N. Engl. J. Med. 2019 Dec 11
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer.
ABSTRACT
BACKGROUND
Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase.
METHODS
We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety.
RESULTS
Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group.
CONCLUSIONS
In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).
Related Questions
Assuming the patient is not a candidate for SRS
New comment by Medical Oncologist at Saint Elizabeth Regional Medical Center ( February 29, 2020)
How would you obtain tucatinib, I am assuming through expanded access trial?
Given the changing landscape of treatment, some patients may have already received capecitabine previously. Would this impact your treatment rec...
New comment by Medical Oncologist at University of Texas MD Anderson Cancer Center ( August 23, 2020)
The main evidence is that responses in the tucatinib trials were seen in patients who have received prior lapatinib (both systemically and CNS). However, head to head tr...
Patient received adjuvant chemotherapy and anti-Her2 therapy 3 years ago.
New answer by Medical Oncologist at Mayo Clinic (June 24, 2020)
I certainly would, given the CNS activity seen in the HER2CLIMB trial. I would follow the same paradigm and combine it with capecitabine and trastuzumab.
New comment by Medical Oncologist at University of Nebraska Medical Center ( September 12, 2020)
I agree with @Praveen Vikas. If this patient had not already had her surgery, docetaxel, trastuzumab, and pertuzumab (CLEOPATRA regimen), could have been considered neoadjuvan...
Which regimen is preferred in second line for these patients? What is the efficacy of TDXd vs tucatinib in CNS metastases?
Are there other systemic therapy considerations to help achieve sufficient CNS control?
New answer by Medical Oncologist at UC San Diego School of Medicine (March 18, 2024)
Absolutely. The HER2CLIMB regimen is well known to have good CNS penetration. There is an ongoing trial looking at this regimen in Her2+ leptomeningeal disease (TBCRC049). Giv...