The CLEAR Trial: Lenvatinib Plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma - Episode 7

Tailoring Therapy for Patients With mRCC

Next steps investigating novel-based therapies for newly diagnosed metastatic renal cell carcinoma.

Chung-Han Lee, MD, PhD: The RCC [renal cell carminoma] treatment space has rapidly evolved over the last 5 to 10 years. We have multiple regimens that are FDA approved, broadly falling into 1 of 3 categories of drugs: immune checkpoint inhibitors, multitargeted tyrosine kinase inhibitors, and mTOR inhibitors. Historically, we had always used this as monotherapy but more recently we’ve seen the transition to using combination therapy with improved outcomes. What I do expect to see going forward is that we’ll probably become a lot more adept at using these combinations together.

One thing that remains an active question is, what’s the optimal to sequence these patients? The other question is, how do these drugs interact with one another? Is there is some temporal relationship between the 2 medications or the combinations that should be used? Those are studies that probably do need to be done. The other thing is related to monoclonal agents. Most recently, there was the FDA approval of belzutifan, which is an HIF2 inhibitor for patients with VHL [von Hippel–Lindau]disease. As you all know, clear cell kidney cancer has high rates of mutation and loss of VHL, so belzutifan is another drug that may become very interesting for us to understand whether there’s a role for HIF2-directed therapy.

Historically speaking, kidney cancer is also been a malignancy of altered metabolism. Although telaglenastat, which was recently studied in a large randomized phase 3 trial, did not show improved efficacy when using combination with cabozantinib over cabozantinib alone. That doesn’t necessarily mean that there’s not a wolf we’re looking at, metabolic inhibitors in the future. Whether it’s a drug with telaglenastat in a more selected population or if it’s other metabolic inhibitors, it remains to be seen.

Also, when we think about immunotherapies, there are multiple immune checkpoint inhibitors or immune checkpoints available. Targets such as LAG3 and TIM3 and agonists like LT4 all play a significant role in altering immune responses. As we better understand the biology and the attraction of the medications, that will do a lot more in terms of tailoring the specific treatments to the disease state of the patients.

Transcript edited for clarity.