Tucatinib

Tucatinib is a targeted anticancer medicine used in combination with other treatments for HER2-positive metastatic breast cancer and for RAS wild-type, HER2-positive metastatic colorectal cancer. It is taken by mouth as a tablet, twice a day.

Tucatinib is a tyrosine kinase inhibitor. It blocks HER2 (human epidermal growth factor receptor 2), a protein on the surface of cells that signals them to grow and divide. Some cancers make far too much HER2, which drives uncontrolled growth. Tucatinib blocks the signal HER2 sends inside the cell, which slows the growth of cancer cells that depend on it.

In laboratory studies, tucatinib blocked the activation of both HER2 and a related protein, HER3, which switched off two growth signaling pathways inside the cell (MAPK and AKT) and slowed cell division. The combination of tucatinib and trastuzumab worked better than either medicine on its own.

Tucatinib is always given with at least one other medicine. For breast cancer, it is given with trastuzumab and capecitabine, or with trastuzumab and pertuzumab as maintenance treatment. For colorectal cancer, it is given with trastuzumab.

Tucatinib was approved by the US Food and Drug Administration (FDA) in 2020 for HER2-positive metastatic breast cancer. The colorectal cancer use was added in January 2023. The breast cancer maintenance use, with trastuzumab and pertuzumab, was added in October 2026. It is sold under the brand name Tukysa.

Does tucatinib reach the brain?

Yes. At steady state, levels of tucatinib and its main breakdown product in the cerebrospinal fluid, the fluid around the brain and spinal cord, were similar to the unbound levels in the blood. This matters because the breast cancer indication specifically includes people whose cancer has spread to the brain, and the clinical trial that supported approval enrolled people with brain metastases, including some whose brain lesions were untreated or growing.

Tucatinib is a prescription medicine used to treat adults with:

• HER2-positive breast cancer that is locally advanced and cannot be removed by surgery, or that has spread to other parts of the body, as maintenance treatment after initial (induction) treatment. Tucatinib is used with trastuzumab and pertuzumab for this. In the clinical trial, induction treatment was 4 to 8 cycles of trastuzumab, pertuzumab and a taxane chemotherapy, and the cancer had not grown during that time.
• HER2-positive breast cancer that is advanced and cannot be removed by surgery, or that has spread to other parts of the body, including the brain. Tucatinib is used with trastuzumab and capecitabine in people who have already received one or more anti-HER2 treatments for advanced disease.
• RAS wild-type, HER2-positive colorectal cancer that cannot be removed by surgery or has spread to other parts of the body, and that has grown despite treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Tucatinib is used with trastuzumab for this.

The colorectal cancer use was granted accelerated approval based on how many tumors shrank and how long the response lasted, rather than on how long people lived. Continued approval for this use may depend on confirmatory trials showing a clinical benefit.

It is not known whether tucatinib is safe and effective in children.

Testing before treatment for colorectal cancer

Before tucatinib is started for colorectal cancer, your tumor must be tested to confirm it makes too much HER2 protein or carries extra copies of the HER2 gene, and that it is RAS wild-type, meaning it does not carry a RAS mutation. There is currently no FDA-approved test for detecting HER2 in colorectal cancer, so laboratories use validated tests of their own. RAS testing is done with an approved test.

• Take tucatinib exactly as your healthcare provider tells you.
• Take it twice a day, with or without food.
• Take your doses about 12 hours apart, at the same times each day.
• Swallow the tablets whole. Do not chew, crush, or split them.
• Do not take a tablet that is broken, cracked, or damaged.
• Keep taking tucatinib for as long as your healthcare provider tells you to. In the clinical trials, treatment continued until the cancer grew or the side effects became too difficult to manage.
• Your healthcare provider will tell you the dose of trastuzumab and, for breast cancer, capecitabine or pertuzumab, and how these will be given. Capecitabine is taken within 30 minutes after a meal and can be taken at the same time as tucatinib.

Tucatinib has a boxed warning, the FDA's most serious type of warning, for liver problems.

Liver problems. Tucatinib can cause severe liver injury, which can be fatal, particularly if tucatinib is restarted after being stopped for liver problems. Your healthcare provider will check your liver with blood tests before you start, every 2 weeks for the first 2 months, then every 3 weeks while you are taking it, and at any other time if needed. If tucatinib is paused for liver problems and then restarted, your liver tests will be checked every week. Tell your healthcare provider straight away if you have itching, yellowing of the skin or eyes, dark or tea-colored urine, pain in the upper right side of your abdomen, unusual tiredness, loss of appetite, or bruising or bleeding more easily than normal.

Diarrhea. Diarrhea is the most common side effect of tucatinib and can be severe. Severe diarrhea can lead to dehydration, low blood pressure, sudden kidney injury and, rarely, death. Tell your healthcare provider about any change in your bowel habits. You may be given medicine to control diarrhea, and your tucatinib dose may be paused, lowered, or stopped depending on how bad it is.

Harm to an unborn baby. Tucatinib can harm a developing baby. Effective contraception is needed during treatment and for 1 week after the last dose, for both women who can become pregnant and men whose partners can become pregnant.

Tucatinib is always taken with trastuzumab, and with either capecitabine or pertuzumab as well if you are being treated for breast cancer. Read the patient information that comes with those medicines too, since they have their own warnings.

Tucatinib has no contraindications. There is no group of people the label says must never receive it.

Before you start tucatinib, tell your healthcare provider about all of your medical conditions, including if you:

• have liver problems. If you have severe liver impairment, your dose will be lower.
• have kidney problems. Tucatinib combined with capecitabine and trastuzumab is not recommended if you have severe kidney impairment, because capecitabine must not be used in that situation.
• are pregnant, might be pregnant, or are planning a pregnancy. A pregnancy test is done before treatment starts.
• are breastfeeding or planning to breastfeed.
• are trying to have a child now or in the future. Animal studies suggest tucatinib may affect fertility in both men and women.

Tell your healthcare provider about every medicine you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Tucatinib has a number of important interactions. See the interactions section below.

Pregnancy and breastfeeding

Tucatinib can harm an unborn baby. In animal studies, tucatinib given during pregnancy caused the loss of the pregnancy, lower birth weight, and birth defects at doses similar to or above those used in people. There is no information on its use in pregnant women.

Females who can become pregnant:

• Your healthcare provider will do a pregnancy test before you start tucatinib.
• Use effective contraception during treatment and for 1 week after your last dose.
• Tell your healthcare provider straight away if you become pregnant or think you might be.

Males with a female partner who can become pregnant should use effective contraception during treatment and for 1 week after the last dose.

Do not breastfeed during treatment with tucatinib or for 1 week after the last dose. It is not known whether tucatinib passes into breast milk.

Trastuzumab, pertuzumab and capecitabine have their own pregnancy and contraception requirements, which may be longer. Check the information for those medicines as well.

Serious side effects

Tucatinib may cause serious side effects, including:

• Diarrhea. In the breast cancer trial, 81% of people taking tucatinib had diarrhea, and it was severe in 12%. Diarrhea typically started about 12 days after treatment began and lasted around 8 days. Two people had life-threatening diarrhea, and both died. In the colorectal cancer trial, 64% had diarrhea, and it was severe in 3.5%. In the breast cancer maintenance trial, 73% had diarrhea, and it was severe in 6%. It typically started about 11 days after treatment began and lasted around 2 days.
• Liver problems. Tucatinib can cause severe liver injury that can be fatal, particularly when it is restarted after being stopped for liver problems. In the breast cancer trial, 8% of people had ALT more than 5 times the upper limit of normal, 6% had AST more than 5 times the upper limit, and 1.5% had a significant rise in bilirubin. Liver problems led to a lower dose in 8% of people and to stopping tucatinib in 1.5%. In the breast cancer maintenance trial, 18% had ALT more than 5 times the upper limit of normal, 10% had AST more than 5 times the upper limit, and 1.2% had a significant rise in bilirubin. Five people developed serious drug-induced liver injury, with both raised liver enzymes and raised bilirubin, and one of them died. All five cases happened after tucatinib was restarted. Liver problems led to a lower dose in 16% of people and to stopping tucatinib in 8%.
• Harm to an unborn baby. Based on animal studies, tucatinib can cause the loss of a pregnancy and birth defects.

How common are tucatinib side effects?

The figures below are for the side effects reported in at least 20% of people in each trial. The three columns come from different trials in different cancers, using different partner medicines, so they should not be read as a direct comparison.

Other side effects reported in 10% or more of people taking tucatinib for breast cancer were joint pain (15%), a rise in creatinine (14%), weight loss (13%), nerve pain or numbness in the hands and feet (13%) and nosebleeds (12%). In colorectal cancer, they were chills (19%), high blood pressure (17%), back pain (17%), joint pain (16%), cough (16%), vomiting (16%), constipation (14%), shortness of breath (14%), muscle aches (13%), anemia (10%), and anxiety (10%). As maintenance treatment for breast cancer, they were itching (19%), headache (19%), cough (18%), upper respiratory tract infection (16%), muscle spasms (14%), COVID-19 (14%), constipation (11%) and weight loss (11%).

Your healthcare provider may change your dose, pause treatment, or stop tucatinib permanently depending on which side effects you have and how severe they are.

Why has my creatinine gone up?

Creatinine is a blood test used to estimate kidney function, and it rises by about a third in the first three weeks of tucatinib treatment in most people. This is not kidney damage. Tucatinib blocks the transporters the kidney uses to move creatinine out into the urine, so creatinine builds up in the blood while the kidney itself keeps filtering normally. The level stays raised during treatment and comes back down afterward. If your creatinine stays high, your healthcare provider may use a different test to check how your kidneys are actually working.

Tucatinib may cause fertility problems in both men and women, which may affect the ability to have children. Talk to your healthcare provider about this before you start if it is a concern.

These are not all of the possible side effects of tucatinib. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Adult dose of tucatinib

The recommended dose is 300 mg taken by mouth twice daily, with or without food, for both breast cancer and colorectal cancer. This includes maintenance treatment for breast cancer with trastuzumab and pertuzumab. Treatment continues until the disease progresses or side effects become unacceptable.

Dose reductions for side effects

If you have a significant side effect, treatment is usually paused until it settles and then restarted at a lower dose:

• First reduction: 250 mg twice daily
• Second reduction: 200 mg twice daily
• Third reduction: 150 mg twice daily

Tucatinib is stopped permanently if you cannot tolerate 150 mg twice daily. It is also stopped permanently for the most severe (grade 4) diarrhea, for the most severe liver test abnormalities, and for any other grade 4 side effect.

For liver problems, tucatinib is also stopped permanently if liver enzymes (ALT or AST) are more than 3 times the upper limit of normal together with bilirubin more than 2 times the upper limit of normal, or if liver enzymes rise above 5 times the upper limit of normal again after tucatinib has been restarted. If liver enzymes rise above 5 times the upper limit of normal, tucatinib is paused and the blood tests are repeated within 48 to 72 hours to see whether they are getting worse. Your healthcare provider will then decide whether to stop tucatinib permanently or restart it at a lower dose once your liver tests have improved.

Dose in severe liver impairment

If you have severe liver impairment (Child-Pugh C), the recommended dose is 200 mg twice daily. No change is needed for mild or moderate liver impairment.

Dose with a strong CYP2C8 inhibitor

Strong CYP2C8 inhibitors should be avoided. If one cannot be avoided, the tucatinib dose is reduced to 100 mg twice daily, and returned to the previous dose once the other medicine has been out of the body for long enough.

Tucatinib was studied in three trials. HER2CLIMB compared tucatinib plus trastuzumab and capecitabine against placebo plus the same two medicines in 612 people with HER2-positive metastatic breast cancer, almost half of whom had brain metastases. MOUNTAINEER was a single-arm trial of tucatinib plus trastuzumab in 84 people with HER2-positive, RAS wild-type metastatic colorectal cancer, with no comparison group. HER2CLIMB-05 (NCT05132582) compared tucatinib plus trastuzumab and pertuzumab against placebo plus the same two medicines as maintenance treatment in 654 people with HER2-positive metastatic breast cancer whose cancer had not grown during initial treatment with trastuzumab, pertuzumab and a taxane.

In breast cancer, adding tucatinib reduced the risk of the cancer growing by 46% and the risk of dying by 34% compared with trastuzumab and capecitabine alone. The benefit in people with brain metastases was similar to the benefit in everyone else. As maintenance treatment for breast cancer, adding tucatinib to trastuzumab and pertuzumab reduced the risk of the cancer growing by 36%. It is not yet known whether it helps people live longer, because survival data were not mature at the time of the analysis. In colorectal cancer, of the people whose tumors responded, 81% were still responding at 6 months and 34% at 12 months.

If you miss a dose of tucatinib, or if you vomit after taking a dose, do not take an extra tablet. Take your next dose at its usual scheduled time.

Tucatinib has several important interactions. Tell your healthcare provider and pharmacist about every medicine, vitamins, and herbal supplement you take, and check before starting anything new.

Medicines that make tucatinib less effective

Strong CYP3A inducers and moderate CYP2C8 inducers lower the amount of tucatinib in your blood and should be avoided. In a study, rifampin halved tucatinib levels.

Medicines that increase tucatinib levels

Strong CYP2C8 inhibitors raise tucatinib levels and increase the risk of side effects, and should be avoided. In a study, gemfibrozil tripled tucatinib exposure. If a strong CYP2C8 inhibitor cannot be avoided, the tucatinib dose is reduced to 100 mg twice daily. With moderate CYP2C8 inhibitors, closer monitoring for side effects is needed.

Medicines whose levels tucatinib increases

• CYP3A substrates. Tucatinib raises the levels of medicines broken down by CYP3A. In a study, tucatinib increased exposure to midazolam almost sixfold. Medicines in this group where a small rise in level could cause serious harm should be avoided, or their dose reduced.
• P-glycoprotein substrates. Tucatinib raises the levels of medicines carried by P-glycoprotein. In a study, it increased exposure to digoxin by half. The dose of these medicines may need to be lowered.
• Metformin. Tucatinib increased metformin exposure by about 40% by slowing its removal by the kidney, without affecting kidney filtration.
• Repaglinide. Tucatinib increased repaglinide exposure by about 70%.

No clinically important interaction was seen with omeprazole or tolbutamide.

• Children: the safety and effectiveness of tucatinib in children have not been established.
• Adults aged 65 and over: in the breast cancer trial, serious side effects occurred in 34% of people aged 65 and over, compared with 24% of younger people. The most common serious side effects in this group were diarrhea, vomiting and nausea. Tucatinib worked as well in older adults as in younger ones. There were too few people aged 75 and over to draw conclusions. In the breast cancer maintenance trial, severe (grade 3 or higher) side effects occurred in 57% of people aged 65 and over, compared with 40% of younger people, and tucatinib worked as well in older adults as in younger ones.
• Kidney problems: no dose change is needed for mild or moderate kidney impairment. Tucatinib with capecitabine and trastuzumab is not recommended in severe kidney impairment, because capecitabine must not be used then. The effect of severe kidney impairment on tucatinib itself is not known.
• Liver problems: no dose change is needed for mild or moderate liver impairment. The dose is reduced to 200 mg twice daily in severe liver impairment.

• Store tucatinib at controlled room temperature, 20°C to 25°C (68°F to 77°F). Brief periods between 15°C and 30°C (59°F to 86°F) are acceptable.
• Keep tucatinib in its original bottle. The bottle contains a desiccant packet to keep the tablets dry. Leave the desiccant in the bottle.
• Close the bottle tightly after each dose.
• Use tucatinib within 3 months of opening the bottle. Throw away any tablets left 3 months after opening.
• Keep tucatinib and all medicines out of reach of children.

Tucatinib comes as yellow film-coated tablets in two strengths:

• 50 mg: round, debossed with TUC on one side and 50 on the other
• 150 mg: oval, debossed with TUC on one side and 150 on the other

Active ingredient: tucatinib

Inactive ingredients, tablet core: copovidone, crospovidone, sodium chloride, potassium chloride, sodium bicarbonate, colloidal silicon dioxide, magnesium stearate, and microcrystalline cellulose.

Inactive ingredients, tablet coating: polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, and yellow iron oxide, non-irradiated.

Each 50 mg tablet contains 10.10 mg of potassium and 9.21 mg of sodium. Each 150 mg tablet contains 30.29 mg of potassium and 27.64 mg of sodium. Tell your healthcare provider if you are on a restricted potassium or sodium diet.