1470P - Transcriptomic signature and immune infiltrate in metastatic collecting duct renal cell carcinoma patients treated with first-line cabozantinib: Results of exploratory endpoints from BONSAI trial (Meeturo 2)

Background

The prospective phase II BONSAI trial (n=25; NCT03354884) met its primary endpoint demonstrating cabozantinib effects in untreated metastatic collecting duct carcinoma (mCDC). We aimed at investigating if baseline mCDC transcriptome is associated with outcome and/or predictive immune signatures.

Methods

FFPE samples from 18 mCDC patients from BONSAI trial were sequenced and the data processed with STAR and htseq. Globaltest and edgeR in R were used to assess the correlation between transcriptional and survival data, and GSVA to estimate variation of gene sets enrichment. Patients were divided into high and low groups based on the median gene expression z-score.

Results

A 22-gene signature (BONSAI) clusters patients into a first group (n=6) with increased expression of 19/22 genes (BONSAI^high) and longer PFS and OS, and a second group (n=12) with opposite expression trend associated with disease progression. BONSAI^high patients exhibit best response rate to cabozantinib, while no clear association with metastasis localization, tumor mutational burden and LOH state is observed. BONSAI^high tumors display enrichment of the predictive “angiogenesis” and “T-cell immunity” IMmotion150 trial (McDermott 2018). Conversely tumors from BONSAI^low patients are enriched in CDC-specific gene signature (Gargiuli 2021), myeloid genes associated with therapy resistance and poor outcome, as well as specific immunosuppressive signature linked to myeloid derived suppressor cells (MDSC) activity in progressive clear-cell renal carcinoma (ccRCC; Rinchai 2021).

Conclusions

mCDC is featured by a prognostic signature associating T cell immunity and angiogenesis with good clinical outcome and sensitivity to cabozantinib, differently from ccRCC. MDSC signatures linked with drug resistance and poor prognosis may warrant using myeloid-targeting drugs to achieve disease control. The study of blood MDSC of these patients is ongoing and will provide insights of role of MSDC in mCDC. A further validation of this signature will be performed in the ongoing CICERONE trial.

Clinical trial identification

NCT03354884.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Ipsen.

Disclosure

E. Verzoni: Other, Personal, Advisory Board: MSD; Other, Personal, Speaker’s Bureau: Eisai, Pfizer; Other, Personal, Invited Speaker: Ipsen. All other authors have declared no conflicts of interest.