Antibody‑Drug Conjugates as Novel Therapeutic Agents for Non‑Small Cell Lung Carcinoma with or without Alterations in Oncogenic Drivers

Sep 21, 2026

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Antibody-drug conjugates (ADCs) are an emerging therapeutic class for lung cancer. ADCs combine an antibody targeting a cell-surface protein with a cytotoxic payload linked by a linker. Multiple targets have been identified, including TROP2, c-MET, CEACAM5, HER2, and HER3. Standard first-line therapy differs by molecular status: platinum chemotherapy plus PD1/PDL1 inhibitors for driver-unaltered NSCLC, and TKIs for EGFR-mutated or ALK-rearranged disease, yet progression remains common. This review summarizes efficacy and tolerability of ADCs targeting key antigens in metastatic NSCLC with and without oncogenic driver alterations.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Introduction

Lung cancer and treatment landscape

Rationale for ADCs

Structure of Antibody‑Drug Conjugates (ADCs)

Four-component architecture

BioDrugs (2024) 38:487–497 [https://doi.org/10.1007/s40259-024-00660-7](https://doi.org/10.1007/s40259-024-00660-7) Antibody‑Drug Conjugates as Novel Therapeutic Agents for Non‑Small Cell Lung Carcinoma with or without Alterations in Oncogenic Drivers Laura Bender Somme1 · Christos Chouaid2 · Fabien Moinard‑Butot1 · Jean‑Baptiste Barbe‑Richaud1 · Laurent Greillier3 · Roland Schott1 Accepted: 22 April 2024 / Published online: 20 May 2024 © The Author(s) 2024 Abstract Antibody-drug conjugates (ADCs) are an emerging class of therapeutics for lung cancer, and several are currently in development for this malignancy. The structure of these molecules is based on an antibody that targets a protein on the lung cancer cell surface and a cytotoxic payload attached by a linker. Many protein targets, including TROP2, c-MET, CEACAM5, HER2, and HER3 have been identified. In metastatic non-small cell lung carcinoma (NSCLC) without alterations in oncogenic drivers, platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) targeting the programmed death-1/ programmed death-ligand 1 (PD1/PDL1) interaction are the standard first-line treatments. In patients with EGFR-mutated or ALK-rearranged NSCLC, tyrosine kinase inhibitors (TKIs) are recommended. However, although the prognosis of patients with metastatic NSCLC differs between such with and without alterations in oncogenic drivers, most patients eventually experience disease progression. A novel therapeutic class is needed in routine practice to overcome the mechanisms of resistance to ICIs and EGFR/ALK TKIs. Several ADCs have already been approved for other cancers, such as breast cancer and urothelial carcinoma. This review summarizes the knowledge about the efficacy and tolerance profiles of ADCs targeting TROP2, HER2, HER3, CEACAM5 and c-MET in metastatic NSCLC with and without alterations in oncogenic drivers. * Laura Bender Somme [l.bender@icans.eu](l.bender@icans.eu) Christos Chouaid [christos.chouaid@chicreteil.fr](christos.chouaid@chicreteil.fr) [Fabien Moinard-Butot](Fabien Moinard-Butot) [f.moinard-butot@icans.eu](f.moinard-butot@icans.eu) Jean-Baptiste Barbe-Richaud [jb.barbe-richaud@icans.eu](jb.barbe-richaud@icans.eu) Laurent Greillier [laurent.greillier@ap-hm.fr](laurent.greillier@ap-hm.fr) Roland Schott [r.schott@icans.eu](r.schott@icans.eu) 1 Oncology Department, Institut de Cancérologie Strasbourg, 17 avenue Albert Calmette, 67200 Strasbourg, France 2 Pneumology Department, Hôpital Intercommunal de Créteil, 40 avenue de Verdun, 94010 Creteil, France 3 Multidisciplinary Oncology and Therapeutic Innovations Department, Assistance Publique-Hôpitaux de Marseille, Aix Marseille University, Chemin des Bourrely, 13915 Marseille, France 1 Introduction Lung cancer (LC) is expected to be a major contributor to total global cancer-related deaths in 2023 [1] . Non-small cell lung cancer (NSCLC) accounts for 85% of all LC cases; however, this population is heterogeneous, and molecular analysis of non-squamous NSCLC distinguished patients with oncogenic driver alterations from those without such alterations. In recent years, the therapeutic landscape for LC has changed with the discovery of epidermal growth factor receptor (EGFR)-activating alterations or anaplastic lymphoma kinase (ALK) gene rearrangements that both can be targeted by tyrosine kinase inhibitors (TKIs). The prognosis of the LC population harbouring EGFR or ALK alterations is good, with a 1-year overall survival (OS) rate of between 89 and 84%[2 , 3] . Other oncogenic drivers, including BRAF, HER2, KRAS, ROS and MET, have been shown tobe associated with a less favourable prognosis than EGFR or the ALK population. Personalized treatments, mainly including dabrafenib (TKI against BRAF) and trametinib (TKI against MEK), have been developed for V600EBRAFmutated NSCLC, and sotorasib or adagrasib (TKI against KRAS) have been used for KRAS G12C-mutated NSCLC. At diagnosis, t

FAQs

What are antibody-drug conjugates (ADCs) and how are they constructed?

ADCs consist of four components: an antigen, an antibody, a cytotoxic payload, and a linker. The antibody targets a protein on the lung cancer cell surface, and the payload is delivered via the linker.

What are the standard first-line treatments for metastatic NSCLC with or without oncogenic driver alterations?

Without driver alterations, treatment typically uses platinum-based chemotherapy plus PD1/PDL1 immune checkpoint inhibitors. With EGFR mutations or ALK rearrangements, tyrosine kinase inhibitors are recommended.

Why is there a need for new therapies despite existing options?

Even though prognosis differs by molecular status and initial responses can occur, most patients with metastatic NSCLC eventually progress. The review highlights mechanisms of resistance to ICIs and EGFR/ALK TKIs and the lack of effective therapy for some progressing patients.

Sep 21, 2026

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