After a series of disappointing trial results in metastatic renal cell carcinoma (RCC), the combination of vascular endothelial growth factor (VEGF)-directed and mammalian target of rapamycin (mTOR)-directed therapies has had a victory in a small trial of patients. The results were recently published in the Journal of Clinical Oncology.1

Researchers combined the VEGF-directed drug, bevacizumab, with the mTOR-directed drug, everolimus, in a group of 35 patients with treatment-naive metastatic non-clear-cell (ncc) RCC. Among 34 evaluable patients, the median progression-free survival was 11 months, with a response rate of 29%.

In an editorial that accompanied these results, Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center, and colleagues, called these results “encouraging,” and discussed what clinicians and researchers can learn from them in the greater context of RCC research.2

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VEGF/mTOR Combinations

The combination of VEGF and mTOR inhibitors has been tested in multiple trials of metastatic RCC. After 2 phase 2 trials of bevacizumab plus everolimus showed modest activity among patients with metastatic disease, the regimen was tested in a randomized phase 2 trial, comparing it with bevacizumab plus interferon-alpha 2a. This randomized trial failed to show a difference in outcomes between the 2 arms.

A phase 3 trial compared bevacizumab plus temsirolimus with bevacizumab plus interferon-alpha, and, again, the trial showed no benefit to the VEGF/mTOR-directed combination.

These trials evaluating VEGF/mTOR-directed combinations in RCC included mostly patients with clear-cell disease.

“‘Non-clear cell renal cell carcinoma’ is an umbrella term that includes a wide array of different tumor types. Each has a distinct biology, and may or may not be sensitive to the treatments applied in clear cell RCC,” Dr Pal explained. “Thus, there is a need to replicate examination of new drugs and combinations in these histologies, rather than extrapolating from data based in clear cell disease.”

Among the histologies grouped into nccRCC, papillary RCC is the most common, representing about 15% to 20% of all kidney cancer cases, Dr Pal said. Chromophobe is the next most common subtype, representing about 5% of cases.

“Beyond that, there is a mix of various exquisitely rare subtypes. Subtypes such as collecting duct and medullary represent less than 1% of cases,” he said.

The present study included 15% of patients with papillary disease, 15% of patients with chromophobe disease, and 5% with medullary disease. Sixty-five percent of patients, however, were labeled as having unclassified RCC. Although 61% of cases defined as unclassified had features of papillary disease, they did not meet the criteria for formal categorization.

According to Dr Pal and colleagues, the encouraging results seen were driven by these “unclassified” patients with papillary features. Among these patients, the median progression-free survival was 12.9 months, and the response rate was 43%.

Digging Deeper

When the researchers searched for common features among these “unclassified” patients with papillary features, next-generation sequencing identified clusters of genetic alterations. Among those patients with papillary features sequenced, 5 of 14 had ARID1A mutations. Those same 5 patients benefited from the bevacizumab/everolimus combination.

“That ARID1A mutations fully account for the clinical benefit observed in this cohort is unlikely because peppered in this series of patients were those with mutations in MTOR and TSC2 who also had prolonged responses to therapy,” Dr Pal and colleagues wrote in the editorial. “Although it is appealing to link genomic data to response, in this series, histology seems to be a more compelling predictor, with the presence of papillary features being the single most important determinant of clinical outcomes with bevacizumab plus everolimus.”

Based on these results, Dr Pal said that it is the responsibility of investigators to develop randomized trials that investigate these rare subtypes of RCC.

Dr Pal is leading the largest prospective trial in papillary RCC to date. The trial, known as S1500, will randomly assign 250 patients to either the VEGF-inhibitor, sunitinib, or to 1 of 3 inhibitors of MET, a protein that is thought to drive many cases of papillary RCC.

“The study by Dr Voss provides an important lesson for investigators: namely, any study done in a rare histology needs to be accompanied by intensive translational studies,” Dr Pal said. “The added insight gained from genomic profiling in this study is critical. Further studies may investigate markers such as ARID1A for their predictive value with this regimen.”

Case reports and small studies like that of the present study should be viewed as hypothesis-generating.

“As investigators, we must band together and compose clinical trials that prospectively assess novel, biologically relevant therapies for nccRCC, and we must ensure that these studies are randomized, so we can build upon existing standards,” Dr Pal said.


  1. Voss MH, Molina AM, Chen YB, et al. Phase II trial and correlative genomic analysis of everolimus plus bevacizumab in advanced non–clear cell renal cell carcinoma. J Clin Oncol. 2016 Sep 6. doi: 10.1200/JCO.2016.67.9084 [Epub ahead of print]
  2. Pal SK, Karam JA, Bergerot P, Agarwal N. Developing a clear path forward for non-clear-call renal carcinoma. J Clin Oncol. 2016 Sep 6. doi: 10.1200/JCO.2016.69.3572 [Epub ahead of print]