Expanding Treatment Horizons: Novel Approaches in RCC and Non-Clear Cell Disease

At the 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium, a roundtable of expert panelists convened to discuss the latest research and practice updates related to advanced kidney cancer. Dr. Karine Tawagi of University of Illinois was joined by Drs. Regina Barragan-Carrillo, Benjamin Maughan, Laurence Albiges, and David McDermott in the discussion.

In the final part of the roundtable, the panel concludes with opinions on the most exciting future directions in RCC, including HIF inhibitors, biomarker-guided adjuvant strategies, personalized vaccines, immune effector cell therapies for refractory disease, and histology-specific trials for non-clear cell subtypes, marking a shift toward more targeted and effective treatments.

View the previous segments.

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Dr. Tawagi: In terms of future directions for RCC, what clinical trials or research areas are you most excited about?

Dr. McDermott: I think the most interesting new data is the HIF inhibitor data that will be presented on Saturday. The abstract has already been released. It is very similar in design to belzutifan. It is always beneficial to have more than one drug with the same mechanism of action to test in a particular disease. Based on the abstract, this drug appears to be active. We will have to see the full data, but the unconfirmed response rate was greater than 30 percent, which is encouraging. If this drug moves into the clinic, I would like to see us study it upfront in selected patients as a single agent, which is not currently Merck’s strategy with belzutifan. They are moving it upfront, but in combinations, which makes sense to some extent. However, having more than one drug with this mechanism will hopefully improve outcomes for our patients.

Dr. Albiges: Yes, I have my eye on the adjuvant trials because we are now waiting for combination strategies in the adjuvant setting. In the coming years, we will have belzutifan plus pembrolizumab. Is there a rationale to give this drug earlier? I hope we can develop a biomarker-guided strategy in the adjuvant setting. We have discussed efforts to develop personalized vaccine strategies. Recently, there was a very nice publication from Boston by Dr. Toni Choueiri’s team and Dr. David Braun, who worked on personalized vaccine strategies. This was published in Nature, involving only nine patients, but there was an immune response and no relapses. This approach is being taken to the next level with V-940, which is also a personalized vaccine strategy. The idea is to use specimens from nephrectomy or tumorectomy to generate a personalized vaccine in addition to pembrolizumab. This is a phase two trial for RCC, but it has already demonstrated proof of concept in melanoma. This is another strategy I would like to see. Ultimately, if we are able to do this, having neoadjuvant trials to see if we can replicate the success seen in melanoma is important. What about treating patients when the tumor is still present? Could this provide an enhanced benefit compared to pembrolizumab as an adjuvant strategy? I am particularly interested in the perioperative setting.

Dr. Maughan: Yes, I was going to say something similar. I am very excited about all the data being generated in the largely adjuvant setting, but particularly the aspect I am enthusiastic about is using tools like KIM-1 to better select patients in the future. Roughly half of patients with high-risk, locally advanced disease are cured with surgery, so these tools could help enrich future adjuvant trials. In the refractory setting, we are still largely struggling with how to address the disease once it has become immune checkpoint inhibitor refractory. There is promising early data with various immune effector cell approaches like CAR-T compounds, and I am eagerly watching for additional results on these therapies.

Dr. Tawagi: I think there will be a session on Saturday about immunotherapy-refractory RCC, so I am sure we will hear more about some of those trials.

Dr. Tawagi: We have not really discussed non-clear cell RCC yet. Is there anything you are excited about in this area? I know we have seen some data in the past year, and there is an abstract or two on Saturday as well.

Dr. Barragan-Carrillo: Before we move on, I will take the opportunity to give my biased opinion. In the future, I am very excited about microbiome-based interventions. From a global perspective, these could be cost-effective and demonstrate very low toxicity. I am aware that the information we currently have comes from early phase one trials with 30 to 50 patients, but based on what we learned from the trial presented at ESMO, I think microbiome-based interventions are an interesting approach. This could be replicated on a global scale without increasing toxicity. That being said, the early data is promising, and I am excited about the potential.

Now, returning to non-clear cell RCC, this is a field that is evolving, but it is still very heterogeneous. Some important efforts have been made, for example, with the SUNNIFORECAST trial presented at ASCO, which compared the combination of nivolumab and ipilimumab to TKIs like cabozantinib. This combination showed some significant activity. However, I am cautiously optimistic, as the endpoint showed an improvement in overall survival at 12 months, but we still need stronger data. We also have promising data with TKI combinations, such as LEN-PEMBRO and NIVO-CAVO. I believe we are making progress, but there is still more work to be done. The PAPMET trial will likely provide answers to many of the lingering questions.

Dr. Maughan: I hope so as well. But I must say that it has been exciting to witness the increasing focus on research in non-clear cell RCC. Before I started as an oncologist, trials like ASPEN and ESPN included all non-clear cell cancers and reported on the data in aggregate. Now, we are starting to see trials focused on specific disease histologies. These trials may still include patients with all non-clear cell histologies, but they report data in a much more specific manner, like the Keynote trial with pembrolizumab monotherapy or KEYNOTE-B61, which included a variety of histologies but reported results specific to each disease type. At this meeting, we also have an abstract on FH-deficient disease. This is very exciting because it is through these specific trials that we can move the needle for patients who desperately need progress, rather than assuming that what works for clear cell RCC will work for chromophobe RCC or renal medullary carcinoma.

Dr. Tawagi: Absolutely. I like the plug for papillary cancer as we wrap up.