Studies (14.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

2.1 Recommended Dosage

The recommended dosage of JAYPIRCA is 200 mg orally once daily until disease progression or unacceptable toxicity.

Advise patients of the following:

• Swallow tablets whole with water. Do not cut, crush, or chew tablets.
• Take JAYPIRCA at the same time each day. JAYPIRCA may be taken with or without food.
• If a dose of JAYPIRCA is missed by more than 12 hours, do not make up the dose and take the next dose as scheduled.

2.2 Dosage Modifications for Adverse Reactions

Recommended dosage modifications of JAYPIRCA for adverse reactions are presented in Table 1 [see Warnings and Precautions (5.1, 5.2, 5.3, and 5.4)].

2.3 Dosage Modifications for Patients with Severe Renal Impairment

For patients with severe renal impairment (eGFR 15-29 mL/min), reduce the JAYPIRCA dose to 100 mg once daily if the current dose is 200 mg once daily otherwise reduce the dose by 50 mg. If the current dosage is 50 mg once daily, discontinue JAYPIRCA [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. No dosage adjustment of JAYPIRCA is recommended in patients with mild to moderate renal impairment (eGFR 30-89 mL/min).

2.4 Dosage Modifications for Concomitant Use with Strong CYP3A Inhibitors

Avoid concomitant use of strong CYP3A inhibitors with JAYPIRCA [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. If concomitant use of a strong CYP3A inhibitor is unavoidable, reduce the JAYPIRCA dose by 50 mg. If the current dosage is 50 mg once daily, interrupt JAYPIRCA treatment for the duration of strong CYP3A inhibitor use. After discontinuation of a strong CYP3A inhibitor for 5 half-lives, resume the JAYPIRCA dose that was taken prior to initiating the strong CYP3A inhibitor.

2.5 Dosage Modifications for Concomitant Use with CYP3A Inducers

Avoid concomitant use of strong or moderate CYP3A inducers with JAYPIRCA [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. If concomitant use with moderate CYP3A inducers is unavoidable and the current dosage of JAYPIRCA is 200 mg once daily, increase the dose to 300 mg. If the current dosage is 50 mg or 100 mg once daily, increase the dose by 50 mg.

5.1 Infections

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients treated with JAYPIRCA. In the clinical trial, Grade 3 or higher infections occurred in 17% of 583 patients, most commonly pneumonia (9%), with fatal infections occurring in 4.1% of patients. Sepsis occurred in 4.5% of patients and febrile neutropenia in 2.9%. Opportunistic infections after treatment with JAYPIRCA have included, but are not limited to, Pneumocystis jirovecii pneumonia and fungal infection.

Consider prophylaxis, including vaccinations and antimicrobial prophylaxis, in patients who are at increased risk for infections, including opportunistic infections. Monitor patients for signs and symptoms of infection, evaluate promptly, and treat appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue JAYPIRCA [see Dosage and Administration (2.2)].

5.2 Hemorrhage

Fatal and serious hemorrhage has occurred with JAYPIRCA. Major hemorrhage (defined as Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 2.4% of 583 patients treated with JAYPIRCA, including gastrointestinal hemorrhage; fatal hemorrhage occurred in 0.2% of patients. Bleeding of any grade, excluding bruising and petechiae, occurred in 14% of patients.

Major hemorrhage occurred in 1.7% of patients taking JAYPIRCA without antithrombotic agents and 0.7% of patients taking JAYPIRCA with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with JAYPIRCA. Monitor patients for signs of bleeding. Based on severity of bleeding, reduce dose, temporarily withhold, or permanently discontinue JAYPIRCA [see Dosage and Administration (2.2)].

Consider the benefit-risk of withholding JAYPIRCA for 3 to 7 days pre- and post-surgery depending upon the type of surgery and risk of bleeding.

5.3 Cytopenias

Grade 3 or 4 cytopenias, including neutropenia (24%), anemia (11%), and thrombocytopenia (11%) have developed in patients treated with JAYPIRCA. In the clinical trial, Grade 4 neutropenia developed in 13% of patients and Grade 4 thrombocytopenia developed in 5% of patients.

Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue JAYPIRCA [see Dosage and Administration (2.2)].

5.4 Atrial Fibrillation and Atrial Flutter

Atrial fibrillation and atrial flutter were reported in recipients of JAYPIRCA. Atrial fibrillation or flutter were reported in 2.7% of patients, with Grade 3 or 4 atrial fibrillation or flutter reported in 1.0% of 583 patients in the clinical trial. Patients with cardiac risk factors, such as hypertension, or previous arrhythmias may be at increased risk.

Monitor for signs and symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea) and manage appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue JAYPIRCA [see Dosage and Administration (2.2)].

5.5 Second Primary Malignancies

Second primary malignancies, including non-skin carcinomas, developed in 6% of 583 patients treated with JAYPIRCA monotherapy. The most frequent malignancy was non-melanoma skin cancer, reported in 3.8% of 583 patients. Other second primary malignancies included solid tumors (including genitourinary and breast cancers) and melanoma. Advise patients to use sun protection and monitor patients for the development of second primary malignancies.

5.6 Embryo-Fetal Toxicity

Based on findings in animals, JAYPIRCA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of pirtobrutinib to pregnant rats during the period of organogenesis caused embryo-fetal toxicity including embryo-fetal mortality and malformations at maternal exposures (AUC) approximately 3-times the recommended dose of 200 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in the general patient population.

The data in the WARNINGS AND PRECAUTIONS reflect exposure to JAYPIRCA as a single-agent, administered at 200 mg once daily in 583 patients with hematologic malignancies in the BRUIN study. Among these 583 patients, the median duration of exposure was 7.5 months, 56% were exposed for at least 6 months and 29% were exposed for at least one year.

In this pooled safety population, the most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased neutrophil count (41%), decreased hemoglobin (37%), decreased platelet count (27%), fatigue (27%), musculoskeletal pain (26%), decreased lymphocyte count (24%), bruising (20%), and diarrhea (20%).

7.1 Effect of Other Drugs on JAYPIRCA

7.2 Effect of JAYPIRCA on Other Drugs

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

Based on findings from animal studies, JAYPIRCA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

Safety and effectiveness of JAYPIRCA have not been established in pediatric patients.

8.5 Geriatric Use

Of the patients with MCL who received the 200 mg dose of JAYPIRCA in BRUIN, 93 (78%) were 65 years of age and older and 39 (33%) were 75 years and older [see Clinical Studies (14.1)]. Clinical studies of JAYPIRCA did not include sufficient numbers of patients with MCL who were less than 65 years of age to determine whether older patients respond differently from younger adult patients.

In the pooled safety population in patients with hematologic malignancies, 392 (67%) were 65 years of age and older, while 153 (26%) were 75 years of age and older. Patients aged 65 years and older experienced higher rates of Grade 3 and higher adverse reactions and serious adverse reactions compared to patients who were less than 65 years of age.

8.6 Renal Impairment

Severe renal impairment (eGFR15-29 mL/min) increases pirtobrutinib exposure [see Clinical Pharmacology (12.3)]. Reduce the JAYPIRCA dosage in patients with severe renal impairment [see Dosage and Administration (2.3)]. No dosage adjustment of JAYPIRCA is recommended in patients with mild (60-89 mL/min) or moderate (30-59 mL/min) renal impairment.

8.7 Hepatic Impairment

No dosage adjustment of JAYPIRCA is recommended in patients with mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST), or severe hepatic impairment (total bilirubin > 3 × ULN and any AST) [see Clinical Pharmacology (12.3)].

12.1 Mechanism of action

Pirtobrutinib is a small molecule, noncovalent inhibitor of BTK. BTK is a signaling protein of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. Pirtobrutinib binds to wild type BTK and BTK harboring C481 mutations, leading to inhibition of BTK kinase activity. In nonclinical studies, pirtobrutinib inhibited BTK-mediated B-cell CD69 expression and inhibited malignant B-cell proliferation. Pirtobrutinib showed dose-dependent anti-tumor activities in BTK wild type and BTK C481S mutant mouse xenograft models.

12.2 Pharmacodynamics

At the recommended dosage of 200 mg once daily, pirtobrutinib trough concentrations exceeded the BTK IC96. BTK occupancy is maintained throughout the dosing interval, regardless of the intrinsic rate of BTK turnover.

12.3 Pharmacokinetics

The pharmacokinetics of pirtobrutinib were characterized in healthy subjects and in patients with cancer. Pirtobrutinib exposure (AUC) and Cmax increases proportionally following single oral doses ranging from 300 mg to 800 mg (1.5 to 4 times the approved recommended dosage) and once daily doses ranging from 25 – 300 mg (0.125 to 1.5 times the recommended dosage). Steady state was achieved within 5 days of once daily dosing, and the mean (CV%) accumulation ratio was 1.63 (26.7%) based on AUC after administration of 200 mg dosages.

Following administration of the recommended dosage, the geometric mean (CV%) steady-state AUC and Cmax of pirtobrutinib were 91300 h*ng/mL (41%) and 6460 ng/mL (26%), respectively. The geometric mean (CV%) AUC0-24 and Cmax of pirtobrutinib on Cycle 1 Day 8 were 81800 h*ng/mL (66.6%) and 3670 ng/mL (89.5%), respectively.

13.1 Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenicity studies have not been conducted with pirtobrutinib.

Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenic in in vitro micronucleus assays using human peripheral blood lymphocytes. Pirtobrutinib was not genotoxic in an in vivo rat bone marrow micronucleus assay at doses up to 2000 mg/kg.

Studies to assess the effects of pirtobrutinib on fertility have not been conducted. In repeat-dose toxicity studies of up to 3-months duration conducted with pirtobrutinib in rats and dogs, no effects on male or female reproductive organs were identified.

14.1 Mantle Cell Lymphoma

The efficacy of JAYPIRCA in patients with MCL was evaluated in BRUIN [NCT03740529], an open-label, international, single-arm study of JAYPIRCA as monotherapy. Efficacy was based on 120 patients with MCL treated with JAYPIRCA who were previously treated with a BTK inhibitor. JAYPIRCA was given orally at a dose of 200 mg once daily and was continued until disease progression or unacceptable toxicity. Patients with active central nervous system lymphoma or allogeneic hematopoietic stem cell transplantation (HSCT) or CAR-T cell therapy within 60 days were excluded.

The median age was 71 years (range: 46 to 88 years); 79% were male; 78% were White, 14% Asian, 1.7% Black or African American. Seventy-eight percent of patients had the classic/leukemic variant of MCL, 12% had pleomorphic MCL, and 11% had blastoid MCL. The simplified Mantle Cell Lymphoma International Prognostic Index (sMIPI) score was low in 15%, intermediate in 59%, and high in 26% of patients. Patients received a median number of 3 prior lines of therapy (range: 1 to 9) with 93% having received 2 or more prior lines. All received 1 or more prior lines of therapy containing a BTK inhibitor; other prior therapies included chemoimmunotherapy in 88%, HSCT in 20%, lenalidomide in 18%, and CAR-T therapy in 9%. The most common prior BTK inhibitors received were ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%). Patients may have received more than one prior BTK inhibitor; 83% of patients discontinued the last BTK inhibitor for refractory or progressive disease, 10% discontinued for toxicity, and 5% discontinued for other reasons.

Efficacy was based on overall response rate (ORR) and duration of response (DOR), as assessed by an independent review committee (IRC) using 2014 Lugano criteria. Efficacy results are shown in Table 4. Additionally, the Kaplan-Meier estimate for the DOR rate at 6 months was 65.3% (95% CI: 49.8, 77.1).

Infections

Advise patients that JAYPIRCA can cause serious infections that may be fatal. Advise patients to report any signs or symptoms of infection (e.g., fever, chills, weakness) [see Warnings and Precautions (5.1)].

Hemorrhage

Inform patients to report signs or symptoms of bleeding. Inform patients that JAYPIRCA may need to be interrupted for major surgeries [see Warnings and Precautions (5.2)].

Cytopenias

Advise patients of the need for periodic monitoring of blood counts during treatment with JAYPIRCA [see Warnings and Precautions (5.3)].

Atrial Fibrillation and Atrial Flutter

Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Warnings and Precautions (5.4)].

Second Primary Malignancies

Inform patients that other malignancies have been reported in patients who have been treated with JAYPIRCA, including skin cancer and other solid tumors. Advise patients to use sun protection and to have monitoring for development of other cancers [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)].

Advise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose [see Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with JAYPIRCA and for one week after the last dose [see Use in Specific Populations (8.2)].

Administration

Inform patients to take JAYPIRCA orally once daily at approximately the same time each day with or without food and how to make up a missed dose. Advise patients to swallow tablets whole with water. Advise patients not to cut, crush, or chew tablets [see Dosage and Administration (2.1)].

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