RCC Paradigm Continues Moving Forward With New Combination Regimens on the Horizon

For Kidney Cancer Awareness Month, CancerNetwork® spoke with Chung-Han Lee, MD, PhD, about research in renal cell carcinoma that has the greatest potential to impact the standard of care.

For Kidney Cancer Awareness Month, CancerNetwork® spoke with Chung-Han Lee, MD, PhD, about promising research emerging in the renal cell carcinoma (RCC) space and about his outlook for the future.

During the 2022 Genitourinary Symposium, results of pivotal clinical trials were presented that either brought new combination regimens to the frontline space or re-confirmed evidence that these approaches are the accepted standard of care. The use of treatments such as lenvatinib (Lenvima) plus pembrolizumab (Keytruda) have paved the way for better survival, supplanting former single-agent tyrosine kinase inhibitors (TKIs) that were commonly use in this setting just a few short years ago.

Lee, assistant attending physician for the Genitourinary Oncology Service at Memorial Sloan Kettering Cancer Center in New York City, discussed the use of TKIs and immunotherapy as well as which upcoming trials will be most valuable to clinicians.

CancerNetwork®: What emerging research in RCC do you think has the greatest potential for clinical impact?

Lee: Over the last several years, we have seen multiple treatment regimens gain regulatory approval, and we’ve seen multiple permutations of TKIs plus immunotherapy [combinations]. The big questions that we have right now is first, what is the optimal sequencing of the various treatments that we already have available; second is the big treatment decision that is made up front [regarding] whether you treat with combination immunotherapy or with a TKI plus immunotherapy. [Another] question that we have is [should treatment become] more intense. [This includes] thinking about some type of triplet therapy, using 2 immunotherapy agents plus a TKI. A very important question is whether the clinical outcome by using more intense therapy warrants the potential of clinical toxicity. [Finally, we need to consider] the development of new pathways. Historically, we have agents that target the immune system. Now, there are agents that target the blood vessels and metabolic inhibitors. [Investigators should look to] whether there are any novel agents that can target different pathways that are directed towards RCC pathogenesis.

What ongoing clinical trials in RCC are you eager to see the results of?

One of the big studies that I’m quite eager to see the results of are [from] COSMIC-313 [NCT03937219].1 This is a randomized clinical trial looking at cabozantinib [Cabometyx] plus ipilimumab [Yervoy] and nivolumab [Opdivo] versus ipilimumab and nivolumab. This will help answer the question of [whether] there’s an added benefit from doing triplet therapy over a doublet therapy with 2 immunotherapy agents. That will be an exciting study to look at.

Other studies that I’m personally interested in looking at the results of include the Merck [KEYNOTE-]B61 study [NCT04704219], looking at the combination of lenvatinib plus pembrolizumab in the non–clear cell RCC space.2 Historically speaking, most of the large phase 3 clinical trials that have been done have focused on clear cell kidney cancer and have excluded all patients with non–clear cell disease, which represents about 20% of patients with kidney cancer. In the past, responses to systemic therapy have often been a little bit worse for the non–clear cell population as opposed to [those with] clear cell. It is going to be interesting to see whether lenvatinib plus pembrolizumab, which has had very robust activity in clear cell disease, has similar types of activity within the non–clear cell space.

Is there anything else you want to add?

RCC is currently an exciting space in which every year we’re seeing multiple regimens gain regulatory approval; we’re seeing positive studies in this space. As a result, it’s a rapidly evolving field in which biomarker development is going to become critical for us to make decisions. All the recent studies have randomized [experimental therapy] against sunitinib [Sutent] as the control arm and have demonstrated superiority. This is the initial front-line TKI that has long been the standard of care. With all these studies being positive, we really haven’t compared these regimens to each other. Given the complexity and the difficulty of doing a cross-trial study, we don’t have robust data for us to know how to choose between them. Much of the work in the biomarker development space will help us with that clinical decision of [choosing] which regimens we should prioritize [for] patients.


1. Choueiri TK, Albiges L, Powles T, Scheffold C, Wang F, Motzer R. A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk. J Clin Oncol. 2020; 38(suppl_6). doi: 10.1200/JCO.2020.38.6_suppl.TPS767

2. Lee CH, Li C, Perini R, Hoehn D, Albiges L. KEYNOTE-B61: Open-label phase 2 study of pembrolizumab in combination with Lenvatinib as first-line treatment for non-clear cell renal cell carcinoma (nccRCC). J Clin Oncol. 2021; 39(suppl_15). doi: 10.1200/JCO.2021.39.15_suppl.TPS4595