Radionuclide-Drug Conjugates (RDCs) for Lung Cancer Pivot to 177Lu-SSTR Peptides, with 30 RDCs in Clinical Trials

Lung cancer remains the leading cause of cancer-related mortality globally, presenting significant challenges due to prevalent drug resistance and inherent tumor heterogeneity. Current therapeutic strategies often struggle to achieve sustained, targeted efficacy, leading to suboptimal patient outcomes. Radionuclide-drug conjugates (RDCs) offer a promising theranostic platform, designed to deliver precise radiation directly to tumor cells while minimizing systemic toxicity. This approach addresses the critical need for more targeted and effective treatments by leveraging specific tumor-associated biomarkers and receptors.

This systematic review analyzed preclinical and clinical data on radionuclide-drug conjugates (RDCs) for lung cancer, retrieved from PubMed and ClinicalTrials.gov, with records reviewed up to January 2026. Researchers exhaustively surveyed studies across most radionuclides relevant to RDCs, following the periodic table for comprehensive coverage. The analysis aimed to outline the landscape of RDC advances and provide a forward-looking perspective on next-generation strategies, including novel targets, delivery platforms, and radionuclide types.

The review identified a total of 66 RDCs screened for lung cancer, with 30 of these having progressed into early-phase clinical trials. A significant transition was observed in completed trials, moving from initial 131I- or 90Y-labeled antibodies towards 177Lu-labeled somatostatin receptor (SSTR)-targeting peptides. SSTR remains the dominant target, but with a notable shift from agonists to antagonists. Growing attention is also being paid to fibroblast activation protein (FAP), epidermal growth factor receptor (EGFR), and programmed death-ligand 1 (PD-L1) as emerging targets. Peptides and antibodies are equally employed, with advanced formats like bispecific antibodies (bsAbs), single-domain antibodies (sdAbs), and cyclic peptides advancing rapidly. Nanoparticles (NPs) are also emerging as versatile platforms, and strategies like pretargeting or dual-targeting are under development to enhance both efficacy and safety. Crown chelators and bipyridine derivatives are providing more stable chelating options. While 177Lu remains the mainstay radionuclide, alpha emitters and mixed-decay radionuclides such as 161Tb are gaining ground. > Combination therapies are actively being investigated to enable first-line application of RDCs, marking a significant step towards broader clinical integration.