Advances in antibody-drug conjugate-based combination therapy strategies for non-small cell lung cancer

INTRODUCTION: Non-small cell lung cancer (NSCLC) continues to be one of the leading causes of cancer death worldwide. Although targeted therapies and immune checkpoint inhibitors have meaningfully improved outcomes for some patients, many still lack targetable mutations or quickly develop resistance. Antibody-drug conjugates (ADCs), which combine tumor-specific antibodies with potent cytotoxic payloads, have become an increasingly promising option. AREAS COVERED: This review looks at ADC-based combination strategies in NSCLC, grouped by key molecular targets such as Trop-2, HER2, HER3, c-Met, B7-H3, CEACAM5, and ITGβ6, along with bispecific ADCs. The literature was identified through searches of PubMed, ClinicalTrials.gov, and major oncology conference proceedings (including ASCO, ESMO, and WCLC). We examined published trial results, conference abstracts, and ongoing registered studies covering combinations with immune checkpoint inhibitors, EGFR tyrosine kinase inhibitors, chemotherapy, and other agents. EXPERT OPINION: ADC combinations are a fast-moving and exciting area in NSCLC. Trop-2 ADC plus ICI approaches show efficacy that appears strongly linked to PD-L1 levels, while certain EGFR-directed strategies, especially bispecific ADCs like izalontamab brengitecan with osimertinib, have demonstrated promising preliminary clinical activity. Still, success will hinge on strong single-agent activity, clear synergy, and reliable biomarkers for patient selection.