Antibody-drug conjugates (ADCs) have shown promise as treatment for patients with advanced breast cancer. These agents have been first tested in heavily pretreated patients and have begun moving into earlier stages of treatment based on clinical trial outcomes. In an in-person Case-Based Roundtable event moderated by Kit Yu Lu, MD, a medical oncologist at UPMC Hillman Cancer Center in Harrisburg, Pennsylvania, the data for the 3 approved ADCs were presented and participants considered the line of therapy where they were used as well as the efficacy and unique tolerability profile of each agent.
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Targeted Oncology: What are the ADCs in use to treat metastatic breast cancer?
Kit Yu Lu, MD: We now have 3 ADCs in the market. There are 2 TROP2-directed ADCs, sacituzumab govitecan [Trodelvy] that’s been approved and then recently came the approval of datopotomab deruxtecan [Datroway]. Both are TROP2-targeted with a topoisomerase-1 [inhibitor and] payload: 1 is SN38, the other one is DXd. Then we have a HER2-directed ADC with trastuzumab deruxtecan [T-DXd; Enhertu]. As we know, T-DXd has been approved since 2019 for HER2-positive metastatic breast cancer and then [received] subsequent approval for HER2-low recently. In January 2025, it was approved for the first-line indication for HER2-low, and then that study [DESTINY-Breast06; NCT04494425] also included the subset of patients who are HER2-ultra low.
What updates have there been in the NCCN guidelines in the endocrine-refractory setting?
The NCCN guidelines are for those patients who are considered endocrine refractory, not just the patients with impending visceral crisis, but…in terms of the systemic therapy we would consider, T-DXd is now one of the category 1 preferred agents in the first-line setting [for HER2-low].1 There are also other recommended regimens. Before we go into the first line, we’re going to review 2 studies in the second and subsequent lines of therapy.
What trial data support the use of sacituzumab in this setting?
TROPiCS-02 [NCT03901339] was a phase 3 study looking at metastatic hormone receptor–positive HER2–negative patients. They had to have at least 1 endocrine therapy, a taxane, and CDK4/6 in any setting, and then they had to have at least 2 but no more than 4 lines of chemotherapy. These were patients whose disease progressed and was endocrine refractory. They were candidates for chemotherapy, and they were in the later lines of therapy. Patients were randomly assigned on a 1:1 basis to sacituzumab vs physician’s choice of chemotherapy, and that was eribulin, capecitabine, vinorelbine, and gemcitabine—typical chemotherapy that we would consider when they go through those subsequent lines of therapy. The primary end point was looking at progression-free survival [PFS] by blinded independent review committee, and then a whole host of secondary end points.
The baseline characteristics are pretty well balanced, with good performance status.2 The main thing is looking at the lines of therapy, the majority of the patients, about 60%, had 3 or 4 lines of therapy, and then about 40% had 2.
The study did meet the primary end point with sacituzumab; the median PFS was 5.5 months vs 4.0 months with chemotherapy. It’s modest, although this was subsequent to many lines of therapy. At the prespecified landmark analysis, we do see that the improvement was consistent throughout the different landmarks. At 6 months, about 46% of the patients were still alive and progression free, compared with 30% in the treatment of physician’s choice. Then you see a consistent improvement even at the later time points.
The overall survival [OS] final analysis also met the study end point. There was a statistically improvement in survival in favor of sacituzumab. The median OS was 14.4 months vs 11.2 months with the standard chemotherapy arm, and that HR for OS was maintained with 5 additional months of follow-up [HR, 0.79; 95% CI, 0.65-0.96; P = .020].2,3
How was sacituzumab tolerated in this trial?
In terms of treatment-emergent adverse events [AEs], they were well balanced, although there was a little bit more grade 3 AEs with sacituzumab vs chemotherapy and a bit more dose delay and reduction.2 No additional safety signals were found in additional follow-up. Some of the AEs that we have to be mindful of [include] neutropenia…there was more grade 3 neutropenia in the sacituzumab arm, although in that study, granulocyte colony–stimulating factor was not mandated for prophylaxis. We now know how to handle the neutropenia. Diarrhea is also another treatment-emergent grade 3 AE that we have to keep in mind; 10% of the patients had grade 3 toxicity vs just 1% in the treatment of physician’s choice. I think we have to just be cognizant about the cytopenia and the gastrointestinal symptoms.
Can sacituzumab be used earlier in treatment of metastatic breast cancer?
Because of the improvement in PFS and OS and the ASCENT trial [NCT02574455], we now have an emerging trial with ASCENT-07 [NCT05840211]. PFS is the primary end point. It will be completed in September 2025. This is looking at sacituzumab in an earlier-line setting, in the first-line setting, comparing with standard chemotherapy. We’ll see what the data show and see what else we have in terms of our treatment in the first-line setting. It’s getting more confusing, because now we have better treatment up front.
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DISCLOSURES: Lu previously reported consulting or advisory role with AstraZeneca, Daiichi Sankyo, and Gilead Sciences; and speakers’ bureau with AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merck, Seagen, and Stemline Therapeutics.
References:
1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer; version 4.2025. Accessed March 31, 2025. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
2. Tolaney SM, Bardia A, Marmé F, et al. Final overall survival (OS) analysis from the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in patients (pts) with hormone receptor–positive/HER2-negative (HR+/HER2–) metastatic breast cancer (mBC). J Clin Oncol. 2023;41(suppl 16):1003. doi:10.1200/JCO.2023.41.16_suppl.1003
3. Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423-1433. doi:10.1016/S0140-6736(23)01245-X