Safety and tolerability for patients with previously treated R/R MCL in the BRUIN trial
Common ARs were mostly grade 1/21
Adverse reactions reported (≥10%) in patients with R/R MCL previously treated with a BTKi1
aEach term listed includes other related terms.1
bIncludes 1 fatality from COVID-19 pneumonia.1
cIncludes 1 fatality from hemorrhage.1
The following adverse reaction results (≥10%) were reported in patients with previously treated R/R MCL who received Jaypirca 200 mg once daily (N=128). The all-grades adverse reactions reported were general disorders: fatigue (29%), edema (18%), and fever (13%); musculoskeletal and connective tissue disorders: musculoskeletal pain (27%) and arthritis/arthralgia (12%); gastrointestinal disorders: diarrhea (19%), constipation (13%), abdominal pain (11%) and nausea (11%); respiratory, thoracic, and mediastinal disorders: dyspnea (17%) and cough (14%); injury: bruising (16%); infections: pneumonia (16%) and upper respiratory tract infections (10%); nervous system disorders: peripheral neuropathy (14%) and dizziness (10%); skin and subcutaneous disorders: rash (14%); and vascular disorders: hemorrhage (11%).1
The Grade 3 or 4 adverse reactions reported for patients with MCL who received Jaypirca were fatigue (1.6%), edema (0.8%), musculoskeletal pain (3.9%), arthritis/arthralgia (0.8%), abdominal pain (0.8%), dyspnea (2.3%), pneumonia (14%), upper respiratory tract infections (0.8%), peripheral neuropathy (0.8%), and hemorrhage (3.1%).1
Fatigue, edema, fever, musculoskeletal pain, arthritis/arthralgia, diarrhea, constipation, abdominal pain, nausea, dyspnea, cough, bruising, pneumonia, upper respiratory tract infections, peripheral neuropathy, dizziness, rash, and hemorrhage included other related terms.1
The incidence of all-grade pneumonia includes one fatality from COVID-19 pneumonia.1
The incidence of all-grade hemorrhage includes one fatality from hemorrhage.1
Of 128 patients with MCL, 36% were exposed to Jaypirca for 6 months or longer and 10% were exposed for ≥1 year.1
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%).1
SELECT IMPORTANT SAFETY INFORMATION
Fatal Adverse Reactions (ARs): Fatal ARs within 28 days of the last dose of Jaypirca occurred in 7% of patients with MCL, most commonly due to infections (4.7%), including COVID-19 (3.1%).
Select treatment-emergent adverse events observed in patients with R/R MCL in the BRUIN trial (n=128)1,2
- All-grade atrial fibrillation or atrial flutter was observed in 3.9% of patients (n=128)2*
Select treatment-emergent adverse events occurring in <10% of patients who received Jaypirca 200 mg once daily (n=128)1,2
*ECG was routinely performed at regular intervals throughout the trial.2
The select all-grades treatment-emergent adverse events reported for patients were peripheral edema (9 percent), vision changes (7 percent), memory changes (7 percent), headache (6 percent), urinary tract infection (6 percent), atrial fibrillation or atrial flutter (3.9 percent), herpesvirus infection (2.3 percent), hypertension (2.3 percent), and tumor lysis syndrome (0.8 percent).
The Grade 3 or 4 treatment-emergent adverse events reported for patients were vision changes (0.8 percent), headache (0.8 percent), atrial fibrillation or atrial flutter (1.6 percent), herpesvirus infection (0.8 percent), and tumor lysis syndrome (0.8 percent).
Fatal and serious infections (including bacterial, viral, fungal) and opportunistic infections have occurred in patients treated with Jaypirca. Consider prophylaxis in patients at increased risk. Monitor for signs/symptoms, evaluate promptly, and treat appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.
Patients with cardiac risk factors, such as hypertension or previous arrhythmias, may be at increased risk for atrial fibrillation and atrial flutter when treated with Jaypirca. Monitor for signs and symptoms of arrhythmias and manage appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.
The AEs presented were deemed of clinical interest based upon the known safety profile of BTKi therapies, preclinical toxicology, and emerging safety data during the conduct of the study.
Select laboratory abnormalities† (≥10%) that worsened from baseline1
†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.1
The following laboratory abnormality results were reported for patients who received Jaypirca 200 mg once daily. The all-grades laboratory abnormalities reported for patients were hemoglobin decreased (42 percent), platelet count decreased (39 percent), neutrophil count decreased (36 percent), lymphocyte count decreased (32 percent), creatinine increased (30 percent), calcium decreased (19 percent), AST increased (17 percent), potassium decreased (13 percent), sodium decreased (13 percent), lipase increased (12 percent), alkaline phosphatase increased (11 percent), ALT increased (11 percent), potassium increased (11 percent).1
The Grades 3 or 4 laboratory abnormalities reported for patients were hemoglobin decreased (9 percent), platelet count decreased (14 percent), neutrophil count decreased (16 percent), lymphocyte count decreased (15 percent), creatinine increased (1.6 percent), calcium decreased (1.6 percent), AST increased (1.6 percent), potassium decreased (1.6 percent), lipase increased (4.4 percent), ALT increased (1.6 percent), potassium increased (0.8 percent).1
Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (10%), platelets decreased (7%), and lymphocytes decreased (6%).
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 patients with MCL 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.
AR=adverse reaction; BTK=Bruton's tyrosine kinase; ECG=electrocardiogram; MCL=mantle cell lymphoma; R/R=relapsed/refractory.
Few patients permanently discontinued due to adverse reactions1
Discontinuation Rate Due to ARs in Patients with MCL1
9 percent of patients with MCL (n equals 12 out of 128) permanently discontinued treatment due to adverse reactions
Due to treatment-emergent ARs in the 128 patients with MCL,
- 4.7% (6/128 patients) required dose reductions1‡
- 32% (41/128 patients) experienced treatment interruption1
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 pneumonia1
‡See the full Prescribing Information for information about dose modifications due to adverse reactions.1
References:
- Jaypirca (pirtobrutinib). Prescribing Information. Lilly USA, LLC.
- Data on File, Lilly USA, LLC, DOF-PT-US-0006.
Indication
Jaypirca is a kinase inhibitor indicated for the treatment of adult patients with relapsed or refractory (R/R) 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Important Safety Information
Infections: Fatal and serious infections (including bacterial, viral, or fungal) and opportunistic infections have occurred in patients treated with Jaypirca. In the clinical trial, Grade ≥3 infections occurred in 17% of 583 patients with hematologic malignancies, most commonly pneumonia (9%); fatal infections occurred in 4.1% of patients. Sepsis (4.5%) and febrile neutropenia (2.9%) occurred. Opportunistic infections after Jaypirca treatment included, but are not limited to, Pneumocystis jirovecii pneumonia and fungal infection. Consider prophylaxis, including vaccinations and antimicrobial prophylaxis, in patients at increased risk for infection, including opportunistic infections. Monitor patients for signs and symptoms, evaluate promptly, and treat appropriately. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.
Hemorrhage: Fatal and serious hemorrhage has occurred with Jaypirca. Major hemorrhage (Grade ≥3 bleeding or any central nervous system bleeding) occurred in 2.4% of 583 patients with hematologic malignancies 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 patients taking Jaypirca with (0.7%) and without (1.7%) antithrombotic agents. Consider risks/benefits of co-administering antithrombotic agents with Jaypirca. Monitor patients for signs of bleeding. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Consider benefit/risk of withholding Jaypirca 3-7 days pre- and post-surgery depending on type of surgery and bleeding risk.
Cytopenias: Grade 3 or 4 cytopenias, including neutropenia (24%), anemia (11%), and thrombocytopenia (11%) have developed in patients with hematologic malignancies treated with Jaypirca. In a clinical trial, Grade 4 neutropenia (13%) and Grade 4 thrombocytopenia (5%) developed. Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.
Atrial Fibrillation and Atrial Flutter: Atrial fibrillation or atrial flutter were reported in 2.7% of patients, with Grade 3 or 4 atrial fibrillation or flutter reported in 1% of 583 patients with hematologic malignancies treated with Jaypirca. 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.
Second Primary Malignancies: Second primary malignancies, including non-skin carcinomas, developed in 6% of 583 patients with hematologic malignancies treated with Jaypirca monotherapy. The most frequent malignancy was non-melanoma skin cancer (3.8%). Other second primary malignancies included solid tumors (including genitourinary and breast cancers) and melanoma. Advise patients to use sun protection and monitor for development of second primary malignancies.
Embryo-Fetal Toxicity: Based on animal findings, Jaypirca can cause fetal harm in pregnant women. Administration of pirtobrutinib to pregnant rats during organogenesis caused embryo-fetal toxicity, including embryo-fetal mortality and malformations at maternal exposures (AUC) approximately 3-times the recommended 200 mg/day dose. Advise pregnant women of potential risk to a fetus and females of reproductive potential to use effective contraception during treatment and for one week after last dose.
Adverse Reactions (ARs) in Patients with Mantle Cell Lymphoma Who Received Jaypirca
Serious ARs occurred in 38% of patients. Serious ARs occurring 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 ARs within 28 days of last dose of Jaypirca occurred in 7% of patients, most commonly due to infections (4.7%), including COVID-19 (3.1%).
Dose Modifications and Discontinuations: ARs led to dosage reductions in 4.7%, treatment interruption in 32%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dosage modification in >5% of patients included pneumonia and neutropenia. ARs resulting in permanent discontinuation of Jaypirca in >1% of patients included pneumonia.
ARs (all Grades %; Grade 3-4 %) in ≥10% of Patients: fatigue (29; 1.6), musculoskeletal pain (27; 3.9), diarrhea (19; -), edema (18; 0.8), dyspnea (17; 2.3), pneumonia (16; 14), bruising (16; -), peripheral neuropathy (14; 0.8), cough (14; -), rash (14; -), fever (13; -), constipation (13; -), arthritis/arthralgia (12; 0.8), hemorrhage (11; 3.1), abdominal pain (11; 0.8), nausea (11; -), upper respiratory tract infections (10; 0.8), dizziness (10; -).
Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥10% of Patients: hemoglobin decreased (42; 9), platelet count decreased (39; 14), neutrophil count decreased (36; 16), lymphocyte count decreased (32; 15), creatinine increased (30; 1.6), calcium decreased (19; 1.6), AST increased (17; 1.6), potassium decreased (13; 1.6), sodium decreased (13; -), lipase increased (12; 4.4), alkaline phosphatase increased (11; -), ALT increased (11; 1.6), potassium increased (11; 0.8). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (10), platelets decreased (7), lymphocytes decreased (6).
All grade ARs with higher frequencies in the total BRUIN population of patients with hematologic malignancies (n=583) were decreased neutrophil count (41%), bruising (20%), diarrhea (20%).
Drug Interactions
Strong CYP3A Inhibitors: Concomitant use with Jaypirca increased pirtobrutinib systemic exposure, which may increase risk of Jaypirca adverse reactions. Avoid use of strong CYP3A inhibitors during Jaypirca treatment. If concomitant use is unavoidable, reduce Jaypirca dosage according to the approved labeling.
Strong or Moderate CYP3A Inducers: Concomitant use with Jaypirca decreased pirtobrutinib systemic exposure, which may reduce Jaypirca efficacy. Avoid concomitant use of Jaypirca with strong or moderate CYP3A inducers. If concomitant use with moderate CYP3A inducers is unavoidable, increase Jaypirca dosage according to the approved labeling.
Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP Substrates: Concomitant use with Jaypirca increased their plasma concentrations, which may increase risk of adverse reactions related to these substrates for drugs that are sensitive to minimal concentration changes. Follow recommendations for these sensitive substrates in their approved labeling.
Use in Special Populations
Pregnancy and Lactation: Inform pregnant women of potential for Jaypirca to cause fetal harm. Verify pregnancy status in females of reproductive potential prior to starting Jaypirca and advise use of effective contraception during treatment and for one week after last dose. Presence of pirtobrutinib in human milk and effects on the breastfed child or on milk production is unknown. Advise women not to breastfeed while taking Jaypirca and for one week after last dose.
Geriatric Use: In the pooled safety population of patients with hematologic malignancies, 392 (67%) were ≥65 years of age. Patients aged ≥65 years experienced higher rates of Grade ≥3 ARs and serious ARs compared to patients <65 years of age.
Renal Impairment: Severe renal impairment (eGFR 15-29 mL/min) increases pirtobrutinib exposure. Reduce Jaypirca dosage in patients with severe renal impairment according to the approved labeling. No dosage adjustment is recommended in patients with mild or moderate renal impairment.
PT HCP ISI MCL APP
Please see full Prescribing Information and Patient Information for Jaypirca.