Paolo Tarantino, MD, on the Current and Future Landscape of Antibody-Drug Conjugates

At IBC East, I had the opportunity to speak about antibody-drug conjugates, both those that are cur-rently present in our treatment algorithms, and also the ones that are coming. I think it's really an exciting field right now because we are being able to deliver chemotherapy in a more effective way, even among patients with breast cancer that have chemotherapy-refractory disease. We saw this with trastuzumab deruxtecan, an anti-HER2 antibody-drug conjugate that first showed to improve outcomes in pretreated patients in a metastatic setting in DESTINY-Breast04, and more recently, also in patients that received prior endocrine treatment but never received chemother-apy. Also shown to benefit much more for T-DXd compared to traditional chemotherapy in DESTINY-Breast06. And this is why, currently, we consider T-DXd, trastuzumab deruxtecan, an option for pa-tients that have hormone receptor-positive or even triple-negative metastatic breast cancer that have previously received chemotherapy, or even in certain cases, before the first line of chemo-therapy. Whereas, regarding other antibody-drug conjugates, sacituzumab govitecan was the first anti-TROP2 antibody-drug conjugate to be approved for pretreated triple-negative metastatic breast cancer, and more recently, also for hormone receptor-positive metastatic breast cancer. So putting all this together, where we used to have only traditional chemotherapy, now we have two new antibody-drug conjugates. And there's a third that may come soon, datopotamab derux-tecan, that also is a similar highly-potent topoisomerase inhibitor-based antibody-drug conjugate targeting TRROP2 that has positive phase III data in hormone receptor-positive disease. All of these agents raise both challenges and opportunities. The challenges being that having differ-ent ADCs, we have similar payload, we don't know yet if we can effectively sequence them in the clinic and achieve the same activity within clinical trials. And so there has been some retrospective studies showing that the second or third ADC seemed to have impaired activity compared to the first, but we really don't have a perfect answer and we need prospective trials in this field, which are ongoing. And then we have the lack of effectively predicting biomarkers. I mentioned T-DXd is approved for patients with HR-positive disease, even triple-negative. We used to think that you needed HER2-low expression for this drug to be active, meaning either 1+ or 2+ non-amplified. But, in truth, re-cently we saw that even HER2 0 patients can benefit until there is some ultra low-HER2 expression. Whereas with sacituzumab govitecan and Dato-DXd, there was no TROP2 selection. And, in truth, what we're realizing is that immunohistochemistry that we've been using for a long time to select patients may really not be the best assay to look at the target of these antibody-drug conjugates and we may need to develop more quantitative and refined and sensitive assays, which we are de-veloping. And by the end of the year we hope to show some data in this setting. And then another challenge pertains to toxicity profiles, because ADCs were developed as a matter to increase the activity of chemo, but also make it more tolerable. Because the idea is that you bind the chemotherapy to an antibody through a molecular linker in order for the chemotherapy to selectively reach the tumor cells. But, in truth, we still don't see this enough as we would like to see. There is still some chemotherapy achieving bystander toxicities, toxicities that are not on target, and we do see alopecia, nausea, fatigue, peripheral neuropathy, and all side effects we used to see with chemotherapy. I do believe that in order to improve upon this and to achieve a new generation of ADCs do not harbor these toxicities, we have to remember that ADCs are modular in the way they're construct-ed. And so you can decide to optimize, to fine tune each part of the ADC, either the monoclonal antibody and to make it masked, meaning that you add a peptide mask that does not allow the ADC to bind to normal tissues, or you can also make it bispecific or trispecific in order to increase the binding affinity to tumor cells. Or you can modify the linker. Most of the linkers that we utilize are currently cleavable linkers that detach based on some feature of the tumor microenvironment, either the acidic microenvironment or some capsaicin present in the microenvironment. But, in truth, we're starting to develop site-specific, much more stable linkers for ADCs that may hope to make these ADCs less toxic in the future. Finally, I think we need to differentiate the payloads. The ADCs of the future are not going to carry early topoisomerase inhibitors or microtubule inhibitors as most of the ADCs currently, but they may also harbor more than one type of chemotherapy or they may deliver immunotherapy mole-cules, radioisotopes, or even protein degraders. There's every potential molecules that could be delivered in a selective way through ADCs. And there's dozens of new ADCs that are in the pipeline in phase I and II testing, and I do believe that in the next five years, we're going to see more and more ADCs be approved and hopefully improved not only the prognosis of our patients with meta-static breast cancer, but hopefully even be able to cure more patients from early breast cancer, with some phase III trials already ongoing for which I think there is a lot of optimism right now.