CLL Efficacy & Study Design | Jaypirca® (pirtobrutinib)

In adults with CLL/SLL after ≥2 prior lines, including a BTKi and BCL2i (n=108)

Jaypirca delivered a robust ORR¹

ORR with 200 mg daily (n=108)^1,2*

ORR for Jaypirca CLL/SLL — In adults with chronic lymphocytic leukemia/small lymphocytic lymphoma previously treated with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor (n=108), the overall response rate with Jaypirca 200 mg daily was 72% with a 95% confidence interval of 63 to 80; 72% of patients achieved a partial response and 7% had stable disease.^1,2*

Majority responded to Jaypirca or had stable disease^1,2

Disease control rate (DCR) (n=108)
80% (95% CI: 71, 87; 7% SD; 72% PR; 0% CR)²

^*ORR, the primary endpoint, includes patients with a best response of PR or better and was assessed by IRC using 2018 iwCLL criteria.¹

DCR was not a prespecified endpoint and is a post-hoc calculation. DCR is defined as ORR + SD.^2,3

Per iwCLL criteria, SD is defined as not achieving a CR or PR, and not exhibiting PD.⁴

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.

In addition to CR and PR, BRUIN included additional response categories, such as PR-L; 10% of patients were considered to have PR-L as assessed by IRC. However, the regulatory primary endpoint ORR does not include PR-L.^2,5

Due to rounding, percentages may not reflect the absolute figures.

BCL2i=B-cell lymphoma 2 inhibitor; BTKi=Bruton’s tyrosine kinase inhibitor; CI=confidence interval; CLL=chronic lymphocytic leukemia; CR=complete response; IRC=independent review committee; iwCLL=International Workshop on Chronic Lymphocytic Leukemia; ORR=overall response rate; PD=progressive disease; PR=partial response; PR-L=partial response with lymphocytosis; SD=stable disease; SLL=small lymphocytic lymphoma.

See BRUIN trial design

SELECT IMPORTANT SAFETY INFORMATION

Hemorrhage: Fatal and serious hemorrhage occurred in patients with hematologic malignancies treated with Jaypirca. Major hemorrhage occurred (3%), including gastrointestinal hemorrhage; fatal hemorrhage occurred (0.3%). Bleeding of any grade, excluding bruising and petechiae, occurred in 17%. Major hemorrhage occurred in patients taking Jaypirca with (0.7%) and without (2.3%) antithrombotic agents. 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.

In patients with CLL/SLL who responded (n=78)

Jaypirca delivered a durable response¹

Median DoR^1‡§

discontinuation rate for Jaypirca in CLL/SLL — In patients with chronic lymphocytic leukemia/small lymphocytic lymphoma who responded (n=78), the median duration of response for Jaypirca was 12.2 months with a 95% confidence interval of 9.3 to 14.7.^1†‡§

Median DoR in patients who responded was 12.2 months (95% CI: 9.3, 14.7) with an estimated median follow-up of 15.7 months^1†‡§

^†Based on Kaplan-Meier estimation.¹

^‡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.⁶

^§The primary endpoint was ORR. Efficacy was based on 108 patients with CLL/SLL who were previously treated with ≥2 prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.^1,3

BCL-2=B-cell lymphoma 2; BTK=Bruton's tyrosine kinase; DoR=duration of response.

In adults with CLL/SLL after ≥2 prior lines, including a BTKi and BCL2i¹

Median PFS in patients treated with Jaypirca^7¶

Median follow-up for PFS : 19.5 months⁷

Censored (n=46)

Progression-free survival (n=108)⁷

Median PFS for Jaypirca in CLL/SLL — In 108 adults, median PFS with Jaypirca as assessed by IRC was 16.6 months with a 95% confidence interval of 13.8 to 18.7. The median follow-up for PFS was 19.5 months.⁷

^¶As determined by IRC assessment.⁷

PFS was a secondary endpoint in the BRUIN trial and defined as the number of months from the first dose of study drug to progression or death from any cause.⁵

The data have not been reviewed by the FDA or included in the Prescribing Information for Jaypirca.

Time-to-event endpoints such as PFS are not interpretable in a single-arm study. The clinical significance of these data is not known, and this descriptive analysis should be interpreted with caution. Results are subject to change pending longer trial follow-up.

Patients who are alive and without documented PD as of the data analysis cutoff date are censored.⁵

This indication is approved under accelerated approval based on response rate. Continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial.¹

PFS=progression-free survival.

SELECT IMPORTANT SAFETY INFORMATION

Cytopenias: Jaypirca can cause cytopenias, including neutropenia, thrombocytopenia, and anemia. In a clinical trial, Grade 3 or 4 cytopenias, including decreased neutrophils (26%), decreased platelets (12%), and decreased hemoglobin (12%), developed in Jaypirca-treated patients. Grade 4 decreased neutrophils (14%) and Grade 4 decreased platelets (6%) developed. Monitor complete blood counts regularly during treatment; based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.

BRUIN evaluated Jaypirca in adult patients with CLL/SLL who progressed on or were intolerant to a prior BTKi or BCL2i^1,3

Study design for Jaypirca in CLL/SLL — The efficacy and safety of Jaypirca in adult patients with previously treated chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) were evaluated in the BRUIN trial. The trial was an open label, international, multicohort, single-arm, phase 1/2 trial that evaluated Jaypirca as monotherapy. The BRUIN safety population (N=593) included patients with hematologic malignancies.^1,3

The CLL/SLL safety population^a (n=110) included adults with CLL/SLL previously treated with a Bruton’s tyrosine kinase inhibitor^b (BTKi) and B-cell lymphoma 2 inhibitor (BCL2i). The CLL/SLL efficacy population^a (n=108) included adults with CLL/SLL previously treated with two or more prior lines including a BTKi^b and BCL2i.¹

Patients were eligible if they were 18 years of age or older, had an Eastern Cooperative Oncology Group score of 0 to 2, had an active hematologic malignancy and were in need of treatment, were previously treated, had a platelet count of ≥50 x 10⁹/L, had an absolute neutrophil count ≥0.75 x 10⁹/L, and had hepatic transaminases ≤2.5 times the upper limit of normal.¹

The primary endpoint was overall response rate. The key secondary endpoints were duration of response, progression-free survival, and overall survival.^1,3

Patients in the safety population received a median of 5 prior lines of therapy (range: 1-11). Patients in the efficacy population received a median of 5 prior lines of therapy (range: 2-11). Phase 2 dosing was Jaypirca 200 mg once daily until disease progression or unacceptable toxicity. 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.^c Efficacy of Jaypirca was based on response and was assessed by an independent review committee using 2018 International Workshop on Chronic Lymphocytic Leukemia criteria.^1,3

^aTrial excluded patients with active CNS involvement by lymphoma, allogeneic HSCT within 60 days, significant cardiovascular disease, major bleeding, uncontrolled or symptomatic arrhythmias, prolonged QTc interval, or need for strong CYP3A inhibitor or inducer or strong P-gp inhibitor.¹
^bIbrutinib (97%), acalabrutinib (9%), and zanubrutinib (0.9%) in the efficacy population.¹
^cPhase 1 Dosing: 25 mg to 300 mg once daily until disease progression or unacceptable toxicity. Intrapatient dose escalation was allowed by protocol.³

CNS=central nervous system; ECOG=Eastern Cooperative Oncology Group; HSCT=hematopoietic stem cell transplantation; ULN=upper limit of normal.

CLL Patient Characteristics

Give your patients with previously treated CLL another shot at BTK inhibition

Explore the safety data

References:

Jaypirca. Prescribing Information. Lilly USA, LLC.
Data on File, Lilly USA, LLC, DOF-PT-US-0036.
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.
Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.
Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med. 2023;389(protocol):1-161.
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)(suppl app.):1-158.
Data on File, Lilly USA, LLC, DOF-PT-US-0038.

Important Safety Information

Infections: Fatal and serious infections (including bacterial, viral, fungal) and opportunistic infections occurred in Jaypirca-treated patients. In a clinical trial, Grade ≥3 infections occurred in 24% of patients with hematologic malignancies, most commonly pneumonia (14%); fatal infections occurred in 4.4%. Sepsis (6%) and febrile neutropenia (4%) occurred. In patients with CLL/SLL, Grade ≥3 infections occurred (32%), with fatal infections occurring in 8%. Opportunistic infections included 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 3% of patients, including gastrointestinal hemorrhage; fatal hemorrhage occurred (0.3%). Bleeding of any grade, excluding bruising and petechiae, occurred in 17%. Major hemorrhage occurred in patients taking Jaypirca with (0.7%) and without (2.3%) 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: Jaypirca can cause cytopenias, including neutropenia, thrombocytopenia, and anemia. In a clinical trial, Grade 3 or 4 cytopenias, including decreased neutrophils (26%), decreased platelets (12%), and decreased hemoglobin (12%), developed in Jaypirca-treated patients. Grade 4 decreased neutrophils (14%) and Grade 4 decreased platelets (6%) developed. Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.

Cardiac Arrhythmias: Cardiac arrhythmias occurred in patients who received Jaypirca. In a clinical trial of patients with hematologic malignancies, atrial fibrillation or flutter were reported in 3.2% of Jaypirca-treated patients, with Grade 3 or 4 atrial fibrillation or flutter in 1.5%. Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred (0.5%). 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 9% of Jaypirca-treated patients. The most frequent malignancy was non-melanoma skin cancer (4.6%). 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: 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 fetal risk and females of reproductive potential to use effective contraception during treatment and for one week after last dose.

Adverse Reactions (ARs) in Patients Who Received Jaypirca

The most common (≥20%) ARs in the BRUIN pooled safety population of patients with hematologic malignancies (n=593) were decreased neutrophil count (46%), decreased hemoglobin (39%), fatigue (32%), decreased lymphocyte count (31%), musculoskeletal pain (30%), decreased platelet count (29%), diarrhea (24%), COVID-19 (22%), bruising (21%), cough (20%).

Mantle Cell Lymphoma

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 Jaypirca dose occurred in 7% of patients, most commonly due to infections (4.7%), including COVID-19 (3.1% of all patients).

Dose Modifications and Discontinuations: ARs led to dose 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 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).

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Serious ARs occurred in 56% of patients. Serious ARs occurring in ≥5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Fatal ARs within 28 days of last Jaypirca dose occurred in 11% of patients, most commonly due to infections (10%), including sepsis (5%) and COVID-19 (2.7%).

Dose Modifications and Discontinuations: ARs led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dose reductions in >1% included neutropenia; treatment interruptions in >5% of patients included pneumonia, neutropenia, febrile neutropenia, and COVID-19; permanent discontinuation in >1% of patients included second primary malignancy, COVID-19, and sepsis.

ARs (all Grades %; Grade 3-4 %) in ≥10% of Patients: fatigue (36; 2.7), bruising (36; -), cough (33; -), musculoskeletal pain (32; 0.9), COVID-19 (28; 7), pneumonia (27; 16), diarrhea (26; -), abdominal pain (25; 2.7), dyspnea (22; 2.7), hemorrhage (22; 2.7), edema (21; -), nausea (21; -), pyrexia (20; 2.7), headache (20; 0.9), arthritis/arthralgia (19; 1.8), rash (19; 0.9), peripheral neuropathy (16; 3.6), dizziness (15; -), fall (14; 0.9), constipation (14; -), insomnia (14; -), upper respiratory tract infections (13; 2.7), second primary malignancy (13; 2.7), renal insufficiency (12; 6), hypertension (12; 5), neurological changes (12; 2.7), mucositis (12; 0.9), decreased appetite (12; -), respiratory tract infection (11; 1.8), supraventricular tachycardia (10; 5).

Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥20% of Patients: neutrophil count decreased (63; 45), hemoglobin decreased (48; 19), calcium decreased (40; 2.8), platelet count decreased (30; 15), sodium decreased (30; -), lymphocyte count decreased (23; 8), ALT increased (23; 2.8), AST increased (23; 1.9), creatinine increased (23; -), lipase increased (21; 7), alkaline phosphatase increased (21; -). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (23).

Drug Interactions

Strong CYP3A Inhibitors: Concomitant use with Jaypirca increased pirtobrutinib systemic exposure, which may increase risk of Jaypirca ARs. Avoid use of strong CYP3A inhibitors with Jaypirca. If concomitant use is unavoidable, reduce Jaypirca dosage according to 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 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: Due to 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 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, 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 increases pirtobrutinib exposure. Reduce Jaypirca dosage in patients with severe renal impairment according to approved labeling.

PT HCP ISI COMBO DEC2023

Please see full Prescribing Information and Patient Information for Jaypirca.

Indications

Jaypirca is a kinase inhibitor indicated for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.

Jaypirca is also 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.

These indications are approved under accelerated approval based on response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial.

CLL Efficacy

Jaypirca delivered a robust ORR1

Jaypirca delivered a durable response1