RETEVMO

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 )] The most common adverse reactions (≥25%) were edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, constipation, rash, nausea, and headache. ( 6 ) 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. ( 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. RET Gene Fusion or Gene Mutation Positive Solid Tumors The pooled safety population described in the WARNINGS and PRECAUTIONS and below reflects exposure to RETEVMO as a single agent at 160 mg orally twice daily evaluated in 796 patients with advanced solid tumors in LIBRETTO-001 [see Clinical Studies ( 14 )] . 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, 5% were Hispanic/Latino, and 3% were Black. 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 5 summarizes the adverse reactions in LIBRETTO-001. Table 5: Adverse Reactions (≥20%) in Patients Who Received RETEVMO in LIBRETTO-001 1 Diarrhea includes diarrhea, defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence. 2 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain. 3 Edema includes edema, edema peripheral, face edema, periorbital edema, eye edema, eyelid edema, orbital edema, localized edema, lymphedema, scrotal edema, peripheral swelling, scrotal swelling, swelling, swelling face, eye swelling, generalized edema, genital edema. 4 Fatigue includes fatigue, asthenia, malaise. 5 Rash includes rash, rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular. 6 Headache includes headache, sinus headache, tension headache. 7 Includes cough, productive cough, upper airway cough syndrome. 8 Includes dyspnea, dyspnea exertional, dyspnea at rest. 9 Hemorrhage includes hemorrhage, epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, gastric hemorrhage, hemorrhage intracranial, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemorrhoidal hemorrhage, hepatic hemorrhage, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, post procedural hemorrhage, postmenopausal hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma. * Only includes a grade 3 adverse reaction. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Adverse Reaction RETEVMO (n = 796) Grades 1-4 # (%) Grades 3-4 (%) Gastrointestinal Diarrhea 1 47 5* Dry Mouth 43 0 Abdominal pain 2 34 2.5* Constipation 33 0.8* Nausea 31 1.1* Vomiting 22 1.8* Vascular Hypertension 41 20 General Edema 3 49 0.8* Fatigue 4 46 3.1* Arthralgia 21 0.3* Skin Rash 5 33 0.6* Nervous System Headache 6 28 1.4* Respiratory Cough 7 24 0 Dyspnea 8 22 3.1 Investigations Prolonged QT interval 21 4.8* Blood and Lymphatic System Hemorrhage 9 22 2.6 Clinically relevant adverse reactions in ≤15% of patients who received RETEVMO include hypothyroidism (13%); hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all < 2%). Table 6 summarizes the laboratory abnormalities in LIBRETTO-001. Table 6: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-001 1 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 765 to 791 patients. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Laboratory Abnormality RETEVMO 1 Grades 1-4 # (%) Grades 3-4 (%) Chemistry Increased AST 59 11 Decreased calcium 59 5.7 Increased ALT 56 12 Decreased albumin 56 2.3 Increased glucose 53 2.8 Increased creatinine 47 2.4 Decreased sodium 42 11 Increased alkaline phosphatase 40 3.4 Increased total cholesterol 35 1.7 Increased potassium 34 2.7 Decreased glucose 34 1.0 Decreased magnesium 33 0.6 Increased bilirubin 30 2.8 Hematology Decreased lymphocytes 52 20 Decreased platelets 37 3.2 Decreased hemoglobin 28 3.5 Decreased neutrophils 25 3.2 Increased Creatinine In healthy subjects administered RETEVMO 160 mg orally twice daily, serum creatinine increased 18% after 10 days. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology ( 12.3 )] .

4 CONTRAINDICATIONS None. None. ( 4 )

11 DESCRIPTION Selpercatinib is a kinase inhibitor. The molecular formula for selpercatinib is C 29 H 31 N 7 O 3 and the molecular weight is 525.61 g/mol. The chemical name is 6-(2-hydroxy-2-methylpropoxy)-4-(6-(6-((6-methoxypyridin-3-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile. Selpercatinib has the following chemical structure: Selpercatinib is a white to light yellow powder that is slightly hygroscopic. The aqueous solubility of selpercatinib is pH dependent, from sparingly soluble at low pH to practically insoluble at neutral pH. RETEVMO (selpercatinib) is supplied as 40 mg or 80 mg hard gelatin capsules for oral use. Each capsule contains inactive ingredients of microcrystalline cellulose and colloidal silicon dioxide. The 40 mg capsule shell is composed of gelatin, titanium dioxide, ferric oxide black and black ink. The 80 mg capsule shell is composed of gelatin, titanium dioxide, FD&C blue #1 and black ink. The black ink is composed of shellac, potassium hydroxide and ferric oxide black. chemical structure

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 ) Recommended dosage in adults and pediatric patients 12 years of age or older is based on weight ( 2.3 ): Less than 50 kg: 120 mg orally twice daily 50 kg or greater: 160 mg orally twice daily 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 or in tumors other than NSCLC and thyroid cancer is not currently 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 )] . 2.3 Recommended Dosage The recommended dosage of RETEVMO based on body weight is: Less than 50 kg: 120 mg 50 kg or greater: 160 mg Take RETEVMO orally twice daily (approximately every 12 hours) until disease progression or unacceptable toxicity. Swallow the capsules whole. Do not crush or chew the capsules. Do not take a missed dose unless it is more than 6 hours until next scheduled dose. 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 1 . Table 1: Recommended RETEVMO Dose Reductions for Adverse Reactions Dose Reduction Patients Weighing Less Than 50 kg Patients Weighing 50 kg or Greater First 80 mg orally twice daily 120 mg orally twice daily Second 40 mg orally twice daily 80 mg orally twice daily Third 40 mg orally once daily 40 mg orally twice daily Permanently discontinue RETEVMO in patients unable to tolerate three dose reductions. The recommended dosage modifications for adverse reactions are provided in Table 2 . Table 2: 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 resolution. Resume at a reduced dose. Discontinue RETEVMO for recurrent ILD/pneumonitis. Grade 3 or Grade 4 Discontinue RETEVMO for confirmed ILD/pneumonitis. Hypertension [see Warnings and Precautions ( 5.3 )] Grade 3 Withhold RETEVMO for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled. Grade 4 Discontinue RETEVMO. QT Interval Prolongation [see Warnings and Precautions ( 5.4 )] Grade 3 Withhold RETEVMO until recovery to baseline or Grade 0 or 1. Resume at a reduced dose. Grade 4 Discontinue RETEVMO. Hemorrhagic Events [see Warnings and Precautions ( 5.5 )] Grade 3 or Grade 4 Withhold RETEVMO until recovery to baseline or Grade 0 or 1. Discontinue RETEVMO for severe or life-threatening hemorrhagic events. Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] All Grades Withhold RETEVMO until resolution of the event. Initiate corticosteroids. Resume at a reduced dose by 3 dose levels while continuing corticosteroids. Increase dose by 1 dose level each week until the dose taken prior to the onset of hypersensitivity is reached, then taper corticosteroids. Hypothyroidism [see Warnings and Precautions ( 5.9 )] Grade 3 or Grade 4 Withhold RETEVMO until resolution to Grade 1 or baseline. Discontinue RETEVMO based on severity. Other Adverse Reactions [see Adverse Reactions ( 6.1 )] Grade 3 or Grade 4 Withhold RETEVMO until recovery to baseline or Grade 0 or 1. Resume at a reduced dose. 2.6 Dosage Modifications for Concomitant Use of Strong and Moderate CYP3A Inhibitors Avoid concomitant use of strong and moderate CYP3A inhibitors with RETEVMO. If concomitant use of a strong or moderate CYP3A inhibitor cannot be avoided, reduce the RETEVMO dose as recommended in Table 3 . After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume RETEVMO at the dose taken prior to initiating the CYP3A inhibitor [see Drug Interactions ( 7.1 )] . Table 3: Recommended RETEVMO Dosage for Concomitant Use of Strong and Moderate CYP3A Inhibitors Current RETEVMO Dosage Recommended RETEVMO Dosage Moderate CYP3A Inhibitor Strong CYP3A Inhibitor 120 mg orally twice daily 80 mg orally twice daily 40 mg orally twice daily 160 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 2.7 Dosage Modification for Severe Hepatic Impairment Reduce the recommended dosage of RETEVMO for patients with severe hepatic impairment as recommended in Table 4 [see Use in Specific Populations ( 8.7 )] . Table 4: Recommended RETEVMO Dosage for Severe Hepatic Impairment Current RETEVMO Dosage Recommended RETEVMO Dosage 120 mg orally twice daily 80 mg orally twice daily 160 mg orally twice daily 80 mg orally twice daily

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 12 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 ( 1.2 ) Adult and pediatric patients 12 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 ( 1.3 ) Adult patients with locally advanced or metastatic solid tumors with a RET gene fusion 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 12 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. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.2 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). 1.3 RET Fusion-Positive Thyroid Cancer RETEVMO is indicated for the treatment of adult and pediatric patients 12 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). This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.3 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). 1.4 Other RET Fusion-Positive Solid Tumors RETEVMO is indicated for the treatment of adult patients with locally advanced or metastatic solid tumors with a RET gene fusion that have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies ( 14.4 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

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 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 Substrates RETEVMO is a P-gp inhibitor. Concomitant use of RETEVMO with P-gp 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 substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp 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.

12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Exposure-Response Relationship Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (C max ) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent. 12.3 Pharmacokinetics The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. Steady state selpercatinib AUC and C max increased in a slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily [0.06 to 1.5 times the maximum recommended total daily dosage]. Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] C max was 2,980 (53%) ng/mL and AUC 0-24h was 51,600 (58%) ng*h/mL. Absorption The median t max of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects. Effect of Food No clinically significant differences in selpercatinib AUC or C max were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects. Distribution The apparent volume of distribution (V ss /F) of selpercatinib is 191 L. Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7. Elimination The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects. Metabolism Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma. Excretion Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged). Specific Populations The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (27 kg to 179 kg). No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (15 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR ≥15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied. Patients with Hepatic Impairment The selpercatinib AUC 0-INF increased by 7%, 32%, and 77% in subjects with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST), moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, respectively, compared to subjects with normal hepatic function. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC 0-INF and C max when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC 0-INF and C max when RETEVMO was administered with food ( Table 7 ). Table 7: Change in Selpercatinib Exposure After Coadministration with PPI 1 High-fat meal: approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; approximately 800 to 1,000 calories total. 2 Low-fat meal: approximately 390 calories and 10 g of fat. Selpercatinib AUC 0-INF Selpercatinib C max RETEVMO fasting Reference Reference RETEVMO fasting + PPI ↓ 69% ↓ 88% RETEVMO with a high-fat meal 1 + PPI ↑ 2% ↓ 49% RETEVMO with a low-fat meal 2 + PPI No change ↓ 22% H2 Receptor Antagonists: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the RETEVMO dose (administered fasting). Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC 0-INF by 133% and C max by 30%. Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC by 60-99% and C max by 46-76%. Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC 0-INF by 87% and C max by 70%. Moderate CYP3A Inducers: Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the selpercatinib AUC by 40-70% and C max by 34-57%. Weak CYP3A Inducers: Coadministration of multiple doses of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and C max by 26%. CYP2C8 Substrates : Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC 0-INF by 188% and C max by 91%. CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A substrate) increased the midazolam AUC 0-INF by 54% and C max by 39%. P-glycoprotein (P-gp) Substrates: Coadministration of RETEVMO with dabigatran (P-gp substrate) increased the dabigatran AUC 0-INF by 38% and C max by 43%. P-gp Inhibitors: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampin (P-gp inhibitor). MATE1 Substrates: No clinically significant differences in glucose levels were observed when metformin (MATE1 substrate) was coadministered with selpercatinib. In Vitro Studies CYP Enzymes: Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Transporter Systems: Selpercatinib inhibits MATE1 and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Adverse Effects ( 6.1 )] . Selpercatinib is a substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.

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.

12.2 Pharmacodynamics Exposure-Response Relationship Selpercatinib exposure-response relationships and the time course of pharmacodynamic response have not been fully characterized. Cardiac Electrophysiology The effect of RETEVMO on the QTc interval was evaluated in a thorough QT study in healthy subjects. The largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (C max ) observed in patients after administration of 160 mg twice daily. The increase in QTc was concentration-dependent.

12.3 Pharmacokinetics The pharmacokinetics of selpercatinib were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. Steady state selpercatinib AUC and C max increased in a slightly greater than dose proportional manner over the dose range of 20 mg once daily to 240 mg twice daily [0.06 to 1.5 times the maximum recommended total daily dosage]. Steady-state was reached by approximately 7 days and the median accumulation ratio after administration of 160 mg twice daily was 3.4-fold. Mean steady-state selpercatinib [coefficient of variation (CV%)] C max was 2,980 (53%) ng/mL and AUC 0-24h was 51,600 (58%) ng*h/mL. Absorption The median t max of selpercatinib is 2 hours. The mean absolute bioavailability of RETEVMO capsules is 73% (60% to 82%) in healthy subjects. Effect of Food No clinically significant differences in selpercatinib AUC or C max were observed following administration of a high-fat meal (approximately 900 calories, 58 grams carbohydrate, 56 grams fat and 43 grams protein) in healthy subjects. Distribution The apparent volume of distribution (V ss /F) of selpercatinib is 191 L. Protein binding of selpercatinib is 96% in vitro and is independent of concentration. The blood-to-plasma concentration ratio is 0.7. Elimination The apparent clearance (CL/F) of selpercatinib is 6 L/h in patients and the half-life is 32 hours following oral administration of RETEVMO in healthy subjects. Metabolism Selpercatinib is metabolized predominantly by CYP3A4. Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, unchanged selpercatinib constituted 86% of the radioactive drug components in plasma. Excretion Following oral administration of a single radiolabeled 160 mg dose of selpercatinib to healthy subjects, 69% of the administered dose was recovered in feces (14% unchanged) and 24% in urine (12% unchanged). Specific Populations The apparent volume of distribution and clearance of selpercatinib increase with increasing body weight (27 kg to 179 kg). No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (15 years to 92 years), sex, or mild, moderate, or severe renal impairment (eGFR ≥15 to 89 mL/min). The effect of ESRD on selpercatinib pharmacokinetics has not been studied. Patients with Hepatic Impairment The selpercatinib AUC 0-INF increased by 7%, 32%, and 77% in subjects with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST), moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST), and severe (total bilirubin greater than 3 to 10 times ULN and any AST) hepatic impairment, respectively, compared to subjects with normal hepatic function. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Proton-Pump Inhibitors (PPI): Coadministration with multiple daily doses of omeprazole (PPI) decreased selpercatinib AUC 0-INF and C max when RETEVMO was administered fasting. Coadministration with multiple daily doses of omeprazole did not significantly change the selpercatinib AUC 0-INF and C max when RETEVMO was administered with food ( Table 7 ). Table 7: Change in Selpercatinib Exposure After Coadministration with PPI 1 High-fat meal: approximately 150, 250, and 500-600 calories from protein, carbohydrate, and fat, respectively; approximately 800 to 1,000 calories total. 2 Low-fat meal: approximately 390 calories and 10 g of fat. Selpercatinib AUC 0-INF Selpercatinib C max RETEVMO fasting Reference Reference RETEVMO fasting + PPI ↓ 69% ↓ 88% RETEVMO with a high-fat meal 1 + PPI ↑ 2% ↓ 49% RETEVMO with a low-fat meal 2 + PPI No change ↓ 22% H2 Receptor Antagonists: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with multiple daily doses of ranitidine (H2 receptor antagonist) given 10 hours prior to and 2 hours after the RETEVMO dose (administered fasting). Strong CYP3A Inhibitors: Coadministration of multiple doses of itraconazole (strong CYP3A inhibitor) increased the selpercatinib AUC 0-INF by 133% and C max by 30%. Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC by 60-99% and C max by 46-76%. Strong CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the selpercatinib AUC 0-INF by 87% and C max by 70%. Moderate CYP3A Inducers: Coadministration of multiple doses of bosentan or efavirenz (moderate CYP3A inducers) is predicted to decrease the selpercatinib AUC by 40-70% and C max by 34-57%. Weak CYP3A Inducers: Coadministration of multiple doses of modafinil (weak CYP3A inducer) is predicted to decrease the selpercatinib AUC by 33% and C max by 26%. CYP2C8 Substrates : Coadministration of RETEVMO with repaglinide (sensitive CYP2C8 substrate) increased the repaglinide AUC 0-INF by 188% and C max by 91%. CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A substrate) increased the midazolam AUC 0-INF by 54% and C max by 39%. P-glycoprotein (P-gp) Substrates: Coadministration of RETEVMO with dabigatran (P-gp substrate) increased the dabigatran AUC 0-INF by 38% and C max by 43%. P-gp Inhibitors: No clinically significant differences in selpercatinib pharmacokinetics were observed when coadministered with a single dose of rifampin (P-gp inhibitor). MATE1 Substrates: No clinically significant differences in glucose levels were observed when metformin (MATE1 substrate) was coadministered with selpercatinib. In Vitro Studies CYP Enzymes: Selpercatinib does not inhibit or induce CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6 at clinically relevant concentrations. Transporter Systems: Selpercatinib inhibits MATE1 and BCRP, but does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Adverse Effects ( 6.1 )] . Selpercatinib is a substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.

20231128

10

3 DOSAGE FORMS AND STRENGTHS Capsules: 40 mg: gray opaque capsule imprinted with “Lilly”, “3977” and “40 mg” in black ink. 80 mg: blue opaque capsule imprinted with “Lilly”, “2980” and “80 mg” in black ink. Capsules: 40 mg, 80 mg. ( 3 )

RETEVMO selpercatinib selpercatinib selpercatinib microcrystalline cellulose silicon dioxide gelatin, unspecified titanium dioxide ferrosoferric oxide shellac alcohol isopropyl alcohol butyl alcohol propylene glycol water ammonia potassium hydroxide Gray Opaque Lilly;3977;40mg RETEVMO selpercatinib selpercatinib selpercatinib microcrystalline cellulose silicon dioxide gelatin, unspecified titanium dioxide FD&C Blue No. 1 shellac alcohol isopropyl alcohol butyl alcohol propylene glycol water ammonia potassium hydroxide ferrosoferric oxide Blue Opaque Lilly;2980;80mg

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with selpercatinib. Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation. Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the C max at the human dose of 160 mg twice daily. In general toxicology studies, male rats and minipigs exhibited testicular degeneration which was associated with luminal cell debris and/or reduced luminal sperm in the epididymis at selpercatinib exposures approximately 0.4 (rat) and 0.1 (minipig) times the clinical exposure by AUC at the recommended human dose. In a dedicated fertility study in male rats, administration of selpercatinib at doses up to 30 mg/kg/day (approximately twice the clinical exposure by AUC at the 160 twice daily dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display a dose-dependent increase in testicular germ cell depletion and spermatid retention at doses ≥3 mg/kg (~0.2 times the clinical exposure by AUC at the 160 twice daily dose) accompanied by altered sperm morphology at 30 mg/kg. In a dedicated fertility study in female rats treated with selpercatinib for 15 days before mating to Gestational Day 7, there were decreases in the number of estrous cycles at a dose of 75 mg/kg (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). While selpercatinib did not have clear effects on mating performance or ability to become pregnant at any dose level, half of females at the 75 mg/kg dose level had 100% nonviable embryos. At the same dose level in females with some viable embryos there were increases in post-implantation loss. In a 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea at a selpercatinib dose of 15 mg/kg (approximately 0.3 times to the human exposure by AUC at the 160 mg twice daily clinical dose). Corpora luteal cysts were present in the minipig at selpercatinib doses ≥2 mg/kg (approximately 0.07 times the human exposure by AUC at the 160 mg twice daily clinical dose).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with selpercatinib. Selpercatinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or clastogenic in the in vitro micronucleus assay in human peripheral lymphocytes, with or without metabolic activation. Selpercatinib was positive in the in vivo micronucleus assay in rats at concentrations >7 times the C max at the human dose of 160 mg twice daily. In general toxicology studies, male rats and minipigs exhibited testicular degeneration which was associated with luminal cell debris and/or reduced luminal sperm in the epididymis at selpercatinib exposures approximately 0.4 (rat) and 0.1 (minipig) times the clinical exposure by AUC at the recommended human dose. In a dedicated fertility study in male rats, administration of selpercatinib at doses up to 30 mg/kg/day (approximately twice the clinical exposure by AUC at the 160 twice daily dose) for 28 days prior to cohabitation with untreated females did not affect mating or have clear effects on fertility. Males did, however, display a dose-dependent increase in testicular germ cell depletion and spermatid retention at doses ≥3 mg/kg (~0.2 times the clinical exposure by AUC at the 160 twice daily dose) accompanied by altered sperm morphology at 30 mg/kg. In a dedicated fertility study in female rats treated with selpercatinib for 15 days before mating to Gestational Day 7, there were decreases in the number of estrous cycles at a dose of 75 mg/kg (approximately equal to the human exposure by AUC at the 160 mg twice daily clinical dose). While selpercatinib did not have clear effects on mating performance or ability to become pregnant at any dose level, half of females at the 75 mg/kg dose level had 100% nonviable embryos. At the same dose level in females with some viable embryos there were increases in post-implantation loss. In a 3-month general toxicology study in minipigs, there were findings of decreased or absent corpora lutea at a selpercatinib dose of 15 mg/kg (approximately 0.3 times to the human exposure by AUC at the 160 mg twice daily clinical dose). Corpora luteal cysts were present in the minipig at selpercatinib doses ≥2 mg/kg (approximately 0.07 times the human exposure by AUC at the 160 mg twice daily clinical dose).

NDA213246

RETEVMO

selpercatinib

0002-2980

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL - Retevmo 40 mg 60 Count Bottle NDC-0002-3977-60 60 capsules Rx only Retevmo ™ (selpercatinib) capsules 40 mg Each capsule contains 40 mg selpercatinib www.retevmo.com Lilly image of 40mg Capsules - 60 Count Label - principal panel

Indications and Usage ( 1.1 , 1.2 , 1.3 , 1.4 ) 09/2022 Dosage and Administration, Patient Selection ( 2.1 , 2.5 ) 09/2022 Warnings and Precautions ( 5.2 , 5.9 ) 09/2022

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ). Hepatotoxicity Advise patients that hepatotoxicity can occur and to immediately contact their healthcare provider for signs or symptoms of hepatotoxicity [see Warnings and Precautions ( 5.1 )] . Interstitial Lung Disease (ILD)/Pneumonitis Advise patients that ILD/ pneumonitis can occur and to contact their healthcare provider immediately for signs or symptoms of ILD including new or worsening cough or shortness of breath [see Warnings and Precautions ( 5.2 )]. Hypertension Advise patients that they will require regular blood pressure monitoring and to contact their healthcare provider if they experience symptoms of increased blood pressure or elevated readings [see Warnings and Precautions ( 5.3 )] . QT Prolongation Advise patients that RETEVMO can cause QTc interval prolongation and to inform their healthcare provider if they have any QTc interval prolongation symptoms, such as syncope [see Warnings and Precautions ( 5.4 )] . Hemorrhagic Events Advise patients that RETEVMO may increase the risk for bleeding and to contact their healthcare provider if they experience any signs or symptoms of bleeding [ see Warnings and Precautions ( 5.5 )] . Hypersensitivity Reactions Advise patients to monitor for signs and symptoms of hypersensitivity reactions, particularly during the first month of treatment [see Warnings and Precautions ( 5.6 )] . Tumor Lysis Syndrome Advise patients to contact their healthcare provider promptly to report any signs and symptoms of TLS [see Warnings and Precautions ( 5.7 )] . Risk of Impaired Wound Healing Advise patients that RETEVMO may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions ( 5.8 )] . Hypothyroidism Advise patients that RETEVMO can cause hypothyroidism and to immediately contact their healthcare provider for signs or symptoms of hypothyroidism [see Warnings and Precautions ( 5.9 )] . Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential of the possible risk to a fetus. Advise females of reproductive potential to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions ( 5.10 ), Use in Specific Populations ( 8.1 )] . Advise females of reproductive potential to use effective contraception during the treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations ( 8.3 ) ] . Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations ( 8.3 ) ] . Lactation Advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )] . Infertility Advise males and females of reproductive potential that RETEVMO may impair fertility [see Use in Specific Populations ( 8.4 ), Nonclinical Toxicology ( 13.1 )] . Drug Interactions Advise patients and caregivers to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Inform patients to avoid St. John's wort, proton pump inhibitors, H2 receptor antagonists, and antacids while taking RETEVMO. If PPIs are required, instruct patients to take RETEVMO with food. If H2 receptor antagonists are required, instruct patients to take RETEVMO 2 hours before or 10 hours after the H2 receptor antagonist. If locally-acting antacids are required, instruct patients to take RETEVMO 2 hours before or 2 hours after the locally-acting antacid [see Drug Interactions ( 7.1 , 7.2 )] . Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2020, 2022, Eli Lilly and Company. All rights reserved. RET-0003-USPI-20220921

14 CLINICAL STUDIES 14.1 RET Fusion-Positive Non-Small Cell Lung Cancer The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive NSCLC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and patients with locally advanced (stage III who were not candidates for surgical resection or definitive chemoradiation) or metastatic NSCLC without prior systemic therapy in separate cohorts. Identification of a RET gene alteration was prospectively determined in local laboratories using next generation sequencing (NGS), polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH) or other local testing methods. Adult patients received RETEVMO 160 mg orally twice daily until unacceptable toxicity or disease progression; patients enrolled in the dose escalation phase were permitted to adjust their dose to 160 mg twice daily. The major efficacy outcome measures were confirmed overall response rate (ORR) and duration of response (DOR), as determined by a blinded independent review committee (BIRC) according to RECIST v1.1. RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy Efficacy was evaluated in 247 patients with RET fusion-positive NSCLC previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001. The median age was 61 years (range: 23 to 81); 57% were female; 44% were White, 48% were Asian, 4.9% were Black, and 2.8% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3%) and 97% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1–15); 58% had prior anti-PD-1/PD-L1 therapy. RET fusions were detected in 94% of patients using NGS (84.6% tumor samples; 9.3% blood or plasma samples), 4.0% using FISH, 1.6% using PCR and 0.4% by other local testing methods. Efficacy results for previously treated RET fusion-positive NSCLC are summarized in Table 8 . Table 8: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive NSCLC Previously Treated with Platinum Chemotherapy) 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable RETEVMO (n = 247) Overall Response Rate 1 (95% CI) 61% (55%, 67%) Complete response 7.3% Partial response 54% Duration of Response Median in months (95% CI) 28.6 (20, NE) % with ≥ 12 months 2 63% For the 144 patients who received an anti-PD-1 or anti-PD-L1 therapy, either sequentially or concurrently with platinum-based chemotherapy, an exploratory subgroup analysis of ORR was 63% (95% CI: 54%, 70%) and the median DOR was 28.6 months (95% CI: 14.8, NE). Among the 247 patients with previously treated RET fusion-positive NSCLC, 16 had measurable CNS metastases at baseline as assessed by BIRC. One patient received radiation therapy (RT) to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 14 of these 16 patients; 39% of responders had an intracranial DOR of ≥ 12 months. Treatment-naïve RET Fusion-Positive NSCLC Efficacy was evaluated in 69 patients with treatment-naïve RET fusion-positive NSCLC enrolled into a cohort of LIBRETTO-001. The median age was 63 years (range 23 to 92); 62% were female; 70% were White, 19% were Asian, and 6% were Black. ECOG performance status was 0-1 (94%) or 2 (6%) and 99% of patients had metastatic disease. RET fusions were detected in 91% of patients using NGS (60.9% tumor samples; 30.4% in blood), 7.2% using FISH and 1.4% using PCR. Efficacy results for treatment naïve RET fusion-positive NSCLC are summarized in Table 9 . Table 9: Efficacy Results in LIBRETTO-001 (Treatment-Naïve RET Fusion-Positive NSCLC) 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable RETEVMO (n =69) Overall Response Rate 1 (95% CI) 84% (73%, 92%) Complete response 5.8% Partial response 78% Duration of Response Median in months (95% CI) 20.2 (13, NE) % with ≥ 12 months 2 50% Among the 69 patients with treatment-naïve RET fusion-positive NSCLC, 5 had measurable CNS metastases at baseline as assessed by BIRC. Two patients received RT to the brain within 2 months prior to study entry. Responses in intracranial lesions were observed in 4 of these 5 patients; 38% of responders had an intracranial DOR of ≥ 12 months. 14.2 RET -Mutant Medullary Thyroid Cancer The efficacy of RETEVMO was evaluated in patients with RET -mutant MTC enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). The study enrolled patients with advanced or metastatic RET -mutant MTC who had been previously treated with cabozantinib or vandetanib (or both) and patients with advanced or metastatic RET -mutant MTC who were naïve to cabozantinib and vandetanib in separate cohorts. RET -Mutant MTC Previously Treated with Cabozantinib or Vandetanib Efficacy was evaluated in 55 patients with RET- mutant advanced MTC who had previously treated with cabozantinib or vandetanib enrolled into a cohort of LIBRETTO-001. The median age was 57 years (range: 17 to 84); 66% were male; 89% were White, 7% were Hispanic/Latino, and 1.8% were Black. ECOG performance status was 0-1 (95%) or 2 (5%) and 98% of patients had metastatic disease. Patients received a median of 2 prior systemic therapies (range 1 – 8). RET mutation status was detected in 82% of patients using NGS (78% tumor samples; 4% blood or plasma), 16% using PCR, and 2% using an unknown test. The protocol excluded patients with synonymous, frameshift or nonsense RET mutations; the specific mutations used to identify and enroll patients are described in Table 10 . Table 10: Mutations used to Identify and Enroll Patients with RET-Mutant MTC in LIBRETTO-001 1 Somatic or germline mutations; protein change. 2 Extracellular cysteine mutations involving cysteine residues 609, 611, 618, 620, 630, and 634. 3 Other included: K666N (1), D631_L633delinsV (2), D631_L633delinsE (5), D378_G385delinsE (1), D898_E901del (2), A883F (4), E632_L633del (4), L790F (2), T636_V637insCRT(1), D898_E901del + D903_S904delinsEP (1). 4 One patient also had a M918T mutation. RET Mutation Type 1 Previously Treated (n = 55) Cabozantinib/ Vandetanib Naïve (n = 88) Total (n = 143) M918T 33 49 82 Extracellular cysteine mutation 2 7 20 27 V804M or V804L 5 4 6 11 Other 3 10 13 23 Efficacy results for RET- mutant MTC are summarized in Table 11 . Table 11: Efficacy Results in LIBRETTO-001 (RET-Mutant MTC Previously Treated with Cabozantinib or Vandetanib) 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable RETEVMO (n = 55) Overall Response Rate 1 (95% CI) 69% (55%, 81%) Complete response 9% Partial response 60% Duration of Response Median in months (95% CI) NE (19.1, NE) % with ≥6 months 2 76 Cabozantinib and Vandetanib-naïve RET -Mutant MTC Efficacy was evaluated in 88 patients with RET- mutant MTC who were cabozantinib and vandetanib treatment-naïve enrolled into a cohort of LIBRETTO-001. The median age was 58 years (range: 15 to 82) with two patients (2.3%) aged 12 to 16 years; 66% were male; and 86% were White, 4.5% were Asian, and 2.3% were Hispanic/Latino. ECOG performance status was 0-1 (97%) or 2 (3.4%). All patients (100%) had metastatic disease and 18% had received 1 or 2 prior systemic therapies (including 8% kinase inhibitors, 4.5% chemotherapy, 2.3% anti-PD1/PD-L1 therapy, and 1.1% radioactive iodine). RET mutation status was detected in 77.3% of patients using NGS (75.0% tumor samples; 2.3% blood samples), 18.2% using PCR, and 4.5% using an unknown test. The mutations used to identify and enroll patients are described in Table 10 . Efficacy results for cabozantinib and vandetanib-naïve RET- mutant MTC are summarized in Table 12 . Table 12: Efficacy Results in LIBRETTO-001 (Cabozantinib and Vandetanib-naïve RET-Mutant MTC) 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable RETEVMO (n = 88) Overall Response Rate 1 (95% CI) 73% (62%, 82%) Complete response 11% Partial response 61% Duration of Response Median in months (95% CI) 22.0 (NE, NE) % with ≥6 months 2 61 14.3 RET Fusion-Positive Thyroid Cancer The efficacy of RETEVMO was evaluated in patients with advanced RET fusion-positive thyroid cancer enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 27 patients with RET fusion-positive thyroid cancer who were radioactive iodine (RAI)-refractory (if RAI was an appropriate treatment option) and were systemic therapy naïve and patients with RET fusion-positive thyroid cancer who were RAI-refractory and had received sorafenib, lenvatinib, or both, in separate cohorts. The median age was 54 years (range 20 to 88); 52% were male; 74% were White, 11% were Hispanic/Latino, 7.4% were Asian, and 3.7% were Black. ECOG performance status was 0-1 (89%) or 2 (11%). All (100%) patients had metastatic disease with primary tumor histologies including papillary thyroid cancer (78%), poorly differentiated thyroid cancer (11%), anaplastic thyroid cancer (7%) and Hurthle cell thyroid cancer (4%). Patients had received a median of 3 prior therapies (range 1–7). RET fusion-positive status was detected in 93% of patients using NGS tumor samples and in 7% using blood samples. Efficacy results for RET fusion-positive thyroid cancer are summarized in Table 13 . Table 13: Efficacy Results in LIBRETTO-001 (RET Fusion-Positive Thyroid Cancer) 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable RETEVMO Previously Treated (n = 19) RETEVMO Systemic Therapy Naïve (n = 8) Overall Response Rate 1 (95% CI) 79% (54%, 94%) 100% (63%, 100%) Complete response 5.3% 12.5% Partial response 74% 88% Duration of Response Median in months (95% CI) 18.4 (7.6, NE) NE (NE, NE) % with ≥6 months 2 87 75 14.4 Other RET Fusion-Positive Solid Tumors The efficacy of RETEVMO was evaluated in patients with locally advanced or metastatic RET fusion-positive solid tumors enrolled in a multicenter, open-label, multi-cohort clinical trial (LIBRETTO-001, NCT03157128). Efficacy was evaluated in 41 patients with RET fusion-positive tumors other than NSCLC and thyroid cancer with disease progression on or following prior systemic treatment or who had no satisfactory alternative treatment options. The median age was 50 years (range 21 to 85), 54% were female, 68% were White, 24% were Asian, and 4.9% were Black; 7% were Hispanic/Latino. ECOG performance status was 0-1 (95%) or 2 (5%) and 95% of patients had metastatic disease. Thirty-seven patients (90%) received prior systemic therapy (median 2 [range 0 – 9]; 32% received 3 or more). The most common cancers were pancreatic adenocarcinoma (27%), colorectal (24%), salivary (10%) and unknown primary (7%). RET fusion-positive status was detected in 97.6% of patients using NGS and 2.4% using FISH. Efficacy results for RET fusion-positive solid tumors other than NSCLC and thyroid cancer are summarized in Table 14 and Table 15 . Table 14: Efficacy Results in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors) 1 Confirmed overall response rate assessed by BIRC. 2 Based on observed duration of response. NE = not estimable RETEVMO (n = 41) Overall Response Rate 1 (95% CI) 44% (28, 60) Complete response 4.9% Partial response 39% Duration of Response Median in months (95% CI) 24.5 (9.2, NE) % with ≥6 months 2 67% Table 15: Efficacy Results by Tumor Type in LIBRETTO-001 (Other RET Fusion-Positive Solid Tumors) + denotes ongoing response. 1 Confirmed overall response rate assessed by BIRC. 2 Best overall response for each patient is presented for tumor types with ≤2 patients. CI = confidence interval, CR = complete response, DOR = duration of response, NA = not applicable, NE = not evaluable, ORR = overall response rate, PR = partial response, SD = stable disease. Tumor Type Patients (n = 41) ORR 1,2 DOR Range (months) n (%) 95% CI Pancreatic adenocarcinoma 11 6 (55%) (23, 83) 2.5, 38.3+ Colorectal 10 2 (20%) (2.5, 56) 5.6, 13.3 Salivary 4 2 (50%) (7, 93) 5.7, 28.8+ Unknown primary 3 1 (33%) (0.8, 91) 9.2 Breast 2 PR, CR NA 2.3+, 17.3 Sarcoma (soft tissue) 2 PR, SD NA 14.9+ Xanthogranuloma 2 NE, NE NA NA Carcinoid (bronchial) 1 PR NA 24.1+ Carcinoma of the skin 1 NE NA NA Cholangiocarcinoma 1 PR NA 5.6+ Ovarian 1 PR NA 14.5+ Pulmonary carcinosarcoma 1 NE NA NA Rectal neuroendocrine 1 NE NA NA Small intestine 1 CR NA 24.5

8.5 Geriatric Use Of 796 patients who received RETEVMO, 34% (268 patients) were ≥65 years of age and 9% (74 patients) were ≥75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were ≥65 years of age and younger patients.

8.4 Pediatric Use The safety and effectiveness of RETEVMO have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 , 14.3 )] . The safety and effectiveness of RETEVMO have not been established in these indications in patients less than 12 years of age. The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications [see Indications and Usage ( 1 )] . Juvenile Animal Toxicity Data In a juvenile rat toxicity study, animals were dosed daily with selpercatinib from post-natal day 21 to day 70 (approximately equivalent to a human child to late adolescent). Selpercatinib increased physeal thickness of multiple bones, extending into the metaphysis and associated with decreased trabecular bone, which was not reversible at doses approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily. Growth plate changes were associated with impairment of bone modeling, resulting in decreased femur length and with reduction in bone mineral density. Selpercatinib also induced reversible hypocellularity of bone marrow in males at ≥30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily), and reversible alterations of dentin composition at ≥50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Irreversible, dose-dependent degeneration of testicular germinal epithelium, with vacuolation of Sertoli cells and corresponding depletion of spermatozoa in the epididymides, was also observed at ≥ 30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily) and affected male reproductive performance at 50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Females exhibited delay in attainment of vaginal patency, a marker of sexual maturity, at 125 mg/kg (approximately 4 times the adult human exposure at the clinical dose of 160 mg twice daily); this affect was associated with lower mean body weight. Similar effects in irregular thickening of growth plates in adult rats and minipigs, and tooth dysplasia and malocclusion, resulting in tooth loss in adult rats were observed in repeat dose studies of up to 13-week duration with selpercatinib. Monitor growth plates in adolescent patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment.

8.1 Pregnancy Risk Summary Based on findings from animal studies, and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Selpercatinib administration to pregnant rats during the period of organogenesis at oral doses ≥100 mg/kg [approximately 3.6 times the human exposure based on the area under the curve (AUC) at the clinical dose of 160 mg twice daily] resulted in 100% post-implantation loss. At the dose of 50 mg/kg [approximately equal to the human exposure (AUC) at the clinical dose of 160 mg twice daily], 6 of 8 females had 100% early resorptions; the remaining 2 females had high levels of early resorptions with only 3 viable fetuses across the 2 litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax).

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Pediatric Use: Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing RETEVMO if abnormalities occur. ( 8.4 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies, and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , RETEVMO can cause fetal harm when administered to a pregnant woman. There are no available data on RETEVMO use in pregnant women to inform drug-associated risk. Administration of selpercatinib to pregnant rats during the period of organogenesis resulted in embryolethality and malformations at maternal exposures that were approximately equal to the human exposure at the clinical dose of 160 mg twice daily. Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Selpercatinib administration to pregnant rats during the period of organogenesis at oral doses ≥100 mg/kg [approximately 3.6 times the human exposure based on the area under the curve (AUC) at the clinical dose of 160 mg twice daily] resulted in 100% post-implantation loss. At the dose of 50 mg/kg [approximately equal to the human exposure (AUC) at the clinical dose of 160 mg twice daily], 6 of 8 females had 100% early resorptions; the remaining 2 females had high levels of early resorptions with only 3 viable fetuses across the 2 litters. All viable fetuses had decreased fetal body weight and malformations (2 with short tail and one with small snout and localized edema of the neck and thorax). 8.2 Lactation Risk Summary There are no data on the presence of selpercatinib or its metabolites in human milk or on their effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with RETEVMO and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, RETEVMO can cause embryolethality and malformations at doses resulting in exposures less than or equal to the human exposure at the clinical dose of 160 mg twice daily [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating RETEVMO [see Use in Specific Populations ( 8.1 )] . Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. Infertility RETEVMO may impair fertility in females and males of reproductive potential [see Use in Specific Populations ( 8.4 ), Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of RETEVMO have been established in pediatric patients aged 12 years and older for medullary thyroid cancer (MTC) who require systemic therapy and for advanced RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate). Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged 12 years and older [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 , 14.3 )] . The safety and effectiveness of RETEVMO have not been established in these indications in patients less than 12 years of age. The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications [see Indications and Usage ( 1 )] . Juvenile Animal Toxicity Data In a juvenile rat toxicity study, animals were dosed daily with selpercatinib from post-natal day 21 to day 70 (approximately equivalent to a human child to late adolescent). Selpercatinib increased physeal thickness of multiple bones, extending into the metaphysis and associated with decreased trabecular bone, which was not reversible at doses approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily. Growth plate changes were associated with impairment of bone modeling, resulting in decreased femur length and with reduction in bone mineral density. Selpercatinib also induced reversible hypocellularity of bone marrow in males at ≥30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily), and reversible alterations of dentin composition at ≥50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Irreversible, dose-dependent degeneration of testicular germinal epithelium, with vacuolation of Sertoli cells and corresponding depletion of spermatozoa in the epididymides, was also observed at ≥ 30 mg/kg (approximately equivalent to or greater than the adult human exposure at the clinical dose of 160 mg twice daily) and affected male reproductive performance at 50 mg/kg (approximately 3 times the adult human exposure at the clinical dose of 160 mg twice daily). Females exhibited delay in attainment of vaginal patency, a marker of sexual maturity, at 125 mg/kg (approximately 4 times the adult human exposure at the clinical dose of 160 mg twice daily); this affect was associated with lower mean body weight. Similar effects in irregular thickening of growth plates in adult rats and minipigs, and tooth dysplasia and malocclusion, resulting in tooth loss in adult rats were observed in repeat dose studies of up to 13-week duration with selpercatinib. Monitor growth plates in adolescent patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment. 8.5 Geriatric Use Of 796 patients who received RETEVMO, 34% (268 patients) were ≥65 years of age and 9% (74 patients) were ≥75 years of age. No overall differences were observed in the safety or effectiveness of RETEVMO between patients who were ≥65 years of age and younger patients. 8.6 Renal Impairment No dosage modification is recommended for patients with mild to severe renal impairment [estimated Glomerular Filtration Rate (eGFR) ≥15 to 89 mL/min, estimated by Modification of Diet in Renal Disease (MDRD) equation]. The recommended dosage has not been established for patients with end-stage renal disease (ESRD) [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment Reduce the dose when administering RETEVMO to patients with severe [total bilirubin greater than 3 to 10 times upper limit of normal (ULN) and any AST] hepatic impairment [see Dosage and Administration ( 2.7 )] . No dosage modification is recommended for patients with mild (total bilirubin less than or equal to ULN with AST greater than ULN or total bilirubin greater than 1 to 1.5 times ULN with any AST) or moderate (total bilirubin greater than 1.5 to 3 times ULN and any AST) hepatic impairment. Monitor for RETEVMO-related adverse reactions in patients with hepatic impairment [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING RETEVMO (selpercatinib) capsules are supplied as follows: 40 mg: Gray opaque, imprinted with “Lilly”, “3977” and “40 mg” in black ink 60 count bottle NDC 0002-3977-60 80 mg: Blue opaque, imprinted with “Lilly”, “2980” and “80 mg” in black ink 60 count bottle NDC 0002-2980-60 120 count bottle NDC 0002-2980-26 Store at 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F to 86°F) are permitted [see USP Controlled Room Temperature].