Kidney cancer represents 3% of all diagnosed cancers. In France, more than 11,000 new cases were reported in 2011, including 30% of patients with metastases. From a histological point of view, clear-cell renal cell carcinoma (ccrcc) is the most frequent (nearly 80% of kidney cancers).
Previous work conducted by the CARPEM’s teams has allowed to dissociate 4 molecular subgroups of clear-cell renal cell carcinoma (ccrcc1 to ccrcc4) on the basis of transcriptomic data, associated with sensitivity to sunitinib (tyrosine kinase inhibitor) and a distinct immune and angiogenic infiltration of the tumor microenvironment. Tumors that are less responsive to sunitinib have either a low-inflammatory, low-infiltration tumor microenvironment (ccrcc1) or a high-inflammatory, high-infiltration tumor microenvironment with high expression of immune checkpoint markers (ccrcc4). About half of the most sunitinib-responsive tumors are associated with significant angiogenesis and a highly inflammatory immune microenvironment (ccrcc2). Finally, there is a smaller group of tumors with good responsiveness to sunitinib, which show molecular and pathological characteristics close to normal renal tissue (ccrcc3) (Beuselinck B et al., Clin Cancer Res, 2015).
Work by Yann-Alexandre Vano et al, from CARPEM and the Paris CARPEM Cancer Institute, published in the Lancet Oncology, shows the results of the first randomized clinical trial based on molecular subgroups in metastatic renal cell carcinoma.
The authors investigated the hypothesis that the 4 tumor subgroups are able to respond to different therapeutic strategies based on the use of nivolumab (anti-PD1) alone or in combination with ipilimumab (anti-CTLA4), and a VEGFR-TKI (tyrosine kinase inhibitor). To address this issue, a randomized biomarker-driven phase 2 clinical trial was designed to evaluate the objective response rate according to molecular group and assigned therapy in patients with metastatic clear cell renal cell carcinoma. Thus, patients with ccrcc1 or ccrcc4 were randomly assigned to nivolumab alone or nivolumab + ipilimumab, and those with ccrcc2 or ccrcc3 received nivolumab + ipilimumab or a VEGFR-TKI.
The results show that the response to nivolumab alone, nivolumab + ipilimumab, and VEGFR-TKIs varied according to the composition of the tumor microenvironment. The different ccrcc groups are biologically distinct entities in terms of the main characteristics of their tumor microenvironment. Thus, treatment selection based on molecular subgroups appears to be crucial in the management of patients with metastatic clear cell renal cell carcinoma.
This study is the first to demonstrate the feasibility and benefit of prospective patient selection based on tumor molecular phenotype to guide the choice of first-line therapy in metastatic clear cell renal cell carcinoma. These results pave the way for further large-scale biomarker-based clinical trials.