ORCID

0000-0002-1587-0370 (Ismail)

Document Type

Article

Publication Date

2026

DOI

10.3390/biom16050677

Publication Title

Biomolecules

Volume

16

Issue

5

Pages

677

Abstract

Antibody–drug conjugates (ADCs) are a rapidly evolving class of oncology therapeutics that enable precise delivery of potent cytotoxic agents to tumor cells while minimizing systemic toxicity. While HER2-targeted ADCs such as trastuzumab deruxtecan (T-DXd) in HER2-mutant, Datopotamab deruxtecan (Dato-Dxd) in EGFR-mutant, and telisotumumab vedotin (Teliso-V) in MET IHC 3+ expressing lung cancer have already established a clinical role in non-small cell lung cancer (NSCLC), multiple ADCs targeting alternative antigens, including additional TROP2 ADCs, HER3, MET, CEACAM5, B7-H3, Nectin-4, and others, are now in advanced clinical development. This review synthesizes the current evidence for non-HER2 ADCs in NSCLC, highlighting mechanisms of action, clinical efficacy, safety profiles, biomarker strategies, and emerging resistance mechanisms. Key safety concerns, including interstitial lung disease (ILD), ocular toxicity, and peripheral neuropathy, are emphasized alongside approaches for re-challenge following toxicity. We further discuss next-generation ADC platforms, including bispecific and conditionally activated constructs, as well as combination strategies with immunotherapy. Collectively, ADCs beyond HER2 are poised to reshape treatment paradigms in NSCLC, offering hope for patients with limited therapeutic options. This review identifies current gaps, highlights ongoing research priorities, and proposes practical considerations for integrating these therapies into clinical practice.

Rights

© 2026 The Authors.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International (CC BY 4.0) License.

Data Availability

Article states: "No new data were created or analyzed in this study. Data sharing is not applicable to this article."

Original Publication Citation

Ismail, A., Desai, A., Simon, G. R., & Boumber, Y. (2026). Antibody–drug conjugates beyond HER2 in non-small cell lung cancer (NSCLC): Mechanisms, emerging targets, and future directions. Biomolecules, 16(5), Article 677. https://doi.org/10.3390/biom16050677

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