Sequential Antibody Drug Conjugates for Patients With Metastatic Breast Cancer

At the Great Debates and Updates in Women’s Oncology meeting, Neil Iyengar, MD, Memorial Sloan Kettering Cancer Center, New York, New York, participated in a debate on whether antibody drug conjugates (ADCs) should be used sequentially for patients with metastatic breast cancer. Dr Iyengar debated against using ADCs sequentially.

Dr Iyengar explained, “My argument is that we would not want to sequence an ADC that has the same payload as a prior ADC that we used in that setting.”

Transcript:

Hi, I'm Neil Iyengar, medical oncologist and associate attending at Memorial Sloan Kettering Cancer Center in New York. Here at the Great Debates in Women's Oncology, it was my pleasure to argue the stance of, we should not be using ADCs in sequence. In other words, we should not be using antibody drug conjugates after previously using an antibody drug conjugate when treating metastatic breast cancer.

In my presentation, I highlighted the very sparse amount of data that we have available to address this question, but conceptually speaking, if we think about the currently approved ADCs for metastatic breast cancer, they have very similar payloads, essentially topoisomerase 1 inhibitors, and we have different antibody drug targeting, or antibody targeting I should say specifically.

We have HER2-directed ADCs, and we have TROP2-directed ADCs. The issue is part of the efficacy of these ADCs has to do with the bystander effect and the release of the payload, or the chemotherapy, from the protein link. And ultimately, when we think about that being part of the efficacy, we don't sequence chemotherapies that are similar to each other. For example, we don't sequence Taxotere [docetaxel] after Taxol [paclitaxel]. Similarly, my argument is that we would not want to sequence an ADC that has the same payload as a prior ADC that we used in that setting.

When we look at the small retrospective cohort studies that are available, I would argue that the data are consistent with this hypothesis. In other words, the progression-free survival of ADC number two after ADC number one is quite low, generally less than 3 months with ADC number two. And that leaves a lot of room for improvement, but also raises the possibility that there is cross-resistance to ADC number two, typically sacituzumab govetican after trastuzumab deruxtican or vice versa. Either way, we see very limited median PFS for the second ADC. I concluded that we should not be sequencing ADCs at this point until we see data from ongoing clinical trials, prospective randomized controlled trials that will be addressing this question.

Now in clinical practice, I have to say that I really take a patient-by-patient evaluation to decide whether or not this is a strategy that we may want to use. For example, the toxicity profile of standard chemotherapy versus ADC may help in that decision making, if there is a patient who has low-volume disease and either has struggled with chemotherapy in the past or I'm concerned about a particular aspect of chemotherapy, like cytopenia, and I think that an ADC may be better tolerated for that individual, I may choose to sequence that after a prior ADC. But it's really driven by a patient-by-patient decision in clinical practice, and we look forward to the trial data to inform this very relevant question.

Source:

Iyengar, N. “Debate: Antibody Drug Conjugates as the New Frontier: Should We Use Them Sequentially? — No, the Benefit is Really Just for the First ADC.” Presented at Great Debates and Updates in Women’s Oncology. May 3-4, 2024; New York, NY.