Evolving Treatment Paradigms for Renal Cell Carcinoma - Episode 6

Deferred Therapy for Favorable-Risk mRCC Patients


Daniel George, MD: I want to switch over now to the good risk, because in some respects, this is a harder population. We have less data in the specifically good-risk population on some of these regimens, and yet, there are some data here. Rich, do you want to walk us through a little bit of some of the good performance status data that’re out there?

Richard W. Joseph, MD: This is also a major challenge for me in the clinic, too, because a lot of patients come in having read in The New York Times, 60 Minutes, about immunotherapy. Everybody wants immunotherapy. While I agree it’s been great in intermediate-/poor-risk patients, when you look at least at CheckMate-214, it seems to be inferior. Maybe the statistics aren’t there yet, but immunotherapy might be. Certainly, in my clinical experience, when we’ve had patients on study, specifically IMmotion151, atezolizumab plus bevacizumab versus Sutent (sunitinib), and some of my favorable-risk patients are still on study with Sutent 3 and 4 years later, I think that exactly echoes what Walt was saying. Some of these patients do so well with VEGF TKIs, it’s really hard to put them on something that may not have as good of activity, even though we know it’s not VEGF, or not curative. That’s why we think about more with the immunotherapies. It is a big challenge, but I do believe in sticking with VEGF TKIs in my favorable-risk patients.

Walter Stadler, MD: I may want to point out, as the one who has been around for long enough to get some gray hair, that some of the original studies, in terms of risk factors, were from Memorial Sloan Kettering. In the era when the only drug we had was interferon essentially—which, as far as I’m concerned, is a toxic placebo—there were 10% of patients with good risk that were alive 10 years later on, with essentially no therapy. I think that the most difficult conversations in the clinic are these very-good-risk patients, these patients that show up with several lung nodules 10 years after their nephrectomy because someone did a chest x-ray. They’re feeling great, they’re wonderful, and I have to have a conversation with them that the best thing to do is get another CT scan in 3 months and not give any of my poisons. I think it’s a hard discussion, but I think it’s the right discussion.

Daniel George, MD: You were part of our MaRCC (Metastatic Renal Cell Cancer) registry. We had some lessons learned from that, and one of them was around this practice of deferred systemic therapy in exactly the kind of population you just described. What are your takes on how to advise community doctors on what’s the best way to identify somebody appropriate for a deferred systemic therapy?

Walter Stadler, MD: I think these risk categories help. If there has been a long interval since the nephrectomy, more than 3 or 4 years, if there is a low volume of disease, a few nodules in the metastatic sites, patient is completely asymptomatic, the labs are all completely normal, some of those patients are going to be best served by just observation. If you see a patient like that, the first thought should be when do I do my next CT scan, not which drug do I pull off the shelf.

Daniel George, MD: Fair enough.

Robert J. Amato, DO: Pathology has a significant influence. If you’re a clear cell without rhabdoid or sarcomatoid features, and maybe a modest clear cell, that’s going to enter the decision, too. If you’re a chromophobe, slow, that’s indolent, that is going to enter decisions, too, as far as how aggressive one needs to be. Papillary is the same, type 1 or type 2.

Daniel George, MD: Toni, what do you think about that? Bob brings up pathology in the good-risk patients. PD-L1 is a marker in this disease. It’s a prognostic marker, but it also may be somewhat of a predictive marker. Does that help you? In particular, would it help you in the good-risk patients, in terms of how you might manage them, or in other settings?

Toni Choueiri, MD: Let me start with this statement that I came up with yesterday, thinking about all of this with PD-L1, about my discussion that’s going to come Sunday. I think PD-L1, to the biomarker field, is the same as kidney cancer to the internist. I think it’s very muddy, and I think we have to be very, very careful, not just across tumor type, but even inside renal cell; different cutoff, different definition, different antibodies, different disease, and sometimes conflicting results. I’m glad that future studies, starting with CheckMate-214, are considering strongly PD-L1 as a co-primary endpoint or are looking at PD-L1. We will learn from that. But even with CheckMate-214, I am not sure if staining for PD-L1, you’ll want to use the same test that the company used, if you have access to it. This is going to be very important, perhaps in a patient where they really want nivolumab/ipilimumab and there is some relative contraindication, but they are intermediate/poor risk they have high PD-L1 expression. We know in these patients the response rate is 58%, with 16% rate of complete remission. I may consider it, but it may not be the same PD-L1 from one test to another; one by a company will be positive, another one negative. How the PD-L1 is done, that is a problem, so I proceed extremely carefully. And it’s not part of my routine testing at this point.

Walter Stadler, MD: It gets even more complicated because the community oncologist is dealing with all of the lung cancer patients, where we now have even different cutoffs and different descriptions of what PD-L1 positivity means. So, I think it’s going to be more confusing over the next few years than clarifying.

Toni Choueiri, MD: There are a lot of pathologists now issuing statements, where it’s not clean, that it’s negative or positive; it is not conclusive.

Daniel George, MD: I think that’s really the best advice here: that this is really not ready for clinical recommendation as a standard practice yet. But I hope that evolves.

Richard W. Joseph, MD: Even when I treat patients with melanoma as well, I use it as one of many different factors. It’s never like “the” factor that makes you decide one way or the other.

Daniel George, MD: Fantastic. Rich, just as a final point, because we’ve talked about cabozantinib and we’ve talked about sunitinib, are there other VEGF-targeted therapies that have been studied in this good-risk population that would be appropriate choices there?

Richard W. Joseph, MD: Yes. I think we’ve talked about Votrient (pazopanib), and I think that is one of the, in my experience, least toxic. And we know that from COMPARZ that at least most of the patients did seem to do better on that compared to sunitinib. That’s usually my go-to on the frontline.

Daniel George, MD: Toni?

Toni Choueiri, MD: Yes, I mean, there are other TKIs out there we cannot exclude, not just because of tolerability. Lenvatinib in combination with everolimus has very impressive activity in the second-line, and patients progress on sunitinib. This drug is being combined with pembrolizumab in a large trial. We can’t ignore axitinib, a drug we have a great experience with, especially with the dose escalation by 1 mg. I’ve seen some patients not respond on 5 mg BID (twice a day) and respond to 7 mg BID back and forth, and the therapeutic window is very short. This drug is being combined with 2 checkpoint blockers in the first-line setting. So, there are other things I consider, although axitinib is not approved for the frontline setting.

Transcript Edited for Clarity