Medicine Matters oncology

So sarcomatoid and rhabdoid renal cell carcinoma is an aggressive form of RCC that occurs in up to 20% to 25% of patients with metastatic renal cell carcinoma. This form of the disease is overrepresented in patients presenting with metastatic disease and is associated with a poor prognosis historically.

With a targeted therapy era we had much better options with patients with clear-cell RCC, but unfortunately patients that had the sarcomatoid or rhabdoid features responded very poorly to these targeted therapies. I should say that these sarcomatoid and rhabdoid features occur on both a background of clear-cell RCC, but also a background of non-clear-cell RCC.

So very luckily in the recent large randomized controlled trials of immune checkpoint inhibitor-based agents for renal cell carcinoma, the subgroups of patients with sarcomatoid RCC seem to be responding very well to immune checkpoint inhibitors, such as the nivolumab-ipilimumab trial the pembrolizumab-axitinib trial and the avelumab-axitinib trial but also the atezolizumab-bevcizumab trial. All these subgroups, relatively small 50 to 60 patients, showed that there was a benefit to immune checkpoint inhibitors in patients with this disease.

Now what we set out to do is to ask this question at a much larger scale to confirm whether this benefit was in the sarcomatoid but also in the rhabdoid group of patients, and whether it was confirmed in monotherapy immune checkpoint inhibitors or some combination immune checkpoint inhibitors. We asked this question in three cohorts, the first one being Harvard cohort, from Dana Farber, MGH, BWH, and BIDMC.

With more than 200 patients, we found that benefit to immune checkpoint inhibitors in patients with sarcomatoid and rhabdoid RCC. We confirmed these results in the IMDC data set, which is a large data set of patients with metastatic renal cell carcinoma, including more than 900 patients with sarcomatoid and rhabdoid RCC from more than 40 institutions across the world.

We then confirmed that also in subgroup analysis of two clinical trials, the CheckMate 025 and Checkmate 010 clinical trials of single agent nivolumab. We also found an overall survival benefit in that pooled analysis.

So then we set out to ask, what is underlying both the poor prognosis of these patients? Are the molecular features unexplained to them, especially in the target therapy area? And also, why are these patients responding to immune checkpoint inhibitors.

At the DNA level-- and this is a pooled analysis for multiple cohorts. We found that tumors that have sarcomatoid and rhabdoid features seem to be enriched in mutations NF2 and BAP1, deletions at the CDKN2A locus and in amplifications in the EZH2 locus. Which would probably explain the poor prognosis because mutations, in particular in BAP1 and even NF2, have been associated with a poor prognosis in RCC.

Then at the RNA level we found that there was an MIC related signature that was upregulated in these tumors, and also the cell proliferation signature seemed to be up regulated, suggesting that this may be underlying also the poor prognosis in these tumors. We also found that these tumors have a very immune-inflamed phenotype at the transcriptional level with a pathway, such as IL-6/JAK/STAT3 and IL-2/STAT5 signaling increased but also infiltration by CD8 T cells and high expression of PD L1 at on the tumor cells of these tumors.

So in conclusion, I think that sarcomatoid and rhabdoid RCC is historically associated with a poor prognosis. We tried to explain in this study what are the molecular features underlying the poor prognosis of these tumors. We believe it's a combination of DNA and RNA alterations, but also these tumors are now responding very well to immune checkpoint inhibitors. We provide the largest data sets to date showing that, but we also try to get at the mechanisms underlying this improved responsiveness to immune checkpoint inhibitors using a combination of RNA analysis, immunofluorescence and IHC to get at that question and finding that these tumors have a very immune-inflamed phenotype.