The landscape of cancer therapy is evolving with the emergence of TROP2-directed antibody-drug conjugates (ADCs), demonstrating promising efficacy and manageable safety profiles in breast and lung cancers. These therapies target the TROP2 protein, which is overexpressed in various epithelial cancers and associated with increased proliferation and reduced apoptosis of cancer cells. This overexpression makes TROP2 an attractive target for anticancer therapies.
Dato-DXd: A Promising TROP2-Directed ADC
Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed ADC with a stable linker that selectively delivers deruxtecan to tumor cells, exerting a bystander effect on neighboring cells. Phase 3 TROPION-Breast01 study findings, presented at the 2023 European Society for Medical Oncology Congress, revealed that Dato-DXd significantly improved progression-free survival (PFS) compared to chemotherapy in patients with inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer (HR, 0.63; 95% CI, 0.52-0.76; P < .0001). The FDA accepted the biologics license application (BLA) for Dato-DXd in April 2024, with a PDUFA action date of January 29, 2025.
In non-small cell lung cancer (NSCLC), the phase 3 TROPION-Lung01 study evaluated Dato-DXd versus docetaxel in previously treated metastatic NSCLC patients. While the final overall survival (OS) analysis did not meet the study's coprimary endpoint (HR, 0.94; 0.78-1.14; P = .530), a subgroup analysis showed a non-statistically significant OS benefit in patients with nonsquamous histology (HR, 0.84; 95% CI, 0.68-1.05). The FDA accepted the BLA for Dato-DXd in this indication in February 2024, with a PDUFA date expected in the fourth quarter of 2024.
Predictive Biomarkers for Dato-DXd Response
An analysis of TROPION-Lung01 data presented at the 2024 International Association for the Study of Lung Cancer World Conference on Lung Cancer (WCLC 2024) indicated that TROP2 expression, measured by quantitative continuous scoring (QCS) using normalized membrane ratio (NMR), could predict clinical outcomes. Patients with positive TROP2 expression who received Dato-DXd achieved a median PFS of 6.9 months compared to 4.1 months with docetaxel (HR, 0.57; 95% CI, 0.41-0.79). This biomarker is being further investigated in frontline advanced NSCLC in the phase 3 AVANZAR and TROPION-Lung10 studies.
Sacituzumab Tirumotecan: A Novel TROP2-Directed ADC
Sacituzumab tirumotecan, another novel TROP2-targeted ADC, is under investigation in the phase 3 OptiTROP-Breast01 trial for patients with previously treated recurrent or metastatic triple-negative breast cancer (TNBC). Final analysis presented at the 2024 American Society of Clinical Oncology Annual Meeting showed a median PFS of 6.7 months (95% CI, 5.5-8.0) with sacituzumab tirumotecan versus 2.5 months (95% CI, 1.7-2.7) with chemotherapy (HR, 0.32; 95% CI, 0.22-0.44; P < .00001).
Other Emerging TROP2-Directed ADCs
BNT325/DB-1305, another novel TROP2-directed ADC, received fast track designation from the FDA in January 2024 for platinum-resistant ovarian cancer. Preliminary phase 1/2 study results showed an overall response rate (ORR) of 30.4% and a disease control rate of 87.0% in patients with advanced solid tumors, including NSCLC and TNBC.
The Future of TROP2-Directed Therapies
TROP2-directed ADCs are rapidly evolving, with ongoing studies exploring their use in earlier stages of breast cancer and in combination with immunotherapy. As these therapies advance, careful consideration of efficacy and toxicity profiles will be crucial in determining their optimal role in cancer treatment.
