HIF2α gene expression and clinical outcomes in patients with clear cell renal cell carcinoma with and without sarcomatoid differentiation.
Authors: Nawfal Rashad , Semaan Karl , El Zarif Talal , El Hajj Chehade Razane , Eid Marc , Vasseur Damien , Canniff John , Phillips Noa , Savignano Hunter , Lee Gwo-Shu Mary , Gulati Gunsagar Singh , Seo Ji-Heui , McGregor Bradley Alexander , Freedman Matthew , Baca Sylvan C. , Choueiri Toni K. 
Published: February 2025

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Background:
Clear cell renal cell carcinoma (ccRCC) with sarcomatoid differentiation (sRCC) is associated with poor survival. Recent studies have shown downregulation of hypoxia-related pathways in sRCC (Motzer et al., Cancer Cell, 2020; El Zarif, Semaan et al., Cell Reports, 2024). In this study, we sought to compare HIF2α expression levels in ccRCC, with and without sarcomatoid differentiation and investigate clinical outcomes of patients (pts) with sRCC treated with HIF2α inhibitors (HIF2αi).
Methods:
To assess HIF2α gene expression in sRCC, RNA-seq data was collected from 2 clinical trials: JAVELIN Renal 101 (JR101), and IMmotion151 (IM151), as well as publicly available data from The Cancer Genome Atlas (TCGA). Mean HIF2α expression levels were compared between ccRCC with and without sRCC using Wilcoxon Rank-Sum test. To evaluate the clinical outcomes of pts with sRCC treated with HIF2αi, we also collected clinical data from pts with ccRCC who were treated with HIF2αi-based therapies (Belzutifan or AB521). Progression-free survival (PFS) and overall survival (OS) were analyzed using log-rank test and multivariable Cox regression model accounting for IMDC risk group, line of therapy, and type of regimen (HIF2αi; HIF2αi + Vascular endothelial growth factor-targeted therapy (VEGF-TT); HIF2αi + Immunotherapy (IO) + VEGF-TT).
Results:
RNA-seq data from 2,075 pts with renal cell carcinoma with a clear cell component from TCGA (48 sRCC; 493 ccRCC), JR101 (97 sRCC; 639 ccRCC) and IM151 (110 sRCC; 688 ccRCC) were included. Expression of
EPAS1
, which encodes for HIF2α, was significantly downregulated in pts with sRCC in TCGA (log(TPM) mean: 6.63 vs 9.95 in ccRCC ; p < 0.001), JR101 (8.71 vs 8.93 in ccRCC ; p = 0.04) and IM151 (8.05 vs 8.69 in ccRCC ; p < 0.0001). For the clinical cohort, 104 pts treated with HIF2αi were included; 13.5% (14/104) had sRCC. In univariate analysis, sRCC was significantly associated with worse PFS (median PFS = 4.8 months (mo) vs 11.3 mo in ccRCC; p = 0.021) and numerically worse OS (20 mo vs 41.1 mo in ccRCC; p = 0.21). In multivariable analysis, sRCC was associated with worse PFS (HR
adjusted
: 2.55; 95% CI: 1.32–4.90; p=0.005) (Table) and numerically worse OS (HR
adjusted
: 2.14; 95% CI: 0.9–5.1; p=0.08).
Conclusions:
This study suggests that the efficacy of HIF2αi may be limited in sRCC, possibly due to decreased dependency on HIF2α signaling. Our findings highlight the need for novel therapeutic strategies in sRCC.

Multivariable analysis for PFS.

Variable

HR
adjusted

95%CI
p-value

sRCC (yes vs no)
2.55
1.32 – 4.91

0.005

HIF2αi

line of therapy

1.32
1.04 – 1.65

0.018

IMDC group (favorable vs intermediate)
0.95
0.54 – 1.67
0.853

IMDC group (poor vs intermediate)
1.69
0.79 – 3.62
0.176

IMDC group (missing vs intermediate)
1.39
0.54 – 3.57
0.488

Regimen (VEGF-TT + HIF2αi

vs HIF2αi)

0.64
0.30 – 1.37
0.251

Regimen (IO + VEGF-TT + HIF2αi

vs HIF2αi)

0.23
0.03 – 1.95
0.179