Case Analyses in Renal Cell Carcinoma - Episode 7
Renal cell carcinoma panel discusses factors impacting first-line treatment selection and patient monitoring and adverse-event management in patients with intermediate- and poor-risk mRCC.
Robert Motzer, MD: Let’s move on to an overview of the case and your ideas on general management strategies for these patients. We’ve certainly focused on the TKI [tyrosine kinase inhibitor]–I/O [immuno-oncology] data, but nivolumab plus ipilimumab is a strong contender in this space, and for intermediate- and poor-risk patients, we only have four good regimens. How do you choose, Eric, what’s your go-to regimen for your intermediate- and poor-risk patients? How do you decide on 1 program over another?
Eric Jonasch, MD: The key determinant concerning ipilimumab and nivolumab—especially with the data that just came out at ESMO [European Society for Medical Oncology Congress], where giving ipilimumab every 12 weeks instead of every 3 weeks probably makes that regimen less toxic—is that there’s a tail in the curve and a subset of individuals that have durable CRs [complete responses]. Thus, we have to consider it. As I said in the previous slides, the PD [progressive disease] as best response is the warning flag for this regimen. I’d choose ipilimumab-nivolumab for an intermediate- or poor-risk patient that doesn’t look like they have threatening disease. I’d say that if somebody who has bone metastasis or nascent liver metastasis, I’d be nervous about that. Hence, this is a patient I would have thought about ipilimumab-nivolumab as a great choice.
For individuals with threatening disease, where you get the sense that if you don’t get it right the first time around, they’re not going to necessarily make it to that second-line treatment, the I/O–TKI combinations are a great choice. Of lenvatinib-pembrolizumab, pembrolizumab-axitinib, nivolumab-cabozantinib, which do you choose? I don’t think we can say that 1 is clearly better than the other. You have to look at the data, and you have to make a decision based on your sense of that.
Robert Motzer, MD: Thanks. We’ve heard Tom’s choice for lenvatinib-pembrolizumab in this patient. Bradley, what’s your go-to program for a patient like this? What’s your general sense when the patient says, “Give me a recommendation—that’s what I want to do”? Where would you go with this patient?
Bradley McGregor, MD: I echo a lot of what Eric just said. We also got nivolumab-ipilimumab with extended follow-up, in the 5-year follow-up, and we see the median overall survival intent to treat was 57 months. It’s quite remarkable when you think about it: in intermediate- and favorable-risk disease in the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium]…was just under 4 years. There is something about ipilimumab with that durability. We’ve seen data with some of the salvage ipilimumab trials, like the TITAN-RCC or FRACTION-RCC, where you don’t get that same durability when you add ipilimumab in later. You do have that 1 shot for ipilimumab up front. If I have a patient, as Eric said, I feel comfortable that if they’re in that 20% of PD as best response, that I’m going to be able to rescue them with a TKI in that next line of therapy. I can get them to cabozantinib or lenvatinib-everolimus or some other highly active regimen, then after discussion with the patient about the risks of dual immune checkpoint blockade and the increased risk for immune-related adverse events, I will consider nivolumab-ipilimumab in that situation. As Eric said, there does seem to be some durability, and where you get that first shot is where you’re going to get the best chance for that durability.
Robert Motzer, MD: How would you compare the toxicity or the nature of adverse events between nivolumab plus ipilimumab and these VEGF TKI–I/O combinations?
Bradley McGregor, MD: I tell patients that with nivolumab-ipilimumab it’s going to be a roller coaster for the first 3 to 6 months. In the beginning we’re going to be on the lookout for anything. We’re going to be very cognizant of looking for immune-related adverse events—any unusual headache, diarrhea, shortness of breath—and we’re going to be quick to monitor, starting steroids. Often if you get through that first 6 months or so, there’s still that risk for delayed immune-related adverse events, but things tend to calm down and life on single-agent nivolumab tends to be pretty good. When you start looking at TKI–I/O combination, you don’t have that great peak up front. But you have those nagging TKI toxicities that are a baseline nuisance, and maybe they can get a little worse with time, with the fatigue or issues like that. It comes down to a discussion with the patient about what fits their lifestyle, what’s important to them, and how much risk they want to take in the short-term vs long term.
Robert Motzer, MD: Well, this has been a great discussion. One last question that I want to raise to the group. One of the benefits of the more effective therapies is that we’re seeing complete responses in patients who are treated with I/O–I/O therapy or I/O–VEGF–TKI therapy. One question that always comes up is have you seen durable responses in your practice with these regimens, and how do you manage a complete responder? For example, do you continue therapy, or do you stop treatment at a certain point with a CR? Let’s take a poll in wrapping up this case. What’s your management strategy for CRs? Do you continue therapy, stop therapy, continue for a time period? Eric, let’s start with you.
Eric Jonasch, MD: Interestingly, some of the patients I initially stopped were because of toxicities. Several had 1 dose of ipilimumab-nivolumab, for example, who then developed severe consequences, had to stop completely, and then they went into a CR. They forced me into discontinuing their treatment. For those individuals where there fewer dire consequences and I get a complete response, I usually continue therapy when they’re not a study for about 6 or 12 months afterward, and we usually have a conversation with the patient at that point and try to discontinue.
Robert Motzer, MD: Bradley, your management of CRs?
Bradley McGregor, MD: That’s a great point. I will talk to patients, and they often want this down therapy. Given that we have data with all the trials—pembrolizumab, TKI–I/O—that they stop at 2 years, I will probably push to around 2 years of immune checkpoint blockade. The question is, if you have a CR on a TKI–I/O combination, what do you do about that TKI? I don’t think we know, and I tend to keep the TKI going because we don’t know if that CR is from the TKI or the I/O. Depending on the tolerability, I’ll often continue the TKI indefinitely in those situations.
Robert Motzer, MD: Tom, your management for CRs?
Tom Hutson, DO, PharmD: I’ve seen CRs with immune-based therapies, I’ve seen CRs with TKIs. Generally, they’re handled the same way. It’s a discussion with the patient. The first scan that shows a complete response, I’m clearly not going to be suggesting that they stop therapy. Usually, I want to show several scans with maintained CR, usually 3 or 4 scans. That puts it out up to a year, and then we have a frank discussion about stopping. Naturally, there’s a lot of angst among the patient and the family. I’ve seen CRs with single-agent nivolumab in the refractory setting, which had first approval for kidney cancer. Having that series of scans showing that things are stable and that there’s no evidence of disease—they’re in the entity status—gives them a lot more comfort with that. The outcome that I’ve seen is that it’s almost in my hands fifty-fifty. I have a group of patients who have been able to stay off therapy and have been off all therapy for a couple of years. I have another group that’s having visible cancer come back 6, 9, 10 months later, and considering retreatment with them becomes an issue.
Robert Motzer, MD: This has been a great discussion on the management of the intermediate- and poor-risk patient. You’ve all provided such wonderful insight into the treatment strategies and the data and your own personalized management for these patients in the new era with I/O combination therapy.
Transcript edited for clarity.