Gavreto

5 WARNINGS AND PRECAUTIONS Interstitial Lung Disease (ILD)/Pneumonitis : Withhold GAVRETO for Grade 1 or 2 reactions until resolution and then resume at a reduced dose. Permanently discontinue for recurrent ILD/pneumonitis. Permanently discontinue for Grade 3 or 4 reactions. ( 2.3 , 5.1 ) Hypertension : Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure (BP) prior to initiating GAVRETO. Monitor BP after 1 week, at least monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. ( 2.3 , 5.2 ) Hepatotoxicity : Monitor ALT and AST prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose, or permanently discontinue GAVRETO based on severity. ( 2.3 , 5.3 ) Hemorrhagic Events : Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage. ( 2.3 , 5.4 ) Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. ( 2.3 , 5.5 ) Risk of Impaired Wound Healing: Withhold GAVRETO for at least 5 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 GAVRETO after resolution of wound healing complications has not been established. ( 5.6 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective non-hormonal contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Interstitial Lung Disease/Pneumonitis Severe, life-threatening, and fatal interstitial lung disease (ILD) / pneumonitis can occur in patients treated with GAVRETO. Pneumonitis occurred in 12% of patients who received GAVRETO, including 3.3% with Grade 3-4, and 0.2% with fatal reactions. Monitor for pulmonary symptoms indicative of ILD/pneumonitis. Withhold GAVRETO 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 dose or permanently discontinue GAVRETO based on severity of confirmed ILD [see Dosage and Administration (2.3) ] . 5.2 Hypertension Hypertension occurred in 35% of patients, including Grade 3 hypertension in 18% of patients [see Adverse Reactions (6.1) ] . Overall, 8% had their dose interrupted and 4.8% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate GAVRETO in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating GAVRETO. Monitor blood pressure after 1 week, at least monthly thereafter and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue GAVRETO based on the severity [see Dosage and Administration (2.3) ] . 5.3 Hepatoxicity Serious hepatic adverse reactions occurred in 1.5% of patients treated with GAVRETO. Increased AST occurred in 49% of patients, including Grade 3 or 4 in 7% and increased ALT occurred in 37% of patients, including Grade 3 or 4 in 4.8% [see Adverse Reactions (6.1) ]. The median time to first onset for increased AST was 15 days (range: 5 days to 2.5 years) and for increased ALT was 24 days (range: 7 days to 3.7 years). Monitor AST and ALT prior to initiating GAVRETO, every 2 weeks during the first 3 months, then monthly thereafter and as clinically indicated. Withhold, reduce dose or permanently discontinue GAVRETO based on severity [see Dosage and Administration (2.3) ] . 5.4 Hemorrhagic Events Serious, including fatal, hemorrhagic events can occur with GAVRETO. Grade ≥ 3 hemorrhagic events occurred in 4.1% of patients treated with GAVRETO including one patient with a fatal hemorrhagic event. Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage [see Dosage and Administration (2.3) ]. 5.5 Tumor Lysis Syndrome Cases of tumor lysis syndrome (TLS) have been reported in patients with medullary thyroid carcinoma receiving GAVRETO [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. 5.6 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, GAVRETO has the potential to adversely affect wound healing. Withhold GAVRETO for at least 5 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 GAVRETO after resolution of wound healing complications has not been established. 5.7 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman. Oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in malformations and embryolethality at maternal exposures below the human exposure at the clinical dose of 400 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose [see Use in Specific Populations (8.1 , 8.3) ] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.1) ] Hypertension [see Warnings and Precautions (5.2) ] Hepatotoxicity [see Warnings and Precautions (5.3) ] Hemorrhagic Events [see Warnings and Precautions (5.4) ] Tumor Lysis Syndrome [see Warnings and Precautions (5.5) ] Risk of Impaired Wound Healing [see Warnings and Precautions (5.6) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.7) ] The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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 pooled safety population in the WARNINGS AND PRECAUTIONS reflect exposure to GAVRETO as a single agent at 400 mg orally once daily in 540 patients in ARROW [see Clinical Studies (14) ]. Among 540 patients who received GAVRETO, 71% were exposed for 6 months or longer and 57% were exposed for greater than one year. The most common adverse reactions (≥ 25%) were musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough. The most common Grade 3-4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased leukocytes, decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased calcium (corrected), decreased platelets, increased alkaline phosphatase, increased potassium, decreased potassium and increased bilirubin. RET Fusion-Positive Non-Small Cell Lung Cancer The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 281 patients with metastatic rearranged during transfection ( RET fusion-positive) non-small cell lung cancer (NSCLC) in ARROW [see Clinical Studies (14.1) ]. Among the 281 patients who received GAVRETO, 72% were exposed for 6 months or longer and 56% were exposed for ≥1 year. The median age was 60 years (range: 26 to 87 years); 54% were female, 46% were White, 46% were Asian, and 4% were Hispanic/Latino. Serious adverse reactions occurred in 65% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, anemia, pneumonitis, pyrexia, sepsis, urinary tract infection, coronavirus infection, pleural effusion, dyspnea, musculoskeletal pain, pulmonary embolism, and seizure. Fatal adverse reactions occurred in 7% of patients; fatal adverse reactions which occurred in > 1 patient included pneumonia (n=8), sepsis (n=3) and COVID (n=3). Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in ≥ 2% of patients included pneumonitis (3.2%), and pneumonia (2.8%). Dosage interruptions due to an adverse reaction occurred in 73% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included anemia, pneumonia, pneumonitis, neutropenia, hypertension, increased blood creatine phosphokinase, fatigue, pyrexia, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), coronavirus infection, diarrhea, hypophosphatemia, musculoskeletal pain, thrombocytopenia, dyspnea, hemorrhage, leukopenia, lymphopenia, edema, sepsis, and vomiting. Dose reductions due to adverse reactions occurred in 51% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included anemia, neutropenia, pneumonitis, increased blood creatine phosphokinase, leukopenia, hypertension, fatigue, pneumonia, and lymphopenia. Table 5 summarizes the adverse reactions in patients with NSCLC in ARROW. Table 5: Adverse Reactions (≥ 15%) in RET Fusion-Positive NSCLC Patients Who Received GAVRETO in ARROW Adverse reaction GAVRETO N = 281 Grades 1 - 4 (%) Grades 3 or 4 (%) Gastrointestinal disorders Constipation 45 0.7 Diarrhea 30 2.5 Nausea 19 0 Dry mouth 17 0 General Disorders and Administration Site Conditions Edema Includes the preferred terms: Edema, Swelling face, Peripheral swelling, Generalized oedema, Edema peripheral, Face edema, Periorbital edema, Eyelid edema, Swelling, Localized edema 44 0 Fatigue Includes the preferred terms: Fatigue, Asthenia 42 2.5 Pyrexia 29 0.7 Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Includes the preferred terms: Myalgia, Arthralgia, Pain in extremity, Neck pain, Musculoskeletal pain, Back pain, Musculoskeletal chest pain, Bone pain, Musculoskeletal stiffness 44 2.5 Increased Blood Creatine Phosphokinase 19 9 Vascular Hypertension Includes the preferred terms: hypertension, blood pressure increased 38 18 Respiratory, thoracic and mediastinal disorders Cough Includes the preferred terms: Cough, Productive Cough, upper-airway cough syndrome 36 0.4 Dyspnea 21 2.1 Infection and Infestations Pneumonia Includes the preferred terms: Pneumonia, Pneumocystis jirovecii pneumonia, Pneumonia cytomegaloviral, Atypical pneumonia, Lung infection, Pneumonia bacterial, Pneumonia haemophilus, Pneumonia influenzal, Pneumonia streptococcal, Pneumonia viral, Pneumonia pseudomonal 24 13 Urinary tract infection 16 3.6 Metabolism and Nutrition Disorders Decreased appetite 18 1.1 Nervous system disorders Taste disorder Includes the preferred terms: Dysgeusia, Ageusia 17 0 Headache Includes the preferred terms: Headache, Tension Headache 15 1.1 Skin and subcutaneous tissue disorders Rash Includes the preferred terms: Rash, Rash maculo-papular, Dermatitis acneiform, Erythema, Rash generalized, Rash papular, Rash macular, Rash erythematous 17 0 Clinically relevant adverse reactions occurring in < 15% of patients included pneumonitis (14%), vomiting (14%), abdominal pain (14%), and stomatitis (6%). Table 6 summarizes the laboratory abnormalities in ARROW. Table 6: Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in RET Fusion-Positive NSCLC Patients Who Received GAVRETO in ARROW Laboratory Abnormality GAVRETO N=281 Grades 1-4 (%) Grades 3-4 (%) Chemistry Increased AST 80 3.2 Increased ALT 58 3.9 Decreased albumin 52 0 Decreased calcium (corrected) 50 1.8 Decreased phosphate 50 17 Increased creatinine 45 1.4 Increased alkaline phosphatase 43 2.5 Decreased sodium 42 10 Decreased Potassium 27 4.6 Increased Potassium 27 1.8 Decreased Magnesium 25 0 Increased Bilirubin 20 1.8 Hematology Decreased leukocytes 79 11 Decreased hemoglobin 78 18 Decreased lymphocytes 73 32 Decreased neutrophils 70 21 Decreased platelets 33 5 Clinically relevant laboratory abnormalities occurring in < 20% of patients who received GAVRETO included increased magnesium (14%). RET -altered Thyroid Cancer The safety of GAVRETO was evaluated as a single agent at 400 mg orally once daily in 138 patients with RET -altered thyroid cancer (including 19 patients with RET fusion-positive thyroid cancer) in ARROW [see Clinical Studies (14.2 )]. Among the 138 patients who received GAVRETO, 68% were exposed for 6 months or longer, and 40% were exposed for greater than one year. The median age was 59 years (range: 18 to 83 years); 36% were female, 74% were White, 17% were Asian, and 6% were Hispanic/Latino. Serious adverse reactions occurred in 39% of patients who received GAVRETO. The most frequent serious adverse reactions (in ≥ 2% of patients) were pneumonia, pneumonitis, urinary tract infection, pyrexia, fatigue, diarrhea, dizziness, anemia, hyponatremia, and ascites. Fatal adverse reaction occurred in 2.2% of patients; fatal adverse reactions that occurred in > 1 patient included pneumonia (n=2). Permanent discontinuation due to an adverse reaction occurred in 9% of patients who received GAVRETO. Adverse reactions resulting in permanent discontinuation which occurred in > 1 patient included fatigue, pneumonia and anemia. Dosage interruptions due to an adverse reaction occurred in 67% of patients who received GAVRETO. Adverse reactions requiring dosage interruption in ≥ 2% of patients included neutropenia, hypertension, diarrhea, fatigue, pneumonitis, anemia, increased blood creatine phosphokinase, pneumonia, urinary tract infection, musculoskeletal pain, vomiting, pyrexia, increased AST, dyspnea, hypocalcemia, cough, thrombocytopenia, abdominal pain, increased blood creatinine, dizziness, headache, decreased lymphocyte count, stomatitis, and syncope. Dose reductions due to adverse reactions occurred in 44% of patients who received GAVRETO. Adverse reactions requiring dosage reductions in ≥ 2% of patients included neutropenia, anemia, hypertension, increased blood creatine phosphokinase, decreased lymphocyte count, pneumonitis, fatigue and thrombocytopenia. Table 7 summarizes the adverse reactions occurring in RET -altered Thyroid Cancer Patients in ARROW. Table 7: Adverse Reactions (≥ 15%) in RET-altered Thyroid Cancer Patients Who Received GAVRETO in ARROW Adverse Reactions GAVRETO N=138 Grades 1-4 (%) Grades 3-4 (%) Musculoskeletal Musculoskeletal Pain Musculoskeletal Pain includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain 42 0.7 Only includes a Grade 3 adverse reaction Gastrointestinal Constipation 41 0.7 Diarrhea Diarrhea includes colitis, diarrhea 34 5 Abdominal Pain Abdominal Pain includes abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, epigastric discomfort 17 0.7 Dry mouth 17 0 Stomatitis Stomatitis includes mucosal inflammation, stomatitis, tongue ulceration 17 0.7 Nausea 17 0.7 Vascular Hypertension 40 21 General Fatigue Fatigue includes asthenia, fatigue 38 6 Edema Edema includes eyelid edema, face edema, edema, edema peripheral, periorbital edema 29 0 Pyrexia 22 2.2 Respiratory Cough Cough includes cough, productive cough, upper-airway cough syndrome 27 1.4 Dyspnea Dyspnea includes dyspnea, dyspnea exertional 22 2.2 Nervous System Headache Headache includes headache, migraine 24 0 Peripheral Neuropathy Peripheral neuropathy includes dysaesthesia, hyperaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, polyneuropathy 20 0 Dizziness Dizziness includes dizziness, dizziness postural, vertigo 19 0.7 Dysgeusia Dysgeusia includes ageusia, dysgeusia 17 0 Skin and Subcutaneous Rash Rash includes dermatitis, dermatitis acneiform, eczema, palmar-plantar, erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular 24 0 Metabolism and Nutrition Decreased Appetite 15 0 Clinically relevant adverse reactions in < 15% of patients who received GAVRETO included tumor lysis syndrome and increased creatine phosphokinase. Table 8 summarizes the laboratory abnormalities occurring in RET -altered Thyroid Cancer Patients in ARROW. Table 8: Select Laboratory Abnormalities (≥ 20%) Worsening from Baseline in RET-altered Thyroid Cancer Patients Who Received GAVRETO in ARROW Laboratory Abnormality GAVRETO N=138 Grades 1-4 (%) Grades 3-4 (%) Denominator for each laboratory parameter is based on the number of patients with a baseline and post-treatment laboratory value available, which ranged from 135 to 138 patients. Chemistry Decreased calcium (corrected) 70 9 Increased AST 69 4.3 Increased ALT 43 3.6 Increased creatinine 41 0 Decreased albumin 41 1.5 Decreased sodium 28 2.2 Decreased phosphate 28 8 Decreased magnesium 27 0.7 Increased potassium 26 1.4 Increased bilirubin 24 1.4 Increased alkaline phosphatase 22 1.4 Hematology Decreased lymphocytes 67 27 Decreased hemoglobin 63 13 Decreased neutrophils 59 16 Decreased platelets 31 2.9 Clinically relevant laboratory abnormalities in patients who received GAVRETO included increased phosphate (40%).

<table width="75%" ID="Table5"><caption>Table 5: Adverse Reactions (&#x2265; 15%) in RET Fusion-Positive NSCLC Patients Who Received GAVRETO in ARROW</caption><col width="36%" align="left" valign="top"/><col width="32%" align="center" valign="top"/><col width="32%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2">Adverse reaction</th><th styleCode="Rrule" colspan="2">GAVRETO N = 281</th></tr><tr><th styleCode="Rrule" align="center">Grades 1 - 4 (%)</th><th styleCode="Rrule">Grades 3 or 4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">45</td><td styleCode="Rrule">0.7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea</td><td styleCode="Rrule">30</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">19</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry mouth</td><td styleCode="Rrule">17</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General Disorders and Administration Site Conditions</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema<footnote>Includes the preferred terms: Edema, Swelling face, Peripheral swelling, Generalized oedema, Edema peripheral, Face edema, Periorbital edema, Eyelid edema, Swelling, Localized edema </footnote></td><td styleCode="Rrule">44 </td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue<footnote>Includes the preferred terms: Fatigue, Asthenia </footnote></td><td styleCode="Rrule">42</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">29</td><td styleCode="Rrule">0.7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Musculoskeletal and Connective Tissue Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Musculoskeletal pain<footnote>Includes the preferred terms: Myalgia, Arthralgia, Pain in extremity, Neck pain, Musculoskeletal pain, Back pain, Musculoskeletal chest pain, Bone pain, Musculoskeletal stiffness </footnote></td><td styleCode="Rrule">44</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Increased Blood Creatine Phosphokinase</td><td styleCode="Rrule">19</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Vascular</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypertension<footnote>Includes the preferred terms: hypertension, blood pressure increased </footnote></td><td styleCode="Rrule">38</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough<footnote>Includes the preferred terms: Cough, Productive Cough, upper-airway cough syndrome</footnote></td><td styleCode="Rrule">36</td><td styleCode="Rrule">0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspnea</td><td styleCode="Rrule">21</td><td styleCode="Rrule">2.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Infection and Infestations</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pneumonia<footnote>Includes the preferred terms: Pneumonia, Pneumocystis jirovecii pneumonia, Pneumonia cytomegaloviral, Atypical pneumonia, Lung infection, Pneumonia bacterial, Pneumonia haemophilus, Pneumonia influenzal, Pneumonia streptococcal, Pneumonia viral, Pneumonia pseudomonal </footnote></td><td styleCode="Rrule">24</td><td styleCode="Rrule">13</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Urinary tract infection</td><td styleCode="Rrule">16</td><td styleCode="Rrule">3.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Metabolism and Nutrition Disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Decreased appetite</td><td styleCode="Rrule">18</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Nervous system disorders</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Taste disorder<footnote>Includes the preferred terms: Dysgeusia, Ageusia </footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache<footnote>Includes the preferred terms: Headache, Tension Headache </footnote></td><td styleCode="Rrule">15</td><td styleCode="Rrule">1.1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Skin and subcutaneous tissue disorders</content></td></tr><tr><td styleCode="Lrule Rrule"> Rash<footnote>Includes the preferred terms: Rash, Rash maculo-papular, Dermatitis acneiform, Erythema, Rash generalized, Rash papular, Rash macular, Rash erythematous</footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">0</td></tr></tbody></table>

<table width="75%" ID="Table6"><caption>Table 6: Select Laboratory Abnormalities (&#x2265; 20%) Worsening from Baseline in RET Fusion-Positive NSCLC Patients Who Received GAVRETO in ARROW</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2" valign="middle">Laboratory Abnormality</th><th styleCode="Rrule" colspan="2">GAVRETO N=281</th></tr><tr><th styleCode="Rrule" align="center">Grades 1-4 (%)</th><th styleCode="Rrule">Grades 3-4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Chemistry</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased AST</td><td styleCode="Rrule">80</td><td styleCode="Rrule">3.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased ALT</td><td styleCode="Rrule">58</td><td styleCode="Rrule">3.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased albumin</td><td styleCode="Rrule">52</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased calcium (corrected)</td><td styleCode="Rrule">50</td><td styleCode="Rrule">1.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased phosphate</td><td styleCode="Rrule">50</td><td styleCode="Rrule">17</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased creatinine</td><td styleCode="Rrule">45</td><td styleCode="Rrule">1.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased alkaline phosphatase</td><td styleCode="Rrule">43</td><td styleCode="Rrule">2.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased sodium</td><td styleCode="Rrule">42</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased Potassium</td><td styleCode="Rrule">27</td><td styleCode="Rrule">4.6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased Potassium</td><td styleCode="Rrule">27</td><td styleCode="Rrule">1.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased Magnesium </td><td styleCode="Rrule">25</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Increased Bilirubin</td><td styleCode="Rrule">20</td><td styleCode="Rrule">1.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Hematology</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased leukocytes</td><td styleCode="Rrule">79</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased hemoglobin</td><td styleCode="Rrule">78</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased lymphocytes</td><td styleCode="Rrule">73</td><td styleCode="Rrule">32</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Decreased neutrophils</td><td styleCode="Rrule">70</td><td styleCode="Rrule">21</td></tr><tr><td styleCode="Lrule Rrule">Decreased platelets</td><td styleCode="Rrule">33</td><td styleCode="Rrule">5</td></tr></tbody></table>

<table width="75%" ID="Table7"><caption>Table 7: Adverse Reactions (&#x2265; 15%) in RET-altered Thyroid Cancer Patients Who Received GAVRETO in ARROW</caption><col width="40%" align="left" valign="top"/><col width="30%" align="center" valign="top"/><col width="30%" align="center" valign="top"/><thead><tr styleCode="Botrule"><th styleCode="Lrule Rrule" rowspan="2" valign="middle">Adverse Reactions</th><th styleCode="Rrule" colspan="2">GAVRETO N=138</th></tr><tr><th styleCode="Rrule" align="center">Grades 1-4 (%)</th><th styleCode="Rrule">Grades 3-4 (%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Musculoskeletal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Musculoskeletal Pain<footnote>Musculoskeletal Pain includes arthralgia, arthritis, back pain, bone pain, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, spinal pain</footnote></td><td styleCode="Rrule">42</td><td styleCode="Rrule">0.7<footnote ID="foot3">Only includes a Grade 3 adverse reaction</footnote></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Gastrointestinal</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Constipation</td><td styleCode="Rrule">41</td><td styleCode="Rrule">0.7<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Diarrhea<footnote>Diarrhea includes colitis, diarrhea</footnote></td><td styleCode="Rrule">34</td><td styleCode="Rrule">5<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Abdominal Pain<footnote>Abdominal Pain includes abdominal discomfort, abdominal pain, abdominal pain upper, abdominal tenderness, epigastric discomfort</footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">0.7<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dry mouth</td><td styleCode="Rrule">17</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Stomatitis<footnote>Stomatitis includes mucosal inflammation, stomatitis, tongue ulceration</footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">0.7<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Nausea</td><td styleCode="Rrule">17</td><td styleCode="Rrule">0.7<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Vascular</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Hypertension</td><td styleCode="Rrule">40</td><td styleCode="Rrule">21<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">General</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Fatigue<footnote>Fatigue includes asthenia, fatigue</footnote></td><td styleCode="Rrule">38</td><td styleCode="Rrule">6<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Edema<footnote>Edema includes eyelid edema, face edema, edema, edema peripheral, periorbital edema</footnote></td><td styleCode="Rrule">29</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Pyrexia</td><td styleCode="Rrule">22</td><td styleCode="Rrule">2.2<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Respiratory</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Cough<footnote>Cough includes cough, productive cough, upper-airway cough syndrome</footnote></td><td styleCode="Rrule">27</td><td styleCode="Rrule">1.4<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dyspnea<footnote>Dyspnea includes dyspnea, dyspnea exertional</footnote></td><td styleCode="Rrule">22</td><td styleCode="Rrule">2.2<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Nervous System</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Headache<footnote>Headache includes headache, migraine</footnote></td><td styleCode="Rrule">24</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Peripheral Neuropathy<footnote>Peripheral neuropathy includes dysaesthesia, hyperaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, polyneuropathy</footnote></td><td styleCode="Rrule">20</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dizziness<footnote>Dizziness includes dizziness, dizziness postural, vertigo</footnote></td><td styleCode="Rrule">19</td><td styleCode="Rrule">0.7<footnoteRef IDREF="foot3"/></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Dysgeusia<footnote>Dysgeusia includes ageusia, dysgeusia</footnote></td><td styleCode="Rrule">17</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Skin and Subcutaneous</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"> Rash<footnote>Rash includes dermatitis, dermatitis acneiform, eczema, palmar-plantar, erythrodysaesthesia syndrome, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pustular</footnote></td><td styleCode="Rrule">24</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Metabolism and Nutrition</content></td></tr><tr><td styleCode="Lrule Rrule"> Decreased Appetite</td><td styleCode="Rrule">15</td><td styleCode="Rrule">0</td></tr></tbody></table>