Neeraj Agarwal, MD: Yes. I would, obviously, start with the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] risk categorization first. Does this patient belong to a favorable-risk category, intermediate-risk, or poor-risk category? That’s the first decision I have to make after evaluating the patient.

Once we have decided that, based on laboratory tests and based on history, the patient belongs to an intermediate-or poor-risk category, then I look for the regimen with which I will have the most curative potential in this given patient. I used high-dose interleukin-2 for a long time until 2015 for the potential of that 10% chance of long-term remissions. If I look at these regimens in the first-line setting, I look at complete responses first, axitinib/pembrolizumab versus sunitinib; I think if you look at the complete responses with the recent update, 9% versus 3%, so twice as much complete response. If I look at ipilimumab/nivolumab versus sunitinib for intermediate-, and poor-risk patient populations, there is a 10 times increase in the complete responses: 1% with sunitinib, 10% with ipilimumab/nivolumab. That’s the big factor in my mind as far as decision-making is concerned.

I then look at the durability of complete responses. If you look at the durability of complete responses, it’s hard to beat the ipilimumab/nivolumab combination at this point. A 42-month follow-up was presented a few weeks ago at ASCO [the American Society of Clinical Oncology annual meeting] 2020, and we are seeing that one-third of patients are maintaining the responses overall. Their complete responses are more likely to be retained; most of the complete responders are still in response. Those are the factors I take into account for poor- and intermediate-risk patients.

For favorable-risk patients, I would admit that it is more challenging because there are favorable risk, and there are favorable risk. There's a patient with 1 lung nodule that is growing for the last 5 years. We have been monitoring it, and it is not changing at all. I will not do anything; I will go for active surveillance because this patient may be harmed by what I offer in terms of medications. Then, there are some patients who are again in the favorable-risk category, 5 different sites of metastasis, but their labs are completely normal and disease burden is quite high. In these patients, I would think about starting systemic therapy.

Depending upon what the disease volume is, I’d base my choice on the disease volume in the favorable-risk category. For low disease volume, it’s active surveillance. For just 1 or 2 sites of metastasis that are slowly growing and the patient is otherwise doing well, it’s single-agent VEGF/TKI [tyrosine kinase inhibitor]. I’d pick one of the VEGF/TKI options. VEGF/TKI can include pazopanib and sunitinib, but I then look at the CABOSUN trial. Cabozantinib was superior to sunitinib, so I don't hesitate picking up cabozantinib as a VEGF/TKI of choice for these patients. For patients who have more rapidly progressing disease, still in the favorable-risk category, I tend to pick up axitinib/pembrolizumab, for example, in these patients. Thinking about how I practice in my clinic, this is what I have to say.

Daniel J. George, MD: Interesting. That’s a good summary, Neeraj. What I like about that is it's thoughtful; you use the whole armamentarium. There's a place for each of these approaches in frontline patients: it's not one-size-fits-all. A big part of that is the risk stratification that you mentioned.

Transcript Edited for Clarity