239MO - Stratification of pleural mesothelioma patients for combined immunotherapy based on sarcomatoid component and tumour microenvironment markers in the IFCT-MAPS2 study

Background

In the management of pleural mesothelioma (PM), combined immunotherapy has emerged as the first-line treatment, significantly improving overall survival (OS) and progression-free survival (PFS), especially in sarcomatoid PM patients. Concurrently, traditional histological classification distinguishing subtypes has evolved into a more nuanced continuum based on transcriptome analysis of patient biopsies across all histological subtypes. This study aims to refine the stratification of patients for immunotherapy strategy to optimize therapeutic outcomes.

Methods

We performed RNASeq analysis on diagnostic biopsies in the IFCT-MAPS2 clinical trial, which evaluated Nivolumab (anti-PD-1, n=34) alone and in combination with Ipilimumab (anti-CTLA-4, n=38) in pre-treated patients. The sarcomatoid component (via the transcriptomic S-score) and tumour microenvironment (TME) composition were further explored using scRNASeq-based deconvolution algorithms. The immune compartment, notably tumour-associated macrophages (TAMs), was particularly investigated.

Results

Our findings reveal that high S-score patients (n=23) benefit from combined immunotherapy (median PFS 26.1 vs. 4.8 months, P=0.029), while low S-score patients (n=49) showed no significant advantage when treated with the combination compared to Nivolumab alone (18.7 vs. 15.2 months). Additionally, we have revised public PM scRNASeq to explore our cohort TME composition. We show that high TAM infiltration in biopsies was associated with poorer PFS only in patients receiving single Nivolumab. This effect was primarily driven by the TAM subpopulation corresponding to lipid-associated TAMs, previously characterised in pan-cancer TAM subpopulations.

Conclusions

Our findings suggest that patients with high S-score and/or high TAM infiltration benefit from combined immunotherapy, while the majority of patients with lowS-score and lowTAM infiltration do not, regardless of histology. These markers reflect the heterogeneity that extends beyond histological subtypes, and support their integration into the routine clinical practice for better patient stratification in PM immunotherapy.

Clinical trial identification

IFCT-1501 MAPS2 European Union Clinical Trials Register (number 2015004475-75) (number NCT 02716272).

Legal entity responsible for the study

IFCT - Intergroupe Francophone de Cancérologie Thoracique.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.