Molecular Testing and Risk Stratification in Advanced Clear Cell RCC


Expert oncologists give an overview of molecular testing, risk stratification, and treatment guidelines for renal cell carcinoma.


Elizabeth Wulff-Burchfield, MD: For the next question, I’d love to hear from someone. For this gentleman [who is] super healthy, super young, super active, has indolent growth but now has a new measurable node as well as lung metastases, would you start treatment? Dr McGregor, is there anything that speaks to you about initiating treatment, or what are your thoughts?

Bradley McGregor, MD: I think this highlights the importance of shared decision-making with the patient. I want to say, going back to molecular testing, I think molecular testing certainly can be important. I would caution the use of it to guide anything because the markers we generally think of as responders to immunotherapy in other cancers, like PD-L1 status, or microsatellite instability, tumor mutation burden, don’t matter in kidney cancer. So, I would not get it and say, I’m not going to give this therapy because of this marker or that marker. I think as Rana said, it’s helpful for those later lines [of therapy], trying to find that potential niche or the unclassified. But a lot of times, it’s important not to go away from what’s been proven to work independent of all those factors.

But in regard to this patient right now, I think it does come down to that shared decision-making. I have some patients who are incredibly anxious, and with the smallest growth they want to do treatment. If that’s going to help them feel better then I think that’s an important aspect. We know there are data that you can offer surveillance to these patients, specifically favorable-risk patients, for quite some time. It has been published and seen in phase 2 [trials]. So for those patients who want to avoid systemic therapy, I don’t think that’s unreasonable.

I think this is a situation where you talk with the patient. If this patient has reached the point where you’ve been watching them for a while, the growth is at that point where they just don’t feel comfortable monitoring any further, I think treatment makes sense. If they have a lot of things going on in the next 3 months, have a big trip coming up, don’t want do it, I don’t think there’s a rush to do it. Although it does sound like that clock is ticking probably a little louder than it was a year ago in terms of reaching that decision.

Elizabeth Wulff-Burchfield, MD: Thank you so much. Dr Barata, is there anything that either sticks out for you about this case that would lead you to want to start treatment or anything in theory that you think would be a clear indicator?

Pedro Barata, MD: Yes, great question. I agree with my colleagues’ points. Probably molecular testing at the research level at this point. I think there’s the story around metastases, it’s not over, especially for papillary. We have some ongoing studies exploring that further, so that in addition to SC [standard of care], etc., that might help us as well. But I don’t think it’s mandatory. I agree completely with Dr McKay’s thoughts.

Regarding the initiation of systemic therapy, exactly like Dr McGregor mentioned, I don’t think we have data suggesting that starting treatment today will make them live 1 day longer. Definitely we have data, perhaps phase 2 data, showing that time to initiation of systemic therapy for selected patients can be around 8.5 [months] for instance. There’s certainly an amount of time where we can safely watch and wait before we decide to start.

There are a number of things that at some point give us an idea that now is probably the time to do it, like the increase in tumor burden or involvement of different organs, if you will. I think all of us start getting nervous when it involves certain organs that we know are poor prognostic factors. I’m thinking of the liver or even brain. I’m debating myself when restaging these people, do I do a brain MRI for all of them when I see mediastinal disease, for example?

Some of the thoughts I have when I see a patient like this, these patients tend to do great. The secret here is when we have data that predict you’re going to go through it extensively, how do good-risk patients behave on these frontline IO [immunotherapy]-based combinations compared with TKIs [tyrosine kinase inhibitors]? We know they do well in a relatively short period of time. The question is, how do they do over a longer time? I still think we need to take all that into consideration, location of metastases, lack of symptoms, tumor burden. Those are important factors, but at the end of the day, we know to start when the patient is sharing his thoughts with us. Also, we get to the point where we think it’s probably a good idea to start. I completely agree with my colleagues on it.

Elizabeth Wulff-Burchfield, MD: It sounds like there are some clear themes here that it’s medically appropriate, ethically appropriate to order this NGS [next-generation sequencing] testing, but that, at least for clear cell, it shouldn’t probably be used for first-line decision-making. Essentially, it’s something to keep in your back pocket in case we learn more about clinical relevance of certain mutations and findings, but really using it in a very different way than we might for lung and other diseases. It [also] sounds like shared decision-making still is king. I love that. I think there are no clear indicators for this case that are jumping out, but it sounded like sites of metastatic disease, symptoms, and patient anxiety are what are leading folks.

Diving back into the case very briefly, revisiting our risk stratification system. It’s amazing to see the evolution of this over time and the ways we have used different risk stratification systems and the way we derive guidance from it. I think many of us believe that in the future we’re going to see more, maybe not even clinical factors that weigh into this. But as we see here for this gentleman, he would be considered IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] favorable risk. Clearly he has a superior prognosis compared to the rest. I think an important point to reiterate is the fact that for favorable-risk patients, surveillance is not only acceptable, but it can be very much the recommendation for someone who has favorable risk like this gentleman.

In looking at the guidelines, we have such an embarrassment of riches here with a lot of regimens that are appropriate. But also, it can be so nuanced in deciding what to offer each individual patient with some great preferred regimens. [We have] lenvatinib/pembrolizumab, cabozantinib/nivolumab, axitinib/pembrolizumab, as well as other regimens. In some cases, nivolumab/ipilimumab, or a single-agent TKI for favorable-risk [patients].

We’re going come back to that, but let’s get back to the case, and as a brief interlude I’ll share that [we’re working] under the assumption that this gentleman is treated with cabozantinib/nivolumab at the standard dosing. So, we’ll go from there. Although, I would comment that a lot of times folks are using the nivolumab 4-week dosing now rather than the every 2-week dosing. At least that’s what I’m observing and doing the most.

Transcript edited for clarity.

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