Combining both trastuzumab and lapatinib with an anti-VEGFR2 antibody dramatically improved median overall survival in persons with HER2-positive breast cancer who developed brain metastases.

Brain metastases are a serious obstacle in the treatment of patients with human epidermal growth factor receptor-2 (HER2)-amplified breast cancer, explained an investigative team led by Rakesh Jain, PhD, in Proceedings of the National Academy of Sciences of the United States of America. Jain, who is Cook Professor of Radiation Oncology (Tumor Biology) at Harvard Medical School in Boston, Massachusetts, and colleagues noted that because these brain metastases do not respond to therapy, they are frequently the reason for treatment failure.

The researchers developed a mouse model of HER2-amplified breast cancer brain metastasis. As seen in patients, the HER2 inhibitors trastuzumab and lapatinib controlled tumor progression in the mouse breast but did not contain tumor growth in the brain. However, combining an anti-vascular endothelial growth factor receptor-2 (VEGFR2) antibody known as DC101 with one of the HER2 inhibitors significantly slowed tumor growth in the brain, resulting in what Jain’s group described as “a striking survival benefit.”

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The benefit appears to be largely attributable to an enhanced antiangiogenic effect. The combination therapy also led to a marked increase in necrosis of the brain lesions.

But even better antitumor activity was observed after both trastuzumab and lapatinib, rather than just one or the other, were combined with the anti-VEGFR2 antibody: Compared with a control group of mice, this triple-drug approach prolonged median overall survival fivefold, and twofold compared with the combination of either trastuzumab or lapatinib with DC101.

The investigators concluded that these findings support the clinical development of this three-drug regimen for the treatment of brain metastases of HER2-amplified breast cancer.