Larotrectinib

1 INDICATIONS AND USAGE VITRAKVI is indicated for the treatment of adult and pediatric patients with solid tumors that: have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Select patients for therapy based on an FDA-approved test [see Dosage and Administration (2.1) ]. VITRAKVI is a kinase inhibitor indicated for the treatment of adult and pediatric patients with solid tumors that: have a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. Select patients for therapy based on an FDA-approved test. ( 1 , 2.1 )

12.1 Mechanism of Action Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, larotrectinib inhibited TRKA, TRKB, and TRKC with IC 50 values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-fold higher concentration. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines. In in vitro and in vivo tumor models, larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.

2 DOSAGE AND ADMINISTRATION Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion ( 2.1 , 14 ). Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of 1 Meter-Squared or greater: 100 mg orally twice daily ( 2.2 ) Recommended Dosage in Pediatric Patients with Body Surface Area of Less Than 1 Meter-Squared: 100 mg/m 2 orally twice daily ( 2.2 ) 2.1 Patient Selection Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in tumor specimens [see Clinical Studies (14) ] . In patients with secretory breast cancer, mammary analogue secretory cancer (MASC), congenital mesoblastic nephroma (CMN), or infantile fibrosarcoma, consider treatment without confirmation of NTRK rearrangements in tumor specimens. Information on FDA-approved tests is available at http://www.fda.gov/companiondiagnostics. 2.2 Recommended Dosage Recommended Dosage in Adult and Pediatric Patients with Body Surface Area of 1 Meter-Squared or greater The recommended dosage of VITRAKVI is 100 mg orally twice daily, with or without food, until disease progression or until unacceptable toxicity. Recommended Dosage in Pediatric Patients with Body Surface Area Less Than 1 Meter-Squared The recommended dosage of VITRAKVI is 100 mg/m 2 orally twice daily, with or without food, until disease progression or until unacceptable toxicity. 2.3 Dosage Modifications for Adverse Reactions For Grade 2 and higher liver function test abnormalities, refer to Section 2.4, Table 2, Dosage Modifications for Hepatotoxicity. For all other Grade 3 or 4 adverse reactions: Withhold VITRAKVI until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within 4 weeks. Permanently discontinue VITRAKVI if an adverse reaction does not resolve within 4 weeks. The recommended dosage reductions for VITRAKVI for adverse reactions are provided in Table 1. Table 1 Recommended Dosage Reductions for VITRAKVI for Adverse Reactions Dosage Reduction Adult and Pediatric Patients with Body Surface Area of 1 m 2 or Greater Pediatric Patients with Body Surface Area Less Than 1 m 2 First 75 mg orally twice daily 75 mg/m 2 orally twice daily Second 50 mg orally twice daily 50 mg/m 2 orally twice daily Third 100 mg orally once daily 25 mg/m 2 orally twice daily Pediatric patients on 25 mg/m 2 orally twice daily should remain on this dosage even if body surface area becomes greater than 1 m 2 during the treatment. Maximum dose should be 25 mg/m 2 orally twice daily at the third dosage modification. Permanently discontinue VITRAKVI in patients who are unable to tolerate VITRAKVI after three dose modifications. 2.4 Dosage Modifications for Hepatotoxicity The recommended dosage modifications for VITRAKVI liver function test abnormalities are provided in Table 2. For CTCAE Grade 2 ALT and/or AST elevation, monitor liver function frequently as clinically indicated, to establish whether a dose interruption or reduction is required [see Warnings and Precautions (5.3) ] . Table 2 Recommended Dosage Modifications for VITRAKVI for Hepatotoxicity Severity Grading defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Dosage Modification ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal AST or ALT ≥ 5 × ULN with bilirubin ≤ 2 × ULN [see Warnings and Precautions (5.3) ] Withhold VITRAKVI until recovery to ≤ Grade 1 or return to baseline. Resume VITRAKVI at the next lower dose level. Permanently discontinue if a Grade 4 AST and/or ALT elevation occurs after resuming VITRAKVI. AST or ALT > 3 × ULN with total bilirubin > 2 × ULN in the absence of alternative causes Permanently discontinue VITRAKVI. 2.5 Dosage Modifications for Coadministration with Strong CYP3A4 Inhibitors Avoid coadministration of strong CYP3A4 inhibitors with VITRAKVI. If coadministration of a strong CYP3A4 inhibitor

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Central Nervous System Effects [see Warnings and Precautions (5.1) ] Skeletal Fractures [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] The most common (≥ 20%) adverse reactions, including laboratory abnormalities, with VITRAKVI were increased AST, increased ALT, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Unless noted, data in WARNINGS AND PRECAUTIONS and below reflects exposure to VITRAKVI in 444 patients, including 62% patients exposed for greater than 6 months, 44% patients exposed for greater than 1 year, and 30% patients exposed for greater than 2 years. VITRAKVI was studied in one adult dose-finding trial [LOXO-TRK-14001 (n = 75)], one pediatric dose-finding trial [SCOUT (n = 154)], and one single arm trial [NAVIGATE (n = 215)]. All patients had an unresectable or metastatic solid tumor and no satisfactory alternative treatment options or disease progression following treatment. Across these 444 patients, the median age was 44 years (range: 18 days to 90 years); 35% were younger than 18 years; 53% were female; 59% were White, 24% were Asian and, 4% were Black; and 7% were Hispanic/Latino. Most adults (91%) received VITRAKVI 100 mg orally twice daily and 91% of pediatrics (< 18 years) received VITRAKVI 100 mg/m 2 twice daily up to a maximum dose of 100 mg twice daily. The dose ranged from 50 mg daily to 200 mg twice daily in adults and 9.6 mg/m 2 twice daily to 120 mg/m 2 twice daily in pediatrics [see Use in Specific Populations (8.4) ] . The most common serious adverse reactions (≥ 2%) were pneumonia, pyrexia, and dyspnea. Grade 3 or 4 adverse reactions occurred in 60% of patients; adverse reactions leading to dose interruption or modification occurred in 45% and 11% of patients, respectively, and 12% permanently discontinued VITRAKVI for adverse reactions. The most common adverse reactions (1% each) that resulted in permanent discontinuation of VITRAKVI were increased ALT and increased AST. The most common adverse reactions (≥ 3%) resulting in dose interruption were increased ALT (6%), increased AST (5%), neutrophil count decreased (4.7%), pyrexia (4.3%), and vomiting (3.2%). Most (64%) adverse reactions leading to dose interruption occurred during the first three months of exposure. The most common adverse reactions (≥ 20%), including laboratory abnormalities, in order of decreasing frequency were increased AST, increased ALT, anemia, hypoalbuminemia, musculoskeletal pain, increased alkaline phosphatase, leukopenia, lymphopenia, neutropenia, hypocalcemia, fatigue, vomiting, cough, constipation, pyrexia, diarrhea, nausea, abdominal pain, dizziness, and rash. Adverse reactions of VITRAKVI occurring in ≥ 10% of patients and laboratory abnormalities worsening from baseline in ≥ 20% of patients are summarized in Table 3 and Table 4, respectively. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients Treated with VITRAKVI Adverse Reaction The adverse reaction identifies a composite term: VITRAKVI N = 444 All Grades National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v 4.03. (%) Grade 3-4 Grade 4 adverse reaction: 1 of cognitive impairment, 1 of pyrexia. (%) Musculoskeletal and Connective Tissue Musc

5 WARNINGS AND PRECAUTIONS Central Nervous System (CNS) Effects: Advise patients and caretakers of the risk of CNS adverse reactions including dizziness, cognitive impairment, mood disorders, and sleep disturbances. Advise patients not to drive or operate hazardous machinery if experiencing neurotoxicity. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity. ( 2.3 , 5.1 ) Skeletal Fractures: Promptly evaluate patients with signs or symptoms of fractures. ( 5.2 ) Hepatotoxicity: Obtain liver function tests (ALT, AST, ALP and bilirubin) before initiation of VITRAKVI and every 2 weeks during the first 2 months of treatment, then monthly thereafter or as clinically indicated. Temporarily withhold, reduce dose, or permanently discontinue VITRAKVI based on severity. ( 2.4 , 5.3 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. ( 5.4 , 8.3 ) 5.1 Central Nervous System Effects Central nervous system (CNS) adverse reactions occurred in patients receiving VITRAKVI, including dizziness, cognitive impairment, mood disorders, and sleep disturbances. In patients who received VITRAKVI (n=444), all grades CNS effects including cognitive impairment, mood disorders, dizziness and sleep disorders were observed in 40.3% with Grades 3-4 in 3.8% of patients. Cognitive impairment occurred in 11% of patients. The median time to onset of cognitive impairment was 6 months (range: 2 days to 56 months). Cognitive impairment occurring in ≥ 1% of patients included memory impairment (4.1%), disturbance in attention (3.6%), confusional state (2.3%), cognitive disorder (1.6%), delirium (1.4%), and hallucination (1.1%). Grade 3 cognitive adverse reactions occurred in 1.8% of patients and Grade 4 cognitive adverse reactions in 0.2% of patients. Among the 49 patients with cognitive impairment, 6% required a dose modification, and 18% required dose interruption. Mood disorders occurred in 14% of patients. The median time to onset of mood disorders was 3.3 months (range: 1 day to 65 months). Mood disorders occurring in ≥ 1% of patients included anxiety (5%), agitation (3.2%), depression (3.2%), irritability (2.3%), and restlessness (1.1%). Grade 3 mood disorders occurred in 0.9% of patients. Among the 63 patients who experienced mood disorders, no patient required a dose modification, and 1.6% required dose interruption. Dizziness occurred in 22% of patients, and Grade 3 dizziness occurred in 0.9% of patients. Among the 96 patients who experienced dizziness, 6% of patients required a dose modification, and 5% required dose interruption. Sleep disturbances occurred in 12% of patients. Sleep disturbances included insomnia (9%), somnolence (3.4%), and sleep disorder (0.5%). Grade 3 sleep disturbances occurred in 0.2% of patients. Among the 54 patients who experienced sleep disturbances, no patient required a dose modification, and 3.7% required dose interruption. Advise patients and caretakers of these risks with VITRAKVI. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue VITRAKVI based on the severity. If withheld, modify the VITRAKVI dosage when resumed [see Dosage and Administration (2.3) ] . 5.2 Skeletal Fractures Skeletal fractures can occur in patients taking VITRAKVI. Among 444 patients who received VITRAKVI across clinical trials, fractures occurred in 7% of patients; 6% of 290 adult patients and 10% of 154 pediatric patients. Median time to first fracture was 13 months (range 27 days to 73 months) in patients followed per fracture. The most common fractures were of the rib (1.4%), fibula, foot, or wrist (0.7% each). Most fractures were associated with minimal or moderate trauma. Some fractures were associated with radiologic abnormalities suggestive of local tumor involvement. VITRAKVI treatment was interrupted due to fractur

4 CONTRAINDICATIONS None. None. ( 4 )