ASCO 2024 – Pre-treated advanced NSCLC: who could benefit from anti-TROP2?

ASCO 2024 ¹ was rich in new developments in thoracic oncology with 3 studies in plenary session and a session dedicated specifically to metastatic non-small cell lung cancer (NSCLC). During this, a French study attracted attention for its innovative side.

TOO-2 (TROPhoblast cell-surface antigen 2) sees its expression increased in many solid cancers with significantly lower expression in normal tissues. Thus, this glycoprotein is expressed in nearly 80% of NSCLCs. The extent of its expression is associated with a poor prognosis in cases of adenocarcinoma, which is not the case for small cell cancers. No treatment targeting TROP-2 is currently approved for NSCLC.

The French phase 2 trial ICARUS-Lung01

The French ICARUS-Lung01 trial evaluated datopotamab deruxtecan (Dato-Dxd). This conjugated monoclonal antibody, with a longer half-life than sacituzumab govitecan, had already demonstrated in TROPION-Lung01 a statistically significant improvement in progression-free survival (PFS) in cases of already treated advanced or metastatic NSCLC.

The benefit was particularly marked in patients with non-squamous histology, for whom an advantage in overall survival was also found. However, the markers of resistance and response to this molecule are still unknown.

ICARUS-Lung01, the results of which were presented by Professor David Planchard (Institut Gustave Roussy, Villejuif, France), included 100 patients with stage IIIA, IIIB or IV NSCLC progressing after anti-PDL-1 or targeted treatment, to receive Dato-Dxd at a dose of 6 mg/kg every 21 days until progression or unacceptable toxicity.

Replicated efficacy and safety results

In practice, the overall response rate was 26.0% with a median response duration of 7.0 months, more marked in cases of non-squamous histology (30.5% versus 5.6% for squamous forms) or BRAF mutation (50.0% versus 23.2%) or KRAS (63.6% versus 21.6%).

The median PFS follows the same trend: 4.8 months for non-squamous (vs 2.9 months) and is in the same areas as in the TROPION-Lung01 trial, thus confirming that this conjugated antibody is not associated with a positive effect in cases of metastatic squamous adenocarcinoma.

As for tolerance, it was unsurprising, marked mainly by stomatitis, nausea, alopecia and fatigue, but these side effects were rarely grade 3.

An exploratory analysis in search of predictive markers of resistance

This study also draws its strength from its attempt to understand the mechanisms of resistance to Dato-Dxd through an exploratory analysis of biomarkers. It showed that it was patients with TROP-2 expression between 100 and 200 who benefited the most from the treatment. Tissue and blood biopsies were scheduled at inclusion then early (after 3 and 6 weeks of treatment) and at relapse.

For the rest, the data which is still preliminary shows that no driver of an alteration showed a significant association with response or resistance to Dato-Dxd. However, it would seem that the activation of DNA repair and the suppression of pathways linked to immunity after 1 or 2 cycles of dato-Dxd could be associated with resistance to this molecule.

Enough to prepare for the future, particularly by taking into account the importance of the kinetics of TROP2 expression at the level of the tumor cell or even the expression of lymphocytic cells…

This article was originally published on JIM.fr.