TUKYSA (tucatinib 150 mg) Dailymed

Generic: tucatinib is used for the treatment of Breast Neoplasms

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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.

Recent Major Changes Section

Indications and Usage (1.2) 1/2023

Patient Selection (2.1) 1/2023

Warnings and Precautions (5.1), (5.2) 1/2023

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/m² 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
1. Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.032. Abbreviations: ULN = upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase

Adverse Reaction¹ 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.

Hepatotoxicity² [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 × ULN) OR Grade 4 bilirubin (> 10 × ULN) Permanently discontinue TUKYSA.

ALT or AST > 3 × ULN AND Bilirubin > 2 × ULN Permanently discontinue TUKYSA.

Other adverse reactions [see Adverse Reactions (6.1)] Grade 3 Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the next lower dose level.

Grade 4 Permanently discontinue TUKYSA.

2.4 Dosage Modifications for Severe Hepatic Impairment

For patients with severe hepatic impairment (Child-Pugh C), reduce the recommended dosage to 200 mg orally twice daily [ see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

2.5 Dosage Modifications for Concomitant Use with Strong CYP2C8 Inhibitors

Avoid concomitant use of strong CYP2C8 inhibitors with TUKYSA. If concomitant use with a strong CYP2C8 inhibitor cannot be avoided, reduce the recommended dosage to 100 mg orally twice daily. After discontinuation of the strong CYP2C8 inhibitor for 3 elimination half-lives, resume the TUKYSA dose that was taken prior to initiating the inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

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

Table 2: Recommended TUKYSA Dosage Modifications for Adverse Reactions
1. Grades based on National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.032. Abbreviations: ULN = upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase
Adverse Reaction¹	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.
Hepatotoxicity² [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 × ULN) OR Grade 4 bilirubin (> 10 × ULN)	Permanently discontinue TUKYSA.
ALT or AST > 3 × ULN AND Bilirubin > 2 × ULN	Permanently discontinue TUKYSA.
Other adverse reactions [see Adverse Reactions (6.1)]	Grade 3	Hold TUKYSA until recovery to ≤ Grade 1, then resume TUKYSA at the next lower dose level.
	Grade 4	Permanently discontinue TUKYSA.

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)

5 Warnings And Precautions

Diarrhea: Severe diarrhea, including dehydration, acute kidney injury, and death, has been reported. Administer antidiarrheal treatment as clinically indicated. Interrupt dose, then dose reduce, or permanently discontinue TUKYSA based on severity. (2.2, 5.1)

Hepatotoxicity: Severe hepatotoxicity has been reported on TUKYSA. Monitor ALT, AST and bilirubin prior to starting TUKYSA, every 3 weeks during treatment and as clinically indicated. Interrupt dose, then dose reduce, or permanently discontinue TUKYSA based on severity. (2.2, 5.2)

Embryo-Fetal Toxicity: TUKYSA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.3, 8.1, 8.3)Also, refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.

5.1 Diarrhea

TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death [see Adverse Reactions (6.1)].

If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA [ see Dosage and Administration (2.2)].

TUKYSA with trastuzumab and capecitabine

In HER2CLIMB, 81% of patients who received TUKYSA experienced diarrhea, including 0.5% with Grade 4 diarrhea and 12% with Grade 3 diarrhea. Both patients who developed Grade 4 diarrhea subsequently died, with diarrhea as a contributor to death. The median time to onset of the first episode of diarrhea was 12 days and the median time to resolution was 8 days. Diarrhea led to dose reductions of TUKYSA in 6% of patients and discontinuation of TUKYSA in 1% of patients. Prophylactic use of antidiarrheal treatment was not required on HER2CLIMB.

TUKYSA with trastuzumab

In MOUNTAINEER, diarrhea occurred in 64% of patients, including Grade 3 (3.5%), Grade 2 (10%), and Grade 1 (50%).

5.2 Hepatotoxicity

TUKYSA can cause severe hepatotoxicity [see Adverse Reactions (6.1)].

Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA [see Dosage and Administration (2.2)].

TUKYSA with trastuzumab and capecitabine

In HER2CLIMB, 8% of patients who received TUKYSA had an ALT increase > 5 × ULN, 6% had an AST increase > 5 × ULN, and 1.5% had a bilirubin increase > 3 × ULN (Grade ≥3). Hepatotoxicity led to dose reduction of TUKYSA in 8% of patients and discontinuation of TUKYSA in 1.5% of patients.

TUKYSA with trastuzumab

In MOUNTAINEER, 6% of patients had a bilirubin increase > 3 × ULN (Grade ≥3), 6% had an AST increase > 5 × ULN, and 4.7% had an ALT increase > 5 × ULN. Hepatotoxicity led to dose reduction of TUKYSA in 3.5% of patients and discontinuation of TUKYSA in 2.3% of patients.

5.3 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, TUKYSA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of tucatinib to pregnant rats and rabbits during organogenesis caused embryo-fetal mortality, reduced fetal weight and fetal abnormalities at maternal exposures ≥ 1.3 times the human exposure (AUC) at the recommended dose.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose. 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 [see Use in Specific Populations (8.1, 8.3)].

TUKYSA is used in combination with trastuzumab and capecitabine. Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.

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)

Stomatitis includes stomatitis, oropharyngeal pain, oropharyngeal discomfort, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue bulering, lip buler, oral dysesthesia, tongue ulceration, and aphthous ulcer

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

Hepatotoxicity includes hyperbilirubinemia, blood bilirubin increased, bilirubin conjugated increased, alanine aminotransferase increased, transaminases increased, hepatotoxicity, aspartate aminotransferase increased, liver function test increased, liver injury, and hepatocellular injury

Anemia includes anemia, hemoglobin decreased, and normocytic anemia

Due to inhibition of renal tubular transport of creatinine without affecting glomerular function

Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy

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

Stomatitis¹ 32 2.5 0 21 0.5 0

Skin and subcutaneous tissue disorders

Palmar-plantar erythrodysesthesia syndrome 63 13 0 53 9 0

Rash² 20 0.7 0 15 0.5 0

Hepatobiliary disorders

Hepatotoxicity³ 42 9 0.2 24 3.6 0

Metabolism and nutrition disorders

Decreased appetite 25 0.5 0 20 0 0

Blood and lymphatic system disorders

Anemia⁴ 21 3.7 0 13 2.5 0

Musculoskeletal and connective tissue disorders

Arthralgia 15 0.5 0 4.6 0.5 0

Investigations

Creatinine increased⁵ 14 0 0 1.5 0 0

Weight decreased 13 1 0 6 0.5 0

Nervous System Disorders

Peripheral neuropathy⁶ 13 0.5 0 7 1 0

Respiratory, thoracic and mediastinal disorders

Epistaxis 12 0 0 5 0 0

Table 4: Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received TUKYSA and with a Difference of ≥5% Compared to Placebo in HER2CLIMB

The denominator used to calculate the rate varied from 351 to 400 in the TUKYSA arm and 173 to 197 in the control arm based on the number of patients with a baseline value and at least one post-treatment value. Grading was based on NCI-CTCAE v.4.03 for laboratory abnormalities, except for increased creatinine which only includes patients with a creatinine increase based on the upper limit of normal definition for grade 1 events (NCI CTCAE v5.0).

Laboratory criteria for Grade 1 is identical to laboratory criteria for Grade 2.

Due to inhibition of renal tubular transport of creatinine without affecting glomerular function.

There is no definition for Grade 2 in CTCAE v.4.03.

Laboratory Abnormality TUKYSA + Trastuzumab + Capecitabine¹ Placebo + Trastuzumab + Capecitabine¹

All Grades % Grades ≥3 % All Grades % Grades ≥3 %

Hematology

Decreased hemoglobin 59 3.3 51 1.5

Chemistry

Decreased phosphate 57 8 45 7

Increased bilirubin 47 1.5 30 3.1

Increased ALT 46 8 27 0.5

Increased AST 43 6 25 1

Decreased magnesium 40 0.8 25 0.5

Decreased potassium ² 36 6 31 5

Increased creatinine ³ 33 0 6 0

Decreased sodium ⁴ 28 2.5 23 2

Increased alkaline phosphatase 26 0.5 17 0

Increased Creatinine

The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

RAS Wild-Type, HER2-Positive Unresectable or Metastatic Colorectal Cancer

The safety of TUKYSA in combination with trastuzumab or a non-US approved trastuzumab product was evaluated in 86 patients enrolled in MOUNTAINEER with unresectable or metastatic colorectal cancer [see Clinical Studies (14.2)]. The median duration of exposure to TUKYSA was 6.9 months (range 0.7, 49.3).

Serious adverse reactions occurred in 22% of patients. Serious adverse reactions that occurred in ≥ 2% of patients were intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%) and rectal perforation (2.3%).

Permanent discontinuation of TUKYSA due to an adverse reaction occurred in 6% of patients. The adverse reaction which resulted in permanent discontinuation of TUKYSA in ≥2% of patients was increased ALT (2.3%). Dosage interruptions of TUKYSA due to an adverse reaction occurred in 23% of patients. Adverse reactions which required dosage interruption in ≥3% of patients were increased ALT (3.5%) and diarrhea (3.5%). Dose reductions of TUKYSA due to an adverse reaction occurred in 9% of patients. Adverse reactions which required dose reductions in ≥2% of patients were increased ALT (2.3%) and diarrhea (2.3%).

The most common adverse reactions reported in ≥ 20% of patients treated with TUKYSA and trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion related reactions, and pyrexia. The most common laboratory abnormalities reported in ≥ 20% of patients were increased creatinine, increased glucose, increased ALT, decreased hemoglobin, increased AST, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium.

Table 5 summarizes the adverse reactions in MOUNTAINEER.

Table 5: Adverse Reactions (≥10%) in Patients with Unresectable or Metastatic Colorectal Cancer (MOUNTAINEER)
*Includes 1 patient who only received trastuzumab.1. Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain upper.2. Rash includes acne, dermatitis acneiform, dermatitis contact, erythema, erythema multiforme, rash, rash macular, rash maculo-papular, rash papular, rash pustular, skin exfoliation, and urticaria,

Adverse Reaction TUKYSA + Trastuzumab N= 86*

All Grades % Grade 3 %

Gastrointestinal disorders

Diarrhea 64 3.5

Nausea 35 0

Vomiting 16 0

Abdominal pain¹ 21 2.3

Constipation 14 1.2

General disorders

Fatigue 44 2.3

Pyrexia 20 0

Chills 19 1.2

Skin and subcutaneous disorders

Rash² 37 0

Injury, poisoning, and procedural complications

Infusion related reaction 21 0

Metabolism and nutrition disorders

Decreased appetite 19 0

Blood and lymphatic system disorders

Anemia 10 0

Vascular disorders

Hypertension 17 7

Musculoskeletal and connective tissue disorders

Back pain 17 2.3

Arthralgia 16 1.2

Myalgia 13 0

Respiratory, thoracic and mediastinal disorders

Cough 16 0

Dyspnea 14 0

Psychiatric disorders

Anxiety 10 0

Other adverse reactions (<10%) include epistaxis (7%), weight decreased (7%), oropharyngeal pain (5%), oral dysesthesia (1%), and stomatitis (1%).

Table 6: Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients with Unresectable or Metastatic Colorectal Cancer (MOUNTAINEER)
1. Number of patients with both baseline and post-baseline results for each test2. NCI CTCAE v5.0 was used for creatinine increased. NCI CTCAE v4.03 was used for all other laboratory parameters.3. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function

Laboratory Abnormality TUKYSA + Trastuzumab N=85 ¹

All Grades % Grade 3 % Grade 4 %

Hematology

Decreased hemoglobin 46 3.5 0

Decreased lymphocytes 39 12 0

Decreased leukocytes 22 0 0

Decreased platelets 15 0 0

Chemistry

Increased creatinine^2,3 58 0 0

Increased glucose 56 2.4 0

Increased ALT 46 2.4 2.4

Increased AST 33 2.4 3.5

Increased bilirubin 28 3.5 2.4

Increased alkaline phosphatase 25 1.2 0

Decreased albumin 24 1.2 0

Decreased sodium 20 6 0

Decreased potassium 16 1.2 0

Increased Creatinine

The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible in 87% of patients with values outside normal lab limits upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed [see Clinical Pharmacology (12.3)].

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)
Stomatitis includes stomatitis, oropharyngeal pain, oropharyngeal discomfort, mouth ulceration, oral pain, lip ulceration, glossodynia, tongue bulering, lip buler, oral dysesthesia, tongue ulceration, and aphthous ulcer 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 Hepatotoxicity includes hyperbilirubinemia, blood bilirubin increased, bilirubin conjugated increased, alanine aminotransferase increased, transaminases increased, hepatotoxicity, aspartate aminotransferase increased, liver function test increased, liver injury, and hepatocellular injury Anemia includes anemia, hemoglobin decreased, and normocytic anemia Due to inhibition of renal tubular transport of creatinine without affecting glomerular function Peripheral neuropathy includes peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy
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
Stomatitis¹	32	2.5	0	21	0.5	0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	63	13	0	53	9	0
Rash²	20	0.7	0	15	0.5	0
Hepatobiliary disorders
Hepatotoxicity³	42	9	0.2	24	3.6	0
Metabolism and nutrition disorders
Decreased appetite	25	0.5	0	20	0	0
Blood and lymphatic system disorders
Anemia⁴	21	3.7	0	13	2.5	0
Musculoskeletal and connective tissue disorders
Arthralgia	15	0.5	0	4.6	0.5	0
Investigations
Creatinine increased⁵	14	0	0	1.5	0	0
Weight decreased	13	1	0	6	0.5	0
Nervous System Disorders
Peripheral neuropathy⁶	13	0.5	0	7	1	0
Respiratory, thoracic and mediastinal disorders
Epistaxis	12	0	0	5	0	0

Table 4: Laboratory Abnormalities (≥20%) Worsening from Baseline in Patients Who Received TUKYSA and with a Difference of ≥5% Compared to Placebo in HER2CLIMB
The denominator used to calculate the rate varied from 351 to 400 in the TUKYSA arm and 173 to 197 in the control arm based on the number of patients with a baseline value and at least one post-treatment value. Grading was based on NCI-CTCAE v.4.03 for laboratory abnormalities, except for increased creatinine which only includes patients with a creatinine increase based on the upper limit of normal definition for grade 1 events (NCI CTCAE v5.0). Laboratory criteria for Grade 1 is identical to laboratory criteria for Grade 2. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function. There is no definition for Grade 2 in CTCAE v.4.03.
Laboratory Abnormality	TUKYSA + Trastuzumab + Capecitabine¹	Placebo + Trastuzumab + Capecitabine¹
All Grades %	Grades ≥3 %	All Grades %	Grades ≥3 %
Hematology
Decreased hemoglobin	59	3.3	51	1.5
Chemistry
Decreased phosphate	57	8	45	7
Increased bilirubin	47	1.5	30	3.1
Increased ALT	46	8	27	0.5
Increased AST	43	6	25	1
Decreased magnesium	40	0.8	25	0.5
Decreased potassium ²	36	6	31	5
Increased creatinine ³	33	0	6	0
Decreased sodium ⁴	28	2.5	23	2
Increased alkaline phosphatase	26	0.5	17	0

Table 5: Adverse Reactions (≥10%) in Patients with Unresectable or Metastatic Colorectal Cancer (MOUNTAINEER)
*Includes 1 patient who only received trastuzumab.1. Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain upper.2. Rash includes acne, dermatitis acneiform, dermatitis contact, erythema, erythema multiforme, rash, rash macular, rash maculo-papular, rash papular, rash pustular, skin exfoliation, and urticaria,
Adverse Reaction	TUKYSA + Trastuzumab N= 86*
All Grades %	Grade 3 %
Gastrointestinal disorders
Diarrhea	64	3.5
Nausea	35	0
Vomiting	16	0
Abdominal pain¹	21	2.3
Constipation	14	1.2
General disorders
Fatigue	44	2.3
Pyrexia	20	0
Chills	19	1.2
Skin and subcutaneous disorders
Rash²	37	0
Injury, poisoning, and procedural complications
Infusion related reaction	21	0
Metabolism and nutrition disorders
Decreased appetite	19	0
Blood and lymphatic system disorders
Anemia	10	0
Vascular disorders
Hypertension	17	7
Musculoskeletal and connective tissue disorders
Back pain	17	2.3
Arthralgia	16	1.2
Myalgia	13	0
Respiratory, thoracic and mediastinal disorders
Cough	16	0
Dyspnea	14	0
Psychiatric disorders
Anxiety	10	0

Table 6: Laboratory Abnormalities (≥15%) Worsening from Baseline in Patients with Unresectable or Metastatic Colorectal Cancer (MOUNTAINEER)
1. Number of patients with both baseline and post-baseline results for each test2. NCI CTCAE v5.0 was used for creatinine increased. NCI CTCAE v4.03 was used for all other laboratory parameters.3. Due to inhibition of renal tubular transport of creatinine without affecting glomerular function
Laboratory Abnormality	TUKYSA + Trastuzumab N=85 ¹
All Grades %	Grade 3 %	Grade 4 %
Hematology
Decreased hemoglobin	46	3.5	0
Decreased lymphocytes	39	12	0
Decreased leukocytes	22	0	0
Decreased platelets	15	0	0
Chemistry
Increased creatinine^2,3	58	0	0
Increased glucose	56	2.4	0
Increased ALT	46	2.4	2.4
Increased AST	33	2.4	3.5
Increased bilirubin	28	3.5	2.4
Increased alkaline phosphatase	25	1.2	0
Decreased albumin	24	1.2	0
Decreased sodium	20	6	0
Decreased potassium	16	1.2	0

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 patients <65 years. The most frequent serious adverse reactions in patients ≥65 years who received TUKYSA were diarrhea (9%), vomiting (6%), and nausea (5%). There were no observed overall differences in the effectiveness of TUKYSA in patients ≥ 65 years compared to younger patients. There were too few patients ≥75 years to assess differences in effectiveness or safety.

In MOUNTAINEER, 12 patients were ≥65 years of age. There were too few patients ≥65 years to assess differences in effectiveness or safety.

8.6 Renal Impairment

The use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe renal impairment (creatinine clearance [CLcr]: < 30 mL/min estimated by Cockcroft-Gault Equation), because capecitabine is contraindicated in patients with severe renal impairment. Refer to the Full Prescribing Information of capecitabine for additional information in severe renal impairment.

No dose adjustment is recommended for patients with mild or moderate renal impairment (CLcr: 30 to 89 mL/min).

8.7 Hepatic Impairment

Tucatinib exposure is increased in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

No dose adjustment for TUKYSA is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

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 C₂₆H₂₄N₈O₂ 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.

12 Clinical Pharmacology

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.

12.2 Pharmacodynamics

Exposure Response Relationship

Tucatinib exposure-response relationships and the time course of pharmacodynamics response have not been fully characterized.

Cardiac Electrophysiology

No large mean increase in QTc (i.e., > 20 ms) was detected following treatment with TUKYSA at the recommended dose of 300 mg taken orally twice daily.

12.3 Pharmacokinetics

Tucatinib AUC_0-INF and C_max increased proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage). Time to steady state was approximately 4 days. Steady-state pharmacokinetic parameters following administration of TUKYSA 300 mg twice daily for 7 days in patients with mBC and mCRC are described in Table 9. The geometric mean (CV%) tucatinib AUC accumulation ratios ranged from 2.0 (26) fold to 2.5 (28) fold.

Table 9: Tucatinib C_max and AUC

Tumor Type AUC_ss (ng*h/mL) C_max,ss (ng/mL) C_trough,ss (ng/mL)

mBC 5620 (43) 747 (45) 288 (59)

mCRC 3370 (49) 405 (45) 197 (63)

Absorption

The median time to peak plasma concentration of tucatinib was approximately 2 hours (range 1 to 4 hours).

Effects of Food

Following administration of a single oral dose of TUKYSA in 11 subjects after a high-fat meal (approximately 58% fat, 26% carbohydrate, and 16% protein), the mean AUC_0-INF increased by 1.5-fold, the T_max shifted from 1.5 hours to 4 hours, and C_max was unaltered. The effect of food on the pharmacokinetics of tucatinib was not clinically meaningful.

Distribution

The geometric mean (CV%) apparent volume of distribution of tucatinib at steady-state were 903 (42) L and 829 (21) L in patients with mBC and mCRC, respectively. The plasma protein binding was 97.1% at clinically relevant concentrations. At steady-state, concentrations of tucatinib and its metabolite ONT-993 in the cerebrospinal fluid were comparable to unbound plasma concentrations.

Elimination

At steady-state, tucatinib effective half-life was approximately 11.9 hours and geometric mean (CV%) apparent clearance was 53 (43) L/h in patients with mBC. Tucatinib effective half-life was approximately 16.4 hours and geometric mean (CV%) apparent clearance was 89 (49) L/h in patients with mCRC.

Metabolism

Tucatinib is metabolized primarily by CYP2C8 and to a lesser extent via CYP3A.

Excretion

Following a single oral dose of 300 mg radiolabeled tucatinib, approximately 86% of the total radiolabeled dose was recovered in feces (16% of the administered dose as unchanged tucatinib) and 4.1% in urine with an overall total recovery of 90% within 13 days post-dose. In plasma, approximately 76% of the plasma radioactivity was unchanged, 19% was attributed to identified metabolites, and approximately 5% was unassigned.

Specific Populations

Age (18-77 years), albumin (19 to 52 g/L), creatinine clearance (CLcr: 60 to 89 mL/min (n = 63); CLcr 30 to 59 mL/min (n = 6)), body weight (41 to 146 kg), sex (male (n = 170), female (n = 113)) and race (White (n = 205), Black (n = 37), or Asian (n = 25)) did not have a clinically meaningful effect on tucatinib exposure.

Renal Impairment

No clinically significant differences in the pharmacokinetics of tucatinib were observed in patients with mild to moderate renal impairment (CLcr: 30 to 89 mL/min by Cockcroft-Gault). The effect of severe renal impairment (CLcr: < 30 mL/min) on the pharmacokinetics of tucatinib is unknown.

Hepatic Impairment

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on tucatinib exposure. Tucatinib AUC_0-INFwas increased by 1.6 fold in subjects with severe (Child-Pugh C) hepatic impairment compared to subjects with normal hepatic function.

Drug Interaction Studies

Clinical Studies

Table 10: Effect of Other Drugs on TUKYSA

Concomitant Drug (Dose) TUKYSA Dose Ratio (90% CI) of Tucatinib Exposure With and Without Concomitant Drug

C_max AUC

Strong CYP3A Inhibitor Itraconazole (200 mg BID) 300 mg single dose 1.3 (1.2, 1.4) 1.3 (1.3, 1.4)

Strong CYP3A/Moderate 2C8 Inducer Rifampin (600 mg once daily) 0.6 (0.5, 0.8) 0.5 (0.4, 0.6)

Strong CYP2C8 Inhibitor Gemfibrozil (600 mg BID) 1.6 (1.5, 1.8) 3.0(2.7, 3.5)

Table 11: Effect of TUKYSA on Other Drugs
a. Tucatinib reduced the renal clearance of metformin without any effect on glomerular filtration rate    (GFR) as measured by iohexol clearance and serum cystatin C.

Concomitant Drug (Dose) TUKYSA Dose Ratio (90% CI) of Exposure Measures of Concomitant Drug with/without Tucatinib

C_max AUC

CYP2C8 Substrate Repaglinide (0.5 mg single dose) 300 mg single dose 1.7 (1.4, 2.1) 1.7 (1.5, 1.9)

CYP3A Substrate Midazolam (2 mg single dose) 3.0(2.6, 3.4) 5.7 (5.0, 6.5)

P-gp Substrate Digoxin (0.5 mg single dose) 2.4 (1.9, 2.9) 1.5(1.3, 1.7)

MATE1/2-K substrate^a Metformin (850 mg single dose) 1.1 (1.0, 1.2) 1.4 (1.2, 1.5)

No clinically significant difference in the pharmacokinetics of tucatinib were observed when used concomitantly with omeprazole (proton pump inhibitor) or tolbutamide (sensitive CYP2C9 substrate).

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Tucatinib is a reversible inhibitor of CYP2C8 and CYP3A and a time-dependent inhibitor of CYP3A, but is not an inhibitor of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP2D6.

Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) Enzymes: Tucatinib is not an inhibitor of UGT1A1.

Transporter Systems: Tucatinib is a substrate of P-gp and BCRP, but is not a substrate of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, or BSEP.

Tucatinib inhibits MATE1/MATE2-K-mediated transport of metformin and OCT2/MATE1-mediated transport of creatinine. The observed serum creatinine increase in clinical studies with tucatinib is due to inhibition of tubular secretion of creatinine via OCT2 and MATE1.

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with tucatinib.

Tucatinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Tucatinib was not clastogenic in either an in vitro chromosome aberration assay or an in vivo mouse bone marrow micronucleus assay.

Fertility studies in animals have not been conducted. In repeat-dose toxicity studies up to 13 weeks duration, decreased corpora lutea/corpus luteum cyst, increased interstitial cells of the ovary, atrophy of the uterus, and mucification of the vagina were observed in female rats at doses ≥ 6 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose based on AUC). Atrophy and edema of the testes and oligospermia/germ cell debris in the epididymides were observed in male rats at ≥ 120 mg/kg/day (approximately 13 times the human exposure at the recommended dose based on AUC).

14 Clinical Studies

14.1 HER2-Positive Metastatic Breast Cancer

The efficacy of TUKYSA in combination with trastuzumab and capecitabine was evaluated in 612 patients in HER2CLIMB (NCT02614794), a randomized (2:1), double-blind, placebo-controlled trial. Patients were required to have HER2-positive, unresectable locally advanced or metastatic breast cancer, with or without brain metastases, and prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) separately or in combination, in the neoadjuvant, adjuvant or metastatic setting. HER2 positivity was based on archival or fresh tissue tested with an FDA-approved test at a central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive.

Patients with brain metastases, including those with progressing or untreated lesions, were eligible provided they were neurologically stable and did not require immediate radiation or surgery. The trial excluded patients with leptomeningeal disease. Randomization was stratified by the presence or history of brain metastases (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1), and region (U.S., Canada, or rest of world).

Patients received TUKYSA 300 mg or placebo orally twice daily with a trastuzumab or a non-US approved trastuzumab product loading dose of 8 mg/kg on Day 1 of Cycle 1 if needed and then a maintenance dose of 6 mg/kg on Day 1 of every 21-day cycle thereafter and capecitabine 1000 mg/m² orally twice daily on Days 1 through 14 of every 21-day cycle. An alternate trastuzumab dosing regimen was 600 mg administered subcutaneously on Day 1 of every 21-day cycle. Patients were treated until disease progression or unacceptable toxicity. Tumor assessments, including brain-MRI in patients with presence or history of brain metastases at baseline, occurred every 6 weeks for the first 24 weeks and every 9 weeks thereafter.

The major efficacy outcome measure was progression-free survival (PFS) in the first 480 randomized patients assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional efficacy outcome measures were evaluated in all randomized patients and included overall survival (OS), PFS among patients with a history or presence of brain metastases (PFS_BrainMets), and confirmed objective response rate (ORR).

The median age was 54 years (range: 22 - 82); 116 (19%) patients were age 65 or older. The majority were White (73%) and female (99%) and 51% had an ECOG performance status of 1. Sixty percent had estrogen and/or progesterone receptor-positive disease. Forty-eight percent had a presence or history of brain metastases; of these patients, 23% had untreated brain metastases, 40% had treated but stable brain metastases, and 37% had treated but radiographically progressing brain metastases. Seventy-four percent of patients had visceral metastases. Patients had received a median of 4 (range, 2 to 17) prior lines of systemic therapy and a median of 3 (range, 1 to 14) prior lines of systemic therapy in the metastatic setting. All patients received prior trastuzumab and T-DM1 and all but two patients had prior pertuzumab.

Efficacy results are summarized in Table 12 and Figure 1 and 2. Efficacy results were consistent across patient subgroups defined by stratification factors (presence or history of brain metastases, ECOG status, region of world) and hormone receptor status.

Table 12: Efficacy Results in HER2CLIMB
BICR=blinded independent central review; CI=confidence interval; PFS=progression-free survival; OS=overall survival; ORR=objective response rate; CR=complete response; PR=partial response; DOR=duration of response.1. Primary PFS analysis conducted in first 480 randomized patients. 2.     Hazard ratio and 95% confidence intervals are based on stratified Cox proportional         hazards regression model controlling for stratification factors (presence or history of brain         metastases, ECOG status, and region of world)3.     Two-sided p-value based on re-randomization procedure (Rosenberger and Lachin          2002) controlling for stratification factors, compared with the allocated alpha of 0.054. Two-sided p-value based on re-randomization procedure (Rosenberger and Lachin 2002)         controlling for stratification factors, compared with the allocated alpha of 0.0074 for this          interim analysis (with 60% of the planned number of events for final analysis) 5.      Analysis includes patients with history or presence of parenchymal brain metastases at          baseline, including target and non-target lesions. Does not include patients with dural          lesions only. 6.      Two-sided p-value based on re-randomization procedure (Rosenberger and Lachin 2002)          controlling for stratification factors, compared with the allocated alpha of 0.0080 for this           interim analysis (with 71% of the planned number of events for final analysis) 7.      Two-sided 95% exact confidence interval, computed using the Clopper-Pearson method (1934)8. Calculated using the complementary log-log transformation method (Collett, 1994)

TUKYSA + Trastuzumab + Capecitabine Placebo + Trastuzumab + Capecitabine

PFS¹ N=320 N=160

    Number of events (%) 178 (56) 97 (61)

    Median, months (95% CI) 7.8 (7.5, 9.6) 5.6 (4.2, 7.1)

     Hazard ratio (95% CI)² 0.54 (0.42, 0.71)

     P-value³ <0.00001

OS N=410 N=202

     Number of deaths (%) 130 (32) 85 (42)

     Median, months (95% CI) 21.9 (18.3, 31.0) 17.4 (13.6, 19.9)

     Hazard ratio (95% CI)² 0.66 (0.50, 0.87)

     P-value⁴ 0.00480

PFS_BrainMets ⁵ N=198 N=93

     Number of events (%) 106 (53.5) 51 (54.8)

     Median, months (95% CI) 7.6 (6.2, 9.5) 5.4 (4.1, 5.7)

     Hazard ratio (95% CI)² 0.48 (0.34, 0.69)

P-value⁶ <0.00001

Confirmed ORR for Patients with Measurable Disease N=340 N=171

     ORR (95% CI)⁷ 40.6 (35.3, 46.0) 22.8 (16.7, 29.8)

     CR (%) 3 (0.9) 2 (1.2)

     PR (%) 135 (39.7) 37 (21.6)

     P-value³ 0.00008

DOR

     Median, months (95% CI)⁸ 8.3 (6.2, 9.7) 6.3 (5.8, 8.9)

14.2 HER2-Positive Metastatic Colorectal Cancer

The efficacy of TUKYSA in combination with trastuzumab was evaluated in 84 patients in MOUNTAINEER (NCT03043313), an open-label, multicenter trial. Patients were required to have HER2-positive, RAS wild-type, unresectable or metastatic colorectal cancer and prior treatment with fluoropyrimidines, oxaliplatin, irinotecan, and anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb). Patients whose disease had deficient mismatch repair (dMMR) proteins or microsatellite instability-high (MSI-H) must have also received an anti-programmed cell death protein-1 (PD-1) mAb. Patients who received prior anti-HER2 targeting therapy were excluded. HER2 positivity as defined by HER2 overexpression or gene amplification was prospectively determined in local laboratories using immunohistochemistry (IHC), in situ hybridization (ISH), and/or next generation sequencing (NGS) on tumor tissue. RAS status was performed as standard of care prior to study entry based on expanded RAS testing including KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4.

The median age was 55 years (range: 24 to 77); 12 (14%) patients were age 65 or older. Seventy-seven percent of patients were White, 4% were Black, 4% were Asian, and 4% were Hispanic or Latino. Sixty-one percent of patients were male. Seventy percent of patients had lung metastases, 64% had liver metastases, 60% had an ECOG performance status of 0, 37% had an ECOG performance status of 1, and 4% had an ECOG performance status of 2. Ninety-nine percent of patients received prior treatment with fluoropyrimidine, oxaliplatin, and irinotecan and 83% and 52% received anti-VEGF antibodies and anti-EGFR antibodies respectively; 23%, 38%, and 39% received 1, 2, or ≥3 prior lines of therapy, respectively.

Patients received TUKYSA 300 mg orally twice per day with a loading dose of trastuzumab or a non-US approved trastuzumab product 8 mg/kg intravenously on Day 1 of Cycle 1, followed by a maintenance dose of trastuzumab 6 mg/kg on Day 1 of each subsequent 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR) as assessed by blinded independent central review (BICR) according to RECIST version 1.1.

Efficacy results are summarized in Table 13.

Table 13: Efficacy Results in MOUNTAINEER
1. Based on Kaplan-Meier method. 2. Based on observed duration of response.

TUKYSA + trastuzumab N=84

Overall Response Rate (%) (95% CI) 38 (28, 49)

CR (%) 3 (3.6)

PR (%) 29 (35)

Duration of Response N=32

Median¹ , months (95% CI) 12.4 (8.5, 20.5)

Patients with DOR≥6 months² 81%

Patients with DOR≥12 months² 34%

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.

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Diarrhea

Inform patients that TUKYSA has been associated with severe diarrhea. Instruct patients on how to manage diarrhea and to inform their healthcare provider immediately if there is any change in bowel patterns [see Warnings and Precautions (5.1)].

Hepatotoxicity

Inform patients that TUKYSA has been associated with severe hepatotoxicity and that they should report signs and symptoms of liver dysfunction to their healthcare provider immediately [see Warnings and Precautions (5.2)].

Embryo-Fetal Toxicity

Inform pregnant women and females of reproductive potential of the risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1)] .

Advise females of reproductive potential to use effective contraception during treatment with TUKYSA and for 1 week after the last dose [see Use in Specific Populations (8.3)].

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 [see Use in Specific Populations (8.3)].

Refer to the Full Prescribing Information of trastuzumab and capecitabine for pregnancy and contraception information.

Lactation

Advise women not to breastfeed during treatment with TUKYSA and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Refer to the Full Prescribing Information of trastuzumab and capecitabine for lactation information.

Infertility

Advise males and females of reproductive potential that TUKYSA may impair fertility [see Use in Specific Populations (8.3)]. Refer to the Full Prescribing Information of trastuzumab and capecitabine for infertility information.

Manufactured for: Seagen Inc.Bothell, WA 980211-855-4SEAGEN

TUKYSA, Seagen, and  are US registered trademarks of Seagen Inc. © 2023 Seagen Inc., Bothell, WA 98021. All rights reserved. USPI-213411-v04

Spl Patient Package Insert Section

This Patient information has been approved by the U.S. Food and Drug AdministrationRevised: 01/2023

PATIENT INFORMATION TUKYSA^® (too-KYE-sah) (tucatinib) tablets

Important information: If your healthcare provider prescribes TUKYSA in combination with capecitabine for your breast cancer, also read the Patient Information that comes with capecitabine.

What is TUKYSA? TUKYSA is a prescription medicine used to treat adults with:

a type of breast cancer called human epidermal growth factor receptor-2 (HER2)-positive breast cancer. TUKYSA is used with the medicines trastuzumab and capecitabine, when your cancer has spread to other parts of the body such as the brain (metastatic), or cannot be removed by surgery, and you have received one or more anti-HER2 breast cancer treatments.

a type of colorectal cancer called RAS wild-type HER2-positive colorectal cancer. TUKYSA is used with the medicine trastuzumab, when your cancer has spread to other parts of the body (metastatic), or cannot be removed by surgery, and you have received treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and it did not work or is no longer working.

It is not known if TUKYSA is safe and effective in children.

Before taking TUKYSA, tell your healthcare provider about all of your medical conditions, including if you:

have liver problems.

are pregnant or plan to become pregnant. TUKYSA can harm your unborn baby. Females who are able to become pregnant:

Your healthcare provider will do a pregnancy test before you start treatment with TUKYSA.

You should use effective birth control (contraception) during treatment with TUKYSA and for 1 week after the last dose of TUKYSA. Talk with your healthcare provider about forms of birth control that you can use during this time.

Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TUKYSA.

Males with female partner who are able to become pregnant should use effective birth control during treatment with TUKYSA and for 1 week after the last dose of TUKYSA.

are breastfeeding or plan to breastfeed. It is not known if TUKYSA passes into your breast milk. Do not breastfeed during treatment with TUKYSA and for 1 week after the last dose of TUKYSA.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TUKYSA may affect the way your other medicines work, and other medicines may affect the way TUKYSA works. Know the medicines you take. Keep a ul of all the medicines you take and show it to your healthcare provider and pharmacist every time you get a new medicine..

How should I take TUKYSA?

Take TUKYSA exactly as your healthcare provider tells you.

TUKYSA is used with the medicine trastuzumab for colorectal cancer or with trastuzumab and capecitabine for breast cancer. Your healthcare provider will tell you the dose of trastuzumab and capecitabine you will take and how you will receive them.

Take TUKYSA 2 times a day, with or without a meal.

Take TUKYSA about 12 hours apart or at the same times every day.

Swallow TUKYSA tablets whole. Do not chew, crush, or split TUKYSA tablets before swallowing. Do not take TUKYSA tablets if they are broken, cracked, or damaged.

If you vomit or miss a dose of TUKYSA, take your next dose at your regular time.

What are the possible side effects of TUKYSA? TUKYSA may cause serious side effects, including:

Diarrhea. Diarrhea is common with TUKYSA and can sometimes be severe. Tell your healthcare provider if you have a change in your bowel movements or severe diarrhea. Severe diarrhea can lead to loss of too much body fluids (dehydration), low blood pressure, kidney problems and death. Your healthcare provider may prescribe medicines to treat your diarrhea during treatment with TUKYSA.

Liver Problems. TUKYSA can cause severe liver problems. Your healthcare provider will do blood tests to check your liver function before and every 3 weeks during treatment with TUKYSA, or as needed. Tell your healthcare provider right away if you have any signs and symptoms of liver problems including:

itching

yellowing of your skin or eyes

dark or brown urine (tea-colored)

pain in the upper right side of your stomach-area (abdomen)

feel very tired

decreased appetite

bleeding or bruising more easily than normal

The most common side effects of TUKYSA in combination with trastuzumab and capecitabine in adults with HER2-positive breast cancer include:

diarrhea

rash, redness, pain, swelling or bulers on the palms of your hands or soles of your feet

nausea

increased liver function blood tests

vomiting

mouth sores (stomatitis)

decreased appetite

low red blood cell counts (anemia)

rash

The most common side effects of TUKYSA in combination with trastuzumab in adults with RAS wild-type HER2-positive colorectal cancer include:

diarrhea

tiredness

rash

nausea

stomach-area (abdomen) pain

infusion-related reactions

fever

Your healthcare provider may change your dose of TUKYSA, temporarily stop, or permanently stop treatment with TUKYSA if you have certain side effects. TUKYSA may cause fertility problems in males and females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility. These are not all of the possible side effects of TUKYSA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store TUKYSA?

Store TUKYSA at room temperature 68°F to 77°F (20ºC to 25ºC).

Keep TUKYSA in its original container. The TUKYSA bottle contains a desiccant packet to help keep your tablets dry (protect from moisture). Keep the desiccant in the bottle.

Tightly close the bottle of TUKYSA after you take your dose.

TUKYSA must be used within 3 months after opening the bottle. Throw away (discard) any unused tablets 3 months after opening the bottle.

Keep TUKYSA and all medicines out of reach of children.

General information about the safe and effective use of TUKYSA. Medicines are sometimes prescribed for conditions not uled in the Patient Information. Do not use TUKYSA for a condition for which it was not prescribed. Do not give TUKYSA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TUKYSA that is written for healthcare professionals.

What are the ingredients in TUKYSA? Active ingredient: tucatinib Inactive ingredients: Tablet core: copovidone, crospovidone, sodium chloride, potassium chloride, sodium bicarbonate, colloidal silicon Tablet coating: yellow film coat: polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, and yellow iron oxide non-irradiated. Manufactured for Seagen Inc., Bothell, WA 98021 TUKYSA is a registered trademark owned by Seagen Inc. ©2023 Seagen Inc. PPI-213411-v04For more information, call 1-855-473-2436 (1-855-4SEAGEN) or go to www.TUKYSA.com..

Principal Display Panel

NDC 51144-001-60 Rx Only TUKYSA^® (tucatinib) tablets 50 mg* Attention: Dispense and store Tukysain original container to protect from moisture. Seagen^® 60 Tablets * Each tablet contains 50 mg tucatinib. Recommended Dosage: See prescribing information Store at controlled room temperature,20°C to 25°C (68° to 77°F); excursionspermitted from 15°C to 30°C (59°F to 86°F)  [see USP Controlled Room Temperature]. KEEP OUT OF REACH OF CHILDREN Discard unused tablets 3 months after opening. Mfg for: Seagen Inc.Bothell, WA 98021 USATUKYSA and its logo are US registeredtrademarks of Seagen Inc. ©2023 Seagen Inc.All rights reserved. Printed in USA 00000000 GTIN 00351144001607 LOT:  123456EXP:  MMMYYYYSN:    12345678901234

NDC 51144-002-60 Rx Only TUKYSA^® (tucatinib) tablets 150 mg* Attention: Dispense and store Tukysain original container to protect from moisture. Seagen^® 60 Tablets * Each tablet contains 150 mg tucatinib. Recommended Dosage: See prescribing information Store at controlled room temperature,20°C to 25°C (68° to 77°F); excursionspermitted from 15°C to 30°C (59°F to 86°F)  [see USP Controlled Room Temperature]. KEEP OUT OF REACH OF CHILDREN Discard unused tablets 3 months after opening. Mfg for: Seagen Inc.Bothell, WA 98021 USATUKYSA and its logo are US registeredtrademarks of Seagen Inc. ©2023 Seagen Inc.All rights reserved. Printed in USA 00000000 GTIN 00351144002604 LOT:  123456EXP:  MMMYYYYSN:    12345678901234

NDC 51144-002-12 Rx Only TUKYSA^® (tucatinib) tablets 150 mg* Attention: Dispense and store Tukysain original container to protect from moisture. SeaGen^® 120 Tablets * Each tablet contains 150 mg tucatinib. Recommended Dosage: See prescribing information Store at controlled room temperature, 20°C to 25°C (68° to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. KEEP OUT OF REACH OF CHILDREN Discard unused tablets 3 months after opening. Mfg for: Seagen Inc.Bothell, WA 98021 USA TUKYSA and its logo are US registered trademarks of Seagen Inc. ©2021 Seagen Inc.All rights reserved. Printed in USA 1204-02 GTIN 00351144002604 LOT:  123456EXP:  MMMYYYYSN:    12345678901234

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.

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.

Table 9: Tucatinib C_max and AUC
Tumor Type	AUC_ss (ng*h/mL)	C_max,ss (ng/mL)	C_trough,ss (ng/mL)
mBC	5620 (43)	747 (45)	288 (59)
mCRC	3370 (49)	405 (45)	197 (63)

Table 10: Effect of Other Drugs on TUKYSA
Concomitant Drug (Dose)	TUKYSA Dose	Ratio (90% CI) of Tucatinib Exposure With and Without Concomitant Drug
C_max	AUC
Strong CYP3A Inhibitor Itraconazole (200 mg BID)	300 mg single dose	1.3 (1.2, 1.4)	1.3 (1.3, 1.4)
Strong CYP3A/Moderate 2C8 Inducer Rifampin (600 mg once daily)	0.6 (0.5, 0.8)	0.5 (0.4, 0.6)
Strong CYP2C8 Inhibitor Gemfibrozil (600 mg BID)	1.6 (1.5, 1.8)	3.0(2.7, 3.5)

Table 11: Effect of TUKYSA on Other Drugs
a. Tucatinib reduced the renal clearance of metformin without any effect on glomerular filtration rate (GFR) as measured by iohexol clearance and serum cystatin C.
Concomitant Drug (Dose)	TUKYSA Dose	Ratio (90% CI) of Exposure Measures of Concomitant Drug with/without Tucatinib
C_max	AUC
CYP2C8 Substrate Repaglinide (0.5 mg single dose)	300 mg single dose	1.7 (1.4, 2.1)	1.7 (1.5, 1.9)
CYP3A Substrate Midazolam (2 mg single dose)	3.0(2.6, 3.4)	5.7 (5.0, 6.5)
P-gp Substrate Digoxin (0.5 mg single dose)	2.4 (1.9, 2.9)	1.5(1.3, 1.7)
MATE1/2-K substrate^a Metformin (850 mg single dose)	1.1 (1.0, 1.2)	1.4 (1.2, 1.5)

Table 12: Efficacy Results in HER2CLIMB
BICR=blinded independent central review; CI=confidence interval; PFS=progression-free survival; OS=overall survival; ORR=objective response rate; CR=complete response; PR=partial response; DOR=duration of response.1. Primary PFS analysis conducted in first 480 randomized patients. 2. Hazard ratio and 95% confidence intervals are based on stratified Cox proportional hazards regression model controlling for stratification factors (presence or history of brain metastases, ECOG status, and region of world)3. Two-sided p-value based on re-randomization procedure (Rosenberger and Lachin 2002) controlling for stratification factors, compared with the allocated alpha of 0.054. Two-sided p-value based on re-randomization procedure (Rosenberger and Lachin 2002) controlling for stratification factors, compared with the allocated alpha of 0.0074 for this interim analysis (with 60% of the planned number of events for final analysis) 5. Analysis includes patients with history or presence of parenchymal brain metastases at baseline, including target and non-target lesions. Does not include patients with dural lesions only. 6. Two-sided p-value based on re-randomization procedure (Rosenberger and Lachin 2002) controlling for stratification factors, compared with the allocated alpha of 0.0080 for this interim analysis (with 71% of the planned number of events for final analysis) 7. Two-sided 95% exact confidence interval, computed using the Clopper-Pearson method (1934)8. Calculated using the complementary log-log transformation method (Collett, 1994)
	TUKYSA + Trastuzumab + Capecitabine	Placebo + Trastuzumab + Capecitabine
PFS¹	N=320	N=160
Number of events (%)	178 (56)	97 (61)
Median, months (95% CI)	7.8 (7.5, 9.6)	5.6 (4.2, 7.1)
Hazard ratio (95% CI)²	0.54 (0.42, 0.71)
P-value³	<0.00001
OS	N=410	N=202
Number of deaths (%)	130 (32)	85 (42)
Median, months (95% CI)	21.9 (18.3, 31.0)	17.4 (13.6, 19.9)
Hazard ratio (95% CI)²	0.66 (0.50, 0.87)
P-value⁴	0.00480
PFS_BrainMets ⁵	N=198	N=93
Number of events (%)	106 (53.5)	51 (54.8)
Median, months (95% CI)	7.6 (6.2, 9.5)	5.4 (4.1, 5.7)
Hazard ratio (95% CI)²	0.48 (0.34, 0.69)
P-value⁶	<0.00001
Confirmed ORR for Patients with Measurable Disease	N=340	N=171
ORR (95% CI)⁷	40.6 (35.3, 46.0)	22.8 (16.7, 29.8)
CR (%)	3 (0.9)	2 (1.2)
PR (%)	135 (39.7)	37 (21.6)
P-value³	0.00008
DOR
Median, months (95% CI)⁸	8.3 (6.2, 9.7)	6.3 (5.8, 8.9)

Table 13: Efficacy Results in MOUNTAINEER
1. Based on Kaplan-Meier method. 2. Based on observed duration of response.
	TUKYSA + trastuzumab N=84
Overall Response Rate (%) (95% CI)	38 (28, 49)
CR (%)	3 (3.6)
PR (%)	29 (35)
Duration of Response	N=32
Median¹ , months (95% CI)	12.4 (8.5, 20.5)
Patients with DOR≥6 months²	81%
Patients with DOR≥12 months²	34%

DISCLAIMER:

"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."

"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."

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

This Patient information has been approved by the U.S. Food and Drug AdministrationRevised: 01/2023
PATIENT INFORMATION TUKYSA^® (too-KYE-sah) (tucatinib) tablets
Important information: If your healthcare provider prescribes TUKYSA in combination with capecitabine for your breast cancer, also read the Patient Information that comes with capecitabine.
What is TUKYSA? TUKYSA is a prescription medicine used to treat adults with: a type of breast cancer called human epidermal growth factor receptor-2 (HER2)-positive breast cancer. TUKYSA is used with the medicines trastuzumab and capecitabine, when your cancer has spread to other parts of the body such as the brain (metastatic), or cannot be removed by surgery, and you have received one or more anti-HER2 breast cancer treatments. a type of colorectal cancer called RAS wild-type HER2-positive colorectal cancer. TUKYSA is used with the medicine trastuzumab, when your cancer has spread to other parts of the body (metastatic), or cannot be removed by surgery, and you have received treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and it did not work or is no longer working. It is not known if TUKYSA is safe and effective in children.
Before taking TUKYSA, tell your healthcare provider about all of your medical conditions, including if you:
have liver problems. are pregnant or plan to become pregnant. TUKYSA can harm your unborn baby. Females who are able to become pregnant: Your healthcare provider will do a pregnancy test before you start treatment with TUKYSA. You should use effective birth control (contraception) during treatment with TUKYSA and for 1 week after the last dose of TUKYSA. Talk with your healthcare provider about forms of birth control that you can use during this time. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TUKYSA. Males with female partner who are able to become pregnant should use effective birth control during treatment with TUKYSA and for 1 week after the last dose of TUKYSA. are breastfeeding or plan to breastfeed. It is not known if TUKYSA passes into your breast milk. Do not breastfeed during treatment with TUKYSA and for 1 week after the last dose of TUKYSA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TUKYSA may affect the way your other medicines work, and other medicines may affect the way TUKYSA works. Know the medicines you take. Keep a ul of all the medicines you take and show it to your healthcare provider and pharmacist every time you get a new medicine..
How should I take TUKYSA?
Take TUKYSA exactly as your healthcare provider tells you. TUKYSA is used with the medicine trastuzumab for colorectal cancer or with trastuzumab and capecitabine for breast cancer. Your healthcare provider will tell you the dose of trastuzumab and capecitabine you will take and how you will receive them. Take TUKYSA 2 times a day, with or without a meal. Take TUKYSA about 12 hours apart or at the same times every day. Swallow TUKYSA tablets whole. Do not chew, crush, or split TUKYSA tablets before swallowing. Do not take TUKYSA tablets if they are broken, cracked, or damaged. If you vomit or miss a dose of TUKYSA, take your next dose at your regular time.
What are the possible side effects of TUKYSA? TUKYSA may cause serious side effects, including:
Diarrhea. Diarrhea is common with TUKYSA and can sometimes be severe. Tell your healthcare provider if you have a change in your bowel movements or severe diarrhea. Severe diarrhea can lead to loss of too much body fluids (dehydration), low blood pressure, kidney problems and death. Your healthcare provider may prescribe medicines to treat your diarrhea during treatment with TUKYSA. Liver Problems. TUKYSA can cause severe liver problems. Your healthcare provider will do blood tests to check your liver function before and every 3 weeks during treatment with TUKYSA, or as needed. Tell your healthcare provider right away if you have any signs and symptoms of liver problems including:
itching yellowing of your skin or eyes dark or brown urine (tea-colored) pain in the upper right side of your stomach-area (abdomen)	feel very tired decreased appetite bleeding or bruising more easily than normal
The most common side effects of TUKYSA in combination with trastuzumab and capecitabine in adults with HER2-positive breast cancer include:
diarrhea rash, redness, pain, swelling or bulers on the palms of your hands or soles of your feet nausea increased liver function blood tests vomiting	mouth sores (stomatitis) decreased appetite low red blood cell counts (anemia) rash
The most common side effects of TUKYSA in combination with trastuzumab in adults with RAS wild-type HER2-positive colorectal cancer include:
diarrhea tiredness rash	nausea stomach-area (abdomen) pain infusion-related reactions fever
Your healthcare provider may change your dose of TUKYSA, temporarily stop, or permanently stop treatment with TUKYSA if you have certain side effects. TUKYSA may cause fertility problems in males and females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility. These are not all of the possible side effects of TUKYSA. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store TUKYSA?
Store TUKYSA at room temperature 68°F to 77°F (20ºC to 25ºC). Keep TUKYSA in its original container. The TUKYSA bottle contains a desiccant packet to help keep your tablets dry (protect from moisture). Keep the desiccant in the bottle. Tightly close the bottle of TUKYSA after you take your dose. TUKYSA must be used within 3 months after opening the bottle. Throw away (discard) any unused tablets 3 months after opening the bottle.
Keep TUKYSA and all medicines out of reach of children.
General information about the safe and effective use of TUKYSA. Medicines are sometimes prescribed for conditions not uled in the Patient Information. Do not use TUKYSA for a condition for which it was not prescribed. Do not give TUKYSA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TUKYSA that is written for healthcare professionals.
What are the ingredients in TUKYSA? Active ingredient: tucatinib Inactive ingredients: Tablet core: copovidone, crospovidone, sodium chloride, potassium chloride, sodium bicarbonate, colloidal silicon Tablet coating: yellow film coat: polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, and yellow iron oxide non-irradiated. Manufactured for Seagen Inc., Bothell, WA 98021 TUKYSA is a registered trademark owned by Seagen Inc. ©2023 Seagen Inc. PPI-213411-v04For more information, call 1-855-473-2436 (1-855-4SEAGEN) or go to www.TUKYSA.com..

TUKYSA (tucatinib 150 mg) Dailymed

Drug Classes

Version History

Generic: tucatinib is used for the treatment of Breast Neoplasms

FDA Adverse Reactions

1 Indications And Usage

1.1 Metastatic Breast Cancer

1.2 Unresectable or Metastatic Colorectal Cancer

Recent Major Changes Section

2 Dosage And Administration

2.1 Patient Selection

2.2 Recommended Dosage

2.3 Dosage Modifications for Adverse Reactions

2.4 Dosage Modifications for Severe Hepatic Impairment

2.5 Dosage Modifications for Concomitant Use with Strong CYP2C8 Inhibitors

3 Dosage Forms And Strengths

4 Contraindications

5 Warnings And Precautions

5.1 Diarrhea

5.2 Hepatotoxicity

5.3 Embryo-Fetal Toxicity

6 Adverse Reactions

6.1 Clinical Trials Experience

7 Drug Interactions

7.1 Effects of Other Drugs on TUKYSA

7.2 Effects of TUKYSA on Other Drugs

8 Use In Specific Populations

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

11 Description

12 Clinical Pharmacology

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 Clinical Studies

14.1 HER2-Positive Metastatic Breast Cancer

14.2 HER2-Positive Metastatic Colorectal Cancer

16 How Supplied/storage And Handling

16.1 How Supplied

17 Patient Counseling Information

Spl Patient Package Insert Section

Principal Display Panel