JIDEYTRO

1 INDICATIONS AND USAGE 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 )

2 DOSAGE AND ADMINISTRATION Recommended Dosage : 100 mg orally once daily with or without food until disease progression or unacceptable toxicity. ( 2.2 ) 2.1 Recommended Testing and Evaluation Before Initiating JIDEYTRO Before initiating JIDEYTRO, evaluate creatine phosphokinase (CPK) level, electrocardiogram (ECG), electrolytes, lipase and amylase [see Warnings and Precautions ( 5.2 , 5.5 , 5.6 )] . 2.2 Recommended Dosage The recommended dosage of JIDEYTRO is 100 mg taken orally once daily, with or without food, until disease progression or unacceptable toxicity [see Clinical Pharmacology ( 12.3 )] . Swallow JIDEYTRO tablets whole. Do not split, chew, crush, or dissolve the tablet prior to swallowing. Missed Dose If a dose of JIDEYTRO is missed within 12 hours of the regularly scheduled dose, administer the missed dose as soon as possible. If a dose is missed by 12 hours or more, take the next dose at its scheduled time. Vomiting If vomiting occurs at any time after taking JIDEYTRO, take the next dose at its scheduled time. 2.3 Dosage Modifications of JIDEYTRO for Adverse Reactions The recommended dosage reductions of JIDEYTRO for the management of adverse reactions are provided in Table 1 . Table 1: Recommended Dose Reductions for JIDEYTRO Adverse Reactions Dose Reduction Recommended Dose and Schedule First 75 mg once daily Second 50 mg once daily Permanently discontinue JIDEYTRO in patients unable to tolerate 50 mg once daily. After dose reduction of JIDEYTRO for adverse reactions, do not re-escalate the dose. The recommended dosage modifications of JIDEYTRO for the management of adverse reactions are provided in Table 2 . Table 2: Recommended Dosage Modifications for JIDEYTRO Adverse Reactions *Graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. Adverse Reaction Severity* Dosage Modification Central Nervous System Adverse Reactions [see Warnings and Precautions (5.1)] Intolerable Grade 2 Withhold JIDEYTRO until Grade ≤ 1 or baseline. Resume JIDEYTRO at same or reduced dose, as clinically appropriate. Grade 3 Withhold JIDEYTRO until Grade ≤ 1 or baseline. Resume JIDEYTRO at reduced dose. Grade 4 Permanently discontinue JIDEYTRO. QTc Interval Prolongation [see Warnings and Precautions ( 5.2 )] Grade 2 (QTc interval 481-500 msec) Withhold JIDEYTRO until recovery to Grade ≤ 1 or baseline. Correct electrolytes and/or change concomitant medications. Resume JIDEYTRO at same dose. Grade 3 (QTc interval ≥501 msec or QTc interval increase of >60 msec from baseline) Withhold JIDEYTRO until recovery to Grade ≤ 1 or baseline. Correct electrolytes and/or change concomitant medications. Resume JIDEYTRO at a reduced dose. Grade 4 (Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia) Permanently discontinue JIDEYTRO. Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.3)] Grade 1 Withhold JIDEYTRO if ILD/pneumonitis occurs or is suspected until recovery to Grade 0. If resolved within 6 weeks, resume JIDEYTRO at the same dose. If unresolved after 6 weeks, permanently discontinue JIDEYTRO. Recurrence: Permanently discontinue JIDEYTRO. Grade 2 Withhold JIDEYTRO if ILD/pneumonitis occurs or is suspected until recovery to Grade 0 or baseline. If resolved within 6 weeks, resume JIDEYTRO at a reduced dose. If unresolved after 6 weeks, permanently discontinue JIDEYTRO. Recurrence: Permanently discontinue JIDEYTRO. Grade 3 or 4 Permanently discontinue JIDEYTRO. Creatine Phosphokinase (CPK) Elevation [see Warnings and Precautions (5.5)] CPK elevation > 5 times ULN Withhold JIDEYTRO until recovery to baseline or ≤ 2.5 times ULN, then resume JIDEYTRO at same dose. CPK elevation > 10 times ULN or Recurrence of CPK elevation of >5 times ULN Withhold until recovery to baseline or ≤2.5 times ULN, then resume JIDEYTRO at a reduced dose. Increased lipase or amylase [see Warnings and Precautions (5.6)] Grade 3 Withhold JIDEYTRO until …

3 DOSAGE FORMS AND STRENGTHS 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.

4 CONTRAINDICATIONS None. None.

6 ADVERSE REACTIONS 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 r …

7 DRUG INTERACTIONS 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 betw …

12.1 Mechanism of Action 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.

11 DESCRIPTION Zidesamtinib is a kinase inhibitor. The molecular formula for zidesamtinib is C 22 H 22 FN 7 O and the molecular weight is 419.46 Daltons. The chemical name is ( R )-3-Ethyl-16-fluoro-10-methyl-19-methyl-20-oxa-3,4,9,10,11,23-hexaazapentacyclo[19.3.1.0 2,6 .0 8,12 .0 13,18 ]pentacosa-1(24),2(6),4,8,11,13,15,17,21(25),22-decaen-22-ylamine. The chemical structure of zidesamtinib is as follows: Zidesamtinib is a white to tan powder with a pKa of 4.89. The aqueous solubility of zidesamtinib at 37°C is pH dependent, decreasing from 25 mg/mL at pH 2.5 to less than 0.1 mg/mL at pH 7.9. The log of the distribution coefficient (octanol/water) at pH 7.4 is 3.01. JIDEYTRO (zidesamtinib) tablets for oral use are supplied as 25 mg and 100 mg dosage strengths. JIDEYTRO tablets, 25 mg are film-coated, oblong, pink tablets, debossed with "25" on one side and "ZDS" on the other side of the tablet. JIDEYTRO tablets, 100 mg are film-coated, oblong, yellow tablets, debossed with "100" on one side and "ZDS" on the other side of the tablet. Inactive ingredients in the tablet core are hydroxypropyl cellulose, magnesium stearate, mannitol, microcrystalline cellulose and sodium starch glycolate. The 25 mg tablet pink film coating contains the inactive ingredients hypromellose, red iron oxide, titanium dioxide, triacetin, and yellow iron oxide. The 100 mg tablet yellow film coating contains the inactive ingredients hypromellose, titanium dioxide, triacetin, and yellow iron oxide. Zidesamtinib Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied JIDEYTRO (zidesamtinib) is supplied as follows: Tablet Strength Package Configuration Description NDC 25 mg Bottle of 30 tablets packaged in a carton Pink oblong film-coated tablet, with "25" debossed on one side and "ZDS" on the other side 85001-101-01 100 mg Bottle of 30 tablets packaged in a carton Yellow oblong film-coated tablet, with "100" debossed on one side and "ZDS" on the other side 85001-102-01 Storage and Handling Store JIDEYTRO at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature] .