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Experimental Tucatinib Improves Survival in Metastatic HER2-Positive Breast Cancer, May Be New Standard of Care

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Adding the experimental medicine tucatinib to the standard of care of Herceptin (chemical name: trastuzumab) and Xeloda (chemical name: capecitabine) improved both progression-free survival and overall survival in people diagnosed with metastatic HER2-positive breast cancer that had been previously treated with Herceptin, Perjeta (chemical name: pertuzumab), and Kadcyla (chemical name: T-DM1 or ado-trastuzumab emtansine), according to a study.

The results suggest that tucatinib may be a new standard of care for metastatic HER2-positive disease. The study also was notable because it included people who had brain metastases, who are usually excluded from clinical trials.

The research was presented on Dec. 11, 2019, at the 2019 San Antonio Breast Cancer Symposium and published simultaneously in the New England Journal of Medicine. Read the abstract of “Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.”

Listen to a Breastcancer.org podcast on the study with Dr. Rashmi Murthy, the lead researcher.

Progression-free survival is how long a person lives without the cancer growing. Overall survival is how long a person lives, whether or not the cancer grows.

About tucatinib

Tucatinib is a tyrosine kinase inhibitor. Tyrosine kinases are enzymes that help control how cells grow and divide, among other functions. If the enzyme is too active or if a cell has too much of the enzyme, it can make cells grow uncontrollably. Tucatinib blocks a specific area of the HER2 gene in cancer cells, which stops the cells from growing and spreading.

Tucatinib is a pill taken by mouth.

About the study

The HER2CLIMB trial included 612 people diagnosed with metastatic HER2-positive breast cancer. About 99% of the people in the study were women, and everyone in the study had been previously treated with Herceptin, Perjeta, and Kadcyla for metastatic breast cancer; the average was four prior treatment regimens.

The people joined the study between February 2016 and May 2019.

The people were randomly assigned to one of two treatment regimens:

  • tucatinib in combination with Herceptin and Xeloda (410 people)
  • placebo (a dummy pill that looked just like tucatinib) in combination with Herceptin and Xeloda (202 people)

About 48% of the people in the study had brain metastases.

About half the people were followed for longer than 14 months and half were followed for shorter periods of time.

The results showed that tucatinib reduced the risk of the cancer growing by 46% and also reduced the risk of a person dying from breast cancer by 46%.

Average progression-free survival was:

  • 7.8 months for people treated with tucatinib, Herceptin, and Xeloda
  • 5.6 months for people treated with placebo, Herceptin, and Xeloda

Average overall survival was:

  • 21.9 months for people treated with tucatinib, Herceptin, and Xeloda
  • 17.4 months for people treated with placebo, Herceptin and Xeloda

Specifically, for people with brain metastases, adding tucatinib to Herceptin and Xeloda increased overall survival, reducing the risk of death by 34%, and increased progression-free survival by 52%.

“This is a uniquely designed trial in that it allowed patients to enroll if they had untreated, treated stable, or previously treated but progressive brain metastasis,” said lead researcher Rashmi Murthy, M.D., of the University of Texas MD Anderson Cancer Center, who presented the results. “Brain metastasis is a common clinical problem developing in up to half of patients [with metastatic HER2-positive breast cancer], but there are limited systemic treatment options, as most drugs have difficulty crossing the blood brain barrier.”

“Tucatinib is one of the most promising new drugs that we have brought forward for women with stage IV HER2-positive breast cancer, especially those with brain metastases,” said Virginia Borges, M.D., director of the Breast Cancer Research Program and Young Women's Breast Cancer Translational Program at the University of Colorado Cancer Center, in a statement. Borges is also a member of the research team.

Traditionally, clinical trials have excluded people with brain metastases because their relatively poorer prognosis could make an experimental medicine appear less effective. The HER2CLIMB study is the first phase III trial that enrolled people with brain metastasis and who had brain metastases that were progressing.

“The data are striking,” Borges continued, “showing 25% 1-year survival for this patient population with tucatinib, compared with 0% survival for patients treated with standard-of-care.”

Tucatinib side effects

Like most medicines used to treat cancer, tucatinib can cause side effects, some of them severe.

The most common side effects in people treated with tucatinib were:

  • diarrhea
  • hand-foot syndrome
  • nausea
  • fatigue
  • vomiting

The most common severe side effects (grade 3 or higher) in people treated with tucatinib were:

  • hand-foot syndrome
  • diarrhea
  • elevated liver enzymes
  • fatigue

Diarrhea was the most common side effect in people in both treatment groups, and in most cases it was grade 1 or grade 2. People were not required to take anti-diarrhea medicine when they started the study. People who did use anti-diarrhea medicine used it for about 3 days.

Overall, 5.7% of people treated with tucatinib, Herceptin, and Xeloda stopped treatment compared to 3% of people treated with only Herceptin and Xeloda.

“This trial verified that tucatinib is both a safe and effective treatment,” said Murthy. “These results are unprecedented for late line therapy in advanced breast cancer and are a major advance for patients who have significant unmet medical need. Tucatinib in combination with trastuzumab and capecitabine should be the new standard of care for patients pretreated with multiple anti-HER2 agents including patients with brain metastasis.”

What this means for you

If you have been diagnosed with metastatic HER2-positive breast cancer, have received at least three treatment regimens, and are discussing which treatments to try next, you may want to talk to your doctor about this study.

While the HER2CLIMB study is no longer accepting patients, a similar study looking at tucatinib, Herceptin, and Xeloda to treat leptomeningeal metastases, where cancer cells float in the cerebrospinal fluid, is recruiting participants diagnosed with HER2-positive metastatic breast cancer.

Together, you and your doctor can decide if enrolling in a clinical trial studying tucatinib is right for you.

Currently, tucatinib is not approved by the U.S. Food and Drug Administration (FDA). Seattle Genetics, the company that makes tucatinib, has said it plans to ask the FDA for approval in early 2020.

For more information on participating in a study, including the benefits and risks, visit the Breastcancer.org Clinical Trials pages.

Editor’s Note: On April 17, 2020, the FDA approved Tukysa (chemical name: tucatinib) in combination with Herceptin (chemical name: trastuzumab) and Xeloda (chemical name: capecitabine) to treat metastatic HER2-positive breast cancer or locally-advanced HER2-positive disease that can’t be completely removed with surgery, after the cancer has been treated with at least one anti-HER2 medicine.

Written by: Jamie DePolo, senior editor

Reviewed by: Brian Wojciechowski, M.D., medical adviser


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