FDA label 8aaf7f3e-9dc1-4e71-af62-4943f4284e81

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.1 ) Interstitial Lung Disease (ILD)/Pneumonitis: Monitor for new or worsening pulmonary symptoms. Withhold, reduce the dose or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.2 ) Hypertension: Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating RETEVMO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce the dose, or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.3 ) QT Interval Prolongation: Monitor patients who are at significant risk of developing QTc prolongation. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment. Monitor QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on severity. ( 2.5 , 5.4 ) Hemorrhagic Events: Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage. ( 2.5 , 5.5 ) Hypersensitivity: Withhold RETEVMO and initiate corticosteroids. Upon resolution, resume at a reduced dose and increase dose by 1 dose level each week until reaching the dose taken prior to onset of hypersensitivity. Continue steroids until patient reaches target dose and then taper. ( 2.5 , 5.6 ) Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. ( 5.7 ) Risk of Impaired Wound Healing: Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established. ( 5.8 ) Hypothyroidism: Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Withhold until clinically stable or permanently discontinue based on severity. ( 5.9 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the possible risk to a fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 ) Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis (SCFE/SUFE) in Pediatric Patients: Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate ( 5.11 , 6.1 ) 5.1 Hepatotoxicity Serious hepatic adverse reactions occurred in 4.6% of patients treated with RETEVMO. Increased AST occurred in 62% of patients, including Grade 3 or 4 events in 11% and increased ALT occurred in 58% of patients, including Grade 3 or 4 events in 13% [see Adverse Reactions ( 6.1 )] . The median time to first onset for increased AST was 5 weeks (range: 4.9 days to 6 years) and increased ALT was 4.9 weeks (range: 6 days to 5 years). Monitor ALT and AST prior to initiating RETEVMO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration ( 2.5 )] . 5.2 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, and fatal interstitial lung disease (ILD)/pneumonitis can occur in patients treated with RETEVMO. ILD/pneumonitis occurred in 3% of patients who received RETEVMO, including 0.3% with Grade 3 or 4 events, and 0.2% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold RETEVMO and promptly investigate for ILD in any patient who presents with acute or worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough, and fever). Withhold, reduce the dose or permanently discontinue RETEVMO based on severity of confirmed ILD [ see Dosage and Administration ( 2.5 ) ]. 5.3 Hypertension Hypertension occurred in 43% of patients, including Grade 3 hypertension in 20% and Grade 4 in one (0.1%) patient [see Adverse Reactions ( 6.1 )] . Overall, 6.4% had their dose interrupted, 1.5% had their dose reduced, and 0.2% discontinued RETEVMO for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate RETEVMO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating RETEVMO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce the dose, or permanently discontinue RETEVMO based on the severity [see Dosage and Administration ( 2.5 )] . 5.4 QT Interval Prolongation RETEVMO can cause concentration-dependent QT interval prolongation [see Clinical Pharmacology ( 12.2 )] . An increase in QTcF interval to >500 ms was measured in 8% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 22% of patients [see Adverse Reactions ( 6.1 )] . RETEVMO has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia, and hypocalcemia prior to initiating RETEVMO and during treatment. Monitor the QT interval more frequently when RETEVMO is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and reduce the dose or permanently discontinue RETEVMO based on the severity [see Dosage and Administration ( 2.5 )] . 5.5 Hemorrhagic Events Serious including fatal hemorrhagic events can occur with RETEVMO. Grade ≥3 hemorrhagic events occurred in 4.3% of patients treated with RETEVMO, including 4 (0.5%) patients with fatal hemorrhagic events, including cerebral hemorrhage (n = 2), tracheostomy site hemorrhage, and hemoptysis (1 each). Permanently discontinue RETEVMO in patients with severe or life-threatening hemorrhage [see Dosage and Administration ( 2.5 )] . 5.6 Hypersensitivity RETEVMO can cause hypersensitivity, including severe skin reactions such as Stevens-Johnson Syndrome. All grade hypersensitivity occurred in 6% of patients receiving RETEVMO, including Grade 3 in 2%. The median time to onset was 1.9 weeks (range: 5 days to 6.5 years). Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or transaminitis. Stevens Johnsons Syndrome has been observed in the post-marketing setting [see Adverse Reactions ( 6.2 )]. Discontinue RETEVMO in patients with Stevens Johnson Syndrome. If hypersensitivity occurs, withhold RETEVMO and begin corticosteroids at a dose of 1 mg/kg prednisone (or equivalent). Upon resolution of the event, resume RETEVMO at a reduced dose and increase the dose of RETEVMO by 1 dose level each week as tolerated until reaching the dose taken prior to onset of hypersensitivity [see Dosage and Administration ( 2.5 )] . Continue steroids until patient reaches target dose and then taper. Permanently discontinue RETEVMO for recurrent hypersensitivity. 5.7 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) occurred in 0.9% of patients with medullary thyroid carcinoma and 0.3% of patients with non-small cell lung cancer receiving RETEVMO [see Adverse Reactions ( 6.1 )] . Patients may be at risk of TLS if they have rapidly growing tumors, a high tumor burden, renal dysfunction, or dehydration. Closely monitor patients at risk, consider appropriate prophylaxis including hydration, and treat as clinically indicated. 5.8 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, RETEVMO has the potential to adversely affect wound healing. Withhold RETEVMO for at least 7 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of RETEVMO after resolution of wound healing complications has not been established. 5.9 Hypothyroidism RETEVMO can cause hypothyroidism. Hypothyroidism occurred in 15% of patients treated with RETEVMO; all reactions were Grade 1 or 2. Hypothyroidism occurred in 15% of patients (59/390) with thyroid cancer and 14% of patients (65/467) with other solid tumors including NSCLC [see Adverse Reactions ( 6.1 )] . Monitor thyroid function before treatment with RETEVMO and periodically during treatment. Treat with thyroid hormone replacement as clinically indicated. Withhold RETEVMO until clinically stable or permanently discontinue RETEVMO based on severity [see Dosage and Administration ( 2.5 )] . 5.10 Embryo-Fetal Toxicity Based on data from animal reproduction studies and its mechanism of action, RETEVMO can cause fetal harm when administered to a pregnant woman. Administration of selpercatinib to pregnant rats during organogenesis at maternal exposures that were approximately equal to those observed at the recommended human dose of 160 mg twice daily resulted in embryolethality and malformations. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RETEVMO and for 1 week after the last dose. 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 ( 8.1 , 8.3 )] . 5.11 Slipped Capital Femoral Epiphysis/Slipped Upper Femoral Epiphysis in Pediatric Patients Slipped capital femoral epiphysis/slipped upper femoral epiphysis (SCFE/SUFE) occurred in 1 adolescent (2.8% of 36 patients) receiving RETEVMO in LIBRETTO-121 and 1 adolescent (0.5% of 193 patients) receiving RETEVMO in LIBRETTO-531 [see Adverse Reactions ( 6.1 )]. Monitor patients for symptoms indicative of SCFE/SUFE and treat as medically and surgically appropriate.

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: musculoskeletal pain, edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, rash, nausea, constipation, cough, headache, vomiting, dyspnea, and hemorrhage. ( 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), decreased sodium, increased aspartate aminotransferase (AST), decreased calcium, and decreased phosphate. ( 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 857 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 857 patients who received RETEVMO, 74% were exposed for 12 months or longer and 57% were exposed for 24 months or longer. Among these patients, 97% 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); 0.2% were pediatric patients 12 to 16 years of age; 51% were male; and 68% were White, 24% were Asian, and 3% were Black or African American; and 5% were Hispanic/Latino. The most common tumors were NSCLC (43%), MTC (39%), and non-medullary thyroid carcinoma (8%). Serious adverse reactions occurred in 58% of patients who received RETEVMO. The most frequent serious adverse reactions (≥2% of patients) were pneumonia, hemorrhage, abdominal pain, dyspnea, pleural effusion, sepsis, musculoskeletal pain, hyponatremia, vomiting, diarrhea, and increased blood creatinine. Fatal adverse reactions occurred in 3% of patients; fatal adverse reactions included sepsis (n = 6), respiratory failure (n = 5), hemorrhage (n = 4), pneumonia (n = 4), cardiac arrest (n=3), pneumonitis, cardiac failure (n=2 each), sudden death, cerebral infarction and dyspnea (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 ≥0.5% of patients included increased ALT (0.7%), fatigue (0.6%), sepsis (0.5%), pneumonia (0.5%), and increased AST (0.5%). 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, increased AST, diarrhea, hypertension, and QT prolongation. Dose reductions due to an adverse reaction occurred in 45% of patients who received RETEVMO. Adverse reactions requiring dosage reductions in ≥2% of patients included increased ALT, increased AST, fatigue, QT prolongation, diarrhea, drug hypersensitivity, and ascites. The most common adverse reactions (≥25%) were musculoskeletal pain, edema, diarrhea, fatigue, dry mouth, hypertension, abdominal pain, rash, nausea, constipation, headache, vomiting, cough, dyspnea, and hemorrhage. The most common Grade 3 or 4 laboratory abnormalities (≥5%) were decreased lymphocytes, increased alanine aminotransferase (ALT), decreased sodium, increased aspartate aminotransferase (AST), decreased calcium, and decreased phosphate. Table 6 summarizes the adverse reactions in LIBRETTO-001. Table 6: Adverse Reactions (≥20%) in Patients Who Received RETEVMO in LIBRETTO-001 Adverse Reaction RETEVMO (n = 857) Grades 1-4 # (%) Grades 3-4 (%) 1 Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal pain, neck pain, musculoskeletal chest pain, non-cardiac chest pain, bone pain, musculoskeletal stiffness, spinal pain. 2 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, angioedema, penile edema, skin edema, testicular swelling, vulvovaginal swelling 3 Fatigue includes asthenia, malaise. 4 Diarrhea includes defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence. 5 Dry mouth includes mucosal dryness 6 Abdominal pain includes abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain. 7 Vomiting includes regurgitation, retching. 8 Hypertension includes blood pressure increased 9 Rash includes skin exfoliation, rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular, dermatitis, urticaria, dermatitis allergic, rash pustular. 10 Cough includes productive cough, upper airway cough syndrome 11 Dyspnea includes dyspnea exertional, dyspnea at rest 12 Headache includes sinus headache, tension headache. 13 Dizziness includes vertigo, presyncope, dizziness postural. 14 Hemorrhage includes epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, international normalized ratio increased, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, hematocrit decreased, gastric hemorrhage, hemorrhage intracranial, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, arterial hemorrhage, coagulopathy, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye contusion, eye hematoma, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemothorax, hemorrhoidal hemorrhage, hepatic hemorrhage, menorrhagia, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, esophageal hemorrhage, post procedural hemorrhage, postmenopausal hemorrhage, pulmonary hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, activated partial thromboplastin time prolonged, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, subdural hematoma, testicular hemorrhage, tracheal hemorrhage, traumatic hemothorax, tumor hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma. 15 Prolonged QT interval includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal. * Only includes a grade 3 adverse reaction. # Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain 1 59 4.1* General Disorders and Administration Site Conditions Edema 2 53 1.3* Fatigue 3 49 4.7* Gastrointestinal Disorders Diarrhea 4 52 6.2* Dry mouth 5 44 0 Abdominal pain 6 39 3.5* Nausea 36 1.9* Constipation 35 0.8* Vomiting 7 29 2.9* Vascular Disorders Hypertension 8 43 20 Skin and Subcutaneous Tissue Disorders Rash 9 38 0.8* Respiratory, Thoracic and Mediastinal Disorders Cough 10 30 0 Dyspnea 11 28 4.1 Nervous System Disorders Headache 12 30 1.8* Dizziness 13 22 0.5* Blood and Lymphatic System Disorders Hemorrhage 14 26 3.9 Metabolism and Nutrition Disorders Decreased appetite 23 0.9* Investigations Prolonged QT interval 15 21 5* Infections and Infestations Urinary tract infection 20 2.2 * Clinically relevant adverse reactions in ≤15% of patients who received RETEVMO include hypothyroidism (15%); pneumonia (14%), hypersensitivity (6%); interstitial lung disease/pneumonitis, chylothorax, chylous ascites or tumor lysis syndrome (all < 3%). 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 823 to 855 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 62 11 Decreased calcium 61 7 Decreased albumin 61 3.6 Increased ALT 58 13 Increased glucose 56 4.0 Increased creatinine 51 3.6 Decreased sodium 49 13 Increased alkaline phosphatase 43 4.4 Increased potassium 39 3.5 Decreased glucose 39 1.5 Increased total cholesterol 37 1.7 Decreased magnesium 37 0.7 Increased bilirubin 32 2.9 Decreased phosphate 25 5 Hematology Decreased lymphocytes 56 22 Decreased platelets 41 4.0 Decreased hemoglobin 36 4.1 Decreased neutrophils 27 3.8 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 5.0. Laboratory Abnormality RETEVMO 1 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 Laboratory Abnormality 1 RETEVMO Chemotherapy with or without pembrolizumab Grades 1-4 # (%) Grades 3-4 (%) Grades 1-4 # (%) Grades 3-4 (%) 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. 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 includes 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* 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 Laboratory Abnormality RETEVMO 1 Cabozantinib or Vandetanib 1 Grades 1-4 # % Grades 3-4 % Grades 1-4 # % Grades 3-4 % 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 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

<table ID="t06" width="100%"><caption>Table 6: Adverse Reactions (&#x2265;20%) in Patients Who Received RETEVMO in LIBRETTO-001 </caption><col width="33.725%" align="left"/><col width="33.725%" align="left"/><col width="33.725%" align="left"/><thead><tr><th align="left" valign="middle" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content></th><th colspan="2" align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">RETEVMO</content> <content styleCode="bold">(n = 857)</content></th></tr><tr><th align="left" valign="top" styleCode="Toprule Botrule Lrule Rrule"/><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Grades 1-4</content><content styleCode="bold">^#</content> <content styleCode="bold">(%)</content></th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Grades 3-4</content> <content styleCode="bold">(%)</content></th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">¹ Musculoskeletal pain includes back pain, arthralgia, pain in extremity, myalgia, musculoskeletal pain, neck pain, musculoskeletal chest pain, non-cardiac chest pain, bone pain, musculoskeletal stiffness, spinal pain. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">² 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, angioedema, penile edema, skin edema, testicular swelling, vulvovaginal swelling </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">³ Fatigue includes asthenia, malaise. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁴ Diarrhea includes defecation urgency, frequent bowel movements, gastrointestinal hypermotility, anal incontinence. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁵ Dry mouth includes mucosal dryness </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁶ Abdominal pain includes abdominal pain upper, abdominal pain lower, abdominal discomfort, abdominal tenderness, epigastric discomfort, gastrointestinal pain. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁷ Vomiting includes regurgitation, retching. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁸ Hypertension includes blood pressure increased </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁹ Rash includes skin exfoliation, rash erythematous, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, butterfly rash, exfoliative rash, rash follicular, rash generalized, rash vesicular, dermatitis, urticaria, dermatitis allergic, rash pustular. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">¹⁰ Cough includes productive cough, upper airway cough syndrome </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">¹¹ Dyspnea includes dyspnea exertional, dyspnea at rest </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">¹² Headache includes sinus headache, tension headache. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">¹³ Dizziness includes vertigo, presyncope, dizziness postural. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">¹⁴ Hemorrhage includes epistaxis, hematuria, hemoptysis, contusion, rectal hemorrhage, vaginal hemorrhage, ecchymosis, hematochezia, international normalized ratio increased, petechiae, traumatic hematoma, anal hemorrhage, blood blister, blood urine present, cerebral hemorrhage, hematocrit decreased, gastric hemorrhage, hemorrhage intracranial, hemorrhage subcutaneous, spontaneous hematoma, abdominal wall hematoma, angina bullosa hemorrhagica, arterial hemorrhage, coagulopathy, conjunctival hemorrhage, disseminated intravascular coagulation, diverticulum intestinal hemorrhagic, eye contusion, eye hematoma, eye hemorrhage, gastrointestinal hemorrhage, gingival bleeding, hematemesis, hemorrhagic stroke, hemothorax, hemorrhoidal hemorrhage, hepatic hemorrhage, menorrhagia, hepatic hematoma, intraabdominal hemorrhage, laryngeal hemorrhage, lower gastrointestinal hemorrhage, melena, mouth hemorrhage, occult blood positive, esophageal hemorrhage, post procedural hemorrhage, postmenopausal hemorrhage, pulmonary hemorrhage, pelvic hematoma, periorbital hematoma, periorbital hemorrhage, pharyngeal hemorrhage, pulmonary contusion, purpura, activated partial thromboplastin time prolonged, retinal hemorrhage, retroperitoneal hematoma, scleral hemorrhage, skin hemorrhage, subarachnoid hemorrhage, subdural hemorrhage, subdural hematoma, testicular hemorrhage, tracheal hemorrhage, traumatic hemothorax, tumor hemorrhage, upper gastrointestinal hemorrhage, uterine hemorrhage, vessel puncture site hematoma. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">¹⁵ Prolonged QT interval includes electrocardiogram QT prolonged, electrocardiogram QT interval abnormal. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">* Only includes a grade 3 adverse reaction. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">^# Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 </paragraph></td></tr></tfoot><tbody><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Musculoskeletal pain¹</td><td align="center" valign="top" styleCode="Botrule Rrule">59 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.1* </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Edema²</td><td align="center" valign="top" styleCode="Botrule Rrule">53 </td><td align="center" valign="top" styleCode="Botrule Rrule">1.3* </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Fatigue³</td><td align="center" valign="top" styleCode="Botrule Rrule">49 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.7* </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Diarrhea⁴</td><td align="center" valign="top" styleCode="Botrule Rrule">52 </td><td align="center" valign="top" styleCode="Botrule Rrule">6.2* </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Dry mouth⁵</td><td align="center" valign="top" styleCode="Botrule Rrule">44 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Abdominal pain⁶</td><td align="center" valign="top" styleCode="Botrule Rrule">39 </td><td align="center" valign="top" styleCode="Botrule Rrule">3.5* </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Nausea </td><td align="center" valign="top" styleCode="Botrule Rrule">36 </td><td align="center" valign="top" styleCode="Botrule Rrule">1.9* </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Constipation </td><td align="center" valign="top" styleCode="Botrule Rrule">35 </td><td align="center" valign="top" styleCode="Botrule Rrule">0.8* </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Vomiting⁷</td><td align="center" valign="top" styleCode="Botrule Rrule">29 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.9* </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Vascular Disorders</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Hypertension⁸</td><td align="center" valign="top" styleCode="Botrule Rrule">43 </td><td align="center" valign="top" styleCode="Botrule Rrule">20 </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Rash⁹</td><td align="center" valign="top" styleCode="Botrule Rrule">38 </td><td align="center" valign="top" styleCode="Botrule Rrule">0.8* </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Cough¹⁰</td><td align="center" valign="top" styleCode="Botrule Rrule">30 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Dyspnea¹¹</td><td align="center" valign="top" styleCode="Botrule Rrule">28 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.1 </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Headache¹²</td><td align="center" valign="top" styleCode="Botrule Rrule">30 </td><td align="center" valign="top" styleCode="Botrule Rrule">1.8* </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Dizziness¹³</td><td align="center" valign="top" styleCode="Botrule Rrule">22 </td><td align="center" valign="top" styleCode="Botrule Rrule">0.5* </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Blood and Lymphatic System Disorders</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Hemorrhage¹⁴</td><td align="center" valign="top" styleCode="Botrule Rrule">26 </td><td align="center" valign="top" styleCode="Botrule Rrule">3.9 </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased appetite </td><td align="center" valign="top" styleCode="Botrule Rrule">23 </td><td align="center" valign="top" styleCode="Botrule Rrule">0.9* </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Prolonged QT interval¹⁵</td><td align="center" valign="top" styleCode="Botrule Rrule">21 </td><td align="center" valign="top" styleCode="Botrule Rrule">5* </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Infections and Infestations</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Urinary tract infection </td><td align="center" valign="top" styleCode="Botrule Rrule">20 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.2^*</td></tr></tbody></table>

<table ID="t07" width="100%"><caption>Table 7: Select Laboratory Abnormalities (&#x2265;20%) Worsening from Baseline in Patients Who Received RETEVMO in LIBRETTO-001 </caption><col width="32.467%" align="left"/><col width="33.767%" align="left"/><col width="33.767%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">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 823 to 855 patients. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">^# Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03 </paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="left" valign="middle" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Laboratory Abnormality</content></td><td colspan="2" align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">RETEVMO</content><content styleCode="bold">¹</content></td></tr><tr><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Grades 1-4</content><content styleCode="bold">^#</content> <content styleCode="bold">(%)</content></td><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Grades 3-4</content> <content styleCode="bold">(%)</content></td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Chemistry</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased AST </td><td align="center" valign="top" styleCode="Botrule Rrule">62 </td><td align="center" valign="top" styleCode="Botrule Rrule">11 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased calcium </td><td align="center" valign="top" styleCode="Botrule Rrule">61 </td><td align="center" valign="top" styleCode="Botrule Rrule">7 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased albumin </td><td align="center" valign="top" styleCode="Botrule Rrule">61 </td><td align="center" valign="top" styleCode="Botrule Rrule">3.6 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased ALT </td><td align="center" valign="top" styleCode="Botrule Rrule">58 </td><td align="center" valign="top" styleCode="Botrule Rrule">13 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased glucose </td><td align="center" valign="top" styleCode="Botrule Rrule">56 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.0 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased creatinine </td><td align="center" valign="top" styleCode="Botrule Rrule">51 </td><td align="center" valign="top" styleCode="Botrule Rrule">3.6 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased sodium </td><td align="center" valign="top" styleCode="Botrule Rrule">49 </td><td align="center" valign="top" styleCode="Botrule Rrule">13 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased alkaline phosphatase </td><td align="center" valign="top" styleCode="Botrule Rrule">43 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.4 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased potassium </td><td align="center" valign="top" styleCode="Botrule Rrule">39 </td><td align="center" valign="top" styleCode="Botrule Rrule">3.5 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased glucose </td><td align="center" valign="top" styleCode="Botrule Rrule">39 </td><td align="center" valign="top" styleCode="Botrule Rrule">1.5 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased total cholesterol </td><td align="center" valign="top" styleCode="Botrule Rrule">37 </td><td align="center" valign="top" styleCode="Botrule Rrule">1.7 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased magnesium </td><td align="center" valign="top" styleCode="Botrule Rrule">37 </td><td align="center" valign="top" styleCode="Botrule Rrule">0.7 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Increased bilirubin </td><td align="center" valign="top" styleCode="Botrule Rrule">32 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.9 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased phosphate </td><td align="center" valign="top" styleCode="Botrule Rrule">25 </td><td align="center" valign="top" styleCode="Botrule Rrule">5 </td></tr><tr><td colspan="3" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Hematology</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased lymphocytes </td><td align="center" valign="top" styleCode="Botrule Rrule">56 </td><td align="center" valign="top" styleCode="Botrule Rrule">22 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased platelets </td><td align="center" valign="top" styleCode="Botrule Rrule">41 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.0 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased hemoglobin </td><td align="center" valign="top" styleCode="Botrule Rrule">36 </td><td align="center" valign="top" styleCode="Botrule Rrule">4.1 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Decreased neutrophils </td><td align="center" valign="top" styleCode="Botrule Rrule">27 </td><td align="center" valign="top" styleCode="Botrule Rrule">3.8 </td></tr></tbody></table>

<table ID="t08" width="100%"><caption>Table 8: Adverse Reactions (&#x2265;15%) in Patients Who Received RETEVMO in LIBRETTO-121 </caption><col width="40.000%" align="left"/><col width="29.967%" align="left"/><col width="30.033%" align="left"/><thead><tr><th rowspan="2" align="left" valign="middle" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Reactions</content></th><th colspan="2" align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">RETEVMO</content> <content styleCode="bold">N= 36</content></th></tr><tr><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Grades 1-4</content><content styleCode="bold">^#</content> <content styleCode="bold">%</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Grades 3-4</content> <content styleCode="bold">%</content></th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">¹ Musculoskeletal pain includes arthralgia, back pain, bone pain, musculoskeletal chest pain, non-cardiac chest pain, neck pain, pain in extremity </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">² Diarrhea includes anal incontinence </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">³ Abdominal pain includes abdominal pain upper, abdominal discomfort </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁴ Hemorrhage includes epistaxis, hematuria, anal hemorrhage, blood urine present, hemoptysis, menorrhagia, mouth hemorrhage </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁵ Fatigue includes asthenia, malaise </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁶ Edema includes face edema, edema peripheral, periorbital edema, localized edema, generalized edema, gastrointestinal edema, swelling </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁷ Rash includes rash maculopapular, rash erythematous, urticaria </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁸ Urinary tract infection includes cystitis </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">⁹ Hypothyroidism includes blood thyroid stimulating hormone increased, thyroglobulin increased </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">* No Grade 4 events were reported. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">^# Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. </paragraph></td></tr></tfoot><tbody><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Musculoskeletal pain¹</td><td align="center" valign="top" styleCode="Botrule Rrule">58 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Gastrointestinal Disorders</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Diarrhea²</td><td align="center" valign="top" styleCode="Botrule Rrule">47 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.8* </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Nausea </td><td align="center" valign="top" styleCode="Botrule Rrule">42 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.8* </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Abdominal pain³</td><td align="center" valign="top" styleCode="Botrule Rrule">36 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Vomiting </td><td align="center" valign="top" styleCode="Botrule Rrule">31 </td><td align="center" valign="top" styleCode="Botrule Rrule">8* </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Constipation </td><td align="center" valign="top" styleCode="Botrule Rrule">22 </td><td align="center" valign="top" styleCode="Botrule Rrule">6^*</td></tr><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Blood and Lymphatic System Disorders</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Hemorrhage⁴</td><td align="center" valign="top" styleCode="Botrule Rrule">39 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Pyrexia </td><td align="center" valign="top" styleCode="Botrule Rrule">39 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Fatigue⁵</td><td align="center" valign="top" styleCode="Botrule Rrule">31 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Edema⁶</td><td align="center" valign="top" styleCode="Botrule Rrule">25 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Nervous System Disorders</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Headache </td><td align="center" valign="top" styleCode="Botrule Rrule">33 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Respiratory, Thoracic and Mediastinal Disorders</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Cough </td><td align="center" valign="top" styleCode="Botrule Rrule">31 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Oropharyngeal pain </td><td align="center" valign="top" styleCode="Botrule Rrule">22 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Rash⁷</td><td align="center" valign="top" styleCode="Botrule Rrule">28 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Infections and Infestations</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Coronavirus infection </td><td align="center" valign="top" styleCode="Botrule Rrule">28 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Upper respiratory tract infection </td><td align="center" valign="top" styleCode="Botrule Rrule">28 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.8* </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Urinary tract infection⁸</td><td align="center" valign="top" styleCode="Botrule Rrule">19 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.8* </td></tr><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Endocrine Disorders</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Hypothyroidism⁹</td><td align="center" valign="top" styleCode="Botrule Rrule">22 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td colspan="3" align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Investigations</content></td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule">Increased weight </td><td align="center" valign="top" styleCode="Botrule Rrule">19 </td><td align="center" valign="top" styleCode="Botrule Rrule">11* </td></tr></tbody></table>