James J. Hsieh, MD, PhD

CARMENA is a randomized phase 3 noninferiority study showing that for patients with synchronous metastatic clear cell renal carcinoma, the OS is not worse with upfront sunitinib followed by selective nephrectomy than with upfront nephrectomy followed by sunitinib. Cytoreductive nephrectomy plus cytokine treatment demonstrated a survival benefit compared with cytokine treatment alone in the cytokine era, around 2004, the “dark age” of metastatic kidney cancer care. Accordingly, upfront cytoreductive nephrectomy has been the standard of care for 2 decades. The take-home message from this study is: in the targeted therapy era, 2005 to 2014 —  the “modern age” —   whether individual synchronous metastatic clear cell renal cell carcinoma patients require upfront cytoreductive nephrectomy should be reconsidered. As the metastatic kidney cancer care has marched into the targeted/immunotherapy combination/sequencing therapy era, starting in 2015 —  the “golden age” —  this study opens up additional treatment sequencing options, and implicates the need of omics-incorporated precision nomogram to guide future metastatic clear cell renal cell carcinoma management.

In my opinion, besides clinical features, all therapeutic decisions made on these patients should take into consideration their underlying tumor biology. For example, we know clear cell renal cell carcinoma is highly heterogeneous, and data suggest that patients with PBRM1-mutant tumors are likely to do well on anti-VEGFR TKIs, mTORC1 inhibitors and checkpoint inhibitors. These PBRM1-mutant tumors tend to grow slower and upfront cytoreductive nephrectomy should be considered to reduce the extreme tumor heterogeneity and prevent further cancer evolution. On the other hand, patients with BAP1-mutant tumors tend to grow faster and are less responsive to targeted therapy. Accordingly, the benefit of upfront cytoreductive nephrectomy for BAP1 tumors might be questionable. Hence, the question is, should we biopsy primary tumor to analyze genomics before making surgical decisions in the future?

In this single French group OS study, it almost hints that sunitinib alone (18.4 months) is superior to cytoreductive nephrectomy followed by sunitinib (13.9 months). However, as the authors stated, this is not statistically significant, and the study was not designed to show sunitinib alone is superior. Several caveats require attention when we interpret this study. First, for patients randomly assigned to upfront cytoreductive nephrectomy, 22.5% did not receive sunitinib after surgery. Second, for patients randomly assigned to upfront sunitinib, 17% underwent nephrectomy. Third, the 13.9-month OS reported in this study is poor and comparable to the OS reported in the cytokine dark age (~13 months). Nevertheless, this is an important study because it tells us that we can’t treat patients exactly the same.

Sumanta Kumar Pal, MD

Kidney cancer is a disease that affects about 60,000 patients per year in the U.S. Many patients with kidney cancer will evolve to have metastatic disease spread to other organs. The prognosis for advanced kidney cancer has improved markedly over the last decade, thanks to the advent of targeted therapy. We’ve seen an improvement in median survival from 1 year more than a decade ago to closer to 3 years at this point in time, which is on account of the drug-based therapies we’re using in this disease.

One of the practices we have held to is, even in the context of patients with advanced disease whose cancer has spread to other sites, we’ve been removing the kidney. But, admittingly, this isn’t based on a very high level of evidence. This clinical practice is based largely on surveys of national data repositories and data banks performed by investigators like myself and many others. What we have shown in retrospective studies is there seems to be benefit from this approach, but the highest bar is what Dr. Mejean has presented, and that’s a randomized prospective clinical trial.

He has firmly demonstrated, in my opinion, that in the context of the targeted therapy sunitinib, there doesn’t necessarily seem to be a need to remove a kidney in patients with advanced metastatic disease. It flips the existing paradigm we have in the management of advanced kidney cancer is this regard.

We need to take these results with a grain of salt because the treatment landscape for advanced kidney cancer is evolving very rapidly. In January, FDA approved cabozantinib [Cabometyx/Cometriq, Exelixis], a multikinase inhibitor that may potentially obviate treatments like sunitinib that was the base of this particular clinical trial. Perhaps even more of an evolution has taken place since then with the approval of nivolumab [Opdivo, Bristol-Myers Squibb] and ipilimumab [Yervoy, Bristol-Myers Squibb), a dual therapy regimen for advanced kidney cancer that happened in mid-April of this year. In the context of newer therapies, we may potentially have to go back to the drawing board once again and assess the relevance of removing the proper tumor in this case.