Managing Metastatic nccRCC: Historical Approaches and Current Changes

A roundtable discussion, moderated by Laurence Albiges, MD, PhD, discussed the risk stratification and management of metastatic non-clear cell renal cell carcinoma (nccRCC), along with recent advancements in targeted therapies and immuno-agents, treatment sequencing and combination approaches, and adjuvant therapy options. Dr. Albiges was joined by Renée Maria Saliby, MD, MSc; Tian Zhang, MD; and Shahla Bari, MD.

In the second segment of the roundtable series, the panel focuses on the roles of cytoreductive nephrectomy, oligometastatic disease treatment, and advancements in systemic therapies over the past few decades.

View the next segment on Evolution of Combination Therapy in nccRCC, Papillary Subtype.

—

Dr. Albiges: Dr. Zhang, let us discuss the big picture before diving into systemic therapy. When managing patients with metastatic nccRCC, is there a role for cytoreductive nephrectomy? How do you treat oligometastatic disease? Is there anything specific to non-clear cell?

Dr. Zhang: That is a great question. When patients come into our clinics, I really focus on the subtype. I am not a lumper. I consider papillary differently than chromophobe or translocation type.

Regarding cytoreductive nephrectomy or oligometastatic disease, I ask how much systemic therapy will benefit the patient. We will discuss these therapies in detail, but in subtypes where systemic treatments are not very effective, these patients might be good candidates for upfront nephrectomy to address the bulk of their tumor. For patients with oligometastases, if they have only a few metastatic sites, and our systemic therapy is not very effective, we might try localized treatments like surgery or radiation before addressing systemic treatments and their side effects.

Dr. Albiges: It can vary from one tumor type to another. You might approach papillary RCC differently from collecting duct carcinoma. We will discuss that later on.

You mentioned 2 decades of advances where we treated nccRCC the same way as clear cell RCC. What progress has been made over the past 2 decades?

Dr. Zhang: Historically, trials lumped all histologies together. ESPN and ASPEN trials compared sunitinib versus everolimus in the frontline setting. Sunitinib was more effective for most histologies, while everolimus showed some efficacy for chromophobe histologies. However, overall objective responses were low, and progression-free survivals were short. There was a single-agent pembrolizumab trial for nccRCC, a basket trial of all histologies, which showed about a 26% response rate across all histologies. These trials provided the foundation for combination trials.

In the mid-2010s, we started conducting more histology-driven subtype trials. Trials like PAPMET and SAVOIR focused on papillary kidney cancer. PAPMET, conducted in the US NCTN cooperative group setting, started with 4 treatment cohorts and concluded with cabozantinib versus sunitinib after crizotinib and savolitinib showed futility midway. Cabozantinib improved progression-free survival to 9 months compared to 5.6 months for sunitinib, providing our best data for single-agent cabozantinib.

The SAVOIR trial went further by not only selecting for papillary kidney cancers but also focusing on MET selection. You led the trial, which compared savolitinib versus sunitinib. Although it did not show statistical significance, there was a signal of 7 months progression-free survival for savolitinib versus 5.4 months for sunitinib. This highlights the importance of subtypes and molecularly driven subtypes. If MET is the oncogene that can be inhibited, is a pure MET inhibitor the best option? The clinical development of savolitinib suggests there is potential there.

Dr. Albiges: For a long time, we had single-agent TKIs for nccRCC with response rates around 20% or less and median progression-free survival of about 6 months. Cabozantinib, thanks to the PAPMET study, changed the guidelines for papillary RCC.