Gavreto

GAVRETO is a kinase inhibitor indicated for treatment of: Adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer as detected by an FDA approved test (NSCLC). (1.1) Adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). (1.2)

1.1Metastatic

RET Fusion-Positive Non-Small Cell Lung Cancer GAVRETO is indicated for the treatment of adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA approved test. 1.2 RET Fusion-Positive Thyroid Cancer GAVRETO is indicated for the treatment of adult and pediatric patients 12 years of age and older with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). This indication is approved under accelerated approval based on overall response rate and duration of response [see Clinical Studies (14.2)]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Select patients for treatment with GAVRETO based on the presence of a RET gene fusion. (2.1, 14) The recommended dosage in adults and pediatric patients 12 years and older is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO). (2.2)

2.1Patient Selection

Select patients for treatment with GAVRETO based on the presence of a RET gene fusion (NSCLC or thyroid cancer) [see Clinical Studies (14)]. Information on FDA-approved tests for RET gene fusion (NSCLC) is available at http://www.fda.gov/CompanionDiagnostics. An FDA-approved test for the detection of RET gene fusion (thyroid cancer) is not currently available. 2.2 Recommended Dosage The recommended dosage of GAVRETO is 400 mg orally once daily on an empty stomach (no food intake for at least 2 hours before and at least 1 hour after taking GAVRETO) [see Clinical Pharmacology (12.3)]. Continue treatment until disease progression or until unacceptable toxicity. If a dose of GAVRETO is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule for GAVRETO the next day. Do not take an additional dose if vomiting occurs after GAVRETO but continue with the next dose as scheduled. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reductions and dosage modifications for adverse reactions are provided in Table 1 and Table 2. Table 1: Recommended Dose Reductions for GAVRETO for Adverse Reactions Dose Reduction Recommended Dosage First 300 mg once daily Second 200 mg once daily Third 100 mg once daily Permanently discontinue GAVRETO in patients who are unable to tolerate 100 mg taken orally once daily. The recommended dosage modifications for adverse reactions are provided in Table 2. Table 2: Recommended Dosage Modifications for GAVRETO for Adverse Reactions Adverse Reactions Severity Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version

4.03Dosage Modification Serious Infections, Including Opportunistic Infections

[see Warnings and Precautions (5.1)] Grade 2 or 3 Withhold GAVRETO until resolution. Resume at a reduced dose (Table 1). Grade 4 Permanently discontinue GAVRETO. ILD/Pneumonitis [see Warnings and Precautions (5.2)] Grade 1 or 2 Withhold GAVRETO until resolution. Resume by reducing the dose as shown in Table 1. Permanently discontinue GAVRETO for recurrent ILD/pneumonitis. Grade 4 Permanently discontinue GAVRETO. Hypertension [see Warnings and Precautions (5.3)] Grade 3 Withhold GAVRETO for Grade 3 hypertension that persists despite optimal antihypertensive therapy. Resume at a reduced dose when hypertension is controlled. Grade 4 Discontinue GAVRETO. Hepatotoxicity [see Warnings and Precautions (5.4)] Grade 3 or 4 Withhold GAVRETO and monitor AST/ALT once weekly until resolution to Grade 1 or baseline. Resume at reduced dose (Table 1). For recurrent events at Grade 3 or higher, discontinue GAVRETO. Hemorrhagic Events [see Warnings and Precautions (5.5)] Grade 3 or 4 Withhold GAVRETO until recovery to baseline or Grade 0 or 1. Discontinue GAVRETO for severe or life-threatening hemorrhagic events. Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3 or 4 Withhold GAVRETO until improvement to ≤ Grade 2. Resume at reduced dose (Table 1). Permanently discontinue for recurrent Grade 4 adverse reactions. 2.4 Dose Modification for Use with CYP3A and/or P-glycoprotein (P-gp) Inhibitors Avoid coadministration of GAVRETO with any of the following: Strong CYP3A inhibitors Moderate CYP3A inhibitors P-gp inhibitors Combined P-gp and strong CYP3A inhibitors Combined P-gp and moderate CYP3A inhibitors If coadministration with any of the above inhibitors cannot be avoided, reduce the current dose of GAVRETO as recommended in Table 3. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume GAVRETO at the dose taken prior to initiating the inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Table 3: Recommended Dosage Modifications for GAVRETO for Coadministration with CYP3A and/or P-gp Inhibitors Current GAVRETO Dosage Recommended GAVRETO Dosage when Coadministered with: Combined P-gp and Strong CYP3A Inhibitors Strong CYP3A Inhibitors; Moderate CYP3A Inhibitors; P-gp Inhibitors; Combined P-gp and Moderate CYP3A Inhibitors 400 mg orally once daily 200 mg orally once daily 300 mg orally once daily 300 mg orally once daily 200 mg orally once daily 200 mg orally once daily 200 mg orally once daily 100 mg orally once daily 100 mg orally once daily

2.5Dose Modification for

Use with CYP3A Inducers Avoid coadministration of GAVRETO with any of the following: Strong CYP3A inducers Moderate CYP3A inducers If coadministration with any of the above inducers cannot be avoided, increase the starting dose of GAVRETO as recommended in Table 4 starting on Day 7 of coadministration of GAVRETO with the inducer. After the inducer has been discontinued for at least 14 days, resume GAVRETO at the dose taken prior to initiating the inducer [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Table 4: Recommended Dosage Modifications for GAVRETO for Coadministration with CYP3A Inducers Current GAVRETO Dosage Recommended GAVRETO Dosage when Coadministered with: Strong CYP3A Inducers Moderate CYP3A Inducers 400 mg orally once daily 800 mg orally once daily 600 mg orally once daily 300 mg orally once daily 600 mg orally once daily 500 mg orally once daily 200 mg orally once daily 400 mg orally once daily 300 mg orally once daily

Serious Infections, Including Opportunistic Infections: Monitor for signs and symptoms of infection and treat appropriately. Withhold, reduce the dose, or permanently discontinue GAVRETO based on severity. (2.3, 5.1) 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, 5.2) 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, 5.3) 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, 5.4) Hemorrhagic Events: Permanently discontinue GAVRETO in patients with severe or life-threatening hemorrhage. (2.3, 5.5) Tumor Lysis Syndrome: Closely monitor patients at risk and treat as clinically indicated. (2.3, 5.6) 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. (5.7) 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. (5.8, 8.1, 8.3)

5.1Serious Infections, Including Opportunistic Infections

GAVRETO may increase the risk for serious infections, including fatal and opportunistic infections. In the AcceleRET-Lung trial [see Adverse Reactions (6.1)], infections occurred in 72% of patients who received GAVRETO, including 18% with Grade 3, 3.7% with Grade 4, and 7% with fatal outcomes. Among the patients who received chemotherapy/immunotherapy, infections occurred in 52%, including 10% with Grade 3. Infections in the GAVRETO arm included pneumonia, urinary tract infection, opportunistic infections (such as pneumocystis jirovecii pneumonia, and fungal infections) and others. Monitor patients for signs and symptoms of infection and treat appropriately. Withhold, reduce the dose, or permanently discontinue GAVRETO based on severity [see Dosage and Administration (2.3)]. 5.2 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)]. 5.3 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)]. 5.4 Hepatotoxicity 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)]. 5.5 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)]. 5.6 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. 5.7 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. 5.8 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)].

The following clinically significant adverse reactions are described elsewhere in the labeling: Serious Infections, Including Opportunistic Infections [see Warnings and Precautions (5.1)] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2)] Hypertension [see Warnings and Precautions (5.3)] Hepatotoxicity [see Warnings and Precautions (5.4)] Hemorrhagic Events [see Warnings and Precautions (5.5)] Tumor Lysis Syndrome [see Warnings and Precautions (5.6)] Risk of Impaired Wound Healing [see Warnings and Precautions (5.7)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.8)] 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 Rigel Pharmaceuticals, Inc. at 1-800-983-1329 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. In addition to the 540 patients, certain subsections in the WARNINGS AND PRECAUTIONS describe adverse reactions observed with exposure to GAVRETO as a single agent in a randomized, open-label study, AcceleRET-Lung (NCT04222972), which enrolled 223 patients with RET-fusion positive locally advanced unresectable or metastatic NSCLC. 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 hemophilus, 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%). Other Clinical Trials Experience AcceleRET-Lung trial (NCT04222972) In AcceleRET-Lung trial (NCT04222972), single agent GAVRETO (n=108) was compared to chemotherapy/immunotherapy (n=104) in patients with RET fusion-positive NSCLC. Adverse reactions were infections (72% vs.52%), including pneumonia (29% vs. 6%), urinary tract infection (22% vs. 8%), and opportunistic infections (20% vs. 6%). Opportunistic infections included pneumocystis jirovecii pneumonia, fungal infections, legionella pneumonia, cytomegalovirus infection, and herpes simplex.

Lactation: Advise not to breastfeed. (8.2) Pediatric Use: Monitor open growth plates in adolescent patients. Consider interrupting or discontinuing GAVRETO if abnormalities occur. (8.4)

8.1Pregnancy Risk Summary

Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on GAVRETO use in pregnant women to inform drug-associated risk. 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 (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal development study, once daily oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in 100% post-implantation loss at dose levels ≥ 20 mg/kg (approximately 1.8 times the human exposure based on area under the curve [AUC] at the clinical dose of 400 mg). Post-implantation loss also occurred at the 10 mg/kg dose level (approximately 0.6 times the human exposure based on AUC at the clinical dose of 400 mg). Once daily oral administration of pralsetinib at dose levels ≥ 5 mg/kg (approximately 0.2 times the human AUC at the clinical dose of 400 mg) resulted in an increase in visceral malformations and variations (absent or small kidney and ureter, absent uterine horn, malpositioned kidney or testis, retroesophageal aortic arch) and skeletal malformations and variations (vertebral and rib anomalies and reduced ossification). 8.2 Lactation Risk Summary There are no data on the presence of pralsetinib or its metabolites in human milk or their effects on either the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with GAVRETO and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Based on animal data, GAVRETO can cause embryolethality and malformations at doses resulting in exposures below the human exposure at the clinical dose of 400 mg daily [see Use in Specific Populations (8.1)]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating GAVRETO [see Use in Specific Populations (8.1)]. Contraception GAVRETO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females Advise females of reproductive potential to use effective non-hormonal contraception during treatment with GAVRETO and for 2 weeks after the last dose. GAVRETO may render hormonal contraceptives ineffective. Males Advise males with female partners of reproductive potential to use effective contraception during treatment with GAVRETO and for 1 week after the last dose. Infertility Based on histopathological findings in the reproductive tissues of male and female rats and a dedicated fertility study in which animals of both sexes were treated and mated to each other, GAVRETO may impair fertility [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of GAVRETO have been established in pediatric patients aged 12 years and older for RET fusion-positive thyroid cancer. Use of GAVRETO in this age group is supported by evidence from an adequate and well-controlled study of GAVRETO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of pralsetinib, that the exposure of pralsetinib is expected to be similar between adults and pediatric patients age 12 years and older, and that the course of RET fusion-positive thyroid cancer is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. The safety and effectiveness of GAVRETO have not been established in pediatric patients with RET fusion-positive NSCLC or in pediatric patients younger than 12 years old with RET fusion-positive thyroid cancer. Animal Toxicity Data In a 4-week repeat-dose toxicology study in non-human primates, physeal dysplasia in the femur occurred at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. In rats there were findings of increased physeal thickness in the femur and sternum as well as tooth (incisor) abnormalities (fractures, dentin matrix alteration, ameloblast/odontoblast degeneration, necrosis) in both 4- and 13-week studies at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. Recovery was not assessed in the 13-week toxicology study, but increased physeal thickness in the femur and incisor degeneration did not show evidence of complete recovery in the 28-day rat study. Monitor growth plates in adolescent patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment. 8.5 Geriatric Use Of the 540 patients in ARROW who received the recommended dose of GAVRETO at 400 mg once daily, 31% were 65 years or and over, while 7% were 75 years and over. No overall differences in pharmacokinetics (PK), safety or effectiveness were observed between patients aged 65 years or older and younger patients. 8.6 Hepatic Impairment No dose adjustment is required for patients with mild (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST), moderate (total bilirubin > 1.5 to 3 × ULN and any AST) or severe (total bilirubin > 3 × ULN and any AST) hepatic impairment.

Risk Summary Based on findings from animal studies and its mechanism of action, GAVRETO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on GAVRETO use in pregnant women to inform drug-associated risk. 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 (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In an embryo-fetal development study, once daily oral administration of pralsetinib to pregnant rats during the period of organogenesis resulted in 100% post-implantation loss at dose levels ≥ 20 mg/kg (approximately 1.8 times the human exposure based on area under the curve [AUC] at the clinical dose of 400 mg). Post-implantation loss also occurred at the 10 mg/kg dose level (approximately 0.6 times the human exposure based on AUC at the clinical dose of 400 mg). Once daily oral administration of pralsetinib at dose levels ≥ 5 mg/kg (approximately 0.2 times the human AUC at the clinical dose of 400 mg) resulted in an increase in visceral malformations and variations (absent or small kidney and ureter, absent uterine horn, malpositioned kidney or testis, retroesophageal aortic arch) and skeletal malformations and variations (vertebral and rib anomalies and reduced ossification).

The safety and effectiveness of GAVRETO have been established in pediatric patients aged 12 years and older for RET fusion-positive thyroid cancer. Use of GAVRETO in this age group is supported by evidence from an adequate and well-controlled study of GAVRETO in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the pharmacokinetics of pralsetinib, that the exposure of pralsetinib is expected to be similar between adults and pediatric patients age 12 years and older, and that the course of RET fusion-positive thyroid cancer is sufficiently similar in adults and pediatric patients to allow extrapolation of data in adults to pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. The safety and effectiveness of GAVRETO have not been established in pediatric patients with RET fusion-positive NSCLC or in pediatric patients younger than 12 years old with RET fusion-positive thyroid cancer. Animal Toxicity Data In a 4-week repeat-dose toxicology study in non-human primates, physeal dysplasia in the femur occurred at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. In rats there were findings of increased physeal thickness in the femur and sternum as well as tooth (incisor) abnormalities (fractures, dentin matrix alteration, ameloblast/odontoblast degeneration, necrosis) in both 4- and 13-week studies at doses resulting in exposures similar to the human exposure (AUC) at the clinical dose of 400 mg. Recovery was not assessed in the 13-week toxicology study, but increased physeal thickness in the femur and incisor degeneration did not show evidence of complete recovery in the 28-day rat study. Monitor growth plates in adolescent patients with open growth plates. Consider interrupting or discontinuing therapy based on the severity of any growth plate abnormalities and based on an individual risk-benefit assessment.