Villejuif, April 21, 2026

Cancer Cell
A French study reveals the mechanism of action of an innovative drug in patients with advanced lung cancer

The French ICARUS-LUNG01 study, published on April 17 in the journal Cancer Cell, sheds light on how a new antibody-drug conjugate (ADC), a new generation of drugs capable of delivering a toxic substance directly into the heart of cancer cells, acts on lung cancer. Conducted in 100 patients experiencing disease progression on prior treatments, it demonstrates not only encouraging efficacy but also identifies biological leads that make it possible to predict which patients are most likely to respond to treatment.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide. In the vast majority of cases, it is non-small cell lung cancer (NSCLC), which accounts for approximately 85% of diagnoses. Despite considerable advances in recent years (immunotherapy and targeted therapies), many patients remain in therapeutic dead-ends. After the failure of standard treatments, the available options remain limited and of limited efficacy.

ADCs: a next-generation targeting technology 

The development of new therapeutic strategies, in particular antibody-drug conjugates (ADCs), represents a new avenue in thoracic oncology. Datopotamab deruxtecan (Dato-DXd) is an innovative treatment that combines an antibody capable of recognizing and binding to a specific target on the surface of cancer cells, the TROP2 protein, with a powerful anticancer agent, deruxtecan, which causes DNA damage and subsequently cell death. TROP2 is a particularly interesting protein because it is overexpressed on the surface of tumour cells in approximately two thirds of lung cancers, making it a target of choice[1].

Once bound to its target, the complex penetrates inside the tumour cell and releases its therapeutic payload directly within it in order to destroy it in a targeted manner.

Dato-DXd received accelerated approval from the FDA, the American drug regulatory agency, in June 2025, for patients with advanced or metastatic EGFR mutated NSCLC who have received prior EGFR directed therapy and platinum-based chemotherapy.

Background and design of the ICARUS-LUNG01 study

Even though these new treatments are increasingly used, it remains difficult to predict which patients will benefit from them and why some don’t respond, due to the complexity of their mechanism of action, which is likely influenced by multiple factors.

To better understand these mechanisms, specific studies with repeated tumour analyses over time are needed in order to monitor disease progression and understand the effect of treatment at the cellular level and its interactions with the tumour microenvironment.

In this context, ICARUS-LUNG01 is a French phase II, multicentre, translational clinical study, sponsored by Gustave Roussy and conducted across eight centers under the direction of Prof. David Planchard, Head of the Thoracic Pathology Committee at Gustave Roussy, professor at Université Paris-Saclay. It aimed to evaluate the clinical benefit of Dato-DXd, an anti-TROP2 antibody-drug conjugate, in patients with advanced lung cancer who had relapsed after several lines of treatment, to determine its tolerability profile, and to identify biomarkers of response or resistance. It is part of the ICARUS programme, sponsored by Gustave Roussy and led by Dr. Barbara Pistilli, Head of the Breast Pathology Committee at Gustave Roussy, and by Guillaume Montagnac, Inserm Research Director at Gustave Roussy, carried out within the framework of the UNLOCK programme, in collaboration with Daiichi-Sankyo.

The study enrolled 100 patients with metastatic lung cancer who received an intravenous infusion of Dato-DXd every three weeks. Fresh tumour biopsies were performed at three key time points: before the start of treatment, during treatment (at week 3 or 6), and at the end of treatment. The median follow-up duration for patients in the study was 21.5 months.

Notable efficacy in patients in therapeutic failure

Dato-DXd achieved a response (ORR) in 26% of all patients, with a higher rate in patients with non-squamous histology (30.5%) compared with those with squamous cell cancer (5.6%). The median duration during which the disease remained stable (PFS) was 3.6 months, longer in patients with non-squamous tumours than in those with squamous tumours, at 4.8 months versus 2.9 months respectively. Median overall survival was 11.9 months. It reached 12.6 months in patients with non-squamous tumours and 6.3 months in those with squamous cell carcinoma.

In terms of tolerability, 24% of patients experienced a grade 3 or higher treatment-related adverse event. The two most frequent adverse effects of grade 1/2 were stomatitis (48%) and nausea (47%).

These results are consistent with those obtained in nearly 600 patients in the phase III TROPION-Lung01 study, which compared Dato-DXd with docetaxel chemotherapy in pre-treated patients with advanced non-small cell lung cancer.

Understanding the mechanisms of response and resistance

Beyond the efficacy results, ICARUS-LUNG01 also sought to understand why some patients respond to treatment while others do not. Analyses conducted from biopsies taken before, during and after treatment generated rich biological data, contributing to a better understanding of the underlying molecular mechanisms. The techniques used relied on artificial intelligence-assisted digital pathology developed by Central Supelec, as well as genomic, transcriptomic and spatial proteomic approaches.

Tumour analyses before and during treatment suggest that resistance to Dato-DXd may be associated with two main factors: on the one hand, the absence of TROP2 inside tumour cells resulting in a lack of ADC internalization; and on the other hand, the early activation of DNA repair pathways under treatment. A better understanding of the intracellular dynamics of TROP2 could ultimately make it possible to better select patients likely to respond to antibody-drug conjugate therapies.

Conversely, the activation of immunity-related pathways was correlated with a better therapeutic response. Dato-DXd would not merely attack cancer cells; it also appears capable of stimulating the patient's immune response against the tumour. It would therefore not be solely targeted chemotherapy. By damaging the DNA of cancer cells, the treatment triggers the release of cellular fragments acting as warning signals. These debris are detected by the immune system, triggering an inflammatory response favourable to the activation of immune cells.

"This French trial has not only demonstrated the activity of Dato-DXd in a population with no remaining therapeutic options, but has also laid the groundwork for precision medicine based on biomarkers. The results, particularly the marked benefit in patients with non-squamous lung tumours as well as the identification of biological profiles associated with response, open up concrete perspectives for improving patient selection and optimising therapeutic strategies in the years to come," conclude Prof. Planchard and Dr. Pistilli.