IO/IO, IO/TKI Therapy for nccRCC and Its Effect on Next-Line Treatment

In a roundtable focused on non-clear cell renal cell carcinoma, moderator Daniel Joyce, MD, of Vanderbilt University Medical Center, led panelists David McDermott, MD, of Beth Israel Deaconess Medical Center; Katy Beckermann, MD, PhD, of Vanderbilt University Medical Center; and Laurence Albiges, MD, PhD, of Institut Gustave Roussy in a discussion on the management of differing disease states, new approaches such as IO/TKI and PD-L1, novel trials, and adjuvant treatments.

In the fourth part of this roundtable series, Drs. McDermott, Beckermann, and Albiges discuss the use of IO/IO and IO/TKI treatments and how they can affect next-line treatment if patients progress.

Watch the final part of this series: Adjuvant Treatments and Systemic Therapy for nccRCC

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Dr. Joyce:
So what I’m hearing as far as the papillary side of things, go know IO/TKI, maybe TKI single agent, still possible, IO/IO possible. I’m not hearing a clear consensus from you all, but maybe IO/TKI is the way to go. How does that affect next line treatment if and when these patients progress? David, you want to take that?

Dr. McDermott:
So it’s easy to answer that question if you start with IO/IO, because then you pick your favorite VEGF inhibitors. Some would say Cabo based on its meta inhibition. Some would say lenva, particularly in chromophobe cancer, where there’s interesting lenva data. So that’s an easy question because to answer, it’s harder when you’re talking about prior VEGF, it’s usually some other VEGF inhibitor that you’re testing. There isn’t a lot of great second line data about which to choose, but you’re usually picking from one, and it’s partly based on efficacy, but it’s also based on tolerability. How they do with the prior VEGF, what were the issues, could they accept a full dose or not? Because then you might choose something that’s less aggressive or less associated with toxicity if they had trouble with the first one. But there’s not a lot of data in that space, I don’t think.

Dr. Joyce:
So you, once again, led me perfectly into my next question. That’s toxicities of these treatments. These treatments are toxic, specifically the TKIs, the oral TKIs, the quality of life data from a lot of those trials in the clear cell space looks worse than the IO therapies. And so does that come into consideration with you all when you’re deciding on first line treatment and subsequent treatments, and how do you manage those toxicities if and when they arise?

Dr. Beckermann:
I guess maybe the one thing I would jump in and add here in this context of how do we think about sequencing and toxicities? And so especially in the non-clear cell group where we don’t have as much data in the refractory setting. If there’s ever the opportunity for maybe a patient’s having a mixed response or oligo progressive disease, then I may be thinking a little bit more outside the box because we don’t have that subsequent data. So can we treat whether it’s with SBRT, a surgical resection, something that is going to kind of buy me some more time perhaps on that front line therapy, if it’s not a definite multiple new sites of metastatic disease, that’s one area that I will try to grab for.

Dr. Albiges:
Yeah. To me, the second line is a no man’s land. We basically have nothing. So we’re using the agents available in sequence and it may be different from one country to another. So we’re using the TKI we haven’t used yet, but because we know the prognosis is so usually low, I agree with you that you need to go for multidisciplinary approach and use focal treatment and do the most of it.

But with regard to toxicity, I think what’s happening sometimes for non-fierce cell is that some of those patient has highly symptomatic disease. And what you are seeking for when you start your systemic therapy is response rate, basically downsizing or inducing tumor shrinkage. And this is where IO/TKI makes sense because you want to reduce the symptoms related to the disease and you are at risk of side effect, but then you would dose reduce your TKI, for instance. We all know that len/pem, sometimes you have to reduce lenvatinib because the 20mg dose is very high. For cabozantinib is the same story. In the long run, we adjust. It’s usually a toxicity that is driven by the VGF-TKI, from my perspective.

Dr. McDermott:
I think the certain patient advocacy groups have done some interesting work in this space as it relates to side effects. And I think for example, KC Cure surveyed a bunch of patients who were going through treatment largely with TKIs and asked them about, did you ask your doctor about a dose reduction? What are your concerns around that? And what they learned essentially is patients are nervous to reduce the dose. They are anxious about communicating with their doctors. So from an oncologist’s point of view, reaching out to your patient, educating them, making sure they know you can reduce the dose, you can take a break, particularly if the cancer is under control, then I think you’re much more likely to hear from your patients about their issues.

Whereas if patients are just scared that if they stop the drug, their cancer is going to rapidly progress, they’re less likely to ask for those things, more likely to suffer the chronic and annoying side effects are associated with TKIs. So patient education is key.

Dr. Joyce:
How about cost? Does that come into play when you’re deciding on these treatments, the out-of-pocket cost for a patient, what it’s going to take for them to get combination therapy versus single agent therapy versus oral drugs versus IV drugs? Is that a discussion you’re having frequently or is it not something that comes into play?

Dr. Beckermann:
I think it’s a discussion. It’s a worry almost every patient asks. I think I often will have that initial concern come up for my patient in the consult. And there is different reimbursement here in the States for oral versus IV. There are a lot of helpful mechanisms to make sure that patients can get the medicines that they need. But certainly financial toxicity is something that we need to be mindful about. It’s I think, in my experience, the biggest concern that most of my patients have once. We’ve talked about cancer and prognosis, I always will say, “What other questions do you have?” And they say, “Is this going to cause harm to my family? Will I be to afford this?” And so I think being mindful about that is something that we need to consider.