Tukysa

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.

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.

2.1 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.

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.

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.

Permanently discontinue TUKYSA in patients unable to tolerate 150 mg orally twice daily.

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)].

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)].

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.

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.

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)].

Pediatric Use

The safety and effectiveness of TUKYSA in pediatric patients have not been established.

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.

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).

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.

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%).

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.

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.