Therapeutic Potential of Datopotamab Deruxtecan in the Treatment of Advanced Non-Small Cell Lung Cancer: Evidence to Date

Lung cancer is the leading cause of global cancer mortality, accounting for an estimated 2 million diagnoses and 1.8 million deaths annually. Treatment choices for non-small cell lung cancer include surgery, radiation therapy, chemotherapy, immunotherapy, or molecularly targeted therapy. Antibody-drug conjugates (ADCs), often likened to "biological missiles", are rapidly evolving as a targeted therapeutic approach. Trophoblast cell surface antigen 2 (Trop 2) is a 36-kDa cell surface glycoprotein, which is expressed in various cancers. This fuels oncogenic signaling pathways, driving tumor advancement, invasion, and spread. Its limited expression in healthy human tissues underscores its potential as a target for cancer treatment. Datopotamab Deruxtecan (Dato-Dxd) is an investigational ADC that targets Trop-2. This review discusses the current treatment landscape involving therapy with Dato-Dxd for advanced NSCLC. Dato-DXd was first used in metastatic solid tumors in the Phase I TROPION-PanTumor 01 trial, which showed promising antitumor activity in the previously pretreated NSCLC cohort and a manageable safety outline. In TROPION-Lung01, Dato-DXD was studied in metastatic NSCLC patients who were previously treated and showed an objective response rate of 26.4% (Dato-DXd). Other trials, including TROPION PanTumor 02, ICARUS - Lung 01, and TROPION Lung 05, showed comparable results. Dato-DXd used along with pembrolizumab, with or without systemic chemotherapy, in TROPION Lung 02 with promising efficacy results. The most common any-grade treatment-emergent adverse events were stomatitis, nausea, and hair loss, mostly grade 1-2. There are several clinical trials in the pipeline using Dato-DXd in the front-line metastatic setting and resectable NSCLC patients. Dato-DXd is currently pending approval from the US Food and Drug Administration (FDA). If approved, datopotamab deruxtecan will be the first TROP2-directed antibody-drug conjugate for non-small cell lung cancer.