What You Need to Know About the FDA's Approval of Tukysa for HER2-Positive Breast Cancer


The Food and Drug Administration approved the targeted therapy Tukysa as part of a drug combination to treat HER2-positive breast cancer. Here’s what you need to know.

By approving Tukysa (tucatinib) for use with the targeted drug Herceptin (trastuzumab) and the chemotherapy Xeloda (capecitabine), the Food and Drug Administration has provided a meaningful option to heavily pretreated patients with inoperable, locally advanced or metastatic HER2-positive breast cancer, including those with brain metastases, according to Dr. Rashmi Murthy.

This is because of the regimen’s favorable safety profile and ability to cross the blood-brain barrier, said Murthy, lead investigator of the phase 2 HER2CLIMB trial that led to Tukysa’s approval. She noted that the drug sparked an unprecedented survival benefit in this population of patients.

“The key take-home message is that tucatinib, when added to the backbone of trastuzumab and capecitabine, reduced the risk of death by one-third in heavily pretreated patients, including those with brain metastases; it also reduced the risk of progression or death by one-half in this heavily pretreated patient population,” Murthy, assistant professor of breast medical oncology at The University of Texas MD Anderson Cancer Center in Houston, told OncLive®, a sister publication of CURE®. “The strong efficacy data, as well as the tolerability profile, really make it a great treatment option to consider for patients with metastatic HER2-positive breast cancer, in those who have brain metastases and those who do not.”

How Tukysa Fits into Treatment

One in five cases of breast cancer overexpress the protein HER2, leading to a particularly aggressive subtype of the disease. Herceptin, a monoclonal antibody that inhibits the activity of the protein, was the first targeted therapy approved specifically to treat HER2-positive breast cancer. Since then, biosimilar versions of Herceptin have been approved, as has Perjeta (pertuzumab), another drug in the same class. Having more than one anti-HER2 drug available gives patients options if their cancer becomes resistant to one of the drugs; it also provides opportunities to use the drugs in combination.

Tukysa is a member of a different family of HER2-targeting drugs known as kinase inhibitors. One thing that differentiates it is its ability to specifically disrupt HER2 without unintentionally inhibiting the activity of the protein EGFR, Murthy said. That means that the drug causes fewer side effects — specifically, less rash and diarrhea. Tukysa is also able to reach cancer that has spread to the brain in this population, as can its previously approved cousins Tykerb (lapatinib) and Nerlynx (neratinib).

“This is really important, because brain metastases are very frequently seen with HER2-positive breast cancer, and thus, they represent a very significant problem,” Murthy said. “Up to half of patients may develop disease in the brain and there is, we know, continuous risk for this over time. Also, we have not really seen that advances in neoadjuvant or adjuvant targeted therapy have really been able to address this problem.”


The HER2CLIMB trial included more than 600 patients, half of whom had brain metastases and all of whom had prior exposure to Herceptin, Perjeta and an antibody-drug conjugate, Kadcyla (trastuzumab emtansine).

The study’s findings show that those who added Tukysa to Herceptin and capecitabine had a reduced risk of death compared with those who took Herceptin plus capecitabine alone (the control group). Specifically, the median length of survival from the start of treatment in the Tukysa group was 21.9 months versus 17.4 months in the control group. The one- and two-year survival rates in the Tukysa and control arms were 76% versus 62% and 45% versus 27%, respectively.

At one year, 33.1% of those in the Tukysa group had experienced no disease progression, compared with 12.3% of those in the control group. The median length of time until progression was 7.8 months and 5.6 months, respectively.

Importantly, the triplet combination also reduced the risk of disease progression in patients who had brain metastases at baseline. The median time until disease progression in this subgroup was 7.6 months with the Tukysa triplet versus 5.4 months with Herceptin/capecitabine alone. At one year, 25% of patients with brain metastases in the Tukysa group were free of disease progression versus 0% in the control group.

When it comes to delaying disease progression, “we certainly need to do better than 25%,” Murthy said, “but this is a really huge step forward for our patients.”

Side Effects

Adding Tukysa to the two-drug regimen did not add much toxicity, Murthy said. The most common side effects were diarrhea, hand-foot syndrome, nausea, fatigue and vomiting, all mostly low-grade. Tukysa did boost rates of diarrhea and of elevated aminotransferase levels, which can indicate liver damage. All side effects were found to be manageable with supportive therapy, Murthy said.

Six percent of patients in the Tukysa group discontinued treatment due to side effects, compared with 3% in the placebo group.

Looking Ahead

Now that researchers know that Tukysa can be an effective addition to treatment for this population of patients, they hope to answer more questions about the drug, Murthy said — including whether it can be used to treat earlier-stage HER2-positive breast cancer.

“We want to see whether tucatinib could be brought in even earlier lines of treatment, such as the adjuvant (postsurgical) setting, to potentially prevent patients who are at higher risk from developing metastatic disease or disease spread to the brain,” she said. “Efforts in the curable setting are also being made to see whether we can actually prevent patients from developing metastatic disease.”

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