In advanced clear cell renal cell carcinoma (ccRCC), Checkmate214 demonstrated superior response rates (RR) and progression-free survival (PFS) with ipilimumab/nivolumab (IPI/NIVO) in IMDC I/P-risk pts and with sunitinib (SUN) in G-risk pts. We aimed to study the underlying biologic mechanisms.
We have recently proposed four molecular ccRCC subtypes: ccrcc2-tumors, characterized by a pro-angiogenic gene signature, respond well to SUN, while ccrcc1- and 4-tumors are intermediate and poor responders to SUN. We analyzed our ccRCC databank and correlated the IMDC prognostic score at start of systemic therapy with mRNA-expression of genes involved in angiogenesis (HIF1A/2A, VEGFA, VEGFR1/2/3) and in the immunosuppressive microenvironment (PD1, PDL1/2, LAG3, CD8A, CD3G, IFNG, CXCL13) and with the molecular ccrcc1-4 classification of the primary tumor.Table: 869PD
|IMDC G-risk||IMDC I/P-risk||p (+difference in %)||Test|
|MOLECULAR SUBTYPES||ccrcc1||14% (3/22)||34% (47/140)||0.08||Fisher exact|
|ccrcc2||77% (17/22)||41% (59/140)||0.002|
|ccrcc3||9% (2/22)||5% (7/140)||0.35|
|ccrcc4||0% (0/22)||20% (28/140)||0.02|
|PRO-ANGIOGENIC GENE EXPRESSION (deltadeltaCT)||HIF1A||0.82||0.63||0.21 (+29%)||Student’s test|
|OUTCOME ON FIRST-LINE VEGFR-TKI (n = 151)||RR||63%||40%||0.08||Fisher exact|
162 pts were included (14% IMDC G-, 65% I- and 21% P-risk). The majority of G-risk pts (77%) had ccrcc2-tumors. ccrcc1- (14%) and ccrcc4-tumors (0%) were less frequent. In I/P-risk pts, ccrcc2-tumors were less frequent (41%), and ccrcc1- (34%) and ccrcc4-tumors (20%) more frequent. mRNA expression of HIF2A, VEGFR1, -2 and -3 was higher in G-risk pts compared to I/P-risk pts. Identical expression of immune related genes was found across all IMDC subgroups.
The majority of IMDC G-risk ccRCCs pts have ccrcc2-tumors. G-risk pts display a higher expression of the VEGF-dependent pro-angiogenic pathway, compared to I/P-risk pts. This may explain the increased benefit of SUN over IPI/NIVO in G-risk pts in Checkmate214.
Clinical trial identification
Legal entity responsible for the study
University Hospitals Leuven.
La Ligue Contre le Cancer France.
B. Beuselinck: Speeker's fee, Research grant: Pfizer P. Schöffski: Institutional travel grant: Pfizer. S. Oudard: Speeker's fee: Pfizer All other authors have declared no conflicts of interest.