ESMO: Enhertu shows its worth in brain metastases

Women with HER2-positive breast cancer can be treated with AstraZeneca and Daiichi Sankyo's Enhertu, regardless of whether their cancer has spread to the brain, according to a new study.

The results of the open-label DESTINY-Breast12 trial – reported at the ESMO cancer congress in Barcelona this weekend – showed that nearly two-thirds (61.6%) of patients with brain metastases at baseline who were treated with the HER2-directed antibody-drug conjugate (ADC) were alive without disease progression at one year.

There was also a central nervous system progression-free survival (PFS) rate of 58.9%, which was consistent whether or not the brain metastases were stable or actively growing. Patients enrolled into the study had experienced disease progression on two or more prior lines of therapy.

The results – simultaneously published in the journal Nature Medicine – also reveal an objective response rate (ORR) of 62.7% with Enhertu (trastuzumab deruxtecan), of which 9.5% were complete responses.

It's an important result, as brain metastases occur in up to half of all HER2-positive breast cancer patients and, until recently, would require treatment with radiotherapy, explained Dr Nancy Lin of the Dana-Farber Cancer Institute in Boston, US, who is the lead investigator of the trial.

Enhertu has emerged as an important new treatment option for HER2-positive breast cancer, but it was thought that, as a large molecule, it may not be able to penetrate effectively into the CNS. Now, the date helps "further characterise the clinical benefit and safety profile of Enhertu in these patients, which will help guide treatment decisions," said Lin.

The risk of breast cancer spreading into the brain is higher for HER2-positive than HER-negative tumours, with the overall risk for all types at around 10% to 15%. The median overall survival (OS) for patients with breast cancer who have developed brain metastases is around eight months, although that does vary, depending on treatment approaches.

In a statement, AZ and Daiichi Sankyo pointed out that – at the moment – treatment guidelines do not recommend screening patients with breast cancer for brain metastases, and that means when the spread to the CNS is eventually diagnosed it may be in an advanced stage.

The recommended systemic drug treatment for active brain metastases in second-line or later HER2-positive breast cancer is currently Pfizer's small-molecule HER2 inhibitor Tukysa (tucatinib) in combination with anti-HER2 antibody trastuzumab and capecitabine chemotherapy.

"After today's presentation, I believe the preferred option for the second-line treatment should now be trastuzumab deruxtecan, regardless of whether the patient has active brain metastases or not," said Dr Cristina Saura of the Vall d'Hebron University Hospital in Barcelona, Spain, the ESMO discussant for the trial.

The authors of the study write in the Nature Medicine paper that, without a direct comparison between Enhertu and the Tukysa regimen, treatment selection for previously treated patients with patients in this setting should be "balanced between efficacy and toxicity considerations on an individual basis," reflecting the small but well-established risk of respiratory complications with Enhertu, particularly interstitial lung disease (ILD).

Last year, the combination of Tukysa with Roche's rival HER2-directed ADC Kadcyla (trastuzumab emtansine) showed efficacy in the HER2CLIMB-02 study as second-line therapy for HER2-positive breast cancer, including in patients with brain metastases.

To date, however, that combination has not been submitted for approval and Enhertu has become preferred to Kadcyla in previously treated HER2-positive breast cancer.