TUKYSA

Indications and Usage ( 1.2 ) 1/2023 Patient Selection ( 2.1 ) 1/2023 Warnings and Precautions ( 5.1 ), ( 5.2 ) 1/2023

1 INDICATIONS AND USAGE TUKYSA is a kinase inhibitor indicated: • in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. ( 1.1 ) • in combination with trastuzumab for the treatment of adult patients with RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. ( 1.2 ) This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 1.1 Metastatic Breast Cancer TUKYSA is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting. 1.2 Unresectable or Metastatic Colorectal Cancer TUKYSA is indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response [see Clinical Studies (14.2) ]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

2 DOSAGE AND ADMINISTRATION • In patients with unresectable or metastatic colorectal cancer, confirm the presence of HER2 protein overexpression and RAS wild-type in tumor specimens prior to the initiation of TUKYSA ( 2.1 ) • Recommended dosage: 300 mg taken orally twice daily with or without food. ( 2.1 ) • For patients with severe hepatic impairment, the recommended dosage is 200 mg orally twice daily. ( 2.3 , 8.7 ) 2.1 Patient Selection Select patients for treatment of unresectable or metastatic colorectal cancer with TUKYSA based on the presence of: • HER2 overexpression or gene amplification [see Clinical Studies (14.2) ]. FDA-approved tests for the detection of HER2 overexpression and gene amplification in patients with unresectable or metastatic colorectal cancer are not currently available, and • RAS wild-type [see Clinical Studies (14.2) ]. Information on FDA-approved tests for the detection of RAS mutations in patients with unresectable or metastatic colorectal cancer is available at http://www.fda.gov/CompanionDiagnostics . 2.2 Recommended Dosage Metastatic Breast Cancer The recommended dosage of TUKYSA is 300 mg taken orally twice daily in combination with trastuzumab and capecitabine until disease progression or unacceptable toxicity [see Clinical Studies (14.1) ] . Unresectable or Metastatic Colorectal Cancer The recommended dosage of TUKYSA is 300 mg taken orally twice daily in combination with trastuzumab until disease progression or unacceptable toxicity [see Clinical Studies (14.2) ]. Advise patients to swallow TUKYSA tablets whole and not to chew, crush, or split prior to swallowing. Advise patients not to ingest tablet if it is broken, cracked, or not otherwise intact. Advise patients to take TUKYSA approximately 12 hours apart and at the same time each day with or without a meal. If the patient vomits or misses a dose of TUKYSA, instruct the patient to take the next dose at its usual scheduled time. When given in combination with TUKYSA, the recommended dosage of capecitabine is 1000 mg/m 2 orally twice daily taken within 30 minutes after a meal. TUKYSA and capecitabine can be taken at the same time. Refer to the Full Prescribing Information for trastuzumab and capecitabine for additional information. 2.3 Dosage Modifications for Adverse Reactions The recommended TUKYSA dose reductions and dosage modifications for adverse reactions are provided in Tables 1 and 2. Refer to the Full Prescribing Information for trastuzumab and capecitabine for information about dosage modifications for these drugs. Table 1: Recommended TUKYSA Dose Reductions for Adverse Reactions Dose Reduction Recommended TUKYSA Dosage First 250 mg orally twice daily Second 200 mg orally twice daily Third 150 mg orally twice daily Permanently discontinue TUKYSA in patients unable to tolerate 150 mg orally twice daily. Table 2: Recommended TUKYSA Dosage Modifications for Adverse Reactions Adverse Reaction Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 Severity TUKYSA Dosage Modification Diarrhea [see Warnings and Precautions (5.1) ] Grade 3 without anti-diarrheal treatment Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the same dose level. Grade 3 with anti-diarrheal treatment Initiate or intensify appropriate medical therapy. Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the next lower dose level. Grade 4 Permanently discontinue TUKYSA. Hepatotoxicity Abbreviations: ULN = upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase [see Warnings and Precautions (5.2) ] Grade 2 bilirubin (>1.5 to 3 × ULN) Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the same dose level. Grade 3 ALT or AST (> 5 to 20 × ULN) OR Grade 3 bilirubin (> 3 to 10 × ULN) Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the next lower dose level. Grade 4 ALT or AST (> 20 × UL …

3 DOSAGE FORMS AND STRENGTHS Tablets: • 50 mg: round, yellow, film-coated, debossed with “TUC” on one side and “50” on the other side. • 150 mg: oval-shaped, yellow, film-coated, debossed with “TUC” on one side and “150” on the other side. Tablets: 50 mg and 150 mg. ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Diarrhea [see Warnings and Precautions (5.1) ] • Hepatotoxicity [see Warnings and Precautions (5.2) ] • The most common adverse reactions (≥20%) with TUKYSA in combination with trastuzumab and capecitabine in patients with metastatic breast cancer are diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, and rash. ( 6.1 ) • The most common adverse reactions (≥20%) with TUKYSA in combination with trastuzumab in patients with unresectable or metastatic colorectal cancer are diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. To report SUSPECTED ADVERSE REACTIONS, contact Seagen at 1-855-4SEAGEN 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. HER2-Positive Metastatic Breast Cancer The safety of TUKYSA in combination with trastuzumab and capecitabine was evaluated in HER2CLIMB [see Clinical Studies (14) ]. Patients received either TUKYSA 300 mg twice daily plus trastuzumab or a non-US approved trastuzumab product, and capecitabine (n=404) or placebo plus trastuzumab or a non-US approved trastuzumab product and capecitabine (n=197). The median duration of treatment was 5.8 months (range: 3 days, 2.9 years) for the TUKYSA arm. Serious adverse reactions occurred in 26% of patients who received TUKYSA. Serious adverse reactions in ≥ 2% of patients who received TUKYSA were diarrhea (4%), vomiting (2.5%), nausea (2%), abdominal pain (2%), and seizure (2%). Fatal adverse reactions occurred in 2% of patients who received TUKYSA including sudden death, sepsis, dehydration, and cardiogenic shock. Adverse reactions leading to treatment discontinuation occurred in 6% of patients who received TUKYSA. Adverse reactions leading to treatment discontinuation of TUKYSA in ≥1% of patients were hepatotoxicity (1.5%) and diarrhea (1%). Adverse reactions leading to dose reduction occurred in 21% of patients who received TUKYSA. Adverse reactions leading to dose reduction of TUKYSA in ≥2% of patients were hepatotoxicity (8%) and diarrhea (6%). The most common adverse reactions in patients who received TUKYSA (≥20%) were diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, and rash. Table 3 summarizes the adverse reactions in HER2CLIMB. Table 3: Adverse Reactions (≥10%) in Patients Who Received TUKYSA and with a Difference Between Arms of ≥ 5% Compared to Placebo in HER2CLIMB (All Grades) Adverse Reaction TUKYSA + Trastuzumab + Capecitabine N = 404 Placebo + Trastuzumab + Capecitabine N = 197 All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Gastrointestinal disorders Diarrhea 81 12 0.5 53 9 0 Nausea 58 3.7 0 44 3 0 Vomiting 36 3 0 25 3.6 0 Stomatitis Stomatitis includes stomatitis, oropharyngeal pain, oropharyngeal discomfort, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue blistering, lip blister, oral dysesthesia, tongue ulceration, and aphthous ulcer 32 2.5 0 21 0.5 0 Skin and subcutaneous tissue disorders Palmar-plantar erythrodysesthesia syndrome 63 13 0 53 9 0 Rash Rash includes rash maculo-papular, rash, dermatitis acneiform, erythema, rash macular, rash papular, rash pustular, rash pruritic, rash erythematous, skin exfoliation, urticaria, dermatitis allergic, palmar erythema, plantar erythema, skin toxicity, and dermatitis 20 0.7 0 15 0.5 0 Hepatobiliary disorders Hepatotoxicity Hepatotoxicity includes hyperbilirubinemia, blood bilirubin increased, bilirubin conjugated increased, alanine aminotransferase increased, transaminases increased, …

7 DRUG INTERACTIONS • Strong CYP3A Inducers or Moderate CYP2C8 Inducers : Avoid concomitant use. ( 7.1 ) • Strong CYP2C8 Inhibitors : Avoid concomitant use; reduce TUKYSA dose if concomitant use cannot be avoided. ( 2.4 , 7.1 ) • CYP3A Substrates : Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. ( 7.2 ) • P-gp Substrates : Consider reducing the dose of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. ( 7.2 ) 7.1 Effects of Other Drugs on TUKYSA Table 7 summarizes the effect of other drugs on TUKYSA. Table 7: Drug Interactions that Affect TUKYSA Strong CYP3A Inducers or Moderate CYP2C8 Inducers Clinical Impact Concomitant use of TUKYSA with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may reduce TUKYSA activity. Management Avoid concomitant use of TUKYSA with a strong CYP3A inducer or a moderate CYP2C8 inducer. Strong or Moderate CYP2C8 Inhibitors Clinical Impact Concomitant use of TUKYSA with a strong CYP2C8 inhibitor increased tucatinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of TUKYSA toxicity. Management Avoid concomitant use of TUKYSA with a strong CYP2C8 inhibitor. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors. 7.2 Effects of TUKYSA on Other Drugs Table 8 summarizes the effect of TUKYSA on other drugs. Table 8: TUKYSA Drug Interactions that Affect Other Drugs CYP3A Substrates Clinical Impact Concomitant use of TUKYSA with a CYP3A substrate increased the plasma concentrations of CYP3A substrate [see Clinical Pharmacology (12.3) ] , which may increase the toxicity associated with a CYP3A substrate. Management Avoid concomitant use of TUKYSA with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage in accordance with approved product labeling. P-glycoprotein (P-gp) Substrates Clinical Impact Concomitant use of TUKYSA with a P-gp substrate increased the plasma concentrations of P-gp substrate [see Clinical Pharmacology (12.3) ] , which may increase the toxicity associated with a P-gp substrate. Management Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy information. Based on findings in animals and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available human data on TUKYSA use in pregnant women to inform a drug-associated risk. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures ≥ 1.3 times the human exposure (AUC) at the recommended dose (see Data ) . Advise pregnant women and females of reproductive potential of the potential risk to the fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. 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 pilot embryo-fetal development studies, pregnant rats and rabbits received oral doses of tucatinib up to 150 mg/kg/day during the period of organogenesis. In rats, oral administration of tucatinib resulted in maternal toxicity (body weight loss, reduced body weight gain, low food consumption) at doses ≥ 90 mg/kg/day. Fetal effects included reduced number of live fetuses, decreased fetal weight, and fetal abnormalities (increase in skeletal variations, incomplete ossification) at ≥ 90 mg/kg/day (approximately 3.5 times the human exposure at the recommended dose based on AUC). In rabbits, oral administration of tucatinib resulted in increased resorptions, decreased percentages of live fetuses, and skeletal, visceral, and external malformations in fetuses at doses ≥ 90 mg/kg/day (1.3 times the human exposure at the recommended dose based on AUC). Fetal abnormalities included domed head, brain dilation, incomplete ossification of frontal and parietal bones, and a hole in the parietal bone. 8.2 Lactation Risk Summary TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for lactation information. There are no data on the presence of tucatinib or its metabolites in human or animal milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with TUKYSA and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential TUKYSA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for contraception and infertility information. Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating treatment with TUKYSA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose. Infertility Based on findings from animal studies, TUKYSA may impair male and female fertility [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use The safety and effectiveness of TUKYSA in pediatric patients have not been established. 8.5 Geriatric Use In HER2CLIMB, 82 patients who received TUKYSA were ≥ 65 years, of whom 8 patients were ≥ 75 years. The incidence of serious adverse reactions in those receiving TUKYSA was 34% in patients ≥ 65 years compared to 24% in …

12.1 Mechanism of Action Tucatinib is a tyrosine kinase inhibitor of HER2. In vitro, tucatinib inhibits phosphorylation of HER2 and HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, and showed anti-tumor activity in HER2 expressing tumor cells. In vivo, tucatinib inhibited the growth of HER2 expressing tumors. The combination of tucatinib and trastuzumab showed increased anti-tumor activity in vitro and in vivo compared to either drug alone.

11 DESCRIPTION Tucatinib is a kinase inhibitor. The chemical name is (N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine. The molecular formula is C 26 H 24 N 8 O 2 and the molecular weight is 480.52 g/mol. The chemical structure is as follows: TUKYSA (tucatinib) is supplied as 50 mg and 150 mg film-coated tablets for oral use and contain the following inactive ingredients: Tablet core: copovidone, crospovidone, sodium chloride, potassium chloride, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose. Coating: yellow film coat: polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, and yellow iron oxide non-irradiated. Each TUKYSA 50 mg tablet contains 10.10 mg (0.258 mEq) potassium and 9.21 mg (0.401 mEq) sodium. Each TUKYSA 150 mg tablet contains 30.29 mg (0.775 mEq) potassium and 27.64 mg (1.202 mEq) sodium. structural formula

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TUKYSA 50 mg tablets are supplied as yellow, film-coated, round tablets containing 50 mg of tucatinib. Each tablet is debossed with “TUC” on one side and “50” on the other side, and is packaged as follows: 50 mg tablets: 60 count in 75 cc bottle: NDC 51144-001-60 TUKYSA 150 mg tablets are supplied as yellow, film-coated, oval-shaped tablets containing 150 mg of tucatinib. Each tablet is debossed with “TUC” on one side and “150” on the other side, and is packaged as follows: 150 mg tablets: 60 count in 75 cc bottle: NDC 51144-002-60 150 mg tablets: 120 count in 150 cc bottle: NDC 51144-002-12 Store at controlled room temperature, 20oC to 25oC (68oF to 77oF); excursions permitted from 15oC to 30oC (59oF to 86oF) [see USP Controlled Room Temperature]. Dispense to patient in original container only. Store in original container to protect from moisture. Replace cap securely each time after opening. Do not discard desiccant. Once opened, use within 3 months. Discard any unused tablets 3 months after opening the bottle.