Treating Patients With mRCC Beyond Second-Line

Daniel J. George, MD: What about that patient now? We’ve alluded to this several times: The patient who’s been through several lines of therapy. Part of that, for sure, is disease biology. Nobody gets to fourth- or fifth-line therapy without having disease biology that is indolent. Some of this is the treatment effect, but whatever you don’t kill is presumably coming back stronger. However, these are patients who are able to tolerate that higher tumor burden, tolerate those multiple lines of progression, and tolerate those multiple lines of therapy. The patients have to be stronger as well.

You get to these patients in this third-, fourth-, or fifth-line setting. Any philosophy on how you manage those patients in terms of the treatments? For our community guys, there are no clinical trials out there. There are guidelines, but there are no trials. There are no guidelines for fourth or fifth line. It’s all lumped together. What do you tell your colleagues? How do you manage it yourself in terms of these patients? Anybody? I’m opening it up. We’re getting loose; we’re near the end. Anybody, jump in.

Rana R. McKay, MD: I’ll jump in and say that, with the I/O–VEGF and the I/O combos being in the frontline space, whether somebody starts with nivolumab-ipilimumab or starts pembrolizumab-axitinib, they’re going to get 1 of those options. There are data for re-treating post I/O, certainly from the FRACTION-RCC trial, from retrospective series, I/O, post I/O has a response rate around 15%. Just because you’re out of that frontline space, it doesn’t mean you can never give somebody nivolumab-ipilimumab. Yes, there are insurance issues, but if you’re in the fourth or fifth line and have never seen nivolumab-ipilimumab, then you could consider that. If they have never seen pembrolizumab-axitinib or axitinib but have seen nivolumab-ipilimumab, then maybe you would consider giving them pembrolizumab-axitinib. That’s certainly totally off-label, but when you’re getting into that fourth- or fifth-line space and somebody has already received an I/O combo, like cabozantinib or lenvatinib-everolimus, and they’ve already seen a single-agent TKI,then you think, “What am I going to do?” It’s not out of the realm of reason to consider those combinations.

If somebody is still doing well, and you’re considering fourth- and fifth-line therapy, it’s important to think about a tertiary care center close by where you can refer for a clinical trial. There are a lot of interesting agents out there that are in-testing that have shown promise in early studies: The glutaminase inhibitor and the F2 alpha inhibitor. There are a lot of exciting things out there that are also going to change the second-line and post–I/O space, so thinking about those options for patients is important.

Daniel J. George, MD: We’re going to get to that in just 1 second, but I do want to just bring up something. For these patients who get to these fourth- and fifth-line settings, there’s 1 common theme. It’s not universal, but it’s a common theme: They have almost all had, at some point or another, some focal therapy. It may be for the brain metastasis that Monty mentioned, or it may be for bone metastasis. It may be radiation or CyberKnife. It may be a debulking metastasectomy or other symptomatic complication. For my chronic renal patients who get there, part of that is weaving in when to use those focal treatments. I don’t have any trial on this or any data. But from my own experience and looking at my own clinic [the Duke Cancer Center], I look at those long-term survivors, and it’s frequently been a mix. It’s been a multidisciplinary care effort to get them those 6, 7, 8, 10 years of metastatic renal cell carcinoma.

Transcript Edited for Clarity