Tukysa Drug Information

Patient Selection

Select patients for treatment of unresectable or metastatic colorectal cancer with TUKYSA based on the presence of: • HER2 overexpression or gene amplification. 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. 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. Advise patients to swallow TUKYSA tablets whole and not to chew, crush, or split prior to swallowing. Advise patients not to ingest tablet if it is broken, cracked, or not otherwise intact.

Advise patients to take TUKYSA approximately 12 hours apart and at the same time each day with or without a meal. If the patient vomits or misses a dose of TUKYSA, instruct the patient to take the next dose at its usual scheduled time. When given in combination with TUKYSA, the recommended dosage of capecitabine is 1000 mg/m 2 orally twice daily taken within 30 minutes after a meal.

TUKYSA and capecitabine can be taken at the same time. Refer to the Full Prescribing Information for trastuzumab and capecitabine for additional information.

Dosage Modifications for Adverse Reactions

The recommended TUKYSA dose reductions and dosage modifications for adverse reactions are provided in Tables 1 and 2. Table 1: Recommended TUKYSA Permanently discontinue TUKYSA in patients unable to tolerate Hepatotoxicity Abbreviations: ULN = upper limit of normal; ALT = alanine aminotransferase; AST = aspartate aminotransferase

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.

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.

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. 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. 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.

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. 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.

The median duration of exposure to TUKYSA was 6.9 months (range 0.7, 49.3). Serious adverse reactions occurred in 22% of patients. 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.

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, 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, which may increase the risk of TUKYSA toxicity. 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, 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. P-glycoprotein (P-gp) Substrates Clinical Impact Concomitant use of TUKYSA with a P-gp substrate increased the plasma concentrations of P-gp substrate, 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.

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.

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.

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