Pirtobrutinib

1 INDICATIONS AND USAGE JAYPIRCA ® is a kinase inhibitor 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. ( 1.1 ). 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. Adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor. ( 1.2 ). 1.1 Mantle Cell Lymphoma JAYPIRCA ® is indicated for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. This indication is approved under accelerated approval based on response rate [see Clinical Studies ( 14.1 )]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. 1.2 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma JAYPIRCA is indicated for the treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infections [see Warnings and Precautions ( 5.1 )] Hemorrhage [see Warnings and Precautions ( 5.2 )] Cytopenias [see Warnings and Precautions ( 5.3 )] Atrial Fibrillation and Atrial Flutter [see Warnings and Precautions ( 5.4 )] Second Primary Malignancies [see Warnings and Precautions ( 5.5 )] Hepatotoxicity, including DILI [see Warnings and Precautions ( 5.6 )] Most common adverse reactions (≥ 30%), including laboratory abnormalities, are fatigue, neutrophil count decreased, platelet count decreased, hemoglobin decreased, leukocytes decreased, lymphocyte count decreased and calcium decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be compared to rates in the clinical trials of another drug and may not reflect the rates observed in the general patient population. The data in the WARNINGS AND PRECAUTIONS reflect exposure to JAYPIRCA as a single-agent, administered at 200 mg once daily in 704 patients with hematologic malignancies in the BRUIN and the BRUIN-CLL-321 studies. Among these 704 patients, the median duration of exposure was 12 months; 65% were exposed for at least 6 months and 50% were exposed for at least one year. In this pooled safety population, the most common (≥ 30%) adverse reactions, including laboratory abnormalities, were decreased neutrophil count (54%), decreased hemoglobin (43%), decreased leukocytes (32%), fatigue (31%), decreased platelets (31%), decreased lymphocyte count (31%), and calcium decreased (30%) Mantle Cell Lymphoma BRUIN The safety of JAYPIRCA was evaluated in the BRUIN trial, an open-label, multicohort, single-arm study in patients with previously treated MCL who received a prior BTK inhibitor [see Clinical Studies ( 14.1 ) ] . The trial required a platelet count ≥ 50 x 10 9 /L, absolute neutrophil count ≥ 0.75 x 10 9 /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 JAYPIRCA 200 mg once daily N = 128 a Each term listed includes other related terms. b includes 1 fatality from COVID-19 pneumonia. c includes 1 fatality from hemorrhage. Adverse Reactions a All Grades (%) Grade 3-4 (%) General Disorders Fatigue 29 1.6 Edema 18 0.8 Fever 13 - Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 27 3.9 Arthritis or arthralgia 12 0.8 Gastrointestinal Disorders Diarrhea 19 - Constipation 13 - Abdominal pain 11 0.8 Nausea 11 - Respiratory, thoracic, and mediastinal disorders Dyspnea 17 2.3 Cough 14 - Injury Bruising 16 - Infections Pneumonia 16 b 14 Upper respiratory tract infections 10 0.8 Nervous system disorders Peripheral neuropathy 14 0.8 Dizziness 10 - Skin and subcutaneous disorders Rash 14 - Vascular disorders Hemorrhage 11 c 3.1 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. Laboratory Abnormality JAYPIRCA a 200 mg once daily All Grades (%) Grade 3 or 4 (%) Hematology Hemoglobin decreased 42 9 Platelet count decreased 39 14 Neutrophil count decreased 36 16 Lymphocyte count decreased 32 15 Chemistry 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%), 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 Leukemia/Small Lymphocytic Lymphoma BRUIN The safety of JAYPIRCA was evaluated in the BRUIN trial, an open-label, multicohort, single-arm study in 110 patients with relapsed or refractory CLL/SLL, with 98% having received at least two prior lines of systemic therapy including a covalent BTK inhibitor and a BCL-2 inhibitor [see Clinical Studies ( 14.2 ) ] . The trial required a platelet count ≥ 50 x 10 9 /L, absolute neutrophil count ≥ 0.75 x 10 9 /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, uncontrolled or symptomatic arrhythmias, 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 = 110); 60% were exposed for at least 1 year and 14% were exposed for at least two years. The median age was 68 years (range: 41 to 88 years) and 67% of patients were male. Race was reported in 110 (100%) patients; of these patients, 89% were White, 4.5% were Black, 1.8% were Asian, and 1.8% were Hispanic or Latino. The median number of prior therapies was 5 (range: 1-11). Serious adverse reactions occurred in 56% of patients who received JAYPIRCA. Serious adverse reactions that occurred in ≥ 5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Fatal adverse reactions within 28 days of the last dose of JAYPIRCA occurred in 11% of patients, most commonly due to infections (10%), including sepsis (5%) and COVID-19 (2.7%). Adverse reactions led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of JAYPIRCA in 9%. Adverse reactions which resulted in dose reductions of JAYPIRCA in > 1% of patients included neutropenia. Adverse reactions which resulted in treatment interruptions of JAYPIRCA in > 5% of patients included pneumonia, neutropenia, febrile neutropenia, and COVID-19. Adverse reactions which resulted in permanent discontinuation of JAYPIRCA in > 1% of patients included second primary malignancy, COVID-19, and sepsis. The most common adverse reactions (≥ 20%), excluding laboratory terms, were fatigue, bruising, cough, musculoskeletal pain, COVID-19, diarrhea, pneumonia, abdominal pain, dyspnea, hemorrhage, edema, nausea, pyrexia, and headache. Table 4 summarizes select adverse reactions for patients treated on BRUIN. Table 4: Adverse Reactions (≥ 10%) in Patients with CLL/SLL Who Received JAYPIRCA JAYPIRCA 200 mg once daily N = 110 Adverse Reactions a All Grades (%) Grade 3-4 (%) a Each term listed includes other related terms. b Includes COVID-19 pneumonia. Includes 1 fatality from COVID-19 and 2 fatalities from COVID-19 pneumonia. c Includes COVID-19 pneumonia. Includes 2 fatalities from COVID-19 pneumonia and 1 fatality from pneumonia. d Includes preferred terms hemorrhage, intracranial hemorrhage, and gastrointestinal hemorrhage. e Includes preferred terms memory impairment, confusional state, encephalopathy, mental status changes. f Includes preferred terms second primary malignancy and nonmelanoma skin cancers. 1 fatality from metastatic malignant melanoma. g Includes preferred terms renal failure, chronic kidney disease, acute kidney injury. h Includes preferred terms supraventricular tachycardia, sinus tachycardia, atrial fibrillation. General Disorders Fatigue 36 2.7 Edema 21 0 Pyrexia 20 2.7 Injury Bruising 36 0 Fall 14 0.9 Respiratory, thoracic, and mediastinal disorders Cough 33 0 Dyspnea 22 2.7 Mucositis 12 0.9 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 32 0.9 Arthritis or arthralgia 19 1.8 Infections COVID-19 28 b 7 Pneumonia 27 c 16 Upper respiratory tract infections 13 2.7 Respiratory tract infection 11 1.8 Gastrointestinal Disorders Diarrhea 26 0 Abdominal pain 25 2.7 Nausea 21 0 Constipation 14 0 Vascular disorders Hemorrhage 22 d 2.7 Hypertension 12 5 Nervous system disorders Headache 20 0.9 Peripheral neuropathy 16 3.6 Dizziness 15 0 Neurological changes 12 e 2.7 Skin and subcutaneous disorders Rash 19 0.9 Psychiatric disorders Insomnia 14 0 Neoplasms benign, malignant and unspecified Second primary malignancy 13 f 2.7 Renal and urinary disorders Renal insufficiency 12 g 6 Metabolism and nutrition disorders Decreased appetite 12 0 Cardiac disorders Supraventricular tachycardia 10 h 5 Clinically relevant adverse reactions in < 10% include vision changes, lower respiratory tract infection, urinary tract infection, herpesvirus infection, and tumor lysis syndrome. Table 5 summarizes laboratory abnormalities in BRUIN. Table 5: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with CLL/SLL Who Received JAYPIRCA Laboratory Abnormality JAYPIRCA a 200 mg once daily All Grades (%) Grade 3 or 4 (%) a The denominator used to calculate the rate varied from 83 to 108 based on the number of patients with a baseline value and at least one post-treatment value. Hematology Neutrophil count decreased 63 45 Hemoglobin decreased 48 19 Platelet count decreased 30 15 Lymphocyte count decreased 23 8 Chemistry Calcium decreased 40 2.8 Sodium decreased 30 0 ALT increased 23 2.8 AST increased 23 1.9 Creatinine increased 23 0 Lipase increased 21 7 Alkaline phosphatase increased 21 0 Grade 4 laboratory abnormalities in > 5% of patients included neutrophils decreased (23%). **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 64% of CLL/SLL patients in BRUIN. The median time to onset of lymphocytosis was 1.1 weeks, with 75% of cases occurring within 1.1 weeks, and the median duration was 19 weeks. BRUIN-321 The safety of JAYPIRCA was evaluated in BRUIN CLL-321, a randomized, multicenter, open-label active control trial [see Clinical Studies ( 14.2 )] . The trial enrolled patients with relapsed or refractory CLL/SLL who were previously treated with a covalent BTK inhibitor. The trial required a platelet count ≥ 50 x 10 9 /L, absolute neutrophil count ≥ 0.75 x 10 9 /L, and an estimated creatinine clearance ≥ 30 mL/min. The trial excluded patients with significant cardiovascular disease including uncontrolled or symptomatic arrhythmias, or major bleeding on a prior covalent BTK inhibitor. The trial enrolled 238 patients who were randomized in a 1:1 fashion to receive JAYPIRCA given orally once daily at a dose of 200 mg until disease progression or unacceptable toxicity or investigator's choice of either idelalisib in combination with a rituximab product or bendamustine in combination with a rituximab product [see Clinical Studies ( 14.2 )] . One hundred sixteen patients received JAYPIRCA and 109 patients received investigator's choice of idelalisib and rituximab or bendamustine and rituximab. The median duration of treatment with JAYPIRCA was 15 months with 78% on treatment for greater than 6 months and 66% for greater than 12 months. Serious adverse reactions occurred in 47% of patients who received JAYPIRCA. Serious adverse reactions that occurred in ≥ 3% of patients were pneumonia (21%), COVID-19 (5%), and sepsis (3.4%). Fatal adverse reactions within 30 days of the last dose of JAYPIRCA occurred in 8% of patients, most commonly due to infections (7%), COVID-19 (5%) and pneumonia (3.4%). Adverse reactions led to permanent discontinuation of JAYPIRCA in 17% of patients, dose reductions in 10%, and treatment interruption in 51%. Adverse reactions which resulted in dose reductions of JAYPIRCA in > 1% of patients included neutropenia. Adverse reactions which resulted in treatment interruptions of JAYPIRCA in > 5% of patients included pneumonia, neutropenia, hemorrhage and COVID-19. Adverse reactions which resulted in permanent discontinuation of JAYPIRCA in > 1% of patients included pneumonia, COVID-19, neutropenia, anemia, and cardiac arrythmias. The most common adverse reactions (≥ 20%), excluding laboratory terms, were pneumonia and upper respiratory tract infections. Table 6 summarizes select adverse reactions for patients treated on BRUIN CLL-321. Table 6: Adverse Reactions (≥ 10%) in Patients with CLL/SLL Who Received JAYPIRCA (BRUIN CLL-321) a Each term listed includes other related terms. b Includes COVID-19 pneumonia. Includes 3 fatalities from COVID-19 pneumonia, 3 fatalities from pneumonia, for JAYPIRCA; includes 3 fatalities from pneumonia for IR and 1 fatality from COVID-19 pneumonia for BR. c Includes COVID-19 pneumonia. Includes 3 fatalities from COVID-19 pneumonia and 3 fatalities from COVID-19 for JAYPIRCA and 1 fatality from COVID-19 for IR and 1 fatality from COVID-19 pneumonia for BR. JAYPIRCA Investigator's Choice N = 116 N = 109 Adverse Reactions a All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Pneumonia 28 b 16 16 b 11 Upper respiratory tract infections 21 0.9 10 0 COVID-19 17 c 0.9 19 c 4.6 General Disorders Fatigue 19 2.6 26 1.8 Edema 12 0 8 0 Cough 19 0 19 0 Fever 13 0.9 27 0.9 Nausea 11 0.9 20 0 Headache 11 0.9 16 0 Hemorrhage 16 2.6 7 0 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 19 0.9 13 0 Gastrointestinal Disorders Diarrhea 16 0 31 6 Skin and Subcutaneous Disorders Rash 14 2.6 20 4.6 Clinically relevant adverse reactions in <10% in patients who received JAYPIRCA include vision changes, urinary tract infection, herpes virus infection, and hypertension. Table 7 summarizes laboratory abnormalities in BRUIN CLL-321. Table 7: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with CLL/SLL Who Received JAYPIRCA (BRUIN CLL-321) a The denominator used to calculate the rate varied from 113 to 114 in the JAYPIRCA arm and from 29 to 31 for bendamustine plus rituximab, and 75 for idelalisib plus rituximab, based on the number of patients with a baseline value and at least one posttreatment value. Laboratory Abnormality JAYPIRCA a Investigator's Choice a All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Neutrophil count decreased 54 26 67 27 Hemoglobin decreased 45 10 42 8 Platelet count decreased 37 17 42 9 Chemistry ALT increased 25 1.8 46 14 Creatinine increased 25 0 20 1 Calcium decreased 23 0.9 31 0 Sodium decreased 22 0.9 21 1 Bilirubin increased 21 0.9 21 1