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Tucatinib combined with trastuzumab and capecitabine improved brain metastasis survival in a recent clinical trial. The combination was found to be safe and may delay the development of new brain lesions in patients with breast cancer.

Treatments targeting human epidermal growth factor receptor 2  (ERBB2) significantly improve outcomes in patients with ERBB2-positive breast tumors. Despite advancements, brain metastases (BM) are expected in 50% of ERBB2-positive metastatic breast cancer patients. This increases morbidity and lowers survival. Moreover, BM treatment often involves neurosurgery and radiotherapy, which may cause neurological issues.

HER2CLIMB (NCT02614794) is an important clinical trial that evaluates tucatinib in combination with trastuzumab and capecitabine in the treatment of ERBB2-positive metastatic breast cancer patients with prior treatment.

This study, published in JAMA Oncology, reports the overall survival (OS) and intracranial progression-free survival (CNS-PFS) outcomes of tucatinib in combination with trastuzumab and capecitabine in ERBB2-positive metastatic breast cancer with brain metastases. 

Study Population
A total of 612 patients were randomly assigned in a 2:1 ratio to receive either tucatinib combined with trastuzumab and capecitabine or a placebo combined with capecitabine and trastuzumab. The mean age of the patients was 52 years (range: 22–75 years).

Positive Survival Outcome With Tucatinib in Brain Metastases

For all patients with BMs, the tucatinib combination group demonstrated a clinically significant increase in median OS, which was 9.1 months longer than the placebo combination group (21.6 vs. 12.5 months, respectively). 

The tucatinib combination group had an estimated 1-year OS of 70%, while the placebo combination group had an OS of 50.6%. The 2-year OS for these two groups was 48.5% and 25.1%, respectively. Compared to the placebo combination group, the risk of mortality in the tucatinib combination group was reduced by 40% (P < .001).

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Positive Survival Benefits With Tucatinib in Brain Metastasis Patients

The long-lasting beneficial effects of tucatinib in patients with baseline BMs were observed in CNS-PFS. In general, the group that received tucatinib demonstrated a substantial enhancement, as evidenced by a median CNS-PFS that was 5.7 months longer for all BM patients compared to the placebo combination group (9.9 vs. 4.2 months, respectively). The CNS-PFS benefit was observed to be extended by 5.6 months in patients with active BMs, whereas it increased by 8.3 months in those with stable BMs.

Significant Risk Reduction Across Tucatinib Groups

Among all groups, the tucatinib combination group exhibited a substantially decreased risk of progression, with notable reductions spanning from 59.4% to 66.1% (P < .001).

Positive Intracranial Responses With Tucatinib Combination

Compared to the placebo combination group, patients who received the tucatinib combination regimen maintained higher confirmed intracranial objective response rates (ORR-IC) and intracranial duration of response. The confirmed ORR-IC was 47.1% in the tucatinib combination group and 16.7% in the placebo combination group among patients with untreated brain metastases at baseline and measurable intracranial disease (17 in the tucatinib combination group and 6 in the placebo combination group).

Positive Increase in Brain Lesion–Free Survival With Tucatinib Combination

Compared to the placebo combination group, the median new brain lesion-free survival in the tucatinib combination group was 11.1 months longer (24.9 vs. 13.8 months, respectively). The risk of developing new brain lesions at the initial progression or mortality site was reduced by 45.1% in the tucatinib combination group vs. the placebo combination group (P = 0.006).

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Source:

Lin, N. U., Murthy, R. K., Abramson, V. G., Anders, C. K., Bachelot, T., Bédard, P. L., Borges, V. F., Cameron, D., Carey, L. A., Chien, A. J., Curigliano, G., DiGiovanna, M. P., Gelmon, K. A., Hortobágyi, G. N., Hurvitz, S. A., Krop, I. E., Loi, S., Loibl, S., Mueller, V., . . . Winer, E. P. (2023). Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases. JAMA Oncology, 9(2), 197. https://doi.org/10.1001/jamaoncol.2022.5610