Results of the HER2CLIMB trial indicate that third-line use of tucatinib, trastuzumab, and capecitabine resulted in improved progression-free survival and overall survival in patients with HER2-positive metastatic breast cancer compared with trastuzumab, capecitabine, and placebo.1

The trial included 480 patients who were randomly assigned to receive trastuzumab-capecitabine with or without tucatinib, a HER2 inhibitor with minimal inhibition of EGFR. Patients in the study had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Patients with and without brain metastases were included.

Treatment with tucatinib reduced the risk for progression by 46% (hazard ratio [HR], 0.54; 95% CI, 0.42-0.871; P <.001). One-year progression-free survival was 33.1% with the tucatinib combination compared with 12.3% with the placebo combination. The median duration of progression-free survival was 7.8 months in patients who were assigned to receive tucatinib compared with 5.6 months for those in the placebo group.

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Tucatinib was also associated with a 34% decrease in the risk of death compared with placebo (HR, 0.66; 95% CI, 0.50-0.88; P =.005). Median overall survival was 21.9 months for the tucatinib combination compared with 17.4 months for placebo.

In an accompanying editorial, Priyank Sharma, MD, of University of Kansas Medical Center, Kansas City, pointed out the important finding that the benefit of tucatinib was maintained in patients with brain metastases.

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The median duration of progression-free survival among patients with brain metastases was 7.6 months in patients assigned tucatinib compared with 5.4 months in the placebo group (HR, 0.48; 95% CI, .34-.69; P <.001).

“Whether the observed [central nervous system] efficacy is a result of intracranial response in progressive or untreated disease, a delay in or prevention of new brain lesions in patients with treated disease, or both remains to be seen,” Dr Sharma wrote in an accompanying editorial.2

She also pointed out the low rate of drug discontinuation due to adverse events seen with tucatinib (5.7%).

“The remarkable results of the HER2CLIMB trial are bound to be practice changing for patients with HER2-positive metastatic breast cancer who have undergone previous therapy with trastuzumab, pertuzumab, and trastuzumab emtansine, and additional details regarding [central nervous system] activity will further refine the placement of tucatinib in treatment algorithms,” Dr Sharma wrote.


  1. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;doi:10.1056/NEJMoa1914609.
  2. Sharma P. Major strides in HER2 blockade for metastatic breast cancer [published online February 13, 2020].  N Engl J Med. doi: 10.1056/NEJMe1916310