Strategizing ADC Use to Enhance Breast Cancer Outcomes

Paolo Tarantino, MD, PhD, discusses sequencing ADCs, managing cross-resistance, and understanding ADC composition for patients with breast cancer.

The increasing number of approved antibody-drug conjugates (ADCs) for breast cancer presents both significant opportunities and complex challenges for clinicians. As patients cycle through various lines of therapy, the need for diverse treatment options after disease progression becomes critical. However, the growing realization of potential cross-resistance among these agents requires a strategic approach to sequencing.

Paolo Tarantino, MD, PhD, spoke with CancerNetwork® during the 2025 International Congress on the Future of Breast Cancer East, hosted by Physicians Education Resource LLC®, to discuss the current considerations for integrating ADCs into breast cancer treatment paradigms, emphasizing the importance of understanding their composition and managing their unique safety profiles.

Tarantino focused on the challenge of sequencing ADCs, particularly in the absence of extensive prospective data. He also noted that the LEGO-like composition of ADCs—comprising an antibody, linker, and payload—is crucial for clinicians to comprehend. Finally, Tarantino described how the safety profiles of ADCs stem from both on- and off-target toxicities, which he highlighted by recognizing that ADCs are "targeted chemotherapies" and detailing how understanding this dual toxicity profile is essential for patient management.

Overall, Tarantino, a clinical research fellow at Dana-Farber Cancer Institute, emphasized that learning more about these overarching topics may lead to better treatment options for patients with breast cancer.

Given the growing number of approved ADCs for breast cancer, how are you sequencing these agents in different breast cancer subtypes? Are there specific biomarkers beyond the primary target that can inform sequencing?

We’re realizing that having more treatments approved is an important opportunity for our patients, and we do need more treatments because these patients cycle through different lines of therapy. After progression, we want to have options. At the same time, we’re realizing that sequencing these agents can come with some degree of cross-resistance. We conducted a large Flatiron Health study with [1490] patients, and we found that there is cross-resistance between fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu] and sacituzumab govitecan-hziy [Trodelvy], with sacituzumab used after T-DXd leading to a PFS of about 3 months, whereas traditional chemotherapies can lead up to 4 to 5 months.1

In truth, we still don’t have prospective data clarifying the role of sequencing. In the absence of that, I usually tend to do what I call the sandwich strategy, meaning that I try to switch the mechanism of action of my treatment after a TOPO1 ADC. After T-DXd, I consider using maybe a taxane or capecitabine before going back to another TOPO1 ADC. In truth, moving forward, we need to clarify this. We have several prospective trials looking at this: the phase 2 TRADE DXd randomized trial [NCT06533826], the phase 2 SATEEN trial [NCT06100874], [plus a] series of many prospective trials. We will start to see data at the end of this year, probably also next year, which will clarify the role of the sequencing of ADCs.

In which breast cancer settings or patient populations do you foresee ADC combinations having the most significant impact? What are some safety considerations for these approaches?

We are realizing that ADCs are extremely active, but combinations with the right drugs can make them even more active and effective. The first 2 phase 3 trials with ADC combinations that show the major benefit are the DESTINY-Brest09 trial [NCT04784715], which looked at first-line T-DXd and pertuzumab [Perjeta] with an extremely long PFS of 40 months, which is practice-changing.2 The ASCENT-04 trial [NCT05382286] with first-line sacituzumab govitecan and pembrolizumab [Keytruda] for the first-line treatment of metastatic triple-negative breast cancer with PD-L1 positivity also reached a very long PFS of 11 months plus for this type of disease.3

In truth, we’re realizing that adding another agent with a different toxicity profile can be beneficial. Still, combinations can always increase toxicity. It’s important to be mindful, to be rational, and to find the right combinations. In the future, we’re going to start to try combining ADCs. They already did it for urothelial cancer, combining enfortumab vedotin-ejfv [Padcev] and sacituzumab govitecan with very high efficacy, but also with toxicity. We’ll need to modulate the dose of ADCs to maximize their benefit and, in the future, probably combine them just like we combine anthracyclines with cyclophosphamide, carboplatin with paclitaxel, et cetera. It’s a brave new world ahead, and we’re just at the beginning of it.

What innovations in ADC composition, such as linkers and payloads, should nurses and advanced practice providers in oncology be aware of?

I consider ADCs like LEGO. You can switch or change every piece, and this leads to major differences in the clinical profile. Each of the 3 main pieces—antibody, linker, and payload—is extremely important in a very different way.

The payload is very important because it’s the one that can lead to cross-resistance. If you use a TOPO1 ADC, after that, if available, you may want to think of something different, like a microtubule ADC. In terms of resistance, you may want to switch the payload.

The linker is very important for the stability of the ADC. Very unstable linkers tend to lead to a lot of chemotherapy-related adverse effects [AEs], like alopecia, fatigue, and neutropenia. [On the other hand], very stable ADCs switch the toxicity profile toward the antibody, so you see less of the chemotherapy-related AEs but more of the antibody-related [AEs]. With TROP2 ADCs, you may start seeing some stomatitis or some rash, and with HER2, you may see some cardiotoxicity. It’s very important to understand that ADCs are placed on a stability continuum, and the linker is usually the place on this continuum where the ADC is.

Finally, the antibody is very critical for the type of disease you’re treating. We know that HER2 ADCs are very key for breast cancer, not only TROP2 ADCs, Nectin-4 for urothelial cancer, and tissue factor for cervical cancer; we’re learning more. It’s very hard to tell which one of the 3 pieces is most important, but it’s important to understand that each one has important repercussions and learning their repercussions is very important in oncology.

How will changes in ADC composition impact the safety profiles that patients can expect?

It’s critical to realize that the toxicity profile of ADCs comes from on- and off-target toxicities. On-target [toxicity] is related to what the antibody is reaching and binding to. With HER2 ADCs, you can have cardiotoxicity. With TROP2, you can have rash and stomatitis. With Nectin-4, you can have rash and dysgeusia. In general, it’s very important to think of those as on-target toxicity. In truth, what makes ADCs tolerable is the off-target toxicity of the chemotherapy that either gets released from the ADC or just reaches healthy cells in the body. Usually, the chemotherapy payload can lead to different toxicities. If it's a TOPO1 inhibitor, what you see with irinotecan is alopecia, nausea, and fatigue. If it’s a microtubule inhibitor like auristatin [with] MMAE, what you can see is peripheral neuropathy, neutropenia, and so on. It’s important to understand the difference between on-target and off-target toxicity. Every ADC has a mixture of both, but it’s usually the off-target toxicity, which is chemotherapy-related, that determines the maximum tolerated dose. It’s important to take that into account when you administer an ADC because they are targeted drugs, but they’re also chemotherapy. They’re targeted chemotherapies.

References

1. Tarantino P, Lee D, Foldi J, et al. Outcomes with trastuzumab deruxtecan by biomarker status, line of treatment and prior receipt of sacituzumab govitecan in a large real-world database of patients with metastatic breast cancer. ESMO Open. 2025. doi:10.1016/j.esmoop.2025.105330
2. Tolaney S, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):LBA1008. doi:10.1200/JCO.2025.43.17_suppl.LBA1008
3. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109