Nerea Lopetegui-Lia, MD, is a breast medical oncologist and assistant professor at The Ohio State University Comprehensive Cancer Center—James

Dr Lopetegui-Lia on Ongoing ADC Research in Metastatic TNBC

"The aim of the phase 3 TROPION-Breast02 trial is to evaluate the efficacy and safety of Dato-DXd vs investigator’s choice of chemotherapy in patients with locally advanced or metastatic TNBC who are not candidates for PD-L1 or PD-1 inhibitor therapy. The phase 3 TROPION-Breast05 trial is also ongoing."

Nerea Lopetegui-Lia, MD, a breast medical oncologist and assistant professor at The Ohio State University Comprehensive Cancer Center—James, discussed the ongoing development of antibody-drug conjugates (ADCs) for patients with triple-negative breast cancer (TNBC) and their potential effect on the future treatment paradigm.

There are several highly anticipated studies evaluating ADCs coming down the pike in the TNBC field. One such trial is the phase 3 TROPION-Breast02 trial (NCT05374512), which is evaluating the efficacy and safety of datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) vs investigator’s choice of chemotherapy in patients with locally advanced or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-L1 or PD-1 inhibitor therapy, Lopetegui-Lia stated. The phase 3 TROPION-Breast05 trial (NCT06103864) is also ongoing; this study is investigating Dato-DXd with or without durvalumab vs chemotherapy plus pembrolizumab (Keytruda) in patients with PD-L1–positive, locally recurrent, inoperable or metastatic TNBC. Importantly, patients with active brain metastases will be excluded from enrollment, she added.

Ongoing efforts also include the phase 3 ASCENT-04 trial (NCT05382286), which is evaluating sacituzumab govitecan-hziy (Trodelvy) in combination with pembrolizumab vs treatment of physician’s choice plus pembrolizumab in patients with PD-1–positive metastatic TNBC, Lopetegui-Lia noted.

Additionally, the phase 3 OptiTROP-Breast01 trial (NCT05347134) is investigating sacituzumab tirumotecan (SKB264), a novel ADC composed of an anti-TROP2 antibody conjugated to a belotecan-derived cytotoxic payload via a proprietary linker with an average drug-to-antibody ratio of 7.4, Lopetegui-Lia commented. This trial enrolled patients with locally recurrent or metastatic TNBC who had received at least 2 prior chemotherapy regimens and randomly assigned them to receive sacituzumab tirumotecan or physician’s choice of chemotherapy. In this population of heavily pretreated patients, sacituzumab tirumotecan improved both progression-free survival (PFS) and overall survival compared with chemotherapy, according to Lopetegui-Lia.

Lastly, patritumab deruxtecan (HER3-DXd), a first-in-class HER3-directed ADC composed of a fully human anti-HER3 IgG1 monoclonal antibody linked to an exatecan derivative, has demonstrated promising activity across all breast cancer subtypes, Lopetegui-Lia explained. In the phase 1/2 U31402-A-J101 trial (NCT02980341), which included 53 patients with TNBC, HER3-DXd elicited an objective response rate (ORR) of 22.6% (95% CI, 12.3%-36.2%) and a median PFS of 5.5 months (95% CI, 3.9-6.8). Notably, responses were observed regardless of HER3 membrane expression level, Lopetegui-Lia concluded.

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Nerea Lopetegui-Lia, MD, elaborates on several highly anticipated studies evaluating ADCs that could shape the future TNBC treatment paradigm.

Dr Lopetegui-Lia on Adjuvant Therapy for Early-Stage TNBC With Residual Disease

“[One] area of high unmet need is [how to approcah treatment for] patients with early-stage, high-risk TNBC who receive neoadjuvant chemoimmunotherapy and then have residual disease at the time of surgery.”

Nerea Lopetegui-Lia, MD, a breast medical oncologist and assistant professor at The Ohio State University Comprehensive Cancer Center—James, discussed available treatment options for patients with early-stage high-risk triple-negative breast cancer (TNBC) who have residual disease at the time of surgery following neoadjuvant chemoimmunotherapy.

Clinical decision-making for these patients remains complex due to the lack of prospective data on optimal adjuvant therapies in this setting, Lopetegui-Lia began. Two commonly considered therapeutic agents are capecitabine and olaparib (Lynparza), she said. The choice between these agents is largely influenced by a patient’s 

 mutation status, she noted. Capecitabine is typically used in patients who do not have germline 

 mutations, based on data from the phase 3 CREATE-X trial, which demonstrated significant disease-free survival (DFS) and overall survival (OS) benefits with capecitabine vs observation in patients with residual HER2-negative invasive breast cancer post-neoadjuvant chemotherapy, she stated. Notably, the phase 3 KEYNOTE-522 (NCT03036488) regimen—which includes neoadjuvant immunotherapy—was not approved at the time of the CREATE-X trial. Therefore, patients on that trial had not received neoadjuvant immunotherapy, she explained. As such, data on the efficacy of this combination for patients who have already received neoadjuvant chemoimmunotherapy are lacking, although combining capecitabine with pembrolizumab (Keytruda) appears to be safe, she cautioned.

For patients with residual disease who display germline 

 mutations, treatment with olaparib should be considered based on findings from the phase 3 OlympiA trial (NCT02032823), according to Lopetegui-Lia. This trial evaluated 1 year of adjuvant olaparib vs placebo in patients with HER2-negative, high-risk early breast cancer with pathogenic or likely pathogenic 

 mutations. The use of olaparib in this population led to 

 for use in chemotherapy-pretreated patients with germline 

-mutated, high-risk, HER2-negative early breast cancer after it generated improvements in invasive DFS, distant DFS, and OS.

Updated 10-year follow-up data presented at the 

 confirmed the sustained benefit of olaparib in this population and addressed prior safety concerns, she reported. Specifically, the incidence of myelodysplastic syndrome, acute myeloid leukemia, or new primary malignancies—including breast, ovarian, fallopian tube, or pancreatic cancers—did not increase with olaparib compared with placebo, providing further reassurance regarding the long-term safety profile of this agent, she concluded.

Nerea Lopetegui-Lia, MD, discusses treatment options for patients with chemotherapy-pretreated early-stage high-risk TNBC with residual disease at surgery.

Nerea Lopetegui-Lia, MD

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Dr Lopetegui-Lia on Ongoing ADC Research in Metastatic TNBC

Dr Lopetegui-Lia on Adjuvant Therapy for Early-Stage TNBC With Residual Disease