Pedro Barata, MD, MSc: Dr Garmezy, you have a case you’d like to share with us to illustrate what we’re discussing. As we move on with the discussion, now would be a good time for you to share the case and walk us through what happened to your patient.

Benjamin Garmezy, MD: Let’s say a new patient shows up to clinic. The patient I’m thinking about is a 67-year-old man recently with 2 to 3 months of fatigue, hematuria, and a 20-pound weight loss. The primary care provider has already done CT imaging, which shows a large right-sided renal mass, 10.3 cm, but also multiple pulmonary and bone lesions. Diagnostic biopsy has been done. The renal mass is clear cell renal cell carcinoma [RCC], and 1 of the pulmonary lesions confirms metastatic clear cell renal cell carcinoma. Labs are ordered for risk-stratification purposes, and the hemoglobin is 11.1 g/dL, the absolute neutrophil count is 4.5 per mm3, calcium is 10 mg/dL, and platelet count is 316 per mm3. All of this is consistent with an IMDC [International Metastatic RCC Database Consortium Risk Model] intermediate risk categorization.

Pedro Barata, MD, MSc: That’s exactly how we were debating before. Your patient has intermediate-risk RCC, and you’re thinking about what systemic therapy to consider. What happened to your patient?

Benjamin Garmezy, MD: That’s a great question. I had a lot of great options. That’s the trouble of riches in intermediate-risk scores for your frontline metastatic patients. We could do doublet immunotherapy or doublet immunotherapy with VEGF-targeting TKIs [tyrosine kinase inhibitors]. The first decision we have to make is are we going to give an immunotherapy doublet or are we going to give the I/O [immuno-oncology]–TKI doublet? In this case, I often go with I/O–TKI doublets. There are other folks who go with immunotherapy doublets. I chose the most recent data presented with the CLEAR data set with lenvatinib and pembrolizumab. I like this regimen because it has a very high response rate. It has response rates of close to 71%, if I remember correctly, and CR [complete response] rates above 10% to 15%, even though it’s a single-agent immunotherapy.

We have to compare that with the other trials. There’s pembrolizumab and axitinib from the KEYNOTE-426 study, and there’s cabozantinib and nivolumab from the CheckMate 9ER study. These are similar combinations and have more similarities than differences. The difference is the dose in the TKI. When we look at the dose of the TKI used across these studies, that can be why we’re seeing slight differences in response rates. That CLEAR data set with lenvatinib and pembrolizumab had the highest response rate. I believe it was 71%. CheckMate 9ER with cabozantinib and nivolumab had response rates that were closer to the 50%-to-60% range, as did the KEYNOTE-426 data with axitinib and pembrolizumab. The axitinib dosage is 5 mg twice a day, and the cabozantinib dosage is 40 mg twice a day. But in the CLEAR data set, that dose of lenvatinib is 20 mg is a bit higher when you compare the potency of those TKIs with those other TKIs used in those trials. Perhaps that’s why that response rate is a little higher.

We also think about the toxicity differences among these 3 combinations. The CLEAR data set with lenvatinib-pembrolizumab had the highest rates of grade 3 or 4 adverse events, above 80%. More than 4 of 5 patients are going to have a grade 3 or 4 adverse event. That’s not to say that there aren’t high toxicity rates on other regimens as well, because when you combine those high doses of TKIs with immunotherapies, there’s a lot of fatigue, rash, diarrhea, and hypertension. Each has nuances with the data sets, but thinking about the potency of the TKI can help us predict that toxicity.

Transcript edited for clarity.