Patients with HER2-positive (HER2+) cancers that are immunohistochemistry 3 positive (IHC3+) and/or fluorescence in situ hybridization (FISH) amplified have been benefiting from HER2-directed therapy for the last 20-plus years. What has changed in recent years is the gradual addition of more and more HER2-targeted therapies, most recently with ADCs, first with the first-generation ADC T-DM1 and now with the second-generation drugs, particularly T-DXd. 

The phase 2 DESTINY-Breast01 study evaluated T-DXd in patients with metastatic HER2+ breast cancer who had previously received T-DM1, with the study showing a very durable benefit. This led to the initial accelerated approval of T-DXd by the US Food and Drug Administration. Since it was a small study, a larger confirmatory trial was necessary. The phase 3 DESTINY-Breast02 evaluated the same patient population (ie, previously treated with T-DM1) and randomized patients to receive T-DXd or physician’s choice of capecitabine with lapatinib or capecitabine with trastuzumab. The response rate was approximately 70% with T-DXd, and there was a substantial improvement in both progression-free survival (PFS) and overall survival with T-DXd compared with treatment of physician’s choice. There were no new safety signals.  

From a clinical standpoint, in the United States, where T-DXd has been available for some time, we already had data showing the superiority of T-DXd over T-DM1 in earlier lines of therapy (ie, prior treatment with trastuzumab and a taxane). These results came from the phase 3 DESTINY-Breast03 trial, which randomized patients to receive T-DXd or T-DM1. Updated results after 28 months of follow-up showed that PFS was 4 times longer with T-DXd than with T-DM1. This is much longer than we have seen with any other drug in pretreated breast cancer. T-DM1 is a good drug, and the fact that T-DXd was so much more effective is certainly compelling. In terms of drug sequencing, we should probably be using T-DXd before T-DM1 because it is so effective in the second-line setting. To be able to tell heavily pretreated patients that their disease could be controlled for more than 2 years with T-DXd is very compelling and reassuring to them. 

The other major change with regard to HER2-targeted therapy is that we are now successfully targeting HER2-low disease. Roughly 50% of all breast cancers may be HER2-low. The DESTINY-Breast04 trial is the study that demonstrated that T-DXd has a significant amount of efficacy in patients with HER2-low breast cancer. T-DXd produced a PFS that was double what was seen with chemotherapy, as well as a high response rate of approximately 50% in both patients with hormone receptor–positive HER2-low disease and patients with hormone receptor–negative HER2-low disease. There is a lot of ongoing work in this space, but one important thing to highlight here is that HER2-low status can change. So, for instance, in a patient whose primary cancer was HER2-negative, there should be retesting in the metastatic setting to see if the disease has become HER2-low.