Do tissue-based biomarkers in metastatic clear cell renal cell carcinoma perform better when derived from a metastatic site?
Authors: Monda Steven , Vaishampayan Ulka N. , Kaffenberger Samuel , Triner Daniel , Nallandhighal Srinivas , Morgan Todd Matthew , Hafez Khaled , Knuth Zayne , Singhal Udit , Gulati Shuchi , Palapattu Ganesh S. , Salami Simpa Samuel 
Published: February 2025

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Background:
Gene expression and mutation analyses in metastatic clear cell renal cell carcinoma (ccRCCs) have attempted to identify tumors that differentially respond to tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) – broadly an angiogenic and an immunogenic clade. However, ccRCC is genomically heterogeneous and sequencing a single-region of a primary tumor does not necessarily represent the metastatic clone. We re-analyzed the biomarker results of the Phase III IMmotion151 trial, stratifying patients into primary-derived and metastasis-derived sequencing, to assess if metastasis-derived sequencing performed better in differentiating response to therapy.
Methods:
We replicated the IMmotion151 biomarker analyses on transcriptomic clusters and mutations on all patients and then stratified to 198 patients with metastasis-derived and 625 patients with primary-derived sequencing. We assessed progression-free survival (PFS) with Cox proportional hazards while controlling for IMDC risk group for atezolizumab and bevacizumab (atezo + bev) versus sunitinib based on previously-described angiogenic groupings: Cluster 1 (Angiogenic/Stromal), Cluster 2 (Angiogenic), and
PBRM1
mutant tumors; and immunogenic groupings: Cluster 4 (T-effector/Proliferative), Cluster 5 (Proliferative),
PBRM1
wild-type and
CDKN2A
-loss tumors.
Results:
PFS favored Sunitinib in angiogenic Cluster 2 and Clusters 1+2 when sequencing was derived from the metastatic site (HR 3.39, p=0.011; HR 2.91, p=0.005) but not the primary (HR 1.04 p=0.82; HR 1.02, p=0.88) (Table). A similar trend was observed for other angiogenic groups (Cluster 1 &
PBRM1
mutant), but did not reach significance. PFS favoring atezo + bev for immunogenic groupings remained significant when derived from the primary.
Conclusions:
Angiogenic signatures distinctly favored sunitinib in advanced ccRCC when sequencing was derived from the metastasis but not the primary tumor. Immunogenic signatures favored atezo + bev even when derived from the primary site. A prevalent angiogenic signature throughout the primary tumor, that is now always present in the metastatic clone, may explain these results.

Cox proportional hazards results for Atezo + Bev versus Sunitinib corrected for IMDC risk-group. HR >1 favors Sunitinib, HR <1 favors Atezo + Bev.

Marker
All patientsN= 823 for RNA-seqN= 715 patients for mutations
Metastasis-Derived Sequencing OnlyN= 198 for RNA-seqN= 152 patients for mutations
Primary Derived Sequencing OnlyN= 625 for RNA-seqN= 563 patients for mutations

DFS- HR

P- value

DFS- HR

P- value

DFS- HR

P- value

Markers Favoring Angiogenic Response / Sunitinib

Cluster 1- Angio/Stromal(n=98)
1.21
0.48
3.10
0.14
1.02
0.95

Cluster 2- Angio(n=245)
1.22
0.25
3.33

0.024

1.04
0.82

Cluster 1 + 2(n=343)
1.20
0.22
2.66

0.011

1.02
0.88

PBRM1 mutant(n=333)
1.05
0.73
1.72
0.13
0.86
0.33