Daniel George, MD: In this section, we’re going to talk about the sequencing strategies for relapsed and refractory metastatic renal cell carcinoma—particularly in the second line, third line, and beyond—and how we define patients who have disease progression in the frontline setting. Nick, can you tell us a little bit about your thoughts if you have a patient on frontline therapy? What are you looking for? How are you deciding if that disease is enough progression to say that it’s time to switch?

Nicholas J. Vogelzang, MD, FASCO, FACP: Traditionally, we’ve used RECIST, and I think it’s a good reasonable guideline. It uses 20% growth. But if it’s 20% growth in an asymptomatic lung lesion, I don’t get too hot and bothered about that. New lesions worry me. A painful new lesion, certainly a new liver lesion, or new sites of disease anywhere, those are usually signs of progression. We know that the frontline TKIs give us about a year or maybe a little less. So, my feeling is that you should explain that to the patient. On average, these drugs work for about a year, and so when you get to the 8- or 9-month mark, you start setting it up and saying, “Look, we might be running into stormy water here, so let’s start talking about second-line therapy.” It’s not a really hard conversation to have as long as they are still in remission. But if they walk in one day with a new brain metastasis or a painful hip lesion, then you have to think, “OK, now we’ve got to have the discussion.” It varies. Any oncologist worth his or her salt will know how to handle that situation.

Daniel George, MD: You bring up a good point, and I use this. I’m interested in other people’s thoughts on the timing of that progression. You said, “I’m thinking that, on average, these are going to last 12 months. As we get out to 9 months or so, I’m starting to prepare the patient.” To me, I think that’s a really good benchmark. When I look at the data, there have been a couple of these retrospective analyses suggesting that patients who progress at 3 months or progress at 6 months have a much worse survival and patients who are progressing at 9, 12, or 15 months out have a much longer survival. Now, you can say, “Well, that’s obvious, right?” Well, there’s 6 months of difference between those, but it’s a bigger difference in survival than 6 months. It’s years of difference.

Nicholas J. Vogelzang, MD, FASCO, FACP: Yes, it’s called conditional survival, and Lauren Harshman had a nice paper in Lancet Oncology about that and Toni helped get that paper out. It’s actually that if they get a response and their quality of life goes up, their tumor burden goes down and their prognosis improves considerably. And then you can tell them, “Look, you’re doing great. You don’t need to worry so much about this early relapse.” But at the beginning you do. You have to be afraid.

Daniel George, MD: I think that’s a really important thing to me. When I see a patient’s first scan on a therapy 3 months into it and I see growth, that’s not the kind of case where, even if it’s only 20%, I’m going to look at it and say, “Well, let’s just keep watching that and watching that.” That’s the patient who’s going to get into trouble. Or you see new lesions and you say, “Well, they’re small. Maybe I can just watch them.” It doesn’t matter. That’s a bad sign. Whereas if that’s happening at a year, I feel much more comfortable following that patient. Now, what about all of this stuff about immune RECIST criteria? Neeraj, do the same rules apply when we’re dealing with immunotherapy as with TKIs? Because now we’re hearing that there can be these mixed responses. There can be a little bit of pseudoprogression. How do you handle that, knowing that could also be a marker of a really poor prognosis?

Neeraj Agarwal, MD: That’s a really interesting question, and I think we are dealing with it on a day-to-day basis. We know that immunotherapy is not expected to induce objective responses as we have seen with the VEGF TKIs. So, if I see disease stabilization or slight growth in the lesions, I’m not as worried as I am if I see the same thing with TKI. I would like to give more time to immunotherapy before giving up on immunotherapy. That is my practice.

Daniel George, MD: Are there a few caveats? Nick mentioned symptoms. How do you deal with patients who maybe have a little bit of increase where they get some symptoms? Is that an inflammatory symptom? Is that really disease progression? It gets difficult. You can see how there’s a lot of gray area in this space.

Neeraj Agarwal, MD: Again, I don’t think anybody knows the right answer here.

Daniel George, MD: But Nick does.

Neeraj Agarwal, MD: Obviously, if a patient is going downhill and their performance status is really getting worse, that is a very strong signal for me to switch therapy. On the other hand, if the patient is doing well, feeling better, I see the labs, hemoglobin is stable, LDH is not going up, but lesions have gone up a bit, I feel comfortable keeping those patients on immunotherapy.

Robert Alter, MD: They even changed the criteria. The immune RECIST criteria even looks at the patients who have progression of disease and have a response. They actually don’t count your progression as an event. They actually count your response as an event. So, they’re giving a little bit more leeway in recognizing the pseudoprogression or the infiltration of T cells into the tumors; it’s like if you get an atom bomb, you have a little flare, you have the cloud, and it dissipates down. I explain that to the patients. But even when it comes down to our grading of these patients’ responses, the RECIST criteria has adjusted to that.

Transcript Edited for Clarity