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. 
