Use of genomic dedifferentiation signature to predict clinical outcomes with doublet vs triplet therapy in the phase III COSMIC-313 trial
No Thumbnail Available
Authors
Salgia, Nicholas
Valmeekam, Venu
Simmons, Andrew
Motzer, Robert J.
Albiges, Laurence
Pal, Sumanta Kumar
Powles, Thomas
Choueiri, Toni K.
Contact
Check for full-text access
Issue Date
2026
Type
Article
Language
Keywords
Alternative Title
Abstract
Background: The Genomic Dedifferentiation Signature (GDS) has previously been shown to differentiate clinical outcomes to immune checkpoint inhibitor (ICI)-based combinations and anti-VEGFR monotherapy in patients with metastatic renal cell carcinoma (mRCC; Salgia et al. Cancer Cell. 2025). COSMIC-313 is a randomized phase III trial evaluating cabozantinib-nivolumab-ipilimumab (C/N/I) vs nivolumab-ipilimumab (N/I) in mRCC. Here, we evaluated the prognostic and predictive utility of the GDS in COSMIC-313. Methods: Bulk transcriptomic profiling (RNAseq) was obtained for 398 patients (pts) enrolled in COSMIC-313 and used to assign GDS scores by single sample gene set enrichment analysis. Pts were classified as GDShigh or GDSlow based on median GDS expression. Clinicopathologic variables and objective response rates (ORR) were compared using Wilcoxon Rank-Sum and Fisher’s Exact Tests. Progression-free survival (PFS) and overall survival (OS) analyses employed Kaplan-Meier estimates and Cox proportional hazard models. Results: In the ITT population (both trial arms), GDS scores were significantly enriched in pts with IMDC poor vs intermediate risk (p = 0.0097) and in those with vs without sarcomatoid features (p = 2.2x10-5). ORR did not significantly differ between GDShigh and GDSlow pts treated with C/N/I (48% vs. 58%; p = 0.21), though a non-significant improvement in ORR amongst GDShigh vs. GDSlow pts was seen with N/I (50% vs. 35%; p = 0.057). Among GDSlow pts, C/N/I yielded a significantly higher ORR than N/I (58% vs. 35%; p = 0.0019), with no difference between arms in GDShigh pts (48% vs. 50%; p = 0.98). PFS was not significantly different between GDShigh and GDSlow, pts in the ITT, C/N/I, and N/I cohorts, with HRs of 1.0 (95% CI: 0.81–1.3, p = 0.75), 1.2 (95% CI: 0.81–1.7, p = 0.4), and 0.88 (95% CI: 0.62–1.3, p = 0.48), respectively. OS was significantly worse in GDShigh pts in the ITT population (HR: 1.3, 95% CI: 1.0–1.8, p = 0.043), with non-significant differences in the C/N/I and N/I arms (HRs: 1.4 and 1.2, p = 0.14 and 0.36, respectively). Conclusions: Front-line management of mRCC currently relies on ICI-ICI and VEGFR-ICI combinations, though no biomarker yet exists to determine which patients differentially benefit from each strategy. These results not only reinforce the negative prognostic capacity of the GDS, but also support the potential predictive utility of the GDS, suggesting that GDSlow patients disproportionately benefit from the addition of VEGFR-directed agents to ICI-based therapy for the first-line treatment of mRCC.
Description
Citation
Publisher
License
Journal
Journal of Clinical Oncology
Volume
44