Abstract 1957
Background
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.
Methods
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 |
| HIF2A | 1.22 | 0.78 | 0.03 (+57%) | ||
| VEGFA | 7.10 | 4.26 | 0.07 (+67%) | ||
| VEGFR1 | 3.06 | 1.53 | 0.02 (+100%) | ||
| VEGFR2 | 1.37 | 0.60 | 0.009 (+128%) | ||
| VEGFR3 | 1.07 | 0.71 | 0.03 (+52%) | ||
| OUTCOME ON FIRST-LINE VEGFR-TKI (n = 151) | RR | 63% | 40% | 0.08 | Fisher exact |
| PFS (months) | 25 | 10 | 0.03 |
Results
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.
Conclusions
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.
Funding
La Ligue Contre le Cancer France.
Editorial Acknowledgement
Disclosure
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.
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