FDA Approves TUKYSA (Tucatinib) for use in Combination with Trastuzumab and Capecitabine for Treatment of Adult Patients with Advanced Unresectable or Metastatic HER2-Positive Breast Cancer


On April 17, 2020, the U.S. Food and Drug Administration (FDA) approved TUKYSA (tucatinib) for use 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. The approved 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 take TUKYSA approximately 12 hours apart and at the same time each day with or without a meal. 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.

Additional information regarding dosage and administration, including dosage modifications for adverse reactions, as well as important warnings and precautions about diarrhea, hepatotoxicity, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

  • MOA: Tucatinib is a tyrosine kinase inhibitor of HER2.

     

  • General PK: Tucatinib AUC0-INF and Cmax increases proportionally over a dosage range from 50 mg to 300 mg (0.17 to 1 times the approved recommended dosage). Tucatinib exhibited 1.7-fold accumulation for AUC and 1.5-fold accumulation for Cmax following administration of TUKYSA 300 mg twice daily for 14 days. Time to steady state was approximately 4 days.

     

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

     

  • Distribution: The geometric mean (CV%) apparent volume of distribution of tucatinib was approximately 1670 L (66%). The plasma protein binding was 97.1%.

     

  • Elimination: The geometric mean (CV%) half-life of tucatinib was approximately 8.5 (21%) hours and apparent clearance was 148 L/h (55%).

     

  • 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.

 

Drug Interactions

  • Strong CYP3A Inducers or Moderate CYP2C8 Inducers: Avoid concomitant use of TUKYSA with a strong CYP3A inducer or a moderate CYP2C8 inducer. Concomitant use of TUKYSA with a strong CYP3A or moderate CYP2C8 inducer decreased tucatinib plasma concentrations, which may reduce TUKYSA activity.

     

  • Strong or Moderate CYP2C8 Inhibitors: Avoid concomitant use of TUKYSA with a strong CYP2C8 inhibitor. Concomitant use of TUKYSA with a strong CYP2C8 inhibitor increased tucatinib plasma concentrations, which may increase the risk of TUKYSA toxicity. If concomitant use with a strong CYP2C8 inhibitor cannot be avoided, reduce the approved 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. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.

     

  • CYP3A Substrates: 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. 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.

     

  • P-glycoprotein (P-gp) Substrates: Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. 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.

 

Use in Specific Populations

Age (< 65), race (White, Black, or Asian), body weight (41 to 138 kg), or albumin (25 to 52 g/L) did not have a clinically meaningful effect on tucatinib exposure.

  • Renal Impairment: The use of TUKYSA in combination with capecitabine and trastuzumab is not recommended in patients with severe (CLcr < 30 mL/min) renal impairment, because capecitabine is contraindicated in patients with severe renal impairment. Refer to the Full Prescribing Information of capecitabine for additional information. No dose adjustment is recommended for patients with mild or moderate (CLcr 30 to 89 mL/min) renal impairment. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed. 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.

     

  • Hepatic Impairment: Reduce the approved recommended dosage of TUKYSA to 200 mg orally twice daily for patients with severe (Child-Pugh C) hepatic impairment. No dose adjustment for TUKYSA is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. Tucatinib AUC0-INF was increased by 1.6 fold in subjects with severe (Child-Pugh C) hepatic impairment. Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment had no clinically relevant effect on tucatinib exposure.

     

  • Lactation: Advise women not to breastfeed during treatment with TUKYSA and for at least 1 week after the last dose because of the potential for serious adverse reactions in a breastfed child. 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.

 

Efficacy and Safety

The efficacy of TUKYSA in combination with trastuzumab and capecitabine was evaluated in 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. The major efficacy outcome measure was progression-free survival (PFS) assessed by blinded independent central review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 20%) are diarrhea, palmar-plantar, erythrodysesthesia, nausea, fatigue, hepatotoxicity, vomiting, stomatitis, decreased appetite, abdominal pain, headache, anemia, and rash.

Full prescribing information is available at https://go.usa.gov/xvyRX.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.