Jaypirca: an approach to BTK inhibition that can help keep positive treatment momentum going for patients like Marc1*
*Not an actual patient.
Marc,
in his late 60s, with R/R MCL
- Responded well to second-line treatment with a BTK inhibitor, but is now showing early signs of progression
- Determined to maintain his current lifestyle for as long as possible
When a covalent BTK inhibitor is no longer an option, treatment options are limited and historically prognosis has been poor.2
After multiple lines of therapy, many patients with R/R MCL have acquired disease characteristics associated with poor prognosis such as advancing age, high MIPI score, and increasing ECOG score, making some therapeutic options inappropriate.2,3
Do you have patients like Marc?
BTK=Bruton's tyrosine kinase; ECOG=Eastern Cooperative Oncology Group; MCL=mantle cell lymphoma; MIPI=Mantle Cell Lymphoma International Prognostic Index; R/R=relapsed/refractory.
SELECT IMPORTANT SAFETY INFORMATION
Hemorrhage: Fatal and serious hemorrhage occurred in patients with hematologic malignancies treated with Jaypirca (N=583). Major hemorrhage (Grade ≥3 bleeding or any central nervous system bleeding) occurred in 2.4% of patients, including gastrointestinal hemorrhage; fatal hemorrhage occurred in 0.2% of patients. Bleeding of any grade, excluding bruising and petechiae, occurred in 14% of patients. Consider risks/benefits of co-administering antithrombotic agents with Jaypirca and of withholding Jaypirca for 3-7 days pre- and post-surgery. Monitor patients for signs of bleeding and reduce dose, temporarily withhold, or permanently discontinue Jaypirca, based on severity.
BRUIN evaluated Jaypirca in adult patients with R/R MCL who progressed on or were intolerant to a prior BTKi1,4†
The study schema shows the total BRUIN study population, N=583, included patients with hematologic malignancies; the safety population, n=128, consisted of patients with R/R MCL previously treated with BTK inhibitor and the MCL efficacy population, n=120, also assessed patients with R/R MCL previously treated with a BTK inhibitor.
Patients were eligible if they were 18 years or older; had an ECOG status of 0 to 2, had an active hematologic malignancy in need of treatment, and were previously treated. The trial also required patients with a platelet count ≥50 x 109/L, absolute neutrophil count ≥0.75 x 109/L, hepatic transaminases ≤2.5 times ULN.
The primary endpoint was overall response rate. Key secondary endpoints were duration of response, progression-free survival, and overall survival.
Patients received a median of 3 prior lines of therapy (range: 1-9) with 93% having ≥2 prior lines. Phase 2 Dosing of the trial assessed Jaypirca 200 mg once daily until disease progression or unacceptable toxicity. Phase 1 Dosing assessed 25 mg to 300 mg once daily until disease progression or unacceptable toxicity. Intrapatient dose escalation was allowed by protocol.4 Efficacy of Jaypirca was based on response as assessed per IRC using 2014 Lugano Criteria.1
†Ibrutinib (67%), acalabrutinib (30%), and zanubrutinib (8%) in the efficacy population.1
‡Trial excluded patients with significant cardiovascular disease, major bleeding, or grade ≥3 arrhythmia with prior BTKi, prolonged QTc interval, or need for strong CYP3A inhibitor or inducer or strong P-gp inhibitor.1
§Not all patients in the safety population met criteria to be evaluated for efficacy.
||Patients with active CNS lymphoma or allogeneic HSCT or CAR T-cell therapy within 60 days were excluded.1
¶The phase 1 primary outcome was to determine maximum tolerated dose and recommended phase 2 dose. All patients received at least one dose of Jaypirca.4
Jaypirca was studied in patients with MCL who had progressed on or were intolerant to a BTK inhibitor1
Jaypirca was studied in patients with MCL who had been previously treated with a BTK inhibitor.1 83% of patients discontinued their last BTK inhibitor due to refractory or progressive disease and 15% discontinued due to toxicity or other reasons.#** Patients had a median of 3 prior lines of therapy (range: 1 to 9). In addition to BTK inhibitors, patients were also treated with chemoimmunotherapy (88%), lenalidomide (18%), stem cell transplant (20%), and CAR T-cell therapy (9%).
Due to rounding, numbers presented may not add up to the totals indicated and percentages may not reflect the absolute figures.
#10% discontinued for toxicity, 5% discontinued for other reasons.1
**Other reasons for ending last BTK inhibitor include: completed course of planned treatment, physician decision, patient decision, and other.5
BTKi=BTK inhibitor; CAR=chimeric antigen receptor; CNS=central nervous system; HSCT=hematopoietic stem cell transplantation; IRC=independent review committee; ULN=upper limit of normal.
SELECT IMPORTANT SAFETY INFORMATION
Cytopenias: Grade 3 or 4 cytopenias, including neutropenia, anemia, and thrombocytopenia have developed in patients receiving Jaypirca. In a clinical trial of patients with hematologic malignancies (N=583), 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.
In patients with R/R MCL previously treated with a BTK inhibitor (n=120)1
Jaypirca delivered a robust response1
Overall Response Rate (n=120)1††‡‡§§
Jaypirca delivered a 50% ORR (95% CI: 41, 59) in patients with R/R MCL previously treated with a BTK inhibitor (n=120). CR was 13% and PR was 38%.1††‡‡§§
††PET-CT scans were utilized in response assessments (in 41% of patients), with the remainder being assessed by CT scans only.1
‡‡ORR using CT scan-based assessments in all patients was 48% (95% CI: 38, 57) and CR rate was 13%.1
§§ORR, the primary endpoint, includes patients with a best response of CR or PR and was assessed by IRC using 2014 Lugano criteria.1
Due to rounding, percentages may not reflect the absolute figures.
Disease control rate (n=120)1
DCR in patients with R/R MCL previously treated with a BTK inhibitor (n=120)1,6
72% (95% CI: 63, 80) of 120 patients with R/R MCL previously treated with a BTK inhibitor achieved disease control with Jaypirca. 22% had stable disease, 13% had a complete response, and 38% had a partial response.6
DCR was not a prespecified endpoint and is a post hoc calculation. DCR is defined as ORR (CR + PR) + SD.4,6
SD is defined as a <50% decrease from baseline in SPD of up to 6 dominant, measurable nodes and extranodal sites by radiologic assessment per Lugano response criteria.7
In a single-arm trial without a control arm for comparison as would be provided by a randomized trial, the interpretation and clinical relevance of a best overall response of SD are not clear, and no conclusions can be drawn. It is not possible to determine whether SD is a result of natural disease progression or treatment with Jaypirca.
ORR was the primary endpoint and was assessed by IRC.1
Due to rounding, percentages may not reflect the absolute figures.
CI=confidence interval; CR=complete response; CT=computed tomography; DCR=disease control rate; PET=positron emission tomography; PR=partial response; SD=stable disease; SPD=sum of the product of diameters.
In patients who responded (n=60),
Majority were still responding at 6 months1
DoR rate at 6 months1
- 36 of 60 responders had not progressed or died prior to data cutoff (censored)1,8
- Median DoR was 8.3 months|||| (95% CI: 5.7, NE) with a median follow-up of 7.3 months1¶¶##
65% of responders (n=60) were still responding (95% CI: 50, 77).1
||||Based on Kaplan-Meier estimation.
¶¶DoR was calculated for patients who achieved a response of PR or better and was defined as the time from first evidence of response to progression or death from any cause.8
##The primary endpoint was ORR. Efficacy was based on patients with R/R MCL previously treated with a BTK inhibitor.1
DoR=duration of response; NE=not estimable.
References:
- Jaypirca (pirtobrutinib). Prescribing Information. Lilly USA, LLC.
- Hanel W, Epperla N. Emerging therapies in mantle cell lymphoma. J Hematol Oncol. 2020;13(1):79. doi:10.1186/s13045-020-00914-1
- Burkart M, Karmali R. Relapsed/refractory mantle cell lymphoma: beyond BTK inhibitors. J Pers Med. 2022;12(3):376. doi:10.3390/jpm12030376
- Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901.
- Data on File, Lilly USA, LLC, DOF-PT-US-0008.
- Data on File, Lilly USA, LLC, DOF-PT-US-0010.
- Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
- Supplement to: Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892-901.
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.