Second-line Treatment Options for RCC

A roundtable discussion, moderated by Monty Pal, MD, of the City of Hope, focused on updates in renal cell carcinoma (RCC), including treatment in both the frontline and adjuvant settings. Dr. Pal was joined by a panel that included Daniel George, MD; Brad McGregor, MD; and Cristina Suárez Rodríguez, MD.

In the next segment of the roundtable series, the panel discusses the challenges of second-line RCC treatment options and how to sequence therapy after TKI/IO or IO/IO frontline therapy.

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Dr. Pal: The debate that I think is so challenging to opine on is second-line therapy. We don’t really have a lot of ideal second-line trials to address what we should be using after tyrosine kinase inhibitor (TKI)/immuno-oncology (IO) or IO/IO, frankly. With that in mind, when we see these patients in clinic, I get several, probably every month that are referred in, who have gotten multiple lines of immunotherapy—frontline immunotherapy, second-line immunotherapy, third-line immunotherapy. I’ve seen it out to 5 to 6 lines of treatment, with a huge cost burden and presumably some toxicity burden. Brad, what do you think about that? Is it legitimate to continue IO into multiple lines of treatment?

Dr. McGregor: I think we don’t know. I don’t think we have data to justify that at this point in time. My personal preference is I tend to stop the IO because I worry that I may compromise my dose intensity of the TKI by giving it with an IO. Are we going to have liver function test issues? There’s just going to be some complications. I think the ongoing trial is going to answer those questions. There’s ongoing completed trials. Cabozantinib with or without atezolizumab after progression on IO. There’s the ongoing TiNivo-2 trial looking at tivozanib with or without nivolumab. I think that’s going to give us some actual data to help guide this discussion.

We have some great phase 2 data from lenvatinib/pembrolizumab that shows this impressive response rate in patients who had prior immunotherapy, but is that driven by the lenvatinib? What part does the pembrolizumab come into play? I think this really is something where we need data, and I think these trials are going to be critical because we may be doing a harm by continuing with something because now we’re having to give a lower dose of that TKI and maybe they could tolerate without the IO and that may hurt long-term.

Dr. George: It’s a great point, Brad, because I think sometimes these patients are on treatment so long in the frontline setting, we almost forget the side effects. The fatigue is almost something they’ve become accustomed to or whatnot. They live with this, but it’s deconditioning. We’re not measuring their muscle mass or their functional capacity, but it’s affected by these therapies chronically over time.

To your point, we may be doing some disservice. Unless the clinical trials show us that there’s a real benefit, and I think that’s really what we need. It’s interesting to me, when you look at NCCN [National Comprehensive Cancer Network] recently, and I don’t know if people have looked at that, but they’ve changed the guidelines regarding refractory disease. A lot of our older trials that were based on prior frontline therapy of TKI alone are no longer considered level 1 evidence because the frontline therapies have changed. Some people are a little bit frustrated with that, because it’s guidelines, it’s not really telling us what to do. But the truth is, if the data doesn’t really tell you what to do, then we shouldn’t be pretending it does. It creates the unmet need that these newer-generation trials will fill.

It’s a little bit of a transition time that we’re in right now, and I think we’re doing the best we can with the data that we have—level 2 evidence. But I think these next generation of refractory trials are really going to help shed light on exactly how we should be managing TKI alone in this setting or lenvatinib/everolimus or these types of combinations I think are reasonable things to do. If we don’t see a benefit to continued IO, it may be something we study in the third-line setting, having a break and then coming back to that.

Dr. Suarez: That’s a very good point.

Dr. George: I wouldn’t say that kills future IO therapy forever. I think it would just say, we don’t continue it all the way through.

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Continue on to watch the next roundtable segment.