Patients with locally advanced unresectable or metastatic HER2-positive (HER2+) breast cancer now have a new drug option that could potentially become the new standard of care. At the end of 2019, the Food and Drug Administration (FDA) gave a Priority Review to tucatinib used in combination with trastuzumab (Herceptin) and capecitabine (Xeloda)[2]. Tucatinib is a new drug for the treatment of patients with locally advanced unresectable or metastatic HER2+ breast cancer, including patients with brain metastases, who have already received at least 3 prior HER2-targeted drugs. The FDA gave the green light to the drug combination on April 17, 2020[3].
HER2-positive breast cancer
HER2-positive breast cancers account for approximately 15 – 20% of all breast cancer cases in the world and are considered to be more aggressive and more likely to recur than the HER2-negative types. Until tucatinib, there were no approved therapies for HER2-positive metastatic breast cancer that improved progression-free survival or overall survival benefit. 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. This study is unique in that it included people with brain metastasis, even with those showing progression. Traditionally, patients with brain metastasis have been excluded from clinical trials due to their poorer prognosis, which could make an experimental drug appear less effective.
How does tucatinib work?
Tucatinib is an oral medication that is classed as a tyrosine kinase inhibitor. It works by directly blocking the action of the HER2 gene, thus preventing cancer cell growth. It was granted Breakthrough Therapy designation by the FDA, which is a process designed to accelerate the development and review of drugs intended to treat a serious condition and that may demonstrate substantial improvement over available therapy (based on clinically significant endpoint(s))[4].
Encouraging results in the latest clinical trial [5]
Tucatinib demonstrated encouraging results in the recent double-blinded, placebo-controlled HER2CLIMB Phase II study. A total of 612 patients were enrolled in the clinical trial and results were published in The New England Journal of Medicine in December 2019. The clinical trial compared two different drug combinations for the treatment of patients with locally advanced, unresectable or metastatic HER2+ breast cancer who had already been heavily treated with at least 3 previous treatments. The trial also included patients with brain metastases, who are generally excluded from clinical trials. About 48% of the people in the study had brain metastasis. Brain metastasis is a common clinical problem in patients with HER2+ metastatic breast cancer, occurring in about half of patients with metastatic disease. But there are limited systemic treatment options as most drugs cannot penetrate the blood-brain barrier.
The participants were randomly divided into two groups and received one of the following treatment protocols:
A. Tucatinib in combination with trastuzumab and capecitabine (referred as tucatinib triplet)
B. Trastuzumab and capecitabine alone (defined as the control group)
The results were impressive in this heavily pre-treated patient population
- The addition of tucatinib to trastuzumab and capecitabine conferred a significant improvement in progression-free survival (PFS – the length of time during and after treatment that the cancer does not grow or spread further).
- Patients treated with the triplet therapy showed a median PFS of 7.8 months, while the control group showed a median PFS of 5.6 months.
- Additionally, 33% of the patients from the tucatinib group did not see a progression of their cancer at 1 year after enrolling in the trial versus only 12% of the patients in the control group.
- In patients with brain metastases, the benefit of the tucatinib therapy was also significant. Their PFS was 7.6 months versus 5.4 months for the other group.
- Moreover, 25% of the patients with brain metastases and treated with tucatinib did not see their cancer progress after 1 year versus 0% in the control group of patients.
- Patients treated with tucatinib had an overall 34% reduction in risk of death.
- Tucatinib-treated patients survived an overall of 21.9 months after starting the treatment versus 17.4 months for the patients not treated with tucatinib.
- At 2 years after the start of the treatment, 45% of the tucatinib-treated patients were still alive, versus 27% of the patients in the control group.
Additionally, the drug regimen seems to be safe and tolerable as the addition of tucatinib did not add much toxicity and allowed the patients to receive the treatment for a prolonged duration. All in all, these results are very promising and bring hope to a population of heavily pretreated patients who currently have very limited treatment options. This treatment plan is likely to become the standard of care.
References
- FDA Approves First New Drug Under International Collaboration, A Treatment Option for Patients with HER2-Positive Metastatic Breast Cancer | FDA Accessed: 2020-03-23
- Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer | Aditya Bardia, Ingrid A. Mayer et al. | New England Journal of Medicine, 380, 8, 2 2019 | DOI: 10.1056/NEJMoa1814213 | Accessed: 2020-04-23
- FDA approves tucatinib for patients with HER2-positive metastatic breast cancer | FDA Accessed: 2020-05-01
- Seattle Genetics Announces U.S. FDA Grants Breakthrough Therapy Designation for Tucatinib in Locally Advanced or Metastatic HER2-Positive Breast Cancer | Seattle Genetics, Inc. | Accessed: 2020-03-23
- Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer | R. K. Murthy, S. Loi et al. | New England Journal of Medicine, 382, 7, 2 2020 | Accessed: 2020-05-01