Genomic and Transcriptomic Characteristics of Tumors of Patients with Metastatic Clear Cell Renal Cell Carcinoma Clinically Benefiting from First-Line Treatment with Ipilimumab Plus Nivolumab

Abstract

Background: Ipilimumab plus nivolumab is approved as a first-line treatment for intermediate or poor risk metastatic renal cell carcinoma (mRCC). However, ∼35% of patients progress within six months on ipilimumab plus nivolumab, and no validated genomic biomarkers predict the benefit. In this study, we explore the genomic and transcriptomic differences among patients with clear cell mRCC patients who either did or did not experience clinical benefit from first-line ipilimumab plus nivolumab therapy. Method: Patients with clear cell mRCC intermediate or poor IMDC risk scores, with available tumor whole exome with/without transcriptome sequencing before starting systemic therapy were included. Patients who developed a complete response, partial response, or stable disease for at least six months after initiating treatment were categorized into the ‘clinical benefit’ group, whereas the rest were classified as ‘no clinical benefit.’ Genomic alteration frequencies between the groups were assessed with a chi-square test. Differentially expressed genes and gene sets were identified via DeSeq2 and GSEA v4.2.3, respectively. Result: 53 patients with clear cell mRCC (37 clinical benefit and 16 no clinical benefit) were eligible and included. No significant difference was found in the genomic alteration frequencies between these groups. Baseline tumor transcriptomic data were available for 14 patients (9 clinical benefit and 5 no clinical benefit). The apical surface and pathways downregulated by KRAS signaling were enriched in the clinical benefit group, whereas inflammatory pathways were enriched in the no clinical benefit group. Conclusion: These findings suggest that tumor specific gene expression as assessed by RNA sequencing could serve as a potential biomarker of response to ipilimumab plus nivolumab therapy.