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.