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Adding Tucatinib to Trastuzumab and Capecitabine Improves Survival in HER2-Positive Metastatic Breast Cancer

JHOP - April 2020 Vol 10, No 2 - From the Literature, Breast Cancer
COMMENTARY by Robert J. Ignoffo, PharmD, FHOPA, FASHP, FCSHP
Clinical Professor Emeritus, University of California, San Francisco;
Professor Emeritus, Touro University–California, Mare Island, Vallejo, CA
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BACKGROUND: Up to 50% of patients with advanced or metastatic HER2-positive breast cancer may have brain metastases, for which effective treatment options are limited. A phase 1b dose-escalation clinical trial of tucatinib, an oral tyrosine kinase inhibitor, in combination with trastuzumab and capecitabine showed antitumor activity in patients with HER2-positive breast cancer, including patients with brain metastases. In a new study, researchers evaluated the use of tucatinib plus trastuzumab and capecitabine in patients who previously received trastuzumab, pertuzumab, and trastuzumab emtansine for the treatment of metastatic HER2-positive breast cancer. In December 2019, the US Food and Drug Administration granted tucatinib, in combination with trastuzumab and capecitabine, a breakthrough therapy designation for this patient population.

METHODS: HER2CLIMB was a randomized, double-blind, placebo-controlled phase 2 clinical trial that included 612 patients with unresectable locally advanced or metastatic HER2-postive breast cancer, some of whom had brain metastases. The patients were randomized in a 2:1 ratio to trastuzumab and capecitabine plus tucatinib or to placebo.

In all, 47.5% of the patients had brain metastases at baseline. Tucatinib was administered orally at 300 mg twice daily during each 21-day cycle. In both cohorts, the patients received capecitabine 1000 mg/m2 orally twice daily on days 1 to 14 of each 21-day cycle, and trastuzumab 8 mg/kg intravenously on day 1 of cycle 1, followed by 6 mg/kg thereafter on day 1 of each 21-day cycle. The primary end point was progression-free survival (PFS). The secondary end points included overall survival, PFS in patients with brain metastases, and tolerability.

RESULTS: The tucatinib triplet led to a 46% risk reduction for disease progression or death compared with trastuzumab and capecitabine, with a median PFS of 7.8 months and 5.6 months, respectively. The 1-year PFS rates were 33.1% and 12.3%, respectively. Among patients with brain metastases at baseline, the risk for disease progression or death was reduced by 52% in the tucatinib arm, and the median PFS was 7.6 months in the tucatinib arm and 5.4 months in the placebo arm. The 1-year PFS rates were 24.9% and 0%, respectively. The median overall survival was 21.9 months in the tucatinib arm versus 17.4 in the placebo arm. The 2-year overall survival rates were 44.9% versus 26.6%, respectively.

The tucatinib-based regimen was generally well-tolerated, with mostly low-grade adverse events. Grade ≥3 adverse events were 55.2% in the tucatinib arm versus 48.7% in the placebo arm. Diarrhea was the most common all-grade event in both arms; grade ≥3 diarrhea was 12.9% and 8.6%, respectively. Liver transaminase levels were higher in the tucatinib arm, including grade ≥3 aspartate aminotransaminase (4.5%) and alanine aminotransaminase (5.4%). However, these were mostly low-grade, transient, and reversible events.

Source: Schuster Murthy RS, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382:597-609.

Commentary by Robert J. Ignoffo

This phase 3 clinical trial of tucatinib showed improved PFS and overall survival in all subgroups of patients with heavily pretreated, HER2-positive breast cancer, including those with untreated and previously treated brain metastases, which is a population typically excluded from clinical trials. Patients with and without brain metastases showed benefit. Almost 50% of the more than 600 patients in this study had brain metastases; at 2 years, these patients had 4.5-month longer survival than those who received placebo. At 12 months, the proportion of disease-free patients was more than 2.5 times that in the placebo group (33.1% vs 12%, respectively), and the overall survival rate was 34% better in the tucatinib group than in the placebo group.

In a review of real-world data (nonrandomized from 5 institutions in China), trastuzumab plus lapatinib and capecitabine, given as second-line therapy, resulted in a PFS of 11.4 months.1 These results were comparable with the current study showing improvement of 7.8 months in all patients and 7.6 months improvement for those with brain metastases. In the real-world study, the PFS for those with brain metastases was 10.6 months.1

The results from both studies suggest that triple therapy (with a tyrosine kinase inhibitor plus trastuzumab and capecitabine) is effective in patients with heavily treated, metastatic HER2 positive breast cancer. The National Comprehensive Cancer Network (NCCN) has not evaluated the use of tucatinib therapy in its latest treatment recommendation update, but based on the current phase 3 clinical trial, the use of tucatinib as part of a triple therapy for this patient population should be classified as an “other recommended regimen” in the NCCN guidelines.

1. Li Y, Gong C, Lu Q, et al. Real-world data of triplet combination of trastuzumab, lapatinib, and chemotherapy in HER2-positive metastatic breast cancer: a multicenter retrospective study. Front Oncol. 2020;10:271.

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