Zidesamtinib

JIDEYTRO is indicated for the treatment of adult patients with locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC) who received a prior ROS1 kinase inhibitor [see Dosage and Administration ( 2.1 ), Clinical Studies ( 14.1 )] . JIDEYTRO is a kinase inhibitor indicated for the treatment of adult patients with locally advanced or metastatic ROS1 -positive non-small cell lung cancer (NSCLC) who received a prior ROS1 kinase inhibitor.( 1 )

Tablets: 25 mg: pink, oblong, film-coated, debossed with "25" on one side and "ZDS" on the other side. Tablets: 100 mg: yellow, oblong, film-coated, debossed with "100" on one side and "ZDS" on the other side. Tablets: 25 mg and 100 mg.

None. None.

Central Nervous System (CNS) Adverse Reactions (AR): Can cause CNS AR including dizziness, ataxia, cognitive and psychiatric disorders. Based on severity, withhold JIDEYTRO and resume at same or reduced dose, or permanently discontinue. ( 5.1 ) QTc Interval Prolongation: Can cause QTc prolongation. Evaluate ECGs and electrolytes prior to administration of JIDEYTRO and monitor periodically during treatment. Based on severity, withhold JIDEYTRO and resume at the same or reduced dose, or permanently discontinue. ( 5.2 ) Interstitial Lung Disease (ILD)/pneumonitis: Can cause ILD/pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold in patients with suspected ILD/pneumonitis. Based on severity, withhold JIDEYTRO and resume at the same or reduced dose, or permanently discontinue. ( 5.3 ) Skeletal Fractures : Can cause skeletal fractures. Promptly evaluate patients with signs or symptoms of fractures. ( 5.4 ) Myalgia with Creatine Phosphokinase (CPK) Elevation: Can cause CPK elevation. Advise patients to report unexplained muscle pain or tenderness. Monitor serum CPK levels during treatment. Based on severity, withhold JIDEYTRO and resume at same or reduced dose upon recovery to baseline. ( 5.5 ) Pancreatic Toxicity: Evaluate amylase and lipase prior to administration of JIDEYTRO and monitor periodically during treatment. Withhold, dose reduce or permanently discontinue JIDEYTRO based on severity. ( 5.6 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.7 )

5.1 Central Nervous System Adverse Reactions JIDEYTRO can cause central nervous system adverse reactions. In the pooled safety population [see Adverse Reactions ( 6.1) ] , a broad spectrum of central nervous system (CNS) adverse reactions, including dizziness, ataxia, cognitive and psychiatric disorders, occurred in 25% of patients who received JIDEYTRO; of these, 2.5% were Grade 3 or 4. One patient (0.2%) with brain metastases experienced a Grade 3 seizure. Dizziness, including vertigo, presyncope and positional dizziness occurred in 12% of patients who received JIDEYTRO; of these 0.2% were Grade 3. The median time to onset of dizziness was 22 days (range: 1 day to 9 months). Dosage interruption of JIDEYTRO for dizziness was required in 0.4% of patients, and 0.7% of patients required dose reduction. Ataxia, including gait disturbance and balance disorder, occurred in 2% of patients who received JIDEYTRO and were all Grade 1 or 2. The median time to onset of ataxia was 64 days (range: 6 days to 2.5 years). Cognitive impairment occurred in 9% of patients who received JIDEYTRO, of these 1.6% were Grade 3 or 4. Cognitive impairment included memory impairment (3.1%), cognitive disorder (1.6%), hallucination (1.1%), delirium (1.1%), aphasia (0.9%), amnesia (0.7%), confusional state (0.7%), anterograde amnesia (0.2%), disturbance in attention (0.4%), slow speech (0.2%). The median time to onset of cognitive impairment was 43 days (range: 4 days to 1.9 years). Dose interruption of JIDEYTRO for cognitive impairment was required in 1.3% of patients. Psychiatric disorders occurred in 6% of patients who received JIDEYTRO, of these 0.7% were Grade 3 or 4. Psychiatric disorders included anxiety (3.1%), depression (1.3%), agitation (0.7%), affect lability (0.4%), irritability (0.4%), abnormal behavior (0.2%), depressed mood (0.2%), personality change (0.2%), psychotic disorder (0.2%), and suicidal ideation (0.2%). The median time to onset of psychiatric disorders was 57 days (range: 1 day to 10 months). Dosage interruption of JIDEYTRO for psychiatric disorders was required in 0.9% of patients. Advise patients and caregivers of the risk of CNS adverse reactions with JIDEYTRO. Advise patients to avoid engaging in hazardous tasks requiring mental alertness and motor coordination such as operating machinery or driving a motor vehicle if they are experiencing CNS reactions. Monitor patients for CNS adverse reactions and suicidal thoughts and behaviors during treatment with JIDEYTRO. Withhold and then resume at the same or reduced dose upon improvement or permanently discontinue JIDEYTRO based on severity [see Dosage and Administration ( 2.3 )] . 5.2 QTc Interval Prolongation JIDEYTRO can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. JIDEYTRO has not been studied in patients with a history of QTcF >450 msec on more than one assessment prior to initiation. In the pooled safety population [see Adverse Reactions ( 6.1 )], of the 435 patients who underwent at least one post baseline electrocardiogram (ECG) assessment, 2% experienced an increase in QTcF of >60 msec compared to baseline after receiving JIDEYTRO and 0.2% increase in QTcF to >500 msec. The median time from the first dose of JIDEYTRO to the onset of QTc prolongation was 15 days (range: 1 day to approximately 1 month). QTc prolongation led to dose interruption in 0.4% of patients who received JIDEYTRO. Evaluate ECGs and electrolytes prior to administration of JIDEYTRO and monitor periodically during treatment. Adjust the frequency of monitoring based on risk factors such as known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure, and concomitant medications associated with QTc interval prolongation. Withhold, then resume at the same or reduced dose, or permanently discontinue JIDEYTRO based on severity [see Dosage and Administration ( 2.3 )] .

5.3 Interstitial Lung Disease/Pneumonitis JIDEYTRO can cause severe or life-threatening interstitial lung disease (ILD) or pneumonitis. In the pooled safety population [see Adverse Reactions ( 6.1 )] , interstitial lung disease (ILD)/pneumonitis occurred in 1.8% of patients treated with JIDEYTRO, including Grade 3 or 4 in 0.4%. The median time to first onset of ILD/pneumonitis was 4.5 months (range: 8 days to 11 months). ILD/pneumonitis led to dose interruption of JIDEYTRO in 0.7% of patients. ILD/pneumonitis required dose reduction in 0.2% of patients and permanent discontinuation of JIDEYTRO in 0.4% of patients. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold JIDEYTRO in patients with suspected ILD/pneumonitis, then upon recovery resume at the same or reduced dose or permanently discontinue based on severity [see Dosage and Administration ( 2.3 )].

5.4 Skeletal Fractures JIDEYTRO can increase the risk of skeletal fractures. In the pooled safety population [see Adverse Reactions ( 6.1 )] , 5 patients (1.1%) experienced skeletal fractures, and Grade 3 ankle fractures occurred in two patients (0.4%) who received JIDEYTRO. Some fractures occurred in the setting of an accidental fall or other predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions. The median time to fracture was 48 days (range: 32 days to approximately 6 months). JIDEYTRO was interrupted in 0.4% of patients for fractures.

5.5 Myalgia with Creatine Phosphokinase Elevation JIDEYTRO can cause myalgia with creatine phosphokinase (CPK) elevation. In the pooled safety population [see Adverse Reactions ( 6.1 )] , myalgia occurred in 13% of patients who received JIDEYTRO. Based on laboratory values, concurrent myalgia with increased CPK occurred in 2.1% of patients. The median time to onset of myalgia for these patients with CPK elevation was 2 months (range: 8 days to 6 months). Advise patients to report unexplained muscle pain or tenderness. Monitor serum CPK levels prior to administration of JIDEYTRO and every 2 weeks during the first month of treatment and then every 1 to 2 months and as clinically indicated in patients reporting unexplained muscle pain or tenderness. […]

The following clinically significant adverse reactions are described elsewhere in the labeling: Central Nervous System Adverse Reactions [see Warnings and Precautions ( 5.1 )] QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions ( 5.3 )] Skeletal Fractures [see Warnings and Precautions ( 5.4 )] Myalgia with Creatine Phosphokinase Elevation [see Warnings and Precautions ( 5.5 )] Pancreatic Toxicity [see Warnings and Precautions ( 5.6 )] Most common adverse reactions (≥15%) were: edema, peripheral neuropathy, constipation, fatigue, and dyspnea. ( 6.1 ) Most common Grade 3 or 4 laboratory abnormalities (≥2%) were: increased CPK, increased triglycerides, decreased lymphocytes and decreased hemoglobin. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Nuvalent, Inc. at toll-free phone 1-844-NUVL-111 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 described in WARNINGS AND PRECAUTIONS reflects exposure to JIDEYTRO in 446 patients with ROS1-positive NSCLC (n=432) and other solid tumors (n=14) who received JIDEYTRO at a dose of 100 mg orally once daily until disease progression or unacceptable toxicity in ARROS-1 [see Clinical Studies ( 14.1 )] . Among 446 patients who received JIDEYTRO, 44% were exposed for 6 months or longer and 14% were exposed for greater than one year. In this pooled safety population, the most common (≥15%) adverse reactions included: edema (38%), peripheral neuropathy (25%), constipation (17%), fatigue (16%), dyspnea (15%). The most common Grade 3 or 4 laboratory abnormalities (≥2%), were increased lipase (8%), increased creatine phosphokinase (CPK) (4%), increased triglycerides (3.5%), decreased lymphocytes (2.7%), and decreased hemoglobin (2.3%). Previously Treated ROS1-positive NSCLC The safety of JIDEYTRO was evaluated in ARROS-1 [see Clinical Studies ( 14.1 )] . Patients received JIDEYTRO 100 mg orally once daily until disease progression or unacceptable toxicity. Among the 432 patients who received JIDEYTRO, 44% were exposed to JIDEYTRO for 6 months or longer, and 15% were exposed for greater than 1 year. The median age of patients who received JIDEYTRO was 58 years (range: 26 to 87); 62% female; 41% White, 41% Asian, 3.7% Black or African American, 0.2% American Indian or Alaska Native, 14% other races, multiple races or race unknown, and 4.6% of patients were of Hispanic or Latino ethnicity. Serious adverse reactions occurred in 22% of patients who received JIDEYTRO. Serious adverse reactions in ≥2% of patients included pneumonia (6%) and dyspnea (2.5%). Fatal adverse reactions occurred in 2.3% of patients who received JIDEYTRO, including pneumonia (0.5%), cerebrovascular accident (0.2%), COVID-19 (0.2%), dyspnea (0.2%), infectious pleural effusion (0.2%), influenza (0.2%), myocardial infarction (0.2%), myocarditis (0.2%), and respiratory failure (0.2%). Permanent discontinuation of JIDEYTRO due to an adverse reaction occurred in 2.3% of patients. Adverse reactions resulting in permanent discontinuation of JIDEYTRO occurring in ≥2 patients were pneumonia (0.7%) and pneumonitis (0.5%). Dosage interruptions of JIDEYTRO due to an adverse reaction occurred in 30% of patients. Adverse reactions which required dosage interruption in ≥1% of patients included pneumonia (4.6%), increased creatine phosphokinase level (3.0%), peripheral neuropathy (1.9%), peripheral edema (1.6%), COVID-19 (1.4%), and dyspnea and elevated alanine aminotransferase level (each in 1.2%). Dose reductions of JIDEYTRO due to an adverse reaction occurred in 10% of patients. Adverse reactions which required dosage reduction in ≥1% of patients included peripheral edema (1.9%) and peripheral neuropathy (1.2%). Table 3 summarizes the adverse reactions that occurred in the ARROS-1 trial. Table 3: Adverse Reactions (≥10%) in Patients with ROS1-Positive NSCLC Who Received JIDEYTRO in ARROS-1 1 Based on NCI CTCAE v5.0 *Grouped term Adverse Reaction 1 JIDEYTRO N=432 All Grades (%) Grade 3 or 4 (%) General Disorders Edema* 36

0.7 Fatigue* 16

0.7 Nervous System Disorders Peripheral neuropathy * 25

0.9 Dysgeusia * 15 0 Dizziness * 12

0.2 Headache 12

0.2 Gastrointestinal disorders Constipation 17 0 Diarrhea* 11

0.5 Respiratory, thoracic, and mediastinal disorders Dyspnea* 15 3 Cough* 13 0 Musculoskeletal and connective tissue disorders Myalgia* 13 0 Arthralgia 11

0.7 Skin and subcutaneous tissue disorders Rash* 12

0.5 Eye disorders Vision disorders* 12 0 Infections Pneumonia* 11 6 Clinically relevant adverse reactions in <10% of patients receiving JIDEYTRO were cognitive disorders, psychiatric disorders, stomatitis, ataxia, ILD/pneumonitis, QTc prolongation, pancreatitis, and ankle fracture. Table 4 summarizes the laboratory abnormalities in ARROS-1. Table 4: Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with ROS1-Positive NSCLC Who Received JIDEYTRO in ARROS-1 1 Based on NCI CTCAE v5.0 2 The denominator used to calculate the rate varied from 37 to 429 based on the number of patients with a baseline value and at least one post-baseline treatment value. Laboratory Abnormality 1 JIDEYTRO 2 All Grades (%) Grade 3 or 4 (%) Lipid Profile Cholesterol increased 47

1.5 Triglycerides increased 47

3.7 Chemistry Creatine phosphokinase increased 37 4 Aspartate aminotransferase increased 30

0.9 Lipase increased 26 8 Alanine aminotransferase increased 23

1.2 Amylase increased 23 0 Alkaline phosphatase increased 21 0 Hematology Hemoglobin decreased 30

2.1 Eosinophils increased 27 0

Strong and Moderate CYP3A Inhibitors: Avoid concomitant use. ( 7.1 ) Strong and Moderate CYP3A Inducers: Avoid concomitant use. ( 7.1 )

7.1 Effects of Other Drugs on JIDEYTRO Strong and Moderate CYP3A Inhibitors Avoid concomitant use of JIDEYTRO with a strong or moderate CYP3A inhibitor. Zidesamtinib is a CYP3A substrate. Concomitant use with a strong or moderate CYP3A inhibitor increases zidesamtinib exposure [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of JIDEYTRO adverse reactions. Strong and Moderate CYP3A Inducers Avoid concomitant use of JIDEYTRO with strong or moderate CYP3A inducers. Concomitant use of JIDEYTRO with a strong or moderate CYP3A inducer may decrease zidesamtinib exposure [see Clinical Pharmacology ( 12.3 )], which may decrease the effectiveness of JIDEYTRO.

8 USE IN SPECIFIC POPUTLATIONS Lactation : Advise not to breastfeed. ( 8.2 ) Infertility: May impair fertility. ( 8.3 )

8.1 Pregnancy Risk Summary Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies and its mechanism of action [see Clinical Pharmacology ( 12.1 )] , JIDEYTRO can cause fetal harm when administered to a pregnant woman. There are no available data on JIDEYTRO use in pregnant women to inform a drug-associated risk. Oral administration of zidesamtinib to pregnant rats during the period of organogenesis resulted in embryo-fetal mortality, alterations to growth, and structural abnormalities at maternal exposures approximately equivalent to the human exposure at the recommended dose based on AUC ( 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% to 4% and 15% to 20%, respectively. Data Human Data Published reports of individuals with congenital mutations in TRK pathway proteins suggest that decreases in TRK mediated signaling are correlated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis. Animal Data In an embryo-fetal development study, pregnant rats received oral doses of 3, 8, or 30 mg/kg/day of zidesamtinib during the period of organogenesis (gestation day 6 to 17). Zidesamtinib caused decreased fetal body weight, visceral malformations (absent kidneys and ureter), and an increase in the incidence of skeletal variations, including misshapen sternebra and cervical arch and incomplete ossification of the sternebra and thoracic centrum at 3 mg/kg/day (approximately 1.4 times the human exposure at the recommended dose based on AUC). Zidesamtinib resulted in complete litter resorption (post-implantation loss) at doses ≥8 mg/kg/day (approximately ≥3.5 times the human exposure at the recommended dose based on AUC).

8.2 Lactation Risk Summary There are no data on the presence of JIDEYTRO in human milk or their effects on either a 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 JIDEYTRO and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential JIDEYTRO can cause fetal harm when administered to a pregnant woman [ see Use in Specific Populations ( 8.1 ) ]. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating JIDEYTRO [ see Use in Specific Populations ( 8.1 ) ]. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with JIDEYTRO and for 6 months after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with JIDEYTRO and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 ) ] . Infertility Based on findings from animal studies, JIDEYTRO may impair fertility in males and females. The effects on male fertility were reversible. The reversibility of the effect on fertility in females is unknown [see Nonclinical Toxicology ( 13.1 ) ].

8.4 Pediatric Use The safety and effectiveness of JIDEYTRO in pediatric patients has not been established. Juvenile Animal Data Daily oral administration of zidesamtinib to juvenile rats from postnatal day 7 to 28 (approximately equal to a human pediatric age of a neonate to child) resulted in ocular toxicity, including hemorrhage, corneal ulcers, rupture, and vision loss at 8 mg/kg/day (approximately 2.4 times the human exposure based on AUC at the recommended dose).

8.5 Geriatric Use Of the 446 patients who received JIDEYTRO, 21.5% were 65 to 74 years old, and 8% were 75 years of age or older. There were no clinically meaningful differences in safety and efficacy between patients younger than 65 years of age and patients 65 years of age or older.

8.6 Renal Impairment The effect of severe renal impairment (eGFR <30 mL/min) or dialysis on zidesamtinib pharmacokinetics is unknown. No dosage modification is recommended for patients with eGFR 30 to 90 mL/min [see Clinical Pharmacology ( 12.3 )] .

8.7 Hepatic Impairment The effect of severe hepatic impairment (total bilirubin >3 times ULN with any AST) on the zidesamtinib pharmacokinetics is unknown. No dosage modification is recommended for patients with mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) or moderate (total bilirubin >1.5 to 3 times ULN with any AST) hepatic impairment [see Clinical Pharmacology ( 12.3 )] .

Zidesamtinib is an inhibitor of tyrosine kinase ROS1, including ROS1 resistance mutations. In a biochemical assay, zidesamtinib inhibited ROS1 (IC 50 = 0.7 nM) and also showed inhibitory effects on ALK (IC 50 = 3 nM) and tropomyosin receptor kinases (TRKs), TRKB (IC 50 = 54 nM), TRKC (IC 50 = 193 nM) and TRKA (IC 50 = 258 nM). In vitro, zidesamtinib inhibited the viability of cultured cells expressing ROS1 fusion genes and resistance mutations (G2032R, S1986F, F2004C/V, L2026M, D2033N, and G2101A). In mice subcutaneously implanted with tumors harboring ROS1 fusions, including the G2032R mutation, administration of zidesamtinib resulted in tumor growth inhibition. Zidesamtinib had antitumor activity in an intracranial NSCLC xenograft model harboring a ROS1 fusion.