Jul 2026· Expert Opinion on Biological Therapy· Vol 26, pp. 677 - 691· 0 citations· 66 references
Medicine
TL;DR
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.
Abstract
ABSTRACT 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.
The rationale for targeting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation are discussed.
P. Paliogiannis, G. Fara, A. Zinellu et al.· Current Issues in Molecular...· 0 citations
ABSTRACT Introduction The discovery of epidermal growth factor receptor (EGFR) mutations has deeply reshaped the treatment of non-small cell lung cancer (NSCLC). Throughout the last years, third-generation tyrosine kinase inhibitor (TKI) osimertinib in monotherapy has been the standard of care; however, resistance limits durable responses, necessitating novel combinations and sequencing strategies. Areas covered This review discusses recent advances in EGFR-targeted therapies within the molecular landscape of classical and uncommon EGFR mutations, focusing on frontline intensification strategies in metastatic disease—specifically TKI combinations with chemotherapy (FLAURA2) or bispecific antibodies (MARIPOSA)—and emerging post-progression strategies to overcome acquired resistance mechanisms. A comprehensive literature search (January 2021–March 2026) was conducted via PubMed, and recent major oncology conference proceedings (ASCO, ESMO, WCLC, ELCC) and clinical trial registries for ongoing studies. Expert opinion The therapeutic landscape is shifting from a uniform frontline TKI monotherapy approach toward biomarker-driven, risk-stratified, intensification. High-risk patients (e.g. TP53 co-mutations, L858R) derive significant benefit from combination regimens, whereas mono-TKI remains appropriate for favorable prognostic subgroups. Future progress relies on validating predictive biomarkers—particularly circulating tumor DNA (ctDNA) dynamics—to guide adaptive treatment strategies, balancing efficacy gains against toxicity and costs, while ensuring equitable global access to novel therapies.
L. Lucente, Lucrezia Barcellini, B. Ramella Pollone et al.· Expert Opinion on Pharmacoth...· 0 citations
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death. Targeted monotherapies against the actionable oncogenic drivers, including anaplastic lymphoma kinase (ALK) rearrangement and epidermal growth factor receptor (EGFR) dysregulation, are well-established for molecularly selected NSCLC patients. However, therapeutic resistance remains a major clinical challenge, and combinatorial strategies targeting distinct signaling pathways may overcome the limitations of single-agent targeted therapies. LR004-VC-MMAE, a novel EGFR-targeting antibody‒drug conjugate (ADC), shows potent antitumor efficacy in multiple EGFR-positive xenografts, yet its therapeutic potential in ALK-rearranged NSCLC remains largely unexplored. Here, we evaluated a novel combinatorial strategy using ALK inhibitors (crizotinib, ceritinib, alectinib, and lorlatinib) in combination with LR004-VC-MMAE in ALK-rearranged NSCLC models. We found that both ALK and cell-surface EGFR were highly expressed in ALK-rearranged NCI-H3122 and NCI-H2228 cell lines but were expressed at low levels in the ALK-wild-type NCI-H460 cell line. All ALK inhibitor-ADC regimens synergistically suppressed proliferation in ALK-rearranged NSCLC cells, while exerting little synergy in ALK wild-type and EGFR-low counterparts. Moreover, crizotinib or ceritinib combined with LR004-VC-MMAE induced significantly greater apoptosis in NCI-H3122 cells compared with either single agent. Mechanistically, the crizotinib-LR004-VC-MMAE combination markedly downregulated ALK and EGFR expression and triggered apoptosis via mitochondrial depolarization-mediated caspase cascade activation and endoplasmic reticulum stress-induced unfolded protein response. In NCI-H3122 xenografts, this combination achieved synergistic tumor inhibition without increased toxicity compared with either treatment alone. Collectively, our findings demonstrate the synergistic antitumor activity of ALK inhibitor plus LR004-VC-MMAE against ALK-rearranged, EGFR-high NSCLC, providing a mechanistic rationale for further clinical development of this combination strategy.
Continued translational research is therefore essential to identify predictive biomarkers and to optimize novel combination strategies to overcome resistance, as well as the integration of dynamic biomarkers and quantitative tools to define optimal treatment sequencing and improve patient outcomes in this challenging disease setting.
M. Noronha, L. F. Costa de Almeida, V. O. Costa et al.· Therapeutic Advances in Medi...· 0 citations
Antibody–drug conjugates (ADCs) represent a transformative therapeutic class in non-small cell lung cancer (NSCLC), moving precision oncology beyond traditional targeted therapies. These agents, composed of a monoclonal antibody, linker, and potent cytotoxic payload, enable targeted drug delivery to tumor cells expressing specific antigens like TROP2, HER2, and c-MET. Recent clinical trials have demonstrated remarkable efficacy of ADCs, both as monotherapy in molecularly defined populations and in combination with immunotherapy, offering new hope for patients with advanced disease. This review summarizes the latest clinical progress of ADCs in NSCLC, highlighting key agents and their impact, while also addressing the associated challenges and future directions for optimizing this promising treatment modality.
Xi Chen, Sirui Wu, Feiyang Li et al.· Holistic Integrative Oncolog...· 0 citations
Future research should prioritize tumor-selective linker design, novel payload development, bispecific and dual-payload ADC platforms, and rational combination strategies to overcome resistance and further improve the therapeutic index of ADCs in CRC.
L. Zeng, Yuanlin Zhu, Ke Zhang et al.· Biochemical Pharmacology· 0 citations
