Dr Singhi on the Emerging Role of TROP2-Directed ADCs in the Evolving Treatment Algorithm of NSCLC

“ADCs are all of the buzz right now in NSCLC, we’re trying to move beyond conventional chemotherapy, obviously trying to add to our armamentarium of more targeted, directed therapies.”

Eric K. Singhi, MD, an assistant professor in the Department of General Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the emerging role of TROP2-directed antibody–drug conjugates (ADCs) in the evolving treatment algorithm of non–small cell lung cancer (NSCLC) during the Bridging the Gaps Brain Metastases meeting, with particular attention to how these agents may be sequenced relative to established systemic options.

Singhi noted that ADCs have become a prominent area of clinical focus in NSCLC as the field continues to move beyond conventional cytotoxic chemotherapy toward more biologically informed therapies. Although molecularly targeted agents remain foundational for patients with actionable driver alterations, ADCs offer a complementary strategy by combining antigen recognition with intracellular delivery of a cytotoxic payload. TROP2 has emerged as a clinically relevant target given its expression across multiple NSCLC subtypes, including tumors without canonical oncogenic drivers.

In the setting of EGFR-mutated NSCLC, Singhi highlighted the accelerated FDA approval of datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) as an important addition to later-line treatment options. This agent provides a new systemic therapy for patients whose disease has progressed following EGFR-directed TKIs and platinum-based chemotherapy. Within the current treatment paradigm, TROP2-directed ADCs are positioned after exhaustion of standard targeted and cytotoxic approaches, supporting their role as sequential therapies rather than upfront options.

Beyond datopotamab deruxtecan, Singhi referenced emerging clinical data with sacituzumab tirumotecan-hziy (Sac-TMT; Trodelvy), another TROP2-directed ADC under evaluation in NSCLC. Although ADCs vary by antibody backbone, linker chemistry, and payload, these programs collectively underscore the therapeutic potential of TROP2 targeting in NSCLC. Ongoing and future trials will be needed to better define optimal sequencing, comparative efficacy across agents, and whether specific clinical or molecular features can refine patient selection.

Singhi emphasized that integration of TROP2 ADCs into routine practice requires deliberate attention to toxicity prevention and management. Despite targeted delivery, these agents retain chemotherapy-like adverse effects (AEs), including cytopenias, alopecia, and gastrointestinal toxicities such as nausea. Vigilant monitoring for AEs that may be particularly relevant to ADCs, including stomatitis, ocular toxicities, and interstitial lung disease/pneumonitis must also be done. Proactive patient counseling, structured monitoring, and early symptom recognition were underscored as essential to maximize benefit while minimizing treatment-related morbidity.