SABCS 2025 | Real-world outcomes challenge sequential TOP1-ADCs in HER2-low breast cancer
Francois Poumeaud, MD, Oncopole Claudius Regaud, Toulouse, France, discusses findings from the ADC-Low-Europe retrospective real-world cohort evaluating sequential topoisomerase 1 (TOP1) antibody–drug conjugates (ADCs) in HER2-low metastatic breast cancer. In patients treated with sacituzumab govitecan and trastuzumab deruxtecan, outcomes with a second ADC were generally poor, with short progression-free survival and high rates of primary resistance. Results raise concerns about cross-resistance, and highlight the need for optimized selection of initial ADC therapy. This interview took place at the San Antonio Breast Cancer Symposium (SABCS) 2025 Meeting in San Antonio, TX.
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Transcript
This is an international retrospective cohort that we led and which included 475 patients with her2-metastatic breast cancer who received two ADCs targeting topoisomerase-1, sacituzumab-govitecan and trastuzumab-deruxtecan independently of the order. Most of the patients received a classical or recommended ADC sequence so most of patients with triple negative breast cancer received sacituzumab-govitecan as the first ADC...
This is an international retrospective cohort that we led and which included 475 patients with her2-metastatic breast cancer who received two ADCs targeting topoisomerase-1, sacituzumab-govitecan and trastuzumab-deruxtecan independently of the order. Most of the patients received a classical or recommended ADC sequence so most of patients with triple negative breast cancer received sacituzumab-govitecan as the first ADC. So most of patients with triple negative breast cancer receive the Sacituzumab-Govitecan as the first ADC. And most of patients with hormone receptor positive disease receive Sacituzumab as the first ADC. Regarding efficacy, we can see that most of patients that will have experience in objective response with the first ADC, when they are going to be exposed to a second ADC, they will have, for most of them, no response. And the median PFS with a second ADC is only 2.7 months. So that’s really concerning and really disappointing. What’s also really concerning is to consider that even patients that had an objective response to a first ADC will not necessarily have a good response to ADC2. So we cannot assume that based on clinical parameters, we can identify in our population which patients are going to drive a benefit for the second ADC when it’s targeting the same topoisomerase payload. I think there are two questions inside this one. First is, should we give some intermediate chemotherapy between ADC1 and ADC2, which is a sandwiched strategy that we sometimes want to use? What we report in our data is that patients that will have an ADC sequence will have a better effect of the second ADC when there is no treatment between ADC1 and ADC2. So the sandwich technique does not seem to be a good strategy technique to do in our daily practice. And the second question is, is there still some place for an ADC sequencing I think the answer is yes because we are still 30% of our patients that will have a benefit and will have an objective response when given a second ADC even though 70% of patients will progress upon the first evaluation when given a second ADC so we need to identify that subset of patients and I think good candidates to a second ADC might be patients with central nervous system metastasis because we know that TDXD in this population could be at least efficient. So if we’ve got a patient with triple negative breast cancer that had progressed on the systemic treatment and if she progressed in the brain, so maybe she could be a candidate for a second ADC if it is TDXD.
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