26P - Liquid biopsy as promising source of plasma extracellular vesicle biomarkers of response to Cabozantinib (CABO) plus Durvalumab (DURVA) in advanced urothelial carcinoma (UC) or non-UC variant histologies (VH) patients (the Phase 2 ARCADIA trial)

Background

As components of the liquid biopsy, Extracellular Vesicles (EVs) have gained major interest as biomarkers of diagnosis, prognosis and prediction of response/resistance therapies. Here we investigated if plasma EV immune profile, size and concentration with plasma proteomics might discriminate responding from non-responding pts affected by UC or VH undergoing CABO+DURVA.

Methods

We evaluated 40 pts for their plasma EV profile at baseline and at the first reassessment. Baseline samples of 50 pts were evaluated for predictive potential. EVs were profiled using modified MACSplex technology coupled with flow cytometry and nanoparticle tracking analysis. Whole plasma was also searched for further indicators of response/resistance by proteomics (92 analytes, Immune-oncology panel, Olink).

Results

Preliminary analysis of EV markers measured in baseline samples evidenced no major association with response, although VH histology (n=13) showed a significant enrichment of CD1c and CD14 expressing EVs. A significant increase of immune markers were detected on-therapy time point (CD14,CD1c,CD2,CD20,CD8 and CD69; EV markers CD9, CD63 and CD81; platelet markers CD29, CD31 and CD326). This was also reflected by the global distribution of EV markers, which evidenced unexpectedly high levels of EVs exposing CD81 EV marker and CD8 already at baseline, with a further increase after therapy initiation. Finally, the dichotomization by response (responders n=21 vs non-responders n=19) highlighted that a statistically significant increase of immune EVs was detectable almost exclusively in responding.

Conclusions

Our preliminary results suggest that the early dynamics in plasma EVs may inform on the clinical outcome to DURVA plus CABO. The significant increase of EVs expressing immune markers measured at first reassessment in responding may derive from the activation of the immune system induced by therapy. The comprehensive analysis of EV profiles, size and concentration together with plasma proteomics could give rise to predictive/prognostic biomarkers of response, especially in pts with non-UC VHs.

Clinical trial identification

NCT03824691.

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

Funding

AIRC IG-25078, NET-2016-02361632 from Italian Health Ministry.

Disclosure

P. Giannatempo: Financial Interests, Personal, Advisory Board: Pfizer. All other authors have declared no conflicts of interest.