Selpercatinib

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 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). 1.4 Other RET Fusion-Positive Solid Tumors RETEVMO is indicated for the treatment of 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. 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).

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 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 or permanently discontinue RETEVMO. 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 )] Grades 1-3 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. Discontinue RETEVMO for any severe skin reaction including Stevens Johnson Syndrome. Recurrent Grade 3 or Grade 4 Discontinue RETEVMO. 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 4 . 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 4: Recommended RETEVMO Dosage for Concomitant Use of Strong and Moderate CYP3A Inhibitors Current RETEVMO Dosage Recommended RETEVMO Dosage Moderate CYP3A Inhibitor Strong CYP3A Inhibitor 40 mg orally three times daily 40 mg orally once daily 40 mg orally once daily 80 mg orally twice daily 40 mg orally twice daily 40 mg orally twice daily 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 5 [see Use in Specific Populations ( 8.7 )] . Table 5: Recommended RETEVMO Dosage for Severe Hepatic Impairment Current RETEVMO Dosage Recommended RETEVMO Dosage 40 mg orally three times daily 40 mg orally twice daily 80 mg orally twice daily 40 mg orally twice daily 120 mg orally twice daily 80 mg orally twice daily 160 mg orally twice daily 80 mg orally twice daily 2.8 Alternative Administration for Patients Unable to Swallow Tablets or Capsules For patients unable to swallow whole capsules or tablets, the 40 mg tablet may be dispersed and administered orally or via gastrostomy or nasogastric tube. Use only the 40 mg tablet to make the dispersion. RETEVMO 40 mg tablets for Oral Administration To prepare RETEVMO tablet as a dispersion: In a glass or medicine cup, add the correct number of 40 mg RETEVMO tablets required for the prescribed dose (1, 2, 3, or 4 tablets), to approximately 1 tablespoon (15 mL) of room temperature or chilled water or 100% carrot puree. Stir intermittently until tablet(s) have dispersed (approximately 7 to 10 minutes). Some settling may occur and the dispersion may appear cloudy if water is used. Administer the entire dispersion immediately. Add 1 tablespoon (15 mL) of water to the glass or medicine cup, swirl or stir to collect any remaining medicine and administer immediately. Discard RETEVMO dispersion if not taken within 2 hours. RETEVMO 40 mg tablets for Feeding Tubes (Gastrostomy or Nasogastric Tube) Administration Use only polyurethane (French size 8 or larger) or vinyl chloride (French size 10 or larger) nasogastric tube or silicone (French size 14 or larger) gastrostomy tube. In a glass or medicine cup, add the correct number of 40 mg RETEVMO tablet(s) required for the prescribed dose (1, 2, 3, or 4 tablets), to a minimum of 10 mL of room temperature water. Stir intermittently until tablet(s) have dispersed (approximately 7 to 10 minutes). Some settling may occur and the dispersion may appear cloudy. Flush the feeding tube according to manufacturer's instructions. Draw the dispersion into an enteral syringe and administer the dispersion via the feeding tube immediately. Add 5 mL of water to the glass or medicine cup, swirl or stir to collect any remaining medicine, and deliver this rinse via the feeding tube using the same syringe. Repeat rinse as necessary to ensure full dose is delivered. Flush the feeding tube according to manufacturer's instructions. Discard RETEVMO dispersion if not taken within 2 hours.

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 swelling, scrotal swelling, swelling, swelling face, eye swelling, generalized edema, genital edema. 2 Fatigue includes asthenia and malaise. 3 Diarrhea includes defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence. 4 Abdominal pain includes abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain. 5 Rash includes 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 sinus headache, tension headache. 7 Cough includes productive cough, upper airway cough syndrome. 8 Dyspnea includes dyspnea exertional, dyspnea at rest. 9 Hemorrhage includes, 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 (%) General Disorders and Administration Site Conditions Edema 1 49 0.8* Fatigue 2 46 3.1* Arthralgia 21 0.3* Gastrointestinal Disorders Diarrhea 3 47 5* Dry Mouth 43 0 Abdominal pain 4 34 2.5* Constipation 33 0.8* Nausea 31 1.1* Vomiting 22 1.8* Vascular Disorders Hypertension 41 20 Skin and Subcutaneous Tissue Disorders Rash 5 33 0.6* Nervous System Disorders Headache 6 28 1.4* Respiratory, Thoracic and Mediastinal Disorders Cough 7 24 0 Dyspnea 8 22 3.1 Blood and Lymphatic System Disorders Hemorrhage 9 22 2.6 Investigations Prolonged QT interval 21 4.8* Clinically relevant adverse reactions in ≤15% of patients who received RETEVMO include hypothyroidism (13%); pneumonia (11%), hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all < 2%). Table 7 summarizes the laboratory abnormalities in LIBRETTO-001. Table 7: 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 LIBRETTO-121 The safety population described below reflects exposure to RETEVMO as a single agent at 92 mg/m 2 orally twice daily evaluated in 36 patients with advanced solid tumors harboring an activating RET alteration in LIBRETTO-121 [see Clinical Studies ( 14 )] . Among the 36 pediatric and adolescent patients who received RETEVMO, 86% were exposed for 6 months or longer and 72% were exposed for greater than one year. The median age was 13 years (range: 2 to 20 years); 31% were pediatric patients 2 to 12 years of age; 53% were male; and 47% were White, 28% were Asian, and 8% were Black or African American; and 19% were Hispanic/Latino. The most common cancers were MTC (42%), and papillary thyroid cancer (42%). Serious adverse reactions occurred in 42% of patients who received RETEVMO. Serious adverse reactions occurring in more than 1 patient were vomiting and fracture (2 patients each). Dosage interruptions due to an adverse reaction occurred in 42% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, increased AST, ascites, increased bilirubin, decreased neutrophils, and pyrexia. Dose reductions due to an adverse reaction occurred in 22% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included increased ALT, decreased neutrophils, increased weight, and increased bilirubin. The most common adverse reactions (≥25%) were musculoskeletal pain, diarrhea, nausea, hemorrhage, pyrexia, abdominal pain, headache, vomiting, fatigue, cough, rash, coronavirus infection, upper respiratory tract infection, and edema. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, decreased calcium, decreased hemoglobin, decreased neutrophils, increased ALT, decreased magnesium, and decreased potassium. Table 8 summarizes the adverse reactions in LIBRETTO-121. Table 8: Adverse Reactions (≥15%) in Patients Who Received RETEVMO in LIBRETTO-121 Adverse Reactions RETEVMO N= 36 Grades 1-4# % Grades 3-4 % 1 Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, non-cardiac chest pain, neck pain, pain in extremity 2 Diarrhea includes anal incontinence 3 Abdominal pain includes abdominal pain upper, abdominal discomfort 4 Hemorrhage includes epistaxis, hematuria, anal hemorrhage, blood urine present, hemoptysis, menorrhagia, mouth hemorrhage 5 Fatigue includes asthenia, malaise 6 Edema includes face edema, edema peripheral, periorbital edema, localized edema, generalized edema, gastrointestinal edema, swelling 7 Rash includes rash maculopapular, rash erythematous, urticaria 8 Urinary tract infection includes cystitis 9 Hypothyroidism includes blood thyroid stimulating hormone increased, thyroglobulin increased * No Grade 4 events were reported. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 1 58 0 Gastrointestinal Disorders Diarrhea 2 47 2.8* Nausea 42 2.8 * Abdominal pain 3 36 0 Vomiting 31 8* Constipation 22 6 * Blood and Lymphatic System Disorders Hemorrhage 4 39 0 General Disorders and Administration Site Conditions Pyrexia 39 0 Fatigue 5 31 0 Edema 6 25 0 Nervous System Disorders Headache 33 0 Respiratory, Thoracic and Mediastinal Disorders Cough 31 0 Oropharyngeal pain 22 0 Skin and Subcutaneous Tissue Disorders Rash 7 28 0 Infections and Infestations Coronavirus infection 28 0 Upper respiratory tract infection 28 2.8* Urinary tract infection 8 19 2.8* Endocrine Disorders Hypothyroidism 9 22 0 Investigations Increased weight 19 11* Clinically relevant adverse reactions in <15% of patients who received RETEVMO include dizziness (14%), electrocardiogram QT prolonged (14%), hypersensitivity (11%), stomatitis (14%), proteinuria (11%), hypertension (8%), decreased appetite (8%), erectile dysfunction (6%), chylous ascites (2.8%), dry mouth (2.8%), epiphysiolysis (2.8%), and pneumonia (2.8%). Table 9 summarizes the laboratory abnormalities in LIBRETTO-121. Table 9: Select Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-121 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 18 to 36 patients. * No Grade 4 abnormalities were reported. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5. Laboratory Abnormality RETEVMO1 Grades 1-4# (%) Grades 3-4 (%) Chemistry Decreased calcium 61 11 Increased ALT 58 8* Decreased albumin 53 0 Increased alkaline phosphatase 50 0 Increased AST 50 2.8* Increased bilirubin 31 2.8* Increased cholesterol 28 0 Decreased magnesium 28 6 Increased potassium 28 2.8 Increased creatinine 19 2.8 Decreased potassium 19 6 Decreased sodium 17 0 Hematology Decreased neutrophils 40 8 Decreased hemoglobin 36 11* Increased hemoglobin 33 2.8* Decreased platelets 28 2.8* Decreased lymphocytes 28 14 Treatment-naïve RET Fusion-Positive Non-Small Cell Lung Cancer LIBRETTO-431 The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg orally twice daily evaluated in 158 patients with unresectable locally advanced or metastatic RET fusion-positive NSCLC in LIBRETTO-431 [see Clinical Studies ( 14 )]. Among the 158 patients who received RETEVMO, the median duration of exposure was 16.7 months (range: 5 days to 37.9 months); 87% were exposed for 6 months or longer and 70% were exposed for one year or longer. The median age was 61 years (range: 31 to 87 years); 46% were male; and 36% were White, 58% were Asian, 1.3% were Black or African American, 1.3% were American Indian or Alaska Native, and 3.2% were missing. Serious adverse reactions occurred in 35% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pleural effusion, and abnormal hepatic function. Fatal adverse reactions occurred in 4.4% of patients who received RETEVMO; fatal adverse reactions included myocardial infarction (n = 2), respiratory failure (n = 2), cardiac arrest, malnutrition, and sudden death (n = 1, each). Permanent discontinuation due to an adverse reaction occurred in 10% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation in ≥1% of patients included increased ALT (1.3%), and myocardial infarction (1.3%). Dosage interruptions due to an adverse reaction occurred in 72% of patients who received RETEVMO. Adverse reactions requiring dosage interruption in ≥5% of patients included increased ALT, hypertension, increased AST, QT prolongation, diarrhea, and COVID-19 infection. Dose reductions due to an adverse reaction occurred in 51% of patients who received RETEVMO. Adverse reactions requiring dose reductions in ≥5% of patients included increased ALT, increased AST, QT prolongation. The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, diarrhea, edema, dry mouth, rash, fatigue, abdominal pain, and musculoskeletal pain. The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were increased ALT, increased AST, and decreased lymphocytes. Table 10 summarizes the adverse reactions in LIBRETTO-431. Table 10: Adverse Reactions (≥15%) in Patients on Either Arm in LIBRETTO-431 1 Diarrhea includes diarrhea, anal incontinence. 2 Dry mouth includes dry mouth, mucosal dryness. 3 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain. 4 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation. 5 Vomiting includes vomiting, retching, regurgitation. 6 Edema includes edema, edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, orbital edema, eye edema, scrotal edema, penile edema, orbital swelling, periorbital swelling. 7 Fatigue includes fatigue, asthenia, malaise. 8 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash papular, dermatitis allergic, rash pustular, rash vesicular, genital rash. 9 Musculoskeletal pain includes musculoskeletal pain, arthralgia, back pain, bone pain, musculoskeletal chest pain, non-cardiac chest pain, neck pain, pain in extremity. * No Grade 4 abnormalities were reported. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Adverse Reaction RETEVMO (n=158) Chemotherapy with or without pembrolizumab (n=98) Grades 1-4 # (%) Grades 3-4 (%) Grades 1-4 # (%) Grades 3-4 (%) Vascular disorders Hypertension 48 20* 7 3.1* Gastrointestinal disorders Diarrhea 1 44 1.3* 24 2.0* Dry mouth 2 39 0 6 0 Abdominal pain 3 25 0.6* 19 2.0* Constipation 22 0 40 1.0* Stomatitis 4 18 0 16 0 Nausea 13 0 44 1.0* Vomiting 5 13 0 23 1.0* General disorders and administration site conditions Edema 6 41 2.5* 28 0 Fatigue 7 32 3.2* 50 5* Pyrexia 13 0.6* 23 0 Skin and subcutaneous tissue disorders Rash 8 33 1.9* 30 1.0* Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 9 25 0 28 0 Investigations Electrocardiogram QT prolonged 20 9* 1.0 0 Infections and infestations COVID-19 infection 19 0.6* 18 0 Metabolism and nutrition disorders Decreased appetite 17 0 34 2.0* Clinically relevant adverse reactions in <15% of patients who received RETEVMO include headache (14%); hemorrhage (13%); urinary tract infections (12%); hypothyroidism (9%); pneumonia (9%); dizziness (8%); interstitial lung disease/pneumonitis (4.4%); hypersensitivity, chylous ascites, and chylothorax (all < 2%). Table 11 summarizes the laboratory abnormalities in LIBRETTO-431. Table 11: Select Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients on Either Arm in LIBRETTO-431 1 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: RETEVMO (range: 154 to 157 patients) and chemotherapy with or without pembrolizumab (range: 96 to 97 patients). # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Laboratory Abnormality 1 RETEVMO Chemotherapy with or without pembrolizumab Grades 1-4 # (%) Grades 3-4 (%) Grades 1-4 # (%) Grades 3-4 (%) Chemistry ALT increased 81 21 63 4.1 AST increased 77 10 46 0 Alkaline phosphatase Increased 35 1.3 22 0 Total bilirubin Increased 52 1.3 9 0 Blood creatinine Increased 23 0 21 0 Magnesium decreased 16 0.6 8 0 Albumin decreased 25 0 5 0 Calcium decreased 53 1.9 24 1.0 Sodium decreased 31 3.2 41 2.1 Potassium decreased 17 1.3 15 1.0 Hematology Platelets decreased 53 3.2 39 5 Lymphocyte count decreased 53 8 64 15 Hemoglobin decreased 21 0 91 5 Neutrophil count decreased 53 2.0 58 11 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 )] . RET-Mutant Medullary Thyroid Cancer LIBRETTO-531 The safety population described below reflects exposure to RETEVMO as a single agent administered at 160 mg (adults) or at 92 mg/m 2 (adolescent, not to exceed 160 mg) orally twice daily, in patients with progressive, advanced, kinase inhibitor naïve, RET -mutant medullary thyroid cancer in LIBRETTO-531 [see Clinical Studies ( 14.2 )] . Among the 193 patients who received RETEVMO, the observed median duration of exposure was 14.5 months (range: 25 days to 36 months); 80% were exposed for 6 months or longer and 59% were exposed for one year or longer. The median age was 55 years (range: 12 to 84 years); 63% were male; and 69% were White, 28% were Asian, 2.9% were Black or African American and ethnicity was not routinely collected. Serious adverse reactions occurred in 22% of patients who received RETEVMO. The most frequent serious adverse reactions were pneumonia and pyrexia (n = 3, each) and hypertension and urinary tract infection (n = 2, each). Fatal adverse reactions occurred in 2.1% of patients; fatal adverse reactions included COVID-19, diabetic ketoacidosis, multiple organ dysfunction syndrome, and sudden death (n=1 each). Permanent discontinuation due to an adverse reaction occurred in 4.7% of patients who received RETEVMO. Adverse reactions resulting in permanent discontinuation were edema, multiple organ dysfunction syndrome, sudden death, AST increased, diabetic ketoacidosis, chronic kidney disease, retinopathy, COVID-19, and somatic symptom disorder (n = 1, each). Dosage interruptions due to an adverse reaction occurred in 49% of patients who received RETEVMO. Adverse reactions requiring dosage omission in ≥5% of patients included ALT increased (9%) and hypertension (7%). Dose reductions due to an adverse reaction occurred in 39% of patients who received RETEVMO. One adverse reaction, increased ALT (7%), required a dose reduction in ≥5% of patients. The most common adverse reactions (≥25%) in patients who received RETEVMO were hypertension, edema, dry mouth, fatigue, and diarrhea. The most common Grade 3 or 4 laboratory abnormalities (≥5%) in patients who received RETEVMO were decreased lymphocytes, increased ALT, decreased neutrophils, increased ALP, increased blood creatinine, decreased calcium, and increased AST. Table 12 summarizes the adverse reactions in LIBRETTO-531. Table 12: Adverse Reactions (≥10%) in Patients Who Received RETEVMO in LIBRETTO-531 1 Hypertension includes hypertension, blood pressure increased. 2 Edema includes edema peripheral, face edema, periorbital edema, swelling face, peripheral swelling, localized edema, eyelid edema, generalized edema, eye swelling, lymphoedema, orbital edema, eye edema, edema, edema genital, swelling, scrotal edema, scrotal swelling, angioedema, skin edema, testicular swelling, vulvovaginal swelling. 3 Fatigue includes fatigue, asthenia, malaise. 4 Dry mouth includes dry mouth, mucosal dryness. 5 Diarrhea includes diarrhea, anal incontinence, defecation urgency, frequent bowel movements, gastrointestinal hypermotility. 6 Abdominal pain included abdominal pain, abdominal pain upper, abdominal discomfort, abdominal pain lower, gastrointestinal pain. 7 Stomatitis includes stomatitis, mouth ulceration, mucosal inflammation. 8 Headache includes headache, sinus headache, tension headache. 9 Rash includes rash, rash maculopapular, skin exfoliation, rash erythematous, rash macular, dermatitis, urticaria, rash pruritic, exfoliative rash, rash papular, dermatitis allergic, rash follicular, rash generalized, rash pustular, butterfly rash, rash morbilliform, rash vesicular. 10 Electrocardiogram QT prolongation includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal. 11 Hypothyroidism includes hypothyroidism, blood thyroid stimulating hormone increased. * Only includes a Grade 3 adverse reaction # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Adverse Reaction RETEVMO N = 193 Cabozantinib or Vandetanib N = 97 Grades 1-4 # (%) Grades 3-4 (%) Grades 1-4 # (%) Grades 3-4 (%) Vascular disorders Hypertension 1 43 19* 41 18* General disorders and administration-site conditions Edema 2 33 0 5 0 Fatigue 3 28 4.1* 47 9* Pyrexia 12 1.0* 2.1 0 Gastrointestinal disorders Dry mouth 4 32 0.5* 10 1.0* Diarrhea 5 26 3.1* 61 8* Abdominal pain 6 18 0.5* 21 2.1* Constipation 16 0 12 0 Stomatitis 7 14 0.5* 42 13* Pyrexia 12 1.0* 2.1 0 Nausea 10 1.0* 32 5* Nervous system disorders Headache 8 23 0.5* 21 0 Skin and subcutaneous tissue disorders Rash 9 19 1.6* 27 4.1* Reproductive system and breast disorders Erectile dysfunction 16 0 0 0 Investigations Electrocardiogram QT prolonged 10 14 4.7* 13 2.1* Metabolism and nutrition disorders Decreased appetite 12 0.5* 28 5* Endocrine disorders Hypothyroidism 11 11 0 21 0 Clinically relevant adverse reactions in ≤10% of patients who received RETEVMO include dizziness (8%); urinary tract infections (8%); vomiting (8%); pneumonia, interstitial lung disease/pneumonitis, chylous ascites, and hypersensitivity (all < 2%). Table 13 summarizes the laboratory abnormalities in LIBRETTO-531. Table 13: Select Laboratory Abnormalities (≥5%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-531 1 Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available: RETEVMO (range: 183 to 191 patients) and chemotherapy with or without cabozantinib or vandetanib (range: 91 to 94 patients). * Only includes a Grade 3 laboratory abnormality # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 Laboratory Abnormality RETEVMO 1 Cabozantinib or Vandetanib 1 Grades 1-4 # % Grades 3-4 % Grades 1-4 # % Grades 3-4 % Chemistry Calcium decreased 55 5 62 11 ALT increased 53 16 72 7* AST increased 47 5 68 3.2* Alkaline phosphatase increased 37 6 28 5 Total bilirubin increased 32 1.1 30 3.2* Blood creatinine increased 27 6 16 8 Sodium decreased 20 3.2* 16 0 Albumin decreased 11 1.1 7 0 Magnesium decreased 9 3.3 26 9 Potassium decreased 8 0 22 4.4* Hematology Lymphocyte count decreased 41 18 36 13 Neutrophil count decreased 33 14 42 19 Platelets decreased 28 1.1 34 1.1* Hemoglobin decreased 18 2.1* 23 2.1* 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 )] . 6.2 Postmarketing Experience The following adverse reaction has been identified during post-approval use of RETEVMO. Because such reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome

12.3 Pharmacokinetics The pharmacokinetics of selpercatinib capsules were evaluated in patients with locally advanced or metastatic solid tumors administered 160 mg twice daily unless otherwise specified. The capsule and tablet dosage forms of selpercatinib are bioequivalent. 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 For both the capsule and tablet dosage forms 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 203 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 (9.6 kg to 179 kg). No clinically significant differences in the pharmacokinetics of selpercatinib were observed based on age (2 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. Pediatric patients The exposures of selpercatinib in pediatric patients are comparable to those in adult patients administered at the recommended dosages. Patients with Hepatic Impairment The selpercatinib AUC 0-INF increased 1.1-fold in subjects with mild (total bilirubin ≤ ULN with AST > ULN or total bilirubin > 1 to 1.5 × ULN with any AST), 1.3-fold in subjects with moderate (total bilirubin > 1.5 to 3 × ULN and any AST), and 1.8-fold in subjects with severe (total bilirubin > 3 to 10 × ULN and any AST) hepatic impairment, 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 14 ). Table 14: 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 2.3-fold and C max 1.3-fold. Moderate CYP3A Inhibitors: Coadministration of multiple doses of diltiazem, fluconazole, or verapamil (moderate CYP3A inhibitors) is predicted to increase the selpercatinib AUC 1.6 to 2-fold and C max 1.5 to 1.8-fold. 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 2.9-fold and C max 1.9-fold. CYP3A Substrates: Coadministration of RETEVMO with midazolam (sensitive CYP3A substrate) increased the midazolam AUC 0-INF 1.5-fold and C max 1.4-fold. P-glycoprotein (P-gp) Substrates: Coadministration of RETEVMO with dabigatran (P-gp substrate) increased the dabigatran AUC 0-INF 1.4-fold and C max 1.4-fold. BCRP Substrates: Coadministration of RETEVMO with rosuvastatin (BCRP substrate) increased the rosuvastatin AUC 0-INF by 1.9-fold and C max by 1.7-fold. 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. Selpercatinib may increase serum creatinine by decreasing renal tubular secretion of creatinine via inhibition of MATE1 [see Adverse Reactions ( 6.1 )] . Selpercatinib does not inhibit OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, BSEP, and MATE2-K at clinically relevant concentrations. Selpercatinib is a substrate for P-gp and BCRP, but not for OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2-K.