The following article features coverage from the American Society of Clinical Oncology 2020 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Exploratory efficacy analyses of results from a randomized, double-blind phase 2 study comparing tucatinib with placebo, both in combination with capecitabine and trastuzumab, in a subgroup of patients with heavily pretreated, HER2-positive breast cancer characterized by brain metastases found that risk of death was reduced by approximately 50% in patients treated with tucatinib.1

In the HER2CLIMB trial ( Identifier: NCT02614794), patients with HER2-positive advanced breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine were randomly assigned in a 2:1 ratio to receive trastuzumab and capecitabine in combination with either tucatinib, an oral, highly selective HER2 tyrosine kinase inhibitor, or placebo. Stratification factors included the presence or history of brain metastases.

The previously reported results of the primary analysis of HER2CLIMB for the overall study population demonstrated significantly improved progression-free survival (PFS) and overall survival (OS) in patients who received tucatinib compared with placebo, with higher rates of at least grade 3 diarrhea and elevated aminotransferase levels observed in the treatment arm. In addition, a significant improvement in PFS was observed for the subgroup of patients with brain metastases at baseline.2

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In April 2020, tucatinib received approval from the U.S. Food and Drug Administration for the treatment of patients with advanced or metastatic HER2-positive breast cancer, including those with disease characterized by brain metastases, treated with at least 1 prior regimen in the metastatic setting.3

Of the 291 patients with baseline intracranial (IC) metastases, representing 48% of the overall study population, 174 had active brain metastases, which was defined as those with either treated, progressive brain metastases (108 patients) or untreated brain metastases (66 patients). The remaining 117 patients were classified as having treated stable brain metastases.

Baseline characteristics of the subgroup of patients with brain metastases included a median age of 52 to 53 years, depending on study arm, as well as de novo metastatic disease at any location at diagnosis in approximately 40% of patients.

Median PFS in the central nervous system (CNS-PFS) was 9.9 months and 4.2 months for those treated with tucatinib (198 patients) vs placebo (93 patients; hazard ratio [HR], 0.32; 95% CI, 0.22-0.48; P <.00001), with respective rates of 1-year CNS-PFS of 40.2% compared with 0%. Furthermore, the CNS-PFS benefit of tucatinib over placebo was also observed when patients with active brain metastases (HR, 0.36; 95% CI, 0.22-0.57; P <.0001) and those with stable brain metastases (HR, 0.31; 95% CI, 0.14-0.67; P =.002) were separately evaluated.

Median OS in patients with brain metastases was 18.1 months for those in the tucatinib-containing arm compared with 12.0 months for those receiving placebo (0.58; 95% CI, 0.40-0.85; P =.005). At 1-year, the OS rate was 70.1% for those treated with tucatinib versus 46.7% for those receiving placebo. Furthermore, when only patients with active brain metastases were considered, the hazard ratio for risk of death in those treated with tucatinib compared with placebo was 0.49 (95% CI, 0.30-80; P =.004). However, a similar analysis of patients with stable brain metastases did not show a significant difference in OS (HR, 0.88; 95% CI, 0.45-1.70; P =.70).

The intracranial objective response rate (ORR-IC) in those with active metastases that were measureable at baseline was 47% in the tucatinib arm and 20% in the placebo arm (P =.03), with respective durations of IC response of 6.8 months vs 3.0 months.

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A separate analysis of the small subgroup of patients with isolated brain progression who continued on study following local therapy (30 patients) showed that median time from first CNS progression to second CNS progression or death was significantly longer in those treated with tucatinib (7.6 months) compared with placebo (3.1 months; HR, 0.332; 95% CI, 0.13-0.85; P =.02).

In her concluding remarks, Nancy U. Lin, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, first author and presenter of the study, noted that “tucatinib is the first tyrosine kinase inhibitor to demonstrate prolongation of OS in patients with HER2-positive metastatic breast cancer with brain metastases in a randomized controlled trial.”

Dr Lin concluded that “these results together with the HER2CLIMB primary analysis demonstrate that the triplet of tucatinib, trastuzumab, and capecitabine is an active regimen for IC and extracranial disease in patients with HER2-positive metastatic breast cancer.”

Disclosure: Research funding for this study was provided by Seattle Genetics, Inc. For a full list of disclosures please refer to the original study.

Read more of Cancer Therapy Advisor‘s coverage of the ASCO 2021 meeting by visiting the conference page.


  1. Lin NU, Murthy RK, Anders CK, et al, Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). Presented at: ASCO20 Virtual Scientific Program. J Clin Oncol. 2020;38(suppl):abstr 1005.
  2. 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.
  3. Tucatinib (Tukysa) [package insert]. Bothell, WA: Seattle Genetics, Inc.; 2020.