Tucatinib

TUKYSA is a kinase inhibitor indicated: • in combination with trastuzumab and pertuzumab for the maintenance treatment of adult patients with unresectable locally advanced or metastatic HER2-positive breast cancer following induction treatment. • 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. • 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.

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.

• 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. • Recommended dosage: 300 mg taken orally twice daily with or without food. • For patients with severe hepatic impairment, the recommended dosage is 200 mg orally twice daily.

None. None.

Boxed warning (hepatotoxicity • tukysa): can cause severe and fatal hepatotoxicity, particularly after rechallenge. • Obtain liver function tests before initiation and during treatment with TUKYSA. Withhold, reduce dose, or permanently discontinue TUKYSA as recommended based on severity of hepatotoxicity. WARNING: HEPATOTOXICITY • TUKYSA can cause severe and fatal hepatotoxicity, particularly after rechallenge. • Diarrhea: TUKYSA can cause severe diarrhea, including dehydration, hypotension, acute kidney injury, and death. Administer antidiarrheal treatment as clinically indicated. Interrupt dose, reduce dose, or permanently discontinue TUKYSA based on severity. • Embryo-Fetal Toxicity: TUKYSA can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.

The following clinically significant adverse reactions are described elsewhere in the labeling: • Hepatotoxicity • Diarrhea • The most common adverse reactions (≥20%) with TUKYSA in combination with trastuzumab and pertuzumab in patients with unresectable locally advanced or metastatic HER2-positive breast cancer are diarrhea, musculoskeletal pain, hepatotoxicity, nausea, fatigue, rash, and vomiting. • 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.

• Strong CYP3A Inducers or Moderate CYP2C8 Inducers: Avoid concomitant use. • Strong CYP2C8 Inhibitors: Avoid concomitant use, reduce TUKYSA dose if concomitant use cannot be avoided. • CYP3A Substrates: Avoid concomitant use with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. • P-gp Substrates: Consider reducing the dose of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.

Store at controlled room temperature at 20ºC to 25ºC (68ºF to 77ºF), excursions permitted from 15ºC to 30ºC (59ºF to 86ºF). Store in original container to protect from moisture.