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The antibody-drug conjugate trastuzumab-deruxtecan (T-DXd; Enhertu) yielded high intracranial response rates in HER2-positive breast cancer patients with active brain metastases, according to results from the phase II .

The intracranial objective response rate with T-DXd was 73.3% in the intent-to-treat population of 15 patients, and 78.6% in the per-protocol population of 14 patients, reported Rupert Bartsch, MD, of the Medical University of Vienna in Austria.

In addition, the extracranial response rate was 62.5% in the eight patients with measurable extracranial disease at baseline.

No new safety signals were observed with the therapy, and quality of life was maintained over the treatment period, said Bartsch during a presentation at the in Berlin.

"Brain metastases are a common and devastating complication of HER2-positive breast cancer," Bartsch said. "Local therapy has long been the mainstay of treatment but recent years have seen growing interest in systemic treatment options as well."

While the established the combination of tucatinib (Tukysa), trastuzumab (Herceptin), and capecitabine as the standard of care for brain metastases, Bartsch noted that there is less evidence available regarding the activity of larger molecules such as antibody-drug conjugates.

However, initial reports from the and trials "suggested activity in patients with active brain metastases," he said. "TUXEDO-1 adds to the growing body of evidence that systemic treatment is feasible in patients with active brain metastases, and more generally supports further investigations of antibody-drug conjugates in the context of secondary CNS malignancies."

In TUXEDO-1, the clinical benefit rate was 86.7% in the intent-to-treat population and 92.9% in the per-protocol population. Median progression-free survival was 14 months, and median overall survival was not reached.

"This is a special patient population, and in need of effective treatment options," said ESMO discussant Mafalda Oliveira, MD, PhD, of Vall d'Hebron University Hospital in Barcelona. "Given the speculation regarding the ability of a high molecular weight drug such as T-DXd to penetrate the intact blood-brain barrier, it would be interesting to know if there were differences in the efficacy parameters according to whether the patients had received previous treatment for CNS disease, and also what was the impact of T-DXd on improvement of symptoms in these patients."

Bartsch noted that he and his colleagues actually performed that analysis -- with the proviso that the number of patients evaluated was very low -- which showed that patients with de novo brain metastases had a response rate of 100% compared with 66% for patients with progressive brain metastases after prior local therapy.

TUXEDO-1 was a single-arm phase II trial of 15 patients ages 18 and older with active brain metastases (either de novo or metastases that progressed after prior local therapy) who received T-DXd at the standard dose until progression or unacceptable toxicity, or any reason for treatment discontinuation.

As of data cutoff, nine patients had discontinued treatment (three due to progression and six for other reasons). Median patient age was 69 years, and all but one were women. Nine (60%) patients had an ECOG performance status of 0, and six (40%) had neurologic symptoms at baseline. Visceral metastases were present in 12 patients (80%), 40% had de novo brain metastases, and 60% had progressive brain metastases after local therapy.

The most common hematologic adverse events reported were anemia and neutropenia, while non-hematologic adverse events included fatigue, nausea, constipation, and hypokalemia. There were six serious adverse events in a total of four patients.

Quality of life, global heath status, physical function, and emotional function were all maintained over the entire treatment period, despite some declines in the first weeks of therapy. "Importantly, in a trial conducted in patients with active brain metastases, cognitive functioning was maintained over the entire treatment period," Bartsch said.

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