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Tucatinib Combination in Previously Treated HER2-Positive Metastatic Breast Cancer With Brain Metastases


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In an analysis of the pivotal phase III HER2CLIMB trial to be reported at the ASCO20 Virtual Scientific Program, Nancy U. Lin, MD, and colleagues found that tucatinib, a small-molecule tyrosine kinase inhibitor that is highly selective for HER2, plus trastuzumab/capecitabine significantly improved central nervous system (CNS) progression-free survival, overall survival, and intracranial response rate vs placebo plus trastuzumab/capecitabine.1 The study population included patients with HER2-positive metastatic breast cancer and brain metastases at baseline. The report was published simultaneously in the Journal of Clinical Oncology.2 

Nancy U. Lin, MD

Nancy U. Lin, MD

Dr. Lin is Associate Professor of Medicine at Harvard Medical School and Clinical Director of the Breast Oncology Center, Medical Oncology, Dana-Farber Cancer Institute, Boston.

HER2CLIMB Trial

The phase III trial supported the April 2020 approval of tucatinib in combination with trastuzumab/capecitabine in advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti–HER2-based regimens in the metastatic setting.

In the double-blind trial, 612 patients with HER2-positive metastatic breast cancer who had prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine were randomly assigned 2:1 to receive  oral tucatinib at 300 mg twice daily, plus trastuzumab and capecitabine (n = 410) or placebo plus trastuzumab and capecitabine (n = 202). Trastuzumab was given at a loading dose of 8 mg/kg on day 1 of cycle 1 if needed and then at a maintenance dose of 6 mg/kg on day 1 of 21-day cycles thereafter. (An alternative trastuzumab dosing regimen was 600 mg subcutaneously on day 1 of every 21-day cycle.) Capecitabine was given at 1,000 mg/m2 orally twice daily on days 1 through 14 of every 21-day cycle Patients were treated until disease progression or unacceptable toxicity. All patients underwent baseline brain magnetic resonance imaging.

Details of the Analysis

The current analysis included 291 patients (48% of trial population) with brain metastases at baseline, including 98 (48%) in the tucatinib group and 93 (46%) in the control group. The major outcome measures were CNS progression–free survival based on Response Evaluation Criteria in Solid Tumors, v1.1 criteria, overall survival, and intracranial confirmed overall response rate and intracranial response duration in patients with measurable disease. Patients with isolated brain disease progression could continue study therapy after local treatment until second disease progression, with time from randomization to second disease progression or death being assessed.

Key Findings

Median CNS progression–free survival was 9.9 months in the tucatinib group vs 4.2 months in the control group (hazard ratio [HR] = 0.32, 95% confidence interval [CI] = 0.22–0.48, P < .0001). Median overall survival was 18.1 months vs 12.0 months (HR = 0.58, 95% CI = 0.40–0.85, P = .005). Intracranial overall response rate was 47.3% (95% CI = 33.7%–61.2%) vs 20.0% (95% CI = 5.7%–43.7%). Median duration of response was 6.8 months (95% CI = 5.5–16.4 months) vs 3.0 months (95% CI = 3.0–10.3 months).

Among a total of 30 patients with isolated brain disease progression who continued study therapy after local treatment, the median time from randomization to second disease progression or death was 15.9 months vs 9.7 months (HR = 0.33, 95% CI = 0.11–0.02).

The investigators concluded that in patients with heavily pretreated, HER2-positive metastatic breast cancer with brain metastasis, the addition of tucatinib to the combination of trastuzumab and capecitabine “doubled the [intracranial overall response rate],  reduced risk of intracranial progression or death by two-thirds, and reduced risk of death by nearly half.” 

DISCLOSURE: The study was funded by Seattle Genetics. Dr. Lin has served in a consulting or advisory role with Genentech/Roche, Seattle Genetics, Puma Biotechnology, Daiichi Sankyo; has received research funding from Genentech, Pfizer, Seattle Genetics, and Merck; reported patents, royalties, or other intellectual property as follows: Royalties for chapter in Up-to-Date regarding management of breast cancer brain metastases; and received royalties from Jones & Bartlett. For full disclosures of all study authors, visit ascopubs.org.

REFERENCES

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). ASCO20 Virtual Scientific Program. Abstract 1005. Presented May 29, 2020.

2. Lin NU, Borges V, Anders CK, et al: Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial. J Clin Oncol. May 29, 2020 (early release online).

 


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