Updates in Metastatic HER2 Positive Breast Cancer Treatment - Episode 2

DESTINY-Breast03: T-DXd in HER2+ Metastatic Breast Cancer

Expert perspectives on the DESTINY-Breast03 trial, which compared T-DXd to T-DM1 in the setting of relapsed/refractory HER2+ metastatic breast cancer.


Cynthia Lynch, MD: DESTINY-Breast03 trial was a phase 3 randomized trial that was comparing trastuzumab deruxtecan [T-DXd] to trastuzumab emtansine [T-DM1] in the second-line setting, following the use of trastuzumab containing regimen and a taxane. That trial looked to ask that question of, ‘What should be the second-line therapies? What should we be considering as a second-line therapy after patients have progressed on a trastuzumab-containing regimen and a taxane?’ That did include individuals who were metastatic and were progressing on that combination. It also included individuals who had had a metastatic recurrence or unresectable recurrence within 6 months of having completed their neoadjuvant or their adjuvant chemotherapy. As I mentioned previously, the background to that was that previously through the AMELIA trial, that is where T-DM1 had gotten its approval for usage and became the standard second-line therapy. How they differ is, T-DXd is one of the drug antibody conjugates, so it has trastuzumab with a linker molecule attached to a cytotoxic agent. In the case of trastuzumab deruxtecan, it is a topoisonorase1 inhibitor. It’s a little bit different from T-DM1; what we term the payload, how much chemotherapy is packed on there, that ratio is higher with T-DXd than what we have with T-DM1. How that drug works is, sometimes people use the term a smart bomb; it uses the antibody to deliver the chemotherapy directly to those HER2 overexpressing cells. Then there also is some dispersion amongst the cells, even in that region as well that can have cytotoxic effects too. Just to talk a little bit more about the trial design itself; when you look at the randomization, the patient characteristics, and demographics of individuals in each of the two groups, it was well balanced. About a little under ½ of patients on both arms of the trial had received prior chemotherapy in the metastatic setting; about 60% of patients in each of the arms of the trial had received prior pertuzumab. Patients who had brain metastases were allowed to enter the trial, however they had to have stable asymptomatic disease or been previously treated. The percentages for that on each of the group is about 23.8% of patients on the T-DXd group had brain metastases whereas 19.8% on the T-DM1 arm had brain metastases. The overall results showed a 72% reduction in risk of progression compared to looking at that of T-DM1. At 12 months, when you look at the progression-free survival at that point, that was 75.8% with T-DXd versus 34% with T-DM1; a substantial improvement in those percentage of patients who were alive and without progression at 12 months between those 2 arms. As far as investigator-assessed median progression-free survival, it was 25.1 months with T-DXd versus 7 months with T-DM1. Again, a substantial statistically significant improvement in the investigator-assessed progression-free survival. Also, when you look at overall responses seen for T-DXd, it was 79.7% versus 34.2%. There were complete responses seen with around 16% for the T-DXd group versus 8%, so almost a doubling of the complete responses seen with T-DXd. When you look at brain metastases, the median progression-free survival of individuals who had brain metastases was 15 months for T-DXd versus 3 months for T-DM1. If you look at overall response rates, it was 67% versus 20% in favor of T-DXd, and then also they assessed for intracranial responses to therapy where there was an overall 63.8% intracranial response versus 33.3% intracranial response for T-DM1. Again, very significant responses in brain metastases. There were complete responses seen in the brain as well, that was 27.8% versus 2.8% again, in favor of T-DXd.

Transcript edited for clarity.