Review of Key Data Supporting Recent Developments in the HER2+ mBC Landscape

Neil M. Iyengar, MD: So in the second line setting, we now have newer agents available to us, specifically trastuzumab deruxtecan which was compared to T-DM1 in the DESTINY-Breast03 trial. We have data from both the DESTINY-Breast01 trial, the phase two study, as well as the DESTINY-Breast03 trial demonstrating the tolerability, safety and efficacy of the newer antibody drug conjugate trastuzumab deruxtecan in this setting. And specifically in the phase three DESTINY-Breast03, we saw both an overall survival as well as a progression free survival benefit of trastuzumab deruxtecan compared to T-DM1 in the second line setting or beyond. In addition, the adverse effects associated with trastuzumab deruxtecan were overall well tolerated with some concern for interstitial lung disease or pneumonitis. But the overall rate of any grade ILD was about 11% in DESTINY-Breast03, which is consistent with other trials of trastuzumab deruxtecan across the DESTINY-Breast portfolio. Some other side effects to be aware of, of course are nausea and vomiting were increased in trastuzumab with trastuzumab derustecan versus trastuzumab emtansine. Alopecia can also occur with trastuzumab deruxtecan. The grade one rate of alopecia was about 25% in DESTINY-Breast03 and about 10% in DESTINY-Breast01. There of course, are other adverse effects, but I want to mention those specifically because those are things that particularly impact our patients.

We also saw subgroup analysis here at ESMO that looked at the benefit of trastuzumab deruxtecan versus T-DM1 in DESTINY-Breast03 by prognostic factors. Specifically, the benefit of trastuzumab deruxtecan was demonstrated versus T-DM1 in patients who presented with de novo metastatic disease, patients who were early progressors after neoadjuvant or adjuvant treatment, and patients who had previously received two or more prior lines of therapy. So this data really reassures us of the efficacy of trastuzumab deruxtecan across all prognostic subgroups.

So now we have NCCN updated recommendations. CLEOPATRA based regimen, of course, is a category one recommendation in the first line setting. We also now have trastuzumab deruxtecan as a category one recommendation in the second line setting based on data from DESTINY-Breast03. T-DM1 is a category 2A recommendation in the second line setting. I should also mention in terms of NCCN guidelines, that there is a footnote which does suggest or recommend tucatinib and capecitabine with trastuzumab for patients with brain metastasis, which could be considered in the second line as well.