mRCC Risk Assessment and Treatment Options

Robert Alter, MD: Utilizing the risk categorization has now led to the NCCN [National Comprehensive Cancer Network] offering approaches toward systemic therapy for patients with relapsed or stage IV renal cell carcinoma [RCC]. In the category of favorable risk, this is all data-driven, there has been previous approval for the usage of sunitinib or pazopanib single-agent oral tyrosine kinase inhibitor [TKI] therapy. 

Based upon the KEYNOTE-426 clinical trial, the indication of using axitinib and pembrolizumab [Keytruda] or what we call axi-pembro, has gotten approval in the population of patients who are considered to be at favorable risk. In patients who are poor or intermediate risk, we utilize regimens of ipilimumab [Yervoy] and nivolumab [Opdivo], or ipi-nivo, again, axitinib and pembrolizumab. Based upon the CABOSUN clinical trial, cabozantinib has been approved and is a first-line regimen in patients with intimate or poor risk.

There are other regimens one can utilize in favorable risk, poor risk, and intermediate risk patient populations, many of which are based upon clinical trials. There has been an accumulation of data over the last 5 years, but going back to the simplicity of having a patient’s risk categorized during their initial visit or after you get the laboratory results makes it easy for us to think about what regimens we should be considering based upon the clinical trials that we were talking about.

Robert Motzer, MD: The risk factors used in the IMDC [International Metastatic RCC Database Consortium] criteria are a short time from diagnosis to start of systemic therapy of less than a year, high calcium, low performance status, KPS 70 [Karnofsky Performance Status score of 70], anemia, elevated white blood cell count, or an elevated platelet count. If patients have none of those risk factors, those are categorized as patients at favorable risk. If they have 1 or 2, they are of intermediate risk. If they have 3 or more, the patient falls into the poor risk category. For the most part, people with favorable risk, their tumors have small volume disease. They will often relapse a year or so after treatment or have very slow progression of minute nodules in their lungs. They can be asymptomatic, and their condition really doesn’t affect their organ function. In those patients, the tyrosine kinase inhibitors appear to be very effective.

The standard of care has been sunitinib or pazopanib in that population. Most patients live for years in that situation. As a matter of fact, many of those patients do not need systemic therapy immediately. The first management strategy upon discovery of metastasis is often just to monitor the patient, not to treat them with active systemic therapy, which has its toxicities. Then we follow patients along with CT scans. With many of those patients, we can delay systemic therapy for years, or avoid it entirely. The patients with favorable risk are generally the people who have low volume disease and are feeling well. For those in that population, the big studies of IO [immune oncology] combinations showed a benefit in response rate for axitinib plus pembrolizumab and also axitinib plus avelumab in that favorable risk group. They have higher response rates and longer progression-free survival, but a similar survival rate. 

With ipilimumab, nivolumab, the favorable risk group actually had higher response rate and longer progression-free survival with the sunitinib TKI than they did with the ipilimumab, nivolumab. The thought had been that those patients are probably best managed with either TKI monotherapy or TKI plus pembrolizumab or avelumab. There is a case, however, for giving favorable risk patients ipilimumab, nivolumab. For the most part, those patients, because they live a long time, have a slowly progressive disease. They can receive multiple lines of therapy. The tyrosine kinase inhibitors that we use often develop chronic toxicities, which are more problematic over time and which can impair quality of life. With ipilimumab, nivolumab, although the response rate is lower, in general, the quality of life is better overall for the patients, especially when the patient is past the induction period with ipilimumab plus nivolumab.

The responses can be very durable. There is a higher rate of complete responses. There is some controversy in terms of what is the optimal way to treat those patients. There is certainly a school of thought that recommends ipilimumab, nivolumab, at least as initial treatment, to see if we could obtain a durable response and good quality of life for those patients. In the intermediate and poor risk patients, the data are different. In the trials of IO combinations with either ipilimumab plus nivolumab or axitinib plus pembrolizumab, or axitinib plus avelumab, there were higher response rates when the IO treatment was included, with longer progression-free survival rates. For ipilimumab plus nivolumab and axitinib plus pembrolizumab, there was a benefit and overall survival compared to sunitinib. 

For intermediate and poor risk patients, their therapy really needs to include an IO treatment. For the most part, that IO therapy presently is either ipilimumab, nivolumab or axitinib, pembrolizumab. Axitinib, avelumab has not shown a survival benefit. It is unclear as to how effective it is when compared to its cousins. It is therefore not widely used. There are, however, also several breakthrough combinations that follow on the heels of those others. They include cabozantinib and nivolumab, which have been shown to cause improved response, progression-free and overall survival compared to sunitinib. It has been presented at our meeting and we’re awaiting, hopefully, regulatory approval for that, as well as a peer-reviewed publication.

Recently, there was a press release for positive outcomes from the CLEAR trial, which compared lenvatinib, pembrolizumab, and lenvatinib, everolimus, 2 significant first-line treatments. It looks like the IO/TKI therapies have a lot of activity, are closely related, and support each other in terms of the results of these trials.

For patients who are at poor and intermediate risk, then, it comes down to a question of whether we should pursue IO/TKI therapy, or IO/IO therapy. There is no one side to this; some people support one, while some people support the other. For intermediate and poor risk patients, in general, my choice is ipilimumab, nivolumab, because of the fact that we have longer follow-up time frames and more assurance in relation to the data. The survival benefit has been sustained for a long time. The last assessment was a minimum of 42 months. 

Some of the responses are durable, and we are seeing complete responses. There seems to be a leveling off or a tailing of the curve, a flattening of the curve, as one goes out in the months following treatment. We may see the same thing with TKI/IOs, it awaits longer follow-up. There are some patients, though, for whom TKI/IOs are very useful and are preferable. That takes into account that those combinations are associated with universally high response rates. In the case of some patients, if they appear that they’re going to have a clinical deterioration and run into trouble in the short run, there is more assurance that an IO/TKI would work. Mechanism of action is key for RCC, high response rates, and it allows us to avoid the early IO-related toxicity that we see with ipilimumab, nivolumab that can cause us to pause therapy. For patients who are rapidly progressive, there is a degree of assurance in using IO/TKI.

Transcript edited for clarity.