Biomarkers in RCC Treatment: The Role of Sarcomatoid Features and Emerging Technologies

In the second part of this roundtable series, Dr. Michael Atkins moderates a panel of oncology experts as they explore the role of biomarkers in determining treatment strategies for patients with advanced kidney cancer. The panel delves into the utility of sarcomatoid features, PD-L1 status, and emerging biomarkers like KIM 1 and ctDNA in guiding decisions between IO-IO and IO-TKI regimens. The conversation also highlights ongoing clinical trials, such as the OPTIC trial, which aims to tailor treatment based on gene expression profiles.

Watch the third part of this series: What Matters Most: Shared Decision-Making and Treatment Endpoints in RCC

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Dr. Atkins:
Great. So I’ll start with you on the next question, Chandler. So do you use any biomarkers to help decide what treatment regimen you’re going to give patients? 

Dr. Park:
Yeah, I think the main biomarker that I use right now is the sarcomatoid, especially if there are sarcomatoid features with the updated subgroup analysis, you have close to 60% response rate with 25% CR. I think that’s amazing. And so something along that line, I would definitely consider Ipi-Nivo with dual checkpoint inhibitor. Something that’s emerging, I think it’s in the adjuvant setting with the IMmotion010 with the KIM-1. I just have to see how that turns out. But I think this is something that’s going to be studied in future trials and I’m very hopeful for this biomarker. 

Dr. Lattanzi:
Yeah, so obviously this is an area that’s wanting for biomarkers. If we had a way to predict who were that 25% of patients who are going to derive that long-term durable response beyond just the IMDC criteria, which are relatively crude and older risk prognostic stratification. The most important factor for me is honestly the patient’s performance status and how quickly they need a response. But in terms of biomarkers, I don’t tend to think more beyond that. 

Dr. Atkins:
But are your pathology reports coming with a PD-L1 status on them? 

Dr. Lattanzi:
They do not. Yeah. So our pathology reports don’t come with a PD-L1 status routinely for RCC. For lung, for example, of course they would. For gastric, of course they would. But if you want a PD-L1 status, you’re going to have to request it specifically. And then I would of course agree the data in sarcomatoid RCC looks very promising. And those patients I certainly favor an upfront IO/IO approach. 

Dr. Atkins:
And Alan, anything else you use? 

Dr. Tan:
Clinical biomarkers, I mean pathologic biomarkers, I think Chandler hit it right on the nail. Sarcomatoid, IO/IO is pretty much… Should be the gold standard I would say. Not that the IO/TKIs don’t respond as well, but you have such high response rates with that doublet and a tail of the curve and you’re not undergoing the TKI toxicity of those patients. Laurence presented at ASCO, the KIM-1 that’s really compelling. I probably think that’s probably one of the more sensitive ones that we have, but it’s just not readily available right now. The nephrologists are using that as a kidney injury molecule. And there are some caveats with that as well, renal insufficiency may falsely increase that as well. I think CT DNA is not quite ready for prime time yet. That’s one of my research interests, looking at more sensitive biomarkers of CT DNA. I personally think if you don’t shed CT DNA, you’re probably more in that good-risk category. And if you have high-shed of CT DA, you probably have more of that poor or intimate-risk population with visceral disease, so. 

Dr. Atkins:
How about you Laurence? Are you using KIM-1 now? 

Dr. Albiges:
So I’m not using KIM-1, but I think you’re going to like my answer. So we don’t have PD-L1 being reported by our pathologists, this is not routinely being performed. But two years ago EU decided to fund research that they called pragmatic clinical trial, meaning routinely available agent. And so we, meaning a European investigator, applied to get funding and we got funded and we launched a study across eight countries in Europe named KL-1. And the rationale of this study is to look at PD-L1 staining. And the hypothesis is that in PD-L1 positive patient, nivolumab ipilimumab will actually be superior to IO/TKI choice of the investigator because it has to be the one that people are comfortable to use. And that is using PD-L1 as it was developed in the nivolumab ipilimumab trials, so tumor cell staining more than 1%. And we make that locally assessed, meaning the local pathologist. So it requires a bit of training because the pathologists are used to look at immune cells or having other antibodies and so on. But right now the study is enrolling fine and I hope that ultimately PD-L1 will become a biomarker for treatment selection. 

Dr. Atkins:
Yeah, I think a lot of the data about PD-L1 in kidney cancer is confounded by the fact that it’s not really done on the metastatic lesion and it’s often done after an intervening therapy in the second line after they’d already gotten TKIs. And I think a study like you’re proposing is something that needs to be done up. In Vanderbilt, they have the OPTIC trial that is looking at RNA-seq clusters as IMmotion151. What’s your feeling on that trial? 

Dr. Tan:
Yeah, I think it is quite compelling. The downside of a trial like that is if a patient’s highly symptomatic, the turnaround time for one of those gene signatures is approximately three weeks. So if I have a patient that… And I have other trials that I might be able to enroll the patient on more quickly. But I think it’s enrolling well enough and we probably should have some results in the coming years. 

Dr. Atkins:
Okay. Did you want describe the trial? 

Dr. Tan:
Oh, sorry. The OPTIC trial… So we know that from these other trials that good-risk patients have more of an angiogenic signature, but there’s still a little bit of these patients that all have more T-cell enriched or immunogenic signature as well. So as you go onto more intermediate and poor-risk, that flips around where you have more T-cell effector signatures as well. So the thought is if you have one of those clusters that’s more T-cell enriched, you’re going to get assigned to the Ipi-Nivo arm. And if you have more of that angiogenic signature, you will go to nivolumab cabozantinib. 

Dr. Albiges:
And so what you’re looking at is response rates and it was decided in a trial that they want to hit a higher response rate than what we had. But maybe my question is do you think that can be endorsed based on response rate in the future? Because I love the approach, but there is a question of applicability and will response rate be enough to convince on this strategy? 

Dr. Tan:
Right. I think it remains to be seen because immunotherapy with an IO doublet probably doesn’t work quickly enough for patients that are highly symptomatic, as Chandler mentioned. For me, it’s the eyeball test. You see a patient in front of you, they’re on oxygen, they’re in a wheelchair, they have pleural effusions, hypercalcemia. Even if you do have that immunogenic signature, I’m not sure that Ipi-Nivo is going to rescue them quickly enough to where they’re not going to get pulled out of that quicksand quickly enough as IO/TKI can. The primary progressive disease rate of Ipi-Nivo is about 18 to 20%, whereas something like Nivo-Cabo is more like five to 6%. So I think primary progressive disease rate in that population based on a biomarker selection, that’s what I’m really going to be looking for. 

Dr. Atkins:
Yeah. But for example, the angiogenic signatures are going to get an IO/TKI and they’re going to have a higher response rate than if they would’ve gotten an IO doublet. But that may not be the endpoint that is the best measure of the efficacy of IO/IO. And who knows? Two or three years or eight years down the road, their curves might’ve crossed.