Tucatinib Receives FDA Approval for HER2-Positive Breast Cancer through International Collaboration

On 17 April 2020, as part of Project Orbis, the US Food and Drug Administration (FDA) approved, for the treatment of patients with advanced HER2-positive breast cancer in combination with chemotherapy (trastuzumab and capecitabine), the drug tucatinib (Tukysa). To receive this treatment, the patient must have received at least one previous line of treatment, their tumor must be inoperable, and the cancer must have metastasized to other parts of the body, including the brain.

Accounting for approximately one-fifth of breast cancers, HER2-positive breast cancer has too much of a protein that supports human cell growth, called human epidermal growth factor receptor 2 (HER2). In more than 25% of women with metastatic HER2-positive breast cancer, brain metastases will develop.

Tukysa is a small-molecule drug in the tyrosine kinase inhibitor class, taken orally as a pill; in other words, it blocks a type of enzyme (kinase) and helps prevent the growth of cancer cells (see the figure below).

The HER2CLIMB Study That Led to FDA Approval of Tucatinib

The FDA approved Tukysa for patients with advanced HER2-positive breast cancer who had previously received trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1), based on the results of the phase-III HER2CLIMB clinical trial enrolling 612 patients.

• Approximately half of the patients enrolled in the study (48%) had brain metastases. In 60%, both the HER2 receptor and hormone receptors were positive.
• Looking at the entire patient group in the study results, 1-year progression-free survival (PFS, the time from the start of a new treatment until the disease worsens) was an additional 21% better in those taking tucatinib (33% versus 12%), and the average PFS was 2.2 months longer (7.8 versus 5.6 months).
• At 2 years, overall survival was 22% better with tucatinib (45% vs 27), and median survival was 5 months longer (22 versus 17 months).
• The treatment was shown to increase the response rate by 18% (41% versus 23%).
• When subgroups were evaluated, tucatinib was shown to benefit all patient groups.
• It was shown to make a particularly substantial contribution to PFS in patients with brain metastases (1-year PFS 25% versus 0%).
• Regarding drug-related side effects, diarrhea, redness of the hands, and elevated liver enzymes were the most common. However, there was no significant difference between the two groups in treatment discontinuation due to the side effects that occurred.

This study had previously been presented at the 2019 San Antonio Breast Cancer Symposium, while NEJM published it at the same time.

In conclusion, although the patients enrolled in this study had previously received many treatment options, such as T-DM1, pertuzumab, and trastuzumab, adding tucatinib to standard treatment was shown to reduce the risk of death by 1/3 in all patients and by 50% in those with brain metastases in particular, while increasing the treatment response rate by a factor of 2.

The FDA collaborated with the Australian Therapeutic Goods Administration (TGA), Health Canada, the Health Sciences Authority (HSA, Singapore), and Swissmedic (SMC, Switzerland) for this approval. This is the first Project Orbis partnership between the FDA, HSA, and Swissmedic. While the FDA approved Tukysa today, the application is still under review at the other agencies. The early availability of new treatments and their adoption as standard care worldwide may positively influence the increasing international collaboration in cancer clinical trials, potentially accelerating the development of cancer drugs.