Seattle Genetics recently announced that Australian regulatory authorities have approved TUKYSA® (tucatinib) in combination with trastuzumab and capecitabine for the treatment of patients with advanced, unresectable, or metastatic HER2-positive breast cancer, including those with brain metastases. Australia, along with the United States, Switzerland, Canada, and Singapore, forms Project Orbis, an initiative of the US Food and Drug Administration's (FDA) Center of Excellence in Oncology, aimed at facilitating simultaneous review of anti-cancer drugs by international regulatory agencies. In April, TUKYSA became the first new drug approved under Project Orbis in the United States and is currently under review in the European Union.
Tukysa is an oral small-molecule tyrosine kinase inhibitor (TKI) targeting HER2. In vitro (and in laboratory studies), TUKYSA inhibits the phosphorylation of HER2 and HER3, thereby inhibiting downstream MAPK and AKT signaling and cell growth (proliferation), and exhibits anti-tumor activity in HER2-expressing tumor cells. In vivo (in living organisms), TUKYSA inhibits the growth of HER2-expressing tumors. The combination of TUKYSA and the anti-HER2 antibody trastuzumab showed enhanced antitumor activity both in vitro and in vivo compared to either drug alone. In the United States, TUKYSA in combination with trastuzumab and capecitabine is approved for adult patients with advanced, unresectable, or metastatic HER2-positive breast cancer, including those with brain metastases.
Dr. Clay Siegall, Executive Director of Genetics in Seattle, said, “Orbis plans a concurrent global review of TUKYSA, which will bring this novel therapy to market quickly, and we look forward to bringing TUKYSA to patients around the world.”
This approval is based on the results of the pivotal HER2CLIMB (double-blind, placebo-controlled trial) which enrolled 612 patients with HER2-positive, unresectable, locally advanced, or metastatic breast cancer who had previously received trastuzumab, pertuzumab, and ado-trastuzumab emtanssine, alone or in combination. 48% of the patients in this trial had brain metastases or a history of brain metastases. The study results were published in the *New England Journal of Medicine* (NEJM) in December 2019.
The results, published in the NEJM and presented at the San Antonio Breast Cancer Symposium (SABCS) last December, showed that the combination of Tukysa and trastuzumab/capecitabine reduced the risk of cancer progression or death by 46% compared to capecitabine/capecitabine alone. Furthermore, the proportion of patients achieving an objective response rate was doubled in those receiving Tukysa combination therapy compared to trastuzumab/capecitabine alone, at 22.8% and 40.6%, respectively. In patients with brain metastases, the addition of Tukysa reduced the risk of cancer progression or death by 52%.
Seattle Genetics stated that 26% of patients treated with Tukysa experienced serious adverse reactions, the most common being diarrhea, palmar erythema, nausea, fatigue, hepatotoxicity, vomiting, and abdominal pain.
Further Reading:
The tumors of HER2-positive breast cancer patients contain high levels of a protein called human epidermal growth factor receptor 2 (HER2), which promotes the growth of cancer cells. In March 2020, the United States diagnosed 279,100 new breast cancer cases, of which 15% to 20% were HER2-positive breast cancer. Historically, HER2-positive breast cancer has tended to be more aggressive and more prone to recurrence compared to HER2-negative breast cancer. Up to 50% of patients with metastatic HER2-positive breast cancer develop brain metastases over time.
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