Management of Metastatic Non-Clear Cell RCC: Is There a Standard of Care?

During a Saturday afternoon session at the American Urological Association 2023 meeting, Brian Rini, MD, FASCO, Vanderbilt-Ingram Cancer Center, provided an overview of non-clear cell renal cell carcinoma (nccRCC) – including the current state of the field and data pertaining to response to systemic therapy.

He began by showing a diagram of the rare subtypes that make up the collective nccRCC category, noting that all of them have different histologies, biologies, tumor drivers, and targets. However, biologic understanding and treatment has not advanced enough to treat each subtype in its own way. He explained throughout the presentation that targeted therapy and immunotherapy are typically developed for clear cell disease, and once effectiveness is demonstrated, they are tried in nccRCC – usually with minimal and unimpressive effect. This trend is likely because clinical trials are designed to test drug effectiveness in nccRCC as a whole, while not accounting for specific subtypes and their various makeups. Thus, some trials will show response rates of almost 30%— as is the case with KEYNOTE-427— while others will report close to 0%.

Papillary kidney cancer, the predominant type of nccRCC, was the focus of his discussion. He showcased two trials from 2016 that attempted to show benefit from targeted therapy in papillary RCC but ultimately demonstrated minimal activity. The ESPN study evaluated frontline sunitinib and reported a median progression-free survival of 5.7 months compared with 4.1 months from everolimus. The other study, ASPEN, reported 8.1 months and 5.5 months, respectively, with the same therapies.

The largest trial in nccRCC to date is SWOG 1500: PAPMET, which assessed the effectiveness of targeted therapies sunitinib, cabozantinib, and two MET inhibitors: crizotinib and savolitinib. “MET is thought to be important in papillary kidney cancer, but sometimes I believe it and sometimes I don’t,” Dr Rini said. “The role of MET in the biology of nccRCC is really undefined, but this was the rationale to include MET inhibitors in this trial.” The topline results of the study were “not terribly exciting” and the main takeaway was that cabozantinib led to a higher ORR (23%) than sunitinib (4%).

He showed phase 2 data of savolitinib from 2017 as a way to demonstrate that in MET driven subsets of papillary kidney cancer, MET inhibitors are a different type of targeted therapy that might have activity. However, further research is still needed to validate this idea.

Next, he showed waterfall plots of all of the single-arm phase 2 studies of IO/TKI combinations in nccRCC, all of which have demonstrated previous effectiveness in clear cell RCC and denote clear activity and tumor shrinkage in nccRCC. These studies have all been published within the past few years and include cabozantinib plus atezolizumab, cabozantinib plus nivolumab, bevacizumab plus atezolizumab, and lenvatinib plus pembrolizumab. “I think now, VEGF plus immunotherapy probably represents the standard of care in nccRCC,” he commented.

As for where the field is heading, Dr. Rini displayed an ongoing French study evaluating axitinib with or without pembrolizumab with the hopes of “better defining whether two drugs is better than one” in papillary RCC.

In his concluding remarks, Dr. Rini classified nccRCC as a “mixed bag” of histologies, biologies, and response to systemic therapy. MET may be an important component of non-clear cell biology and MET inhibitors have shown activity, though more definitive studies are ongoing. He also cited single-agent immunotherapy and IO/TKI combinations as showing some activity in papillary and unclassified kidney cancer.

While IO/TKI combinations should be considered standard of care in nccRCC at the moment, “we really need better biology, better targets, and frankly, new drugs in this setting,” he stated.