Advanced lung cancer: toward tailored treatments

By Elodie Vaz | Published on April 28, 2026 | 4 min read


Lung cancer remains one of the leading causes of cancer-related death worldwide. Among these tumors, non–small cell lung cancer (NSCLC) accounts for nearly 85% of diagnoses. While immunotherapy and targeted therapies have transformed patient care in recent years, a significant proportion of patients still reach a therapeutic dead end after standard treatments fail.  

This is why antibody-drug conjugates (ADCs) are emerging as a promising new generation of therapies. The French ICARUS-LUNG01 study, published on April 17 in Cancer Cell by physician-researchers from Inserm, Université Paris-Saclay, and Gustave Roussy, investigated the mechanism of action of datopotamab deruxtecan (Dato-DXd), an anti-TROP2 ADC, in patients with advanced lung cancer.

An antibody-drug conjugate targeting TROP2

Dato-DXd is based on a sophisticated targeting technology. It combines an antibody directed against the TROP2 protein with a cytotoxic payload, deruxtecan. Overexpressed on the surface of tumor cells in around 80% of lung cancers, TROP2 appears to be a particularly relevant target.  

Once bound to this protein, the complex is internalized by the cancer cell, where it releases its therapeutic payload. Deruxtecan then induces DNA damage, leading to cell death. The drug received accelerated FDA approval in June 2025 for certain patients with advanced or metastatic NSCLC harboring EGFR mutations.

Understanding who responds… and why

Despite the growing use of ADCs in thoracic oncology, their mechanisms of action remain only partially understood. It is still difficult to predict which patients will derive lasting clinical benefit and which biological mechanisms underlie resistance.  

The ICARUS-LUNG01 study had three main objectives: to evaluate the clinical efficacy of Dato-DXd in patients who relapsed after multiple lines of therapy, to document its safety profile, and to identify predictive biomarkers of response or resistance.

An ambitious translational methodology

This multicenter French clinical study included 100 patients with metastatic lung cancer who had exhausted therapeutic options. All received an intravenous infusion of Dato-DXd every three weeks.  

A key feature of the protocol was the use of serial tumor biopsies at three time points: before treatment, during treatment (week 3 or 6), and at treatment discontinuation. With a median follow-up of 21.5 months, these samples made it possible to track tumor evolution and therapeutic impact over time.  

Analyses relied on digital pathology approaches assisted by artificial intelligence developed by CentraleSupélec, as well as genomic, transcriptomic, and spatial proteomic technologies.  

Improved progression-free survival

Dato-DXd achieved a tumor response in 26% of all patients. This benefit was significantly greater in patients with non-squamous lung cancer, with a response rate of 30.5%, compared to only 5.6% in squamous carcinomas.  

An improvement in progression-free survival and overall survival was also observed in the non-squamous subgroup.  

In terms of safety, 24% of patients experienced grade 3 or higher treatment-related adverse events. The most common side effects, mostly grade 1 or 2, were stomatitis (48%) and nausea (47%).  

These results are consistent with the phase III TROPION-Lung01 trial conducted in nearly 600 patients.  

Toward biomarker-driven precision medicine

Beyond clinical efficacy, ICARUS-LUNG01 sheds light on biological mechanisms that may explain responses and resistance to treatment.  

The analyses suggest that resistance to Dato-DXd may be linked to the absence of TROP2 within tumor cells, as well as early activation of DNA repair pathways during treatment. Conversely, activation of immune pathways is associated with better response. Dato-DXd may therefore not be limited to a targeted cytotoxic effect. By damaging tumor DNA, it could trigger the release of danger signals capable of stimulating the immune system.  

As stated in a press release from the Gustave Roussy Institute, Prof. Planchard and Dr. Pistilli conclude: “This French trial not only demonstrated the activity of Dato-DXd in a population with limited treatment options, but also laid the groundwork for biomarker-driven precision medicine. The results—particularly the marked benefit in patients with non-squamous lung tumors, as well as the identification of biological profiles associated with response—open concrete perspectives for improving patient selection and optimizing therapeutic strategies in the years to come.”  

With ICARUS-LUNG01, French translational research takes another step forward in the detailed understanding of ADCs. In the long term, these data could refine patient stratification and guide the development of combination therapies pairing ADCs with immunotherapy in advanced lung cancer.




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About the Author – Elodie Vaz
Health journalist, CFPJ graduate (2023).
Élodie explores the marks diseases leave on bodies and, more broadly, on human life. A registered nurse since 2010, she spent twelve years at patients’ bedsides before exchanging her stethoscope for a notebook. She now investigates the links between environment and health, convinced that the vitality of life cannot be reduced to that of humans alone.