Selpercatinib

12.1 Mechanism of Action Selpercatinib is a kinase inhibitor. Selpercatinib inhibited wild-type RET and multiple mutated RET isoforms as well as VEGFR1 and VEGFR3 with IC 50 values ranging from 0.92 nM to 67.8 nM. In other enzyme assays, selpercatinib also inhibited FGFR 1, 2, and 3 at higher concentrations that were still clinically achievable. In cellular assays, selpercatinib inhibited RET at approximately 60-fold lower concentrations than FGFR1 and 2 and approximately 8-fold lower concentration than VEGFR3. Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. In in vitro and in vivo tumor models, selpercatinib demonstrated anti-tumor activity in cells harboring constitutive activation of RET proteins resulting from gene fusions and mutations, including CCDC6-RET, KIF5B-RET, RET V804M, and RET M918T. In addition, selpercatinib showed anti-tumor activity in mice intracranially implanted with a patient-derived RET fusion positive tumor.

1 INDICATIONS AND USAGE RETEVMO ® is a kinase inhibitor indicated for the treatment of: Adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test ( 1.1 ) Adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy ( 1.2 ) Adult and pediatric patients 2 years of age and older with advanced or metastatic thyroid cancer with a RET gene fusion, as detected by an FDA-approved test, who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate) ( 1.3 ) Adult and pediatric patients 2 years of age and older with locally advanced or metastatic solid tumors with a RET gene fusion, as detected by an FDA-approved test, that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options 1 ( 1.4 ) 1 This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). 1.1 RET Fusion-Positive Non-Small Cell Lung Cancer RETEVMO ® is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with a rearranged during transfection (RET) gene fusion, as detected by an FDA-approved test. 1.2 RET -Mutant Medullary Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation, as detected by an FDA-approved test, who require systemic therapy. 1.3 RET Fusion-Positive Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 2 years of age and older wi

2 DOSAGE AND ADMINISTRATION Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC, thyroid, or other solid tumors) or specific RET gene mutation (MTC). ( 2.1 , 14 ) Adult and adolescent patients 12 years of age or older : the recommended dosage is based on weight ( 2.3 ): Less than 50 kg: 120 mg orally twice daily 50 kg or greater: 160 mg orally twice daily Pediatric patients 2 to less than 12 years of age: the recommended dosage is based on body surface area ( 2.3 ): 0.33 m 2 to 0.65 m 2 : 40 mg orally three times daily 0.66 m 2 to 1.08 m 2 : 80 mg orally twice daily 1.09 m 2 to 1.52 m 2 : 120 mg orally twice daily ≥1.53 m 2 : 160 mg orally twice daily For patients who cannot swallow, disperse 40 mg RETEVMO tablets and administer orally or via gastrostomy or nasogastric tube ( 2.8 ) Only RETEVMO 40 mg tablets may be used to create the dispersion ( 2.2 ) Reduce RETEVMO dose in patients with severe hepatic impairment. ( 2.7 , 8.7 ) 2.1 Patient Selection Select patients for treatment with RETEVMO based on the presence of a RET gene fusion (NSCLC, thyroid cancer, or other solid tumors) or specific RET gene mutation (MTC) in tumor specimens [see Clinical Studies ( 14 )] . Information on FDA-approved test(s) for the detection of RET gene fusions and RET gene mutations is available at: http://www.fda.gov/CompanionDiagnostics. An FDA-approved companion diagnostic test for the detection of RET gene fusions and RET gene mutations in plasma is not available. 2.2 Important Administration Instructions RETEVMO may be taken with or without food unless coadministered with a proton pump inhibitor (PPI) [see Dosage and Administration ( 2.4 ) , Clinical Pharmacology ( 12.3 )] . Swallow the capsule or tablet whole. Do not crush or chew the capsules or tablets. For patients unable to swallow capsules or tablets or who are using a feeding tube, prepare and administer RETEVMO as a dispersion; only RETEVMO 40 mg tablets may be used to create the dispersion [see Dosage and Administration ( 2.8 )] 2.3 Recommended Dosage The recommended dosage of RETEVMO administered as recommended [see Dosage and Administration ( 2.2 )] given until disease progression or unacceptable toxicity is shown in Table 1 : Table 1: Recommended RETEVMO Dosage Population RETEVMO Dosage Adult and adolescent patients 12 years of age or older based on body weight Less than 50 kg 120 mg twice daily 50 kg or greater 160 mg twice daily Pediatric patients 2 to less than 12 years of age based on body surface area 0.33 to 0.65 m 2 40 mg three times daily 0.66 to 1.08 m 2 80 mg twice daily 1.09 to 1.52 m 2 120 mg twice daily ≥1.53 m 2 160 mg twice daily Dosing pediatric patients with body surface area less than 0.33 m 2 is not recommended Missed Dose Do not take a missed dose unless it is more than 6 hours until next scheduled dose. Vomiting If vomiting occurs after RETEVMO administration, do not take an additional dose and continue to the next scheduled time for the next dose. 2.4 Dosage Modifications for Concomitant Use of Acid-Reducing Agents Avoid concomitant use of a PPI, a histamine-2 (H2) receptor antagonist, or a locally-acting antacid with RETEVMO [see Drug Interactions ( 7.1 )] . If concomitant use cannot be avoided: Take RETEVMO with food when coadministered with a PPI. Take RETEVMO 2 hours before or 10 hours after administration of an H2 receptor antagonist. Take RETEVMO 2 hours before or 2 hours after administration of a locally-acting antacid. 2.5 Dosage Modifications for Adverse Reactions The recommended dose reductions for adverse reactions are provided in Table 2 . Table 2: Recommended RETEVMO Dose Reductions for Adverse Reactions Current RETEVMO Dosage Dose Reduction First Second Third 40 mg three times daily 40 mg twice daily 40 mg once daily permanently discontinue 80 mg twice daily 40 mg twice daily 40 mg once daily permanently discontinue 120 mg twice daily 80 mg twice daily 40 mg twice daily 40 mg once daily 160 mg twice daily 120 mg twice daily 80 mg twice daily 40 mg twice daily Permanently discontinue RETEVMO in patients unable to tolerate three dose reductions. The recommended dosage modifications for adverse reactions are provided in Table 3 . Table 3: Recommended RETEVMO Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Hepatotoxicity [see Warnings and Precautions ( 5.1 )] Grade 3 or Grade 4 Withhold RETEVMO and monitor AST/ALT once weekly until resolution to Grade 1 or baseline. Resume at reduced dose by 2 dose levels and monitor AST and ALT once weekly until 4 weeks after reaching dose taken prior to the onset of Grade 3 or 4 increased AST or ALT. Increase dose by 1 dose level after a minimum of 2 weeks without recurrence and then increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT after a minimum of 4 weeks without recurrence. Interstitial Lung Disease/ Pneumonitis [see Warnings and Precautions ( 5.2 )] Grade 2 Withhold RETEVMO until

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hepatotoxicity [see Warnings and Precautions ( 5.1 )] Interstitial Lung Disease / Pneumonitis [see Warnings and Precautions ( 5.2 )] Hypertension [see Warnings and Precautions ( 5.3 )] QT Interval Prolongation [see Warnings and Precautions ( 5.4 )] Hemorrhagic Events [see Warnings and Precautions ( 5.5 )] Hypersensitivity [see Warnings and Precautions ( 5.6 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.7 )] Risk of Impaired Wound Healing [see Warnings and Precautions ( 5.8 )] Hypothyroidism [see Warnings and Precautions ( 5.9 )] Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Adolescent Patients [see Warnings and Precautions ( 5.11 )] The most common adverse reactions (≥25%) include: Adult patients with solid tumors: edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. ( 6 ) Pediatric patients with solid tumors: musculoskeletal pain, diarrhea, nausea, hemorrhage, pyrexia, abdominal pain, headache, vomiting, fatigue, cough, rash, coronavirus infection, upper respiratory tract infection, and edema. ( 6 ) The most common Grade 3 or 4 laboratory abnormalities (≥5%) include: Adult patients with solid tumors: decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium. ( 6 ) Pediatric patients with solid tumors: decreased lymphocytes, decreased calcium, decreased hemoglobin, decreased neutrophils, increased alanine aminotransferase, decreased magnesium, and decreased potassium. ( 6 ) 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 directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 796 patients with advanced solid tumors in LIBRETTO-001 [see Clinical Studies ( 14 )] . RET Gene Fusion or Gene Mutation Positive Solid Tumors LIBRETTO-001 Among the 796 patients who received RETEVMO, 84% were exposed for 6 months or longer and 73% were exposed for greater than one year. Among these patients, 96% received at least one dose of RETEVMO at the recommended dosage of 160 mg orally twice daily. The median age was 59 years (range: 15 to 92 years); 0.3% were pediatric patients 12 to 16 years of age; 51% were male; and 69% were White, 23% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino. The most common tumors were NSCLC (45%), MTC (40%), and non-medullary thyroid carcinoma (7%). Serious adverse reactions occurred in 44% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pneumonia, pleural effusion, abdominal pain, hemorrhage, hypersensitivity, dyspnea, and hyponatremia. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n = 6), respiratory failure (n = 5), hemorrhage (n = 4), pneumonia (n = 3), pneumonitis (n = 2), cardiac arrest (n=2), sudden death (n = 1), and cardiac failure (n = 1). Permanent discontinuation due to an adverse reaction occurred in 8% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥0.5% of patients included increased ALT (0.6%), fatigue (0.6%), sepsis (0.5%), and increased AST (0.5%). Dosage interruptions due to an adverse reaction occurred in 64% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, diarrhea, and hypertension. Dose reductions due to an adverse reaction occurred in 41% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included increased ALT, increased AST, QT prolongation, fatigue, diarrhea, drug hypersensitivity, and edema. The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), decreased sodium, and decreased calcium. Table 6 summarizes the adverse reactions in LIBRETTO-001. Table 6: Adverse Reactions (≥20%) in Patients Who Received RETEVMO in LIBRETTO-001 1 Edema includes edema peripheral, face edema, periorbital edema, eye edema, eyelid edema, orbital edema, localized edema, lymphedema, scrotal edema, peripheral swellin

7 DRUG INTERACTIONS Acid-Reducing Agents: Avoid coadministration. If coadministration cannot be avoided, take RETEVMO with food (with PPI) or modify its administration time (with H2 receptor antagonist or locally-acting antacid). ( 2.4 , 7.1 ) Strong and Moderate CYP3A Inhibitors: Avoid coadministration. If coadministration cannot be avoided, reduce the RETEVMO dose. ( 2.6 , 7.1 ) Strong and Moderate CYP3A Inducers: Avoid coadministration. ( 7.1 ) CYP2C8 and CYP3A Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. ( 7.2 ) Certain P-gp and BCRP Substrates: Avoid coadministration. If coadministration cannot be avoided, modify the substrate dosage as recommended in its product labeling. ( 7.2 ) 7.1 Effects of Other Drugs on RETEVMO Acid-Reducing Agents Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may reduce RETEVMO anti-tumor activity. Avoid concomitant use of PPIs, H2 receptor antagonists, and locally-acting antacids with RETEVMO. If coadministration cannot be avoided, take RETEVMO with food (with a PPI) or modify its administration time (with a H2 receptor antagonist or a locally-acting antacid) [see Dosage and Administration ( 2.4 )] . Strong and Moderate CYP3A Inhibitors Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of RETEVMO adverse reactions, including QTc interval prolongation. Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of strong and moderate CYP3A inhibitors cannot be avoided, reduce the RETEVMO dosage and monitor the QT interval with ECGs more frequently [see Dosage and Administration ( 2.6 ), Warning and Precautions ( 5.4 )] . Strong and Moderate CYP3A Inducers Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may reduce RETEVMO anti-tumor activity. Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO. 7.2 Effects of RETEVMO on Other Drugs CYP2C8 and CYP3A Substrates RETEVMO is a moderate CYP2C8 inhibitor and a weak CYP3A inhibitor. Concomitant use of RETEVMO with CYP2C8 and CYP3A substrates increases their plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling. Certain P-gp and BCRP Substrates RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling. 7.3 Drugs that Prolong QT Interval RETEVMO is associated with QTc interval prolongation [see Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.2 )] . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.