Advanced Clear Cell Renal Cell Carcinoma: Putting Advances Into Practice - Episode 7

Choosing Upfront Therapy for mRCC

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Daniel J. George, MD: When you have a patient with renal cell carcinoma [RCC] and use our IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] criteria, do you have a sense that, “I have got to pick my best regimen up front because they may not make it to second-line?” What drives that sense of immediacy for treatment?

Sumanta K. Pal, MD: Always. You, Neeraj, Rana, and I have all contributed to several of these data sets, both in the context of IMDC and outside of that context, that reflect the high attrition from first-line to second-line treatment that we saw in the TKI [tyrosine kinase inhibitor] era. For instance, some studies, like the IMDC data sets, reflect how just 50% of patients make it to second-line treatment. Those numbers may be a bit better in the context of VEGF [vascular endothelial growth factor]/IO [immune-oncology], but we just don’t know yet at this point, by and large. I would suggest that data, which implies that a substantial proportion are not going to get the second line, means you can’t save the best for last here; you’ve got to put your best foot forward right up front.

Daniel J. George, MD: I agree with that. You mentioned bone metastasis; to me, symptomatic bone metastasis is one of the things that I worry about in this disease. These patients can run into trouble early on. Another thing is tumor burden. Patients who have symptomatic, high tumor burden when they have progression and they’re already carrying a critical mass of tumor burden…to me, the third is the type of symptoms the patients have. I mentioned pain, and the other to me is weight loss. When I have a patient, and we see this with kidney cancer, the patient has a lot of weight loss. We’d like to think that’s like liposuction and body fat, but it’s mostly muscle. When you lose muscle, it makes everything that much tougher to tolerate and be able to get to your second or third line of therapy. There are a few key factors to me when I’m looking at these patients. Some weigh a bit more than others, and that really makes me think, “Gosh, I have got to take that first best shot.” If they don’t tolerate something, then I can dial it back, but we may not get a chance to do some fantastic salvage regimen if they don’t get some disease reduction in this first-line setting.

I want to be conscious of time, but I want to bring up one more thing that Rana brought up, and then I want to ask about adverse effects because these are the other key things. Rana brought up biomarkers, and biomarkers are key. I know all of us have done studies and invested a lot of time and energy in understanding biomarkers. There is 1 biomarker that’s out there: it’s prevalent, and it may show up on every tumor profile you’ve been getting it in your path reports regularly. It’s the PD-L1 [programmed death-ligand 1] status. I’m curious. When you see a tumor that’s PD-L1 positive or you see a tumor that’s PD-L1 negative, how does that factor in your decision? Does it factor in your decision at all in how you’re going to manage that patient? It’s not part of our IMDC. Neeraj, do you use that information?

Neeraj Agarwal, MD: I get that information, but I don’t use the information. That’s how I report that.

Daniel J. George, MD: Okay.

Neeraj Agarwal, MD: Most of the sequencing platforms report this information.

Daniel J. George, MD: Yes. You’re interested but not enough to act. It’s not going to weigh in your decision on how a patient is treated.

Neeraj Agarwal, MD: I think more about whether I’m going to use a PD-L1 access inhibitor and whether I’m going to use a combination regimen versus a VEGF/TKI-based regimen. That’s a bigger decision-making factor in my clinic at the Huntsman Cancer Institute in Salt Lake City, Utah.

Daniel J. George, MD: Do the others have the same feeling? Rana, you’re smiling. Do you use it a little?

Rana R. McKay, MD : First, we know that PD-L1 status in RCC is prognostic. People who are PD-L1 positive seem to do worse compared with people who are not. When we look at, for example, the 3 first-line trials with approved therapies in the frontline space, each of those trials used a different assay to determine PD-L1 positivity. It may be that the responses are going to be higher in patients who are PD-L1 positive, but patients who are PD-L1 negative can respond. It’s not a pure biomarker. You’re not going to restrict therapy around PD-L1 status. Right now, it hasn’t been integrated in clinical practice. Yes, we get it, we look at it, and we haven’t even validated the right assay yet. There is still a lot that needs to be done.

In each of these studies, there was some elegant work that came out from JAVELIN Renal 101 (NCT02684006) and Checkmate-214 (NCT02231749) evolving, but each trial did its own set of biomarker studies, and there was not a lot of integration across all trials. It urged the field for us to try to synthesize that and integrate the same biomarker panel across these trials, so we can learn something and try to better select our patients beyond just IMDC criteria. I don’t think we’re there yet, so I still think we have a lot of ways to go.

Daniel J. George, MD: It seems like something that could be induced. We’re using archival tissues to describe this, and you’re then treating patients with, say, a VEGF/TKI and an IO, how much of that PD-L1 status is changing in vivo in these patients and we don’t even know it. There are a lot of limitations in that archival tissue, but something that probably doesn’t change is something like a sarcomatoid element, and that’s an aggressive element to a tumor. It’s probably a bit more of an inflammatory element. Certainly, it has a different histology associated with the disease, and we don’t see it that often, but maybe 10%, 15% of the time we’ll see some significant component of a sarcomatoid element….

Sumanta K. Pal, MD: One of the most impressive outputs of all the immunotherapy studies has been the benefit that we see with the application of immunotherapy with sarcomatoid features. If I see a patient with a substantial proportion of sarcomatoid elements, then I’m definitely steering them toward nivolumab/ipilimumab.

Daniel J. George, MD: It’s interesting because you see it not only with the response, but even with a complete response, which, to Neeraj’s point, is remarkable because the sarcomatoid elements are rarely 100%. You usually get 10%, 30%; it’s some proportion of the tumor, yet you’re having much more dramatic effects, and it suggests that there’s some sort of bystander effect once you’ve got that immune activation associated. It starts killing all the tumor, and you can get these remarkable complete responses. We’re not necessarily talking about taking a couple of small lymph nodes and shrinking them away. These are patients with liver and bone metastasis responding. I agree with you. These are the cases for which, even if it seems a little bit of a stretch, I’ll consider that because it has such a dramatic result associated with it.

Transcript Edited for Clarity