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 Pharmacodynamic properties (5.1)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma

Jaypirca as monotherapy is indicated for the treatment of adult patients with relapsed or refractory

chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) who have been previously treated with a BTK inhibitor. 

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 split, 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. 

Dosage Modifications for Adverse Reactions 

Recommended dosage modifications of JAYPIRCA for adverse reactions are presented in Table 1 [see Special warnings and precautions for use (4.4)].

Table 1: Recommended Dosage Modification of JAYPIRCA for Adverse Reactions 

Dose modification is not recommended for asymptomatic lymphocytosis. Asymptomatic lipase increase may not necessarily warrant dose modification.

^a Evaluate the benefit-risk before resuming treatment at the same dose for a Grade 4 non-hematological toxicity.

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 Undesirable effects (4.8), Pharmacokinetic properties (5.2)]. No dosage adjustment of JAYPIRCA is recommended in patients with mild to moderate renal impairment (eGFR 30-89 mL/min). 

Dosage Modifications for Concomitant Use with Strong CYP3A Inhibitors 

Avoid concomitant use of strong CYP3A inhibitors with JAYPIRCA [see Interaction with other medicinal products and other forms of interaction (4.5), Pharmacokinetic properties (5.2)]. 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.

Dosage Modifications for Concomitant Use with CYP3A Inducers 

Avoid concomitant use of strong or moderate CYP3A inducers with JAYPIRCA [see Interaction with other medicinal products and other forms of interaction (4.5), Pharmacokinetic properties (5.2)]. 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.

Method of administration 

Oral use 

Infections 

Fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients treated with JAYPIRCA. Across clinical trials, Grade 3 or higher infections occurred in 24-26% of 704 patients, most commonly pneumonia (14-22%%), with fatal infections occurring in 4. 4-8% of patients. Sepsis occurred in 4.3-6% of patients and febrile neutropenia in 2.6-4.1%. In patients with CLL/SLL, Grade 3 or higher infections occurred in 29-33% of patients, with fatal infections occurring in 3.4-8%. Opportunistic infections after treatment with JAYPIRCA have included, but are not limited to, Pneumocystis jirovecii pneumonia and fungal infection [see Undesirable effects (4.8)]. 

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 Posology and method of administration (4.2)].

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 1.7-2.7%% of 704 patients treated with JAYPIRCA across clinical trials, including gastrointestinal hemorrhage; fatal hemorrhage occurred in 0-0. 3% of patients. Bleeding of any grade, excluding bruising and petechiae, occurred in 11-17% of patients [see Undesirable effects (4.8)]. 

Major hemorrhage occurred in 0.9-2.2% 2.3% of patients taking JAYPIRCA without antithrombotic agents and 0.5-0.9% % 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 Posology and method of administration (4.2)].

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.

Cytopenias 

JAYPIRCA can cause cytopenias, including neutropenia, thrombocytopenia, and anemia.

Across clinical trials, Grade 3 or 4 cytopenias, including decreased neutrophils (26%), decreased platelets (12-17%%), and decreased hemoglobin (10-12%) developed in patients treated with JAYPIRCA. Grade 4 decreased neutrophilsdeveloped in 12-15%% of patients and Grade 4 decreased platelets developed in 6-9% of patients [see Undesirable effects (4.8)].

Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue JAYPIRCA [see Posology and method of administration (4.2)].

Cardiac Arrhythmias 

Cardiac arrhythmias, including atrial fibrillation and atrial flutter, were reported in recipients of JAYPIRCA. Atrial fibrillation or flutter were reported in 2.6-3.6% of patients, with Grade 3 or 4 atrial fibrillation or flutter reported in 1.5-1.7% of 704 patients across clinical trials [see Adverse Reactions (6.1)]. Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred in 0.5-1.7% of patients. 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 Posology and method of administration (4.2)].

Second Primary Malignancies 

Second primary malignancies, including non-skin carcinomas, developed in 7-9% of 704 patients treated with JAYPIRCA monotherapy across clinical trials. The most frequent malignancy was non-melanoma skin cancer, reported in 3.4-4.6% of 704 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.

Hepatotoxicity, Including Drug-Induced Liver Injury

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including JAYPIRCA. Evaluate bilirubin and transaminases at baseline and throughout treatment with JAYPIRCA. For patients who develop abnormal liver tests after JAYPIRCA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold JAYPIRCA. Upon confirmation of DILI, discontinue JAYPIRCA.

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 Fertility, pregnancy and lactation (4.6)].

Effect of Other Drugs on JAYPIRCA 

Strong CYP3A Inhibitors

Pirtobrutinib is a CYP3A substrate. Concomitant use of JAYPIRCA with a strong CYP3A inhibitor increased pirtobrutinib systemic exposure [see Pharmacokinetic properties (5.2)], which may increase the risk of JAYPIRCA adverse reactions. Avoid concomitant use of strong CYP3A inhibitors during treatment with JAYPIRCA. If concomitant use of strong CYP3A inhibitors is unavoidable, reduce the JAYPIRCA dosage [see Posology and method of administration (4.2)]. 

Strong or Moderate CYP3A Inducers

Concomitant use of JAYPIRCA with a strong or moderate CYP3A inducer decreased pirtobrutinib systemic exposure [see Pharmacokinetic properties (5.2)], which may reduce JAYPIRCA efficacy. Avoid concomitant use of JAYPIRCA with strong or moderate CYP3A inducers. If concomitant use of moderate CYP3A inducers is unavoidable, increase the JAYPIRCA dosage [see Posology and method of administration (4.2)].

If the current pirtobrutinib dose is 200 mg, consider increasing the dose to 300 mg once daily when coadministering with moderate or strong CYP3A inducers.Effect of JAYPIRCA on Other Drugs 

Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP Substrates

JAYPIRCA is a P-gp inhibitor, a moderate CYP2C8 and BCRP inhibitor, and a weak CYP2C19 and CYP3A inhibitor. Concomitant use of JAYPIRCA with sensitive P-gp, CYP2C8, BCRP, CYP2C19, or CYP3A substrates increased their plasma concentrations [see Pharmacokinetic properties (5.2)], which may increase the risk of adverse reactions related to these substrates for drugs which are sensitive to minimal concentration changes. Follow recommendations for sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP substrates provided in their approved product labeling.

Pregnancy 

Risk Summary

Based on findings from animal studies, JAYPIRCA can cause fetal harm when administered to a pregnant woman. There are no available data on JAYPIRCA use in pregnant women to evaluate for a drug-associated risk. In an animal reproduction study, administration of pirtobrutinib to pregnant rats during organogenesis resulted in adverse developmental outcomes, including structural abnormalities, altered fetal growth, and embryo-fetal mortality, at maternal exposures approximately 3-times those in patients at the recommended daily dose of 200 mg (see Data). Advise pregnant women of the potential risk to a fetus.

The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In an embryo-fetal development study in rats, pregnant animals were administered oral doses of pirtobrutinib at up to 500 mg/kg twice daily during the period of organogenesis. Doses ≥ 375 mg/kg twice daily caused decreased fetal body weights and increased incidence of malformations and variations in the urinary tract (including absent or abnormal ureters and kidneys), reproductive tract (malpositioned ovaries and misshapen uterus), and bone (misshapen sternebrae). At 500 mg/kg twice daily, total resorption was observed. At 375 mg/kg twice daily in rats, the maternal systemic exposures (AUC) were approximately 3 times the human exposure at 200 mg once daily.

Lactation 

Risk Summary

There are no data on the presence of pirtobrutinib in human milk or the effects on the breastfed child or milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with JAYPIRCA and for one week after the last dose.

Females and Males of Reproductive Potential 

Based on findings from animal studies, JAYPIRCA can cause fetal harm when administered to a pregnant woman [see Fertility, pregnancy and lactation (4.6)].

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating JAYPIRCA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose.

No studies have been conducted to determine the effects of pirtobrutinib on the ability to drive or use machines.

The following clinically significant adverse reactions are described elsewhere in the labeling:

·    Infections [see Special warnings and precautions for use (4.4)].

·    Hemorrhage [see Special warnings and precautions for use (4.4)].

·    Cytopenias [see Special warnings and precautions for use (4.4)].

·    Atrial Fibrillation and Atrial Flutter [see Special warnings and precautions for use (4.4)].

·    Second Primary Malignancies [see Special warnings and precautions for use (4.4)].

·    Hepatotoxicity, including DILI [see Special warnings and precautions for use (4.4)]

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 704 patients with hematologic malignancies in the BRUIN and the BRUIN-CLL-321 studies. Among these 704 patients, the median duration of exposure was 10 months in BRUIN and 15 months in BRUIN CLL-321, 62% were exposed for at least 6 months and 45% were exposed for at least one year in BRUIN, while 78% were exposed for at least 6 months and 66% were exposed for at least one year in BRUIN CLL-321.

The most common (≥ 30%) adverse reactions, including laboratory abnormalities, across clinical trials were: decreased neutrophil count, decreased hemoglobin, fatigue, decreased platelets, decreased leukocytes, and decreased lymphocyte count.

Mantle Cell Lymphoma

BRUIN– Open-label, international, multicohort, single-arm study in previously treated patients with B-cell malignancies Cohort: Patients with MCL who received a prior BTK inhibitor

The safety of JAYPIRCA was evaluated in the BRUIN trial in patients with MCL who received a prior BTK inhibitor [see Special warnings and precautions for use (4.4)]. The trial required a platelet count ≥ 50 x 10⁹/L, absolute neutrophil count ≥ 0.75 x 10⁹/L, hepatic transaminases ≤ 2.5 times upper limit of normal (ULN), and an ECOG performance status of 0 to 2. The trial excluded patients with active central nervous system (CNS) involvement by lymphoma, significant cardiovascular disease, major bleeding or grade ≥ 3 arrhythmia with a prior BTK inhibitor, prolonged QTc interval, or need for a strong CYP3A inhibitor or inducer or strong P-gp inhibitor.

Patients received JAYPIRCA 200 mg orally once daily until disease progression or unacceptable toxicity (n = 128); 36% were exposed for 6 months or longer and 10% were exposed for at least one year. The median number of prior therapies was 3 (range: 1-9). The median age was 71 years (range: 46 to 88 years) and 80% of patients were male. Race was reported for all patients; 78% were White, 14% were Asian, 2.3% were Black, and 2.3% were Hispanic or Latino.

Serious adverse reactions occurred in 38% of patients who received JAYPIRCA. Serious adverse reactions that occurred in ≥ 2% of patients were pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%). Fatal adverse reactions within 28 days of the last dose of JAYPIRCA occurred in 7% of patients, most commonly due to infections (4.7%) including COVID-19 (3.1% of all patients).

Adverse reactions led to dose reductions in 4.7%, treatment interruption in 32%, and permanent discontinuation of JAYPIRCA in 9%. Adverse reactions that resulted in dosage modification in > 5% of patients included pneumonia and neutropenia. Adverse reactions which resulted in permanent discontinuation of JAYPIRCA in > 1% of patients included pneumonia.

The most common adverse reactions (≥ 15%), excluding laboratory terms, were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising.

Table 2 summarizes select adverse reactions in BRUIN.

Table 2:              Adverse Reactions (≥ 10%) in Patients with MCL Who Received JAYPIRCA 

^a Each term listed includes other related terms.

^b includes 1 fatality from COVID-19 pneumonia.

^c includes 1 fatality from hemorrhage.

Clinically relevant adverse reactions in < 10% include vision changes, memory changes, headache, urinary tract infection, herpesvirus infection, and tumor lysis syndrome.

Table 3 summarizes laboratory abnormalities in BRUIN.

Table 3:      Select Laboratory Abnormalities (≥ 10%) That Worsened from Baseline in Patients with MCL Who Received JAYPIRCA 

^a  The denominator used to calculate the rate varied from 90 to 127 based on the number of patients with a baseline value and at least one post-treatment value.

Grade 4 laboratory abnormalities in > 5% of patients included neutrophils decreased (10%), platelets decreased (7%), and lymphocytes decreased (6%).

Lymphocytosis: Upon initiation of JAYPIRCA, a temporary increase in lymphocyte counts (defined as absolute lymphocyte count increased ≥ 50% from baseline and a post-baseline value ≥ 5,000/µL) occurred in 34% of MCL patients in BRUIN. The median time to onset of lymphocytosis was 1.1 weeks, with 75% of cases occurring within 2.1 weeks, and the median duration was 11 weeks.

Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma 

The data described below reflect exposure to JAYPIRCA (200 mg once daily) in 223 CLL/SLL patients from one single-arm, open-label clinical trial (BRUIN) and 116 CLL/SLL patients from one randomized controlled clinical trial (BRUIN CLL-321). 

Table 4: Adverse Drug Reactions in Patients with CLL/SLL Treated with Pirtobrutinib as a Single Agent in BRUIN

^a    Severity grade assignment based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

^b    Consolidated term.

Table 5: Adverse Drug Reactions in Patients with CLL/SLL Treated with Pirtobrutinib as a Single Agent in BRUIN CLL-321

^a    Severity grade assignment based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

^b    Consolidated term.

Pediatric Use 

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

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 Special warnings and precautions for use (4.4)]. 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. Of the patients with CLL/SLL who received the 200 mg once daily dose of JAYPIRCA in BRUIN, 68 (63%) were 65 years of age and older and 21 (19%) were 75 years and older; of the patients with CLL/SLL who received JAYPIRCA in BRUIN CLL-321, 59% were 65 years of age and older and 24% were 75 years and older [see Pharmacodynamic properties(5.1)]. No overall differences in effectiveness were observed between younger and older patients.

In the pooled safety population in patients with hematologic malignancies in BRUIN and BRUIN CLL-321, 467 (66%) were 65 years of age and older, while 181 (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.

Renal Impairment 

Severe renal impairment (eGFR15-29 mL/min) increases pirtobrutinib exposure [see Pharmacokinetic properties (5.2)]. Reduce the JAYPIRCA dosage in patients with severe renal impairment [see Posology and method of administration (4.2)]. No dosage adjustment of JAYPIRCA is recommended in patients with mild (60-89 mL/min) or moderate (30-59 mL/min) renal impairment.

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 Pharmacokinetic properties (5.2)].

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed here.

In case of overdose, use supportive therapy. There is no known antidote for pirtobrutinib overdose.

Pharmacotherapeutic group: {Antineoplastic agents, protein kinase inhibitors}, ATC code: L01EL05 

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.

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.

Cardiac Electrophysiology

The effect of a single 900 mg dose of pirtobrutinib (equivalent to approximately 2 times higher than the concentrations achieved at steady state at the recommended dosage of 200 mg once daily) on the QTc interval was evaluated in a placebo-controlled and positive-controlled study in 30 healthy subjects. Pirtobrutinib had no clinically meaningful effect on the change in QTcF interval (i.e., > 10 ms) and there was no relationship between pirtobrutinib exposure and change in QTc interval.

CLINICAL STUDIES 

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 6. Additionally, the Kaplan-Meier estimate for the DOR rate at 6 months was 65.3% (95% CI: 49.8, 77.1).

Table 6:           Efficacy Results per IRC in Patients with MCL Previously Treated with a BTK Inhibitor  

CI, confidence interval; CR, complete response; DOR, duration of response; PR, partial response; NE, not estimable.

^a PET-CT scans were utilized in response assessments (in 41% of patients), with the remainder being assessed by CT scans only.

^b ORR using CT scan-based assessments in all patients was 48% (95% CI: 38, 57) and CR rate was 13%.

^c Based on Kaplan-Meier estimation. Estimated median follow-up was 7.3 months.

Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma

The efficacy of Jaypirca in patients with BTK-inhibitor pretreated CLL/SLL was evaluated in a randomised, multicentre, international, open-label, actively-controlled trial (BRUIN CLL-321, Study 20020). The trial enrolled 238 patients with CLL/SLL who were previously treated with a BTK inhibitor. Patients were randomised in a 1:1 ratio to receive either Jaypirca given orally once daily at a dose of 200 mg until disease progression or unacceptable toxicity, or Investigator’s choice:

·    Idelalisib plus a rituximab product (IR): Idelalisib 150 mg orally twice daily until disease progression or unacceptable toxicity, in combination with 8 infusions of a rituximab product (375 mg/m2 intravenously on Day 1 of Cycle 1, followed by 500 mg/m2 every 2 weeks for 4 doses and then every 4 weeks for 3 doses), with a 28-day cycle length.

·    Bendamustine plus a rituximab product (BR): Bendamustine 70 mg/m2 intravenously (Day 1 and 2 of each 28-day cycle), in combination with a rituximab product (375 mg/m2 intravenously on Day 1 of Cycle 1, then 500 mg/m2 on Day 1 of subsequent cycles), for up to 6 cycles.

Randomisation was stratified by 17p deletion status (yes/no) and receipt of prior venetoclax treatment (yes/no). Of the 238 patients total, 119 were assigned to Jaypirca monotherapy, 82 to IR and 37 to BR. After confirmed disease progression, patients randomised to IR or BR had the option to cross over to Jaypirca monotherapy. Baseline characteristics were similar between treatment arms. Overall, the median age was 67 years (range: 42 to 90 years), 70 % were male and 81 % were White. Baseline ECOG performance status was 0 or 1 in 93% of patients and 44% of patients had Rai stage III or IV disease. Among those patients with central testing available, 57 % (101 of 176 patients) had 17p deletion and/or TP53 mutation, 86 % (164 of 190 patients) had unmutated IGHV, and 65 % (97 of 149) had complex karyotype.

Patients received a median number of 3 prior lines of therapy (range: 1 to 13) with 57 % having at least 3 prior therapies and 51 % having had prior BCL2-inhibitor therapy. The most common prior BTK inhibitors received were ibrutinib (87 %), acalabrutinib (16 %), and zanubrutinib (7 %). 70 % of patients discontinued the most recent BTK inhibitor for refractory or progressive disease, 15 % discontinued for toxicity, and 15 % discontinued for other reasons.

Efficacy was based on progression-free survival (PFS) of pirtobrutinib monotherapy versus investigator’s choice arm as assessed by an Independent Review Committee (IRC). The study met its primary endpoint at the prespecified time of final analysis for IRC-assessed PFS (29 Aug 2023 cut-off). At an updated analysis (29 Aug 2024 cut-off) with a median follow-up of 19.4 months (range 0.03 to 33.3 months) for pirtobrutinib and 17.7 months (range 0.03 to 27.9 months) for the investigator’s choice arm, improved IRC-assessed PFS was observed with pirtobrutinib compared to the investigator’s choice arm, consistent with the primary analysis. Clinically meaningful efficacy results in favour of pirtobrutinib were observed across important subgroups, including patients who discontinued prior BTK inhibitor therapy due to intolerance or progression and irrespective of number and type of prior therapies. Efficacy results are presented in Table 7. The Kaplan-Meier curve for PFS is shown in Figure 1.

Table 7: Efficacy Results per IRC in Patients with CLL/SLL Previously Treated with a BTK Inhibitor – ITT Population (Study 20020)

CI, confidence interval; HR, hazard ratio.

Data cut-off date 29 Aug 2024

a Efficacy was assessed using the 2018 International Workshop for Chronic Lymphocytic Leukemia (CLL) guidelines

b Based on Kaplan-Meier estimation.

c Based on stratified Cox proportional hazards model.

d 2-sided nominal p-value based on stratified log-rank test.

Figure 1: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL/SLL Previously Treated with a BTK Inhibitor in Study 20020

With a median overall survival (OS) follow-up time of 20.4 months for pirtobrutinib and 19.2 months in investigator’s choice arm, 38 patients (32.0 %) in the pirtobrutinib arm and 32 patients (27.0 %) in the investigator’s choice arm died. Median OS was 29.7 months (95 % CI: 27.1, NE) in the pirtobrutinib arm and not reached in the investigator’s choice arm. The HR was 1.090 (95% CI: 0.679, 1.749; p = 0.7202). OS analysis may be confounded by the 50 out of 119 patients who crossed over from the investigator’s choice arm to pirtobrutinib.

Pharmacokinetics 

The pharmacokinetics of pirtobrutinib were characterized in healthy subjects and in patients with cancer. Pirtobrutinib exposure (AUC) and C_max 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 C_max of pirtobrutinib were 92705 h*ng/mL (39%) and 6503 ng/ml (25%), respectively. The geometric mean (CV%) AUC_0-24 and C_max of pirtobrutinib on Cycle 1 Day 8 were 81800 h*ng/mL (66.6%) and 3670 ng/mL (89.5%), respectively.

Absorption

The absolute bioavailability of pirtobrutinib after a single oral 200 mg dose is 85.5% (range 75.9% to 90.9%). The median time (range) to reach peak plasma concentration (tmax) is approximately 2 hours (0.833 to 4.15 hours).

Effect of Food

No clinically significant differences in the pharmacokinetics of pirtobrutinib were observed following administration of a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150 calories from protein, 250 calories from carbohydrate, and 500 to 600 calories from fat) to healthy subjects. A high-fat meal decreased the C_max of pirtobrutinib by 23% and delayed t_max by 1 hour. There was no effect on pirtobrutinib AUC.

Distribution

The mean apparent central volume of distribution of pirtobrutinib is 34.2 L.  Human protein binding of pirtobrutinib is 96% and is independent of concentration in vitro. Mean blood-to-plasma ratio is 0.79.

Elimination

The effective half-life of pirtobrutinib is approximately 20 hours and the mean (CV%) apparent clearance is 2.05 L/h (35.7 %).

Metabolism

Pirtobrutinib is primarily metabolized by CYP3A4 and direct glucuronidation by UGT1A8 and UGT1A9, in vitro.

Excretion

Following a single radiolabeled dose of pirtobrutinib 200 mg to healthy subjects, 37% of the dose was recovered in feces (18% unchanged) and 57% in urine (10% unchanged).

Specific Populations

There were no clinically significant differences in the pharmacokinetics of pirtobrutinib based on age (range 22 – 95 years), sex, race/ethnicity (White 83%, Asian 9%), body weight (range 35.7 – 152 kg), mild (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), moderate (total bilirubin > 1.5 to 3 × ULN and any AST), or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment. The effect of other races/ethnicities on the pharmacokinetics of pirtobrutinib is unknown.

Patients with Renal Impairment

Following a single 200 mg oral dose, the AUC of pirtobrutinib in subjects with severe renal impairment (eGFR 15-29 mL/min) increased by 62% and mean unbound AUC increased by 68% compared to healthy subjects with normal renal function. There were no clinically significant differences in the pharmacokinetics of pirtobrutinib in subjects with mild (eGFR 60-89 mL/min) or moderate renal impairment (eGFR 30-59 mL/min). The effect of renal impairment requiring dialysis on the pharmacokinetics of pirtobrutinib is unknown.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

Strong CYP3A Inhibitors: Co-administration of a single 200 mg dose of pirtobrutinib with itraconazole (strong CYP3A inhibitor) increased AUC of pirtobrutinib by 49%.

Moderate CYP3A Inhibitors: Verapamil and diltiazem (moderate CYP3A inhibitors) are predicted to increase the AUC of pirtobrutinib by 30% and 20%, respectively.

Strong CYP3A inducers: Coadministration of a single 200 mg dose of pirtobrutinib with rifampin (strong CYP3A inducer) decreased the AUC of pirtobrutinib by 71%.

Moderate CYP3A Inducers: Efavirenz and bosentan (moderate CYP3A inducers) are predicted to decrease the AUC of pirtobrutinib by 49% and 27%, respectively.

Gastric Reducing Agents: No clinically significant differences in pirtobrutinib pharmacokinetics were observed when co‑administered with omeprazole (a proton pump inhibitor).

P-glycoprotein (P-gp) inhibitors: No clinically significant differences in pirtobrutinib pharmacokinetics were observed when co-administered with itraconazole (P-gp inhibitor).

CYP3A Substrates: Pirtobrutinib increased the AUC and C_max of orally administered midazolam (sensitive CYP3A substrate) by 70% and 58%, respectively. Pirtobrutinib did not have a clinically meaningful effect on the exposure of intravenously administered midazolam.

CYP2C8 Substrates: Pirtobrutinib increased the AUC and C_max of repaglinide (sensitive CYP2C8 substrate) by 130% and 98%, respectively.

CYP2C19 Substrates: Pirtobrutinib increased the AUC and C_max of omeprazole (sensitive CYP2C19 substrate) by 56% and 49%, respectively.

P-gp Substrates: A single 200 mg dose of pirtobrutinib increased the AUC and C_max of digoxin (sensitive P-gp substrate) by 17% and 51%, respectively. Multiple doses of pirtobrutinib (200 mg daily) further increased the AUC and C_max of digoxin (sensitive P-gp substrate) up to 35% and 55%, respectively.

BCRP Substrates: Multiple doses of pirtobrutinib (200 mg daily) increased the AUC and C_max of rosuvastatin (sensitive BCRP substrate) by 140% and 146%, respectively.

CYP1A2 and CYP2C9 Substrates: Pirtobrutinib did not have a clinically meaningful effect on the exposures of caffeine (sensitive CYP1A2 substrate) or S-warfarin (moderate sensitive CYP2C9 substrate).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Pirtobrutinib inhibits CYP2C8, CYP2C9, CYP3A, CYP1A2, CYP2B6, CYP2C19, and CYP2D6. Pirtobrutinib induces CYP3A4, CYP3A5, CYP2B6, and CYP2C19.

Transporter Systems: Pirtobrutinib inhibits P-gp and BCRP, but not OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.  Pirtobrutinib is not a substrate of the hepatic transporters. Pirtobrutinib is a substrate of P-gp and BCRP, but not OCT1, OATP1B1, OATP1B3, or BSEP.

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.

50 mg and 100 mg Tablet Excipients:

·         Hypromellose Acetate Succinate

·         Microcrystalline Cellulose

·         Lactose Monohydrate

·         Croscarmellose Sodium

·         Silicon Dioxide

·         Magnesium Stearate

·         Color Mixture Blue 03K105008

·         Purified Wate

Not applicable. No material or container closure incompatibilities were identified.

Store below 30°C.

How Supplied

JAYPIRCA tablets are supplied as follows:

Not all pack sizes may be marketed.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

PATIENT COUNSELING INFORMATION

Advise the patient to read the approved patient labeling (Patient Information).

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 Special warnings and precautions for use (4.4)].

Hemorrhage

Inform patients to report signs or symptoms of bleeding. Inform patients that JAYPIRCA may need to be interrupted for major surgeries [see Special warnings and precautions for use (4.4)].

Cytopenias

Advise patients of the need for periodic monitoring of blood counts during treatment with JAYPIRCA [see Special warnings and precautions for use (4.4)].

Cardiac Arrhythmias

Counsel patients to report any signs of palpitations, dizziness, fainting, chest discomfort, and shortness of breath [see Special warnings and precautions for use (4.4)].

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 Special warnings and precautions for use (4.4)].

Hepatotoxicity, Including Drug-Induced Liver Injury

Inform patients that liver problems, including severe, life-threatening, or fatal hepatitis, drug-induced liver injury and abnormalities in liver tests, may develop during JAYPIRCA treatment. Advise patients to contact their healthcare provider immediately if they experience abdominal discomfort, dark urine, or jaundice [see Special warnings and precautions for use (4.4)].

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 Special warnings and precautions for use (4.4), Fertility, pregnancy and lactation (4.6)].

Advise females of reproductive potential to use effective contraception during treatment with JAYPIRCA and for one week after the last dose [see Fertility, pregnancy and lactation (4.6)].

Lactation

Advise women not to breastfeed during treatment with JAYPIRCA and for one week after the last dose [see Fertility, pregnancy and lactation (4.6)].

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 split, crush, or chew tablets [see Posology and method of administration (4.2)].