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ESMO Breast 2021 | ADCs for HER2+ and HER2-low breast cancer

Rupert Bartsch, MD, Medical University of Vienna, Vienna, Austria, shares an update on the use of antibody-drug conjugates (ADCs) for the treatment of HER2+ and HER2-low breast cancer. Prof. Bartsch gives an overview of the history of ADCs for breast cancer, talking on the limitations of trastuzumab emtansine (T-DM1) and the need for alternative therapies. Prof. Bartsch highlights the recent approval of the tyrosine kinase inhibitor tucatinib in combination with capecitabine, and approval of trastuzumab and trastuzumab deruxtecan by the European Medicines Agency (EMA). Finally, Prof. Bartsch discusses the treatment of HER2-low breast cancer and the role of sacituzumab govetican in the treatment of triple-negative breast cancer. This interview took place at the virtual European Society for Medical Oncology (ESMO) Breast Cancer Congress 2021.

Transcript (edited for clarity)

It’s my pleasure now to give you a short overview about recent developments in the field of antibody-drug conjugates in focus on HER2-positive breast cancer. But as you know, it’s not just in HER2-positive breast cancer, but antibody-drug conjugates are also important, or will be soon important, in HER2-Low breast cancer, a new subtype of breast cancer. And if we think of sacituzumab govitecan also in triple-negative breast cancer...

It’s my pleasure now to give you a short overview about recent developments in the field of antibody-drug conjugates in focus on HER2-positive breast cancer. But as you know, it’s not just in HER2-positive breast cancer, but antibody-drug conjugates are also important, or will be soon important, in HER2-Low breast cancer, a new subtype of breast cancer. And if we think of sacituzumab govitecan also in triple-negative breast cancer.

The whole story of course started with T-DM1, trastuzumab emtansine, so the conjugate of trastuzumab and emtansine derivative, a microtubule inhibitor bound to trastuzumab. T-DM1 is still the standard treatment approach in second line and HER2-positive metastatic breast cancer, a highly active drug, but there are two issues of course. One is that eventually patients will still progress, so we need other treatment options from the third line setting on. And then of course the standard HER2-directed drugs, such as trastuzumab, pertuzumab and also T-DM1, are now being widely used in the neoadjuvant, adjuvant and past neoadjuvant settings. So there will be situations if patients progress after all these standard treatment approaches in early-stage breast cancer, where completely novel drugs will be needed.

And just recently the European Medicines Agency has approved two novel drugs. One is tucatinib, the third-generation tyrosine kinase inhibitor in combination with capecitabine, and trastuzumab, the drug that has shown high activity, improvement of progression-free survival and overall survival and especially considerable activity in patients with active brain metastasis. And then of course, trastuzumab deruxtecan, the third-generation antibody-drug conjugate. And that’s the kind you get, again of trastuzumab and a topoisomerase I inhibitor, deruxtecan. And this is a topoisomerase I inhibitor with a very high inhibitory activity. It’s about ten-fold higher than SN-38, which is the active metabolite of irinotecan. And it also has a higher drug to antibody ratio, which is in the range of about eight to one. And in addition, the chemotherapeutic agent deruxtecan has an increased membrane permeability. So, a bystander effect can be believed that it happens, so, which means that we are able to overcome disease heterogeneity.

What data do we have for trastuzumab deruxtecan? Well, it has been approved based upon the single-arm Phase II trial DESTINY-Breast01, and heavily pretreated patients that received a median of six prior treatment lines received single-agent trastuzumab deruxtecan. And as you know, a very high response rate has been observed in excess of 60%. And at the 2020 virtual San Antonio breast cancer symposium, a prolonged progression-free survival in the range of 19 months was observed. So, this shows the very high activity of trastuzumab deruxtecan. Of course, there’s the caveat that these data come from a single arm Phase II trial, and we’re still awaiting the randomized data, which I believe to be available this year.

What else do we know about trastuzumab deruxtecan? Well, the most important toxicity perhaps, which occurs in the range of about 15% of patients is ILD pneumonitis. This is something the physicians and the patients both need to be aware of, and the patients need to be properly informed. Often, it’s low grade, it usually happens relatively early on during the first six to 12 months with treatment with a lower risk during the later treatment periods. Important to react promptly to the diagnosis of ILD. Interruption of treatment, permanent stop of trastuzumab deruxtecan, if grade two or higher ILD occurs and quick initiation of corticosteroids. So usually, the issue of ILD is manageable with these measures.

It’s important to see that trastuzumab deruxtecan also has activity in a new subtype of breast cancer, newly defined subtype of breast cancer, which we called the HER2-low expressing patients. HER2-low expression means less HER2 protein in the cell membrane by immunohistochemistry, so 1+ or 2+ not 3+. And in case of 2+, no HER2 neogene amplification.

It shows considerable activity there as well. It’s the first HER2-directed agent that also has activity in the subset of HER2-low patients. And it’s important to realize that T-DXd is not the only of those novel antibody drug-conjugates, but there is several in clinical development. For example, one being 6985 trastuzumab duocarmazine, which is a conjugate of trastuzumab again and the alkylating agent duocarmycin.

When we look at different other breast cancer subtypes, such as triple-negative, there is also a great need for novel treatment options. Of course, immunotherapy has some activity there, but the focus is also there on antibody-drug conjugates, and perhaps the most promising drug is sacituzumab govitecan, which was shown in the Phase III ASCENT trial to provide significantly higher activity than conventional chemotherapy in pre-treated patients with clinically relevant and statistically significant prolongation of progression-free survival and overall survival as well.

In summary, I think with better understanding of the antibody-drug conjugate technology this class of drugs will see further use in the different breast cancer subtypes. They are very, very promising. And trastuzumab deruxtecan of course, is one of the most interesting agents in this field.

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Disclosures

Rupert Bartsch, MD, has participated in an advisory role for AstraZeneca, Daiichi, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche and Seagen; has received lecture honoraria from AstraZeneca, Celgene, Eli-Lilly, Novartis, Pfizer, Pierre-Fabre, Roche and Seagen; and has received research support from Daiichi, MSD, Novartis and Roche.