ESMO Gynae 2025 | Can we currently sequence ADCs in ovarian cancer?
Angeles Secord, MD, Duke Cancer Institute, Durham, NC, comments on the limitations of sequencing antibody-drug conjugated (ADCs) in ovarian cancer, highlighting the need for well-designed clinical trials to address the question of prioritizing drugs based on target expression and payload. The current FDA approvals for mirvetuximab soravtansine and trastuzumab deruxtecan provide a starting point, but further research is needed to determine the optimal sequencing and payload combinations. This interview took place at 2025 European Society for Medical Oncology (ESMO) Gynaecological Cancers Congress in Vienna, Austria.
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Transcript
Well, I think in terms of sequencing, we’re very limited by what’s clinically available. So there’s currently mirvetuximab that is FDA approved for patients who have platinum-resistant ovarian cancer that has high levels of FR-alpha expression. And then we have the tumor-agnostic approval for trastuzumab, not dexrazoxane, that targets HER2. And that’s the FDA approvals for patients who have a three-plus expression of HER2...
Well, I think in terms of sequencing, we’re very limited by what’s clinically available. So there’s currently mirvetuximab that is FDA approved for patients who have platinum-resistant ovarian cancer that has high levels of FR-alpha expression. And then we have the tumor-agnostic approval for trastuzumab, not dexrazoxane, that targets HER2. And that’s the FDA approvals for patients who have a three-plus expression of HER2. And then the NCCN compendial listing is a little bit different for both mirvetuximab and trastuzumab, not dextran. So our sequencing is limited to those two drugs right now. But as additional drugs enter the armamentarium, the question of sequencing is going to be very interesting. Like what is the drug that we should prioritize in the setting? And how can we choose that prioritization? Should it be based on the extent of expression that you see in the target? For instance, if somebody has really high expression of FR-alpha, are you going to choose an FR-alpha targeting ADC compared to if their HER2 protein expression is 2 plus? And I, quite frankly, don’t know the answer to this. However, I think it’s really important that we’re conducting clinical trials that address this issue of sequencing. The other issue to take into account is the payload. So you can have two ADCs that target FR-alpha, but if they have different payloads, they’re different drugs. So a patient who’s been on mirvetuximab based on that FDA indication and then progresses may be a candidate for another FR-alpha drug that has a different payload. I’ve had that experience because we had a trial at Duke where the clinical trial drug targeted FR-alpha, but it was a TOP1A payload and had patients that still appear to have a clinical benefit. So the other issue that comes up is maybe you have drugs that target different proteins, but they have the same type of payload. And will patients benefit when you use the same payload, but in the setting of a different target. So many opportunities in the future for us to do well-designed clinical trials that can answer these questions. Right now, I think you just have to use your clinical expertise and what is currently FDA approved or clinically available for patients, keeping in mind of what is the side effect profile and the patient profile.
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