Tucatinib in Combination with Trastuzumab and Capecitabine Provides Survival Benefits and Delays Development of New Brain Metastases in Patients with HER2-Positive MBC

Exploratory subgroup analysis of the HER2CLIMB study shows that tucatinib in combination with trastuzumab and capecitabine provides overall survival (OS) benefits for patients with HER2-positive metastatic breast cancer (MBC), including those with brain metastases, has a manageable safety profile, and may delay development of new brain metastases for all patients. Previous analyses of HER2CLIMB have shown that the addition of tucatinib to trastuzumab and capecitabine provided an OS benefit irrespective of the presence or absence of brain metastases and this exploratory analysis shows a sustained, clinically significant OS benefit for patients with brain metastases, regardless of whether the patient had active or stable brain metastases. OS benefit was also observed in the exploratory subpopulation of patients who had untreated brain metastases. The latest findings are published by Dr. Nancy U. Lin of the Dana-Farber Cancer Institute in Boston, MA, US and colleagues on 1 December 2022 in the JAMA Oncology.

It is estimated that up to 50% of patients with HER2-positive MBC will develop brain metastases which is associated with higher morbidity and shorter OS. Despite the high prevalence and their poor prognosis, patients with brain metastases, especially those with active or untreated brain metastases, have been historically excluded from early- and late-stage clinical studies.

HER2CLIMB is a randomised, double-blind, placebo-controlled clinical study evaluating tucatinib versus placebo, both in combination with trastuzumab and capecitabine, for HER2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1) in any setting (neoadjuvant, adjuvant, and metastatic). In contrast to other studies, nearly half of the enrolled population of HER2CLIMB had brain metastases at baseline, including active brain metastases. Findings from the study primary analysis with a median follow-up of 14.0 months (95% confidence interval [CI] 12.8-14.7) demonstrated that dual HER2 blockade with tucatinib in combination with trastuzumab and capecitabine provided a significant benefit in OS and progression-free survival (PFS) for patients with HER2-positive MBC. At additional follow-up with median follow-up of 29.6 months (95% CI 28.2 to 31.3 months), the OS benefit associated with tucatinib was maintained.

In the initial analysis of HER2CLIMB, tucatinib in combination with trastuzumab and capecitabine provided a PFS benefit with a risk reduction of 52% in overall disease progression or death in patients with brain metastases. In these patients, tucatinib in combination with trastuzumab and capecitabine also reduced the risk of intracranial progression or death by 68%. The confirmed intracranial objective response rate (ORR-IC) was higher in the tucatinib-combination group compared with the placebo-combination group (47.3% vs 20.0%).

In the latest exploratory subgroup analyses published in the JAMA Oncology, the study team reported efficacy outcomes for patients with brain metastases, as well as time to new brain metastasis/metastases as the site of first progression or death in all patients enroled in HER2CLIMB, with an additional 15.6 months of follow-up. Evaluations in this exploratory subgroup analysis included OS and intracranial PFS (CNS-PFS) in patients with brain metastases, confirmed ORR-IC and duration of intracranial response (DoR-IC) in patients with measurable intracranial disease at baseline, and new brain metastases–free survival in all patients. Only OS was prespecified before the primary database lock.

At baseline, 291 of 612 patients (47.5%) had brain metastases. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI 18.1-28.5) versus the placebo-combination group (12.5 months; 95% CI 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS, and ORR-IC compared with the placebo-combination group. The DoR-IC was 8.6 months (95% CI 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain metastases as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group versus the placebo-combination group (hazard ratio 0.55; 95% CI 0.36-0.85).

The authors commented that one limitation of this analysis was that it was exploratory. However, the HER2CLIMB study included a total of 291 patients with HER2-positive MBC and brain metastases, which is the largest patient population to date for a randomised, placebo-controlled clinical study. Since the completion of HER2CLIMB, more studies on HER2-positive MBC have begun to include patients with active brain metastases, including untreated brain metastases, and forthcoming studies should continue to include this patient population to address the high unmet need.

This study was sponsored by Seagen Inc, Bothell, Washington, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, New Jersey, US.

The findings were previously presented at the 2021 San Antonio Breast Cancer Symposium on 8 December, San Antonio, Texas, US.

Reference

Lin NU, Murthy RK, Abramson V, et al. Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. JAMA Oncol; Published online 1 December 2022. doi:10.1001/jamaoncol.2022.5610

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