12P - Epithelial-mesenchymal transition facilitates response to AXL/PD-1 inhibition in relapsed mesothelioma

Background

Context: The AXL receptor tyrosine kinase plays a key role in enabling the immune system and developing resistance to treatment, resulting in a more aggressive tumour. AXL is a receptor tyrosine kinase that is involved in the promotion of epithelial-to-mesenchymal transition and is inhibited by bemcentinib. It also acts as a mechanism of resistance to PD1 or PDL1 targeted immune checkpoint blockade (ICB). Objective: This study aimed to interrogate molecular and cellular mechanisms underlying the response to dual bemcentinib and pembrolizumab (Bem/Pem) treatment in patients with relapsed mesothelioma enrolled in a phase II multicentre clinical trial (MIST3, NCT03654833).

Methods

Archival formalin fixed paraffin embedded tissues and blood samples were collected from the MIST3 cohort to enable whole exome and RNA sequencing. AXL concentration was determined at T0 (pre-treatment) and T1 (after one cycle) time points using ELISA. Treatment response was dichotomized into those exhibiting any shrinkage or no change by RECIST1.1 – the R group (tumour reduction) and the NR group (any growth as the best outcome). We utilised geneset enrichment analysis and machine learning to identify relevant variables in the R vs. NR group.

Results

Histologically, 2 out of the 3 recruited patients with a non-epithelioid phenotype had a partial response or stable disease based on tumour size. Genomic features such as tumour mutation burden, somatic copy number burden, and aneuploidy were compared in R vs. NR, and no statistically significant difference was observed. However, specific copy number alterations involving NF2/22q loss were enriched in the R-group. GSEA revealed a markedly higher transcription related to EMT and pro-inflammatory response in the R-group. In contrast, oxidative phosphorylation and hypoxia were more enriched in the NR group.

Conclusions

This study suggests that EMT transcriptional activation facilitates the response to Bem/Pem in relapsed mesothelioma. Given the role of EMT in causing resistance to ICB, this combination could have a role following progression following standard first line therapy, and especially in patients with non-epithelioid mesotheliomas.

Legal entity responsible for the study

University of Leicester.

Funding

Asthma and Lung UK and Victor Dahdaleh Foundation Bergen Bio.

Disclosure

C. Poile: Other, Institutional, Funding, Research Funding: Boehringer Ingelheim. A. Thomas: Non-Financial Interests, Institutional, Advisory Board: BMS; Non-Financial Interests, Institutional, Speaker’s Bureau: Bristol Myers Squibb; Non-Financial Interests, Institutional, Expert Testimony: BMS. M.G. Krebs: Other, Institutional, Other, Honoraria: Roche; Other, Institutional, Advisory Board: Achilles Therapeutics; Bayer; Guardant Health; Janssen; OM Pharma; Roche; Seagen; Other, Institutional, Speaker’s Bureau: Janssen; Roche; Other, Institutional, Research Funding, Funding: Roche (Inst); Other, Institutional, Other, Travel, Accommodations, Expenses: AstraZeneca; BerGenBio; Immutep. D.A. Fennell: Other, Institutional, Other, Honoraria: Bayer; Boehringer Ingelheim; Bristol Myers Squibb; Inventiva Pharma; Novocure; RS Oncology; Targovax; Other, Institutional, Advisory Role, Consulting or Advisory Role: Bristol Myers Squibb; Inventiva Pharma; Novocure; Roche; Targovax; Other, Institutional, Speaker’s Bureau: BMS; Boehringer Ingelheim; Other, Institutional, Research Funding: Astex Pharmaceuticals; Bayer; Boehringer Ingelheim (Inst); Bristol Myers Squibb (Inst); Fuji Pharma (Inst); lab21 (Inst); Other, Institutional, Other, Travel, Accommodations, Expenses: Bristol Myers Squibb; Janssen Oncology. All other authors have declared no conflicts of interest.