ESMO 2025 | DESTINY-Breast05: T-DXd vs T-DM1 in high-risk HER2+ early breast cancer

DESTINY-Breast05 was really a follow-up study to a previous trial, the Katherine trial, that had established that adjuvant T-DM1 was very beneficial for high-risk patients who did not have a pathologic complete response with neoadjuvant therapy. The trial really created a standard for patients presenting with intermediate to advanced disease to receive HER2-directed therapy, chemotherapy, many of whom will enjoy a pathologic complete response. It means they have a high probability for a cure. If they don’t though, they are at risk for recurrence. And the study showed even small amounts of residual cancer still had the risk. And the great thing was that T-DM1 cut the risk by 50%. It was a very large relative reduction. But we saw in the data that the highest risk patients, patients who presented with locally advanced cancer, what we call T4, or heavy nodal burden, N2, N3, if they had any residual disease, they already, when we first looked at Katherine, by three years, nearly a quarter of them had already recurred so it brought them a long way but it still left this risk. The other group were patients who still had cancer in their lymph nodes; it wasn’t quite as high, it was about 18%, but still you could see because we knew that with time those numbers were only going to get worse and we indeed saw that when we took Katherine out to seven years. But we didn’t wait to start working on something better because we were seeing already at that point what a remarkable drug T-DXd was. And we felt like we had enough evidence from both for efficacy and enough understanding of toxicities to justify taking it into the early setting in high-risk patients, which is what we did in Destiny Breast 05. When we set the study up, we thought we would at least need to be able to see a further reduction by a third over what you could get with T-DM1. So we powered the study to detect a hazard ratio of about 0.67. But we knew that, and we hope, you always hope the drug’s even better than that. And so you create these interim analysis points that will let you detect a larger effect. And we do the interim analysis. The statisticians say, well, you need 207 events to get that hazard of 0.67, you need about three-quarters of that to see something better, and that’s what we saw when we looked at our interim results, we saw a hazard ratio of 0.47, quite a bit better than 0.67, amounting to a 53% reduction in risk for the cancer coming back. The iDFS endpoint, short term for that, is how many patients are alive and cancer-free, which of course is what we want to see. And that’s what the studies show that I was able to report yesterday.

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