By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The Food and Drug Administration (FDA) has approved tucatinib, an oral tyrosine kinase inhibitor with high selectivity for the kinase domain of human epidermal growth factor receptor 2 (HER2), to treat advanced HER2-positive breast cancer. It represents the first new drug approved under international collaboration, called Project Orbis, which included approval actions from the FDA’s equivalents in Australia, Canada, Singapore, and Switzerland.1 Tucatinib was granted a priority review, a breakthrough therapy designation, and orphan status and was approved four months ahead of the FDA’s goal date.1 It is distributed as Tukysa.

Indications

Tucatinib should be prescribed in combination with trastuzumab and capecitabine to treat adults with advanced unresectable or metastatic HER2-positive breast cancer. This includes patients with brain metastases who have received one or more anti-HER2-based regimens in the metastatic setting.2

Dosage

The recommended dosage is 300 mg taken orally twice daily with or without food at the same time each day (approximately 12 hours apart).2 Dose reduction and modifications for adverse reactions (e.g., diarrhea and hepatotoxicity) are provided in the prescribing information. Tucatinib is available as 50 mg and 150 mg tablets.

Potential advantages

The combination of tucatinib, trastuzumab, and capecitabine improved estimated disease-free survival and overall survival, including those with brain metastases in patients with a median of three lines of therapy for metastatic cancer.2,3

Potential Disadvantages

More frequent (> 50%) adverse events compared to the control (trastuzumab/capecitabine and placebo) included diarrhea (81% vs. 53%), nausea (58% vs. 44%), palmar-plantar erythrodysesthesia syndrome (63% vs. 53%), and decreased hemoglobin (59% vs. 51%).2 Tucatinib may cause embryo-fetal toxicity. Effective contraception for the patient and male partner is recommended. Strong CYP3A inducers in combination with moderate CYP2C8 and strong CYP2C8 inhibitors should be avoided.2 Concomitant use with CYP3A substrates with a narrow therapeutic range also should be avoided.

Comments

The efficacy of tucatinib was evaluated in a randomized, double-blind, placebo-controlled trial.2,3 Study participants (n = 612) had HER2-positive, unresectable, locally advanced or metastatic breast cancer, with or without brain metastases. These patients had received treatment with trastuzumab, pertuzumab, or ado-trastuzumab emtansine separately or in combination in the neoadjuvant or metastatic setting. The median age was 54 years, 73% of subjects were white, 60% were estrogen and/or progesterone receptor positive, and 48% had neurologically stable brain metastases. Participants were randomized 2:1 to tucatinib/trastuzumab/capecitabine or placebo/trastuzumab/capecitabine. They were treated until disease progression or unacceptable toxicity. The major efficacy outcome was progression-free survival (PFS). Additional outcomes included overall survival and PFS for subjects with brain metastases. The median time to PFS was 7.8 months for the tucatinib regimen and 5.6 months for the placebo regimen (hazard ratio [HR], 0.54; 95% confidence interval [CI]; 0.42-0.71). The median overall survival was 21.9 months vs. 17.4 months (HR, 0.66; 95% CI, 0.50-0.87). The PFS for subjects with brain metastases was 7.6 months vs. 5.4 months (HR, 0.48; 95% CI, 0.34-0.69). Results were consistent across patient subgroups, including presence or history of brain metastases and hormone receptor status.2

Clinical Implications

The first-line therapy for HER2-positive metastatic breast cancer is trastuzumab + pertuzumab + taxane (e.g., docetaxel). This combination significantly improves overall survival (56.5 months vs. 48 months for trastuzmab and docetaxel plus placebo).4 This improvement was maintained after an additional four-year follow-up.5 For those with disease progression, trastuzumab emtansine is second-line therapy. This improvement in survival increases the risk of brain metastases. Breast cancer is the second most common cause of brain metastases after lung cancer, as 15-30% of patients develop brain metastases.6 There is no standard regimen for treating brain metastases. The usual treatment is surgery with postoperative radiation, stereotactic radiotherapy, or whole brain radiotherapy.6 Tucatinib in combination with trastuzumab and capecitabine provides an option in heavily pretreated patients, including those with brain metastases. The cost of a 30-day supply at 600 mg per day is $18,500.

REFERENCES

  1. U.S. Food and Drug Administration. FDA approves first new drug under international collaboration, a treatment option for patients with HER2-positive metastatic breast cancer. April 17, 2020.
  2. Seattle Genetics. Tukysa Prescribing Information. April 2020.
  3. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 2020;382:597-609.
  4. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015;372:724-734.
  5. Helwick C. CLEOPATRA end-of-study analysis in metastatic breast cancer: 37% alive at 8 years. The ASCO Post, July 10, 2019.
  6. Witzel I, Oliveira-Ferrer L, Pantel K, et al. Breast cancer brain metastases: Biology and new clinical perspectives. Breast Cancer Res 2016;18:8.