Trastuzumab deruxtecan doubles PFS in metastatic breast cancer with low HER2 expression

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Published: 5 Jun 2022
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Dr Shanu Modi - Memorial Sloan Kettering Cancer Centre, Manhattan, USA

Dr Shanu Modi talks to ecancer about her findings from a phase 3 randomised study, known as DESTINY-Breast04, investigating trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-low unresectable and or metastatic breast cancer.

The use of this new HER2-targeting antibody-drug conjugate doubled progression-free survival compared to standard-of-care treatment with conventional chemotherapy.

It also significantly improved overall survival for patients with metastatic breast cancers expressing low levels of the HER2 receptor, regardless of hormone receptor status.


Dr Modi notes that the results and key findings which were that DESTINY-Breast 04 is the first phase 3 trial of a HER-2 directed therapy in patients with HER2-low mBC to show a statistically meaningful benefit in PFS and OS compared to the standard of care treatment, regardless of HR status, with a generally manageable safety profile.

Watch Dr Modi's press conference on the study here

Watch Dr Meisel comment on the study here

Read the news story here 

We presented data from the first randomised trial of trastuzumab deruxtecan which is a new antibody drug conjugate that targets HER2. We randomised this against standard therapy, chemotherapy, for patients that have HER2-low metastatic breast cancer. This is an important study because it’s the first big study that has shown targeting HER2, low levels of HER2, is more effective than standard therapy for this population of patients that has HER2-low metastatic breast cancer. 

In this trial we looked specifically at patients who had advanced staged HER2-low metastatic breast cancer and we defined HER2-low as tumours with one plus or two plus no gene amplification. This was the specific group we enrolled; these patients had to have had at least one or maximum two lines of chemotherapy in the metastatic setting and the hormone positive patients additionally had to have gone through endocrine lines of therapy and be considered endocrine refractory. So it’s a more advanced population. The patients were randomised in a two to one fashion, trastuzumab deruxtecan was given by the approved label and in the chemotherapy arm of physician’s choice there was a number of options – capecitabine, eribulin, gemcitabine, taxol or paclitaxel, nab-paclitaxel – which are among the most commonly used chemotherapies in this setting. 

Our goal, really, the primary endpoint of the trial was to look at progression free survival in the hormone positive HER2-low patients, and then if we saw a positive signal there we would look at the PFS for the whole population of patients and similarly then overall survival for the hormone positive, and then all patients on the study. Our plan was to enrol 540 patients and we tried to balance out the hormone receptor subgroups based on the natural prevalence we see in HER2-low breast cancer. So our goal was to enrol about 480 hormone positive and about 60 hormone receptor negative HER2-low patients. 

What are the differences between the PFS and OS results?

So for the efficacy endpoints, starting with the PFS endpoints for our primary analysis population in the hormone receptor positive patients, the hazard ratio for PFS was 0.51 and this was statistically significant with a p-value of less than 0.0001. What that translated to was an improvement in median progression free survival of 5.4 months up to 10.1 months, which is very significant for a late stage setting in breast cancer. When we looked at the overall study population, we found very similar results; the PFS hazard ratio was nearly identical at 0.5, and very similar improvement in median PFS, approximately five months up to approximately ten months. So that was really great to see, that kind of gain in survival for these late-stage patients. One of the key secondary endpoints, of course, was overall survival, and again we had a statistically significant hazard ratio of 0.64 and we saw improvements in median survival from approximately 16 or 17 months up to almost 24 months. So, again really satisfying to see gains in over six months in survival for this sort of refractory population of patients. We don’t often achieve that in the late-stage metastatic setting.

Are there any key findings from the toxicity report?

So lung toxicity is a known and important toxicity of T-DXd. We monitor for that closely and in this trial we saw an incidence of 12%. The majority of the cases were low grade, so grades 1 and 2 and reversible, but we did have a few high grade events. In total there were three deaths from lung toxicity for an incidence of 0.8%. I think it’s just a reminder again that this is an important toxicity of this drug and it really warrants vigilance and early intervention. Having said that, in spite of these ILD events, overall we’re seeing a very impressive survival advantage from T-DXd, and so I think the risk benefit is still towards this as being an important drug for patients. 

There are two really important points, takeaway messages, from this research. The first is that we have established for the first time a new subgroup of patients which we call HER2-low that have cancers that are targetable, with a HER2 targeted agent. We have really set trastuzumab deruxtecan as the standard of care for this population of patients. Some paradigm shifting discovery in this study. It’s going to force us to rethink about the subgroups within HER2 negative breast cancer. These data really have the potential to impact survival for about half of our patients with metastatic breast cancer.