Retevmo Drug Information

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 . 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

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

Increased

ALT 56 12 Decreased albumin 56

Increased glucose 53 2.8 Increased creatinine 47 2.4 Decreased sodium 42 11

Increased alkaline phosphatase 40

Decreased magnesium 33 0.6 Increased bilirubin 30 2.8 Hematology Decreased lymphocytes 52

20 Decreased platelets 37

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 . 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

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. 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

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

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 . 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 . 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

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 .

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

Effects of Other Drugs on

RETEVMO Acid-Reducing Agents Concomitant use of RETEVMO with acid-reducing agents decreases selpercatinib plasma concentrations , 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) . Strong and Moderate CYP3A Inhibitors Concomitant use of RETEVMO with a strong or moderate CYP3A inhibitor increases selpercatinib plasma concentrations , 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 . Strong and Moderate CYP3A Inducers Concomitant use of RETEVMO with a strong or moderate CYP3A inducer decreases selpercatinib plasma concentrations , which may reduce RETEVMO anti-tumor activity.

Avoid coadministration of strong or moderate CYP3A inducers with RETEVMO.

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 , which may increase the risk of adverse reactions related to these substrates. Avoid coadministration of RETEVMO with CYP2C8 and CYP3A substrates where minimal concentration changes may lead to increased adverse reactions.

If coadministration cannot be avoided, follow recommendations for CYP2C8 and CYP3A substrates provided in their approved product labeling. Certain P-gp and BCRP Substrates RETEVMO is a P-gp and BCRP inhibitor. Concomitant use of RETEVMO with P-gp or BCRP substrates increases their plasma concentrations , which may increase the risk of adverse reactions related to these substrates.

Avoid coadministration of RETEVMO with P-gp or BCRP substrates where minimal concentration changes may lead to increased adverse reactions. If coadministration cannot be avoided, follow recommendations for P-gp and BCRP substrates provided in their approved product labeling.

Drugs that Prolong QT Interval

RETEVMO is associated with QTc interval prolongation . Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

Pregnancy Risk Summary Based on findings from animal studies, and its mechanism of action , 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 resulted in 100% post-implantation loss.

At the dose of 50 mg/kg, 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).

Pediatric Use The safety and effectiveness of RETEVMO have been established in pediatric patients aged 2 years and older for the treatment of: advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation who require systemic therapy advanced or metastatic thyroid cancer with a RET gene fusion who require systemic therapy and are radioactive iodine-refractory (if radioactive iodine is appropriate) 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. Use of RETEVMO for these indications is supported by evidence from adequate and well-controlled studies in adult and pediatric patients with additional pharmacokinetic and safety data in pediatric patients aged 2 years and older . The predicted exposures of selpercatinib in pediatric patients at the recommended dosages were within the range of values observed in patients ≥ 12 years and ≥ 50 kg in body weight receiving the approved recommended dosage of 160 mg twice daily . The safety and effectiveness of RETEVMO have not been established in these indications in patients aged less than 2 years. The safety and effectiveness of RETEVMO have not been established in pediatric patients for other indications . 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 effect 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 pediatric 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.