Patient Selection for IO/IO Versus IO/TKI in the Frontline Setting

A roundtable discussion, moderated by Brian Rini, MD, of the Vanderbilt-Ingram Cancer Center, focused on treatment considerations for frontline and refractory renal cell carcinoma, including a discussion of new data presented at ASCO 2023. Dr. Rini was joined by a panel that included Tian Zhang, MD; Pedro Barata, MD; and Michael Atkins, MD.

In the next segment of the roundtable series, the panel discusses toxicity management related to IO/IO and IO/TKI regimens, as well as the struggle to use precision medicine and biomarkers in the RCC space.

Watch the next segment in this roundtable series.

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Dr. Rini: I’ve been very involved with KEYNOTE-426 and so I will say, and people like yourself and Dave McDermott, MD, and others have been saying this for about 2 decades, and I think it’s finally starting to sink in for me, is that I totally agree with you that upfront potent immune therapy is the way we cure patients. I think the durability of immunotherapy (IO)/tyrosine kinase inhibitor (TKI) response is disappointing. Although again, there is a tail. I think there is a tail, but I agree with you, it’s probably not as high comparing across trials as a dual immune therapy.

Will it change my practice? Yeah, I think so. I mean I think I’ll probably consider ipilimumab/nivolumab more. I just had a patient pass from myocarditis. That’s what worries me. That’s what keeps me up at night is that I know there will be potentially life altering, life-threatening toxicity and I don’t know how to predict that. Whereas I know IO/TKI is safer and you could say, well metastatic cancer is bad and when it progresses that’s not a good thing. I totally agree, but that’s the one balance I have of giving everybody…

Dr. Barata: Brian, if I may add, I don’t think necessarily what you said is in disagreement perhaps. Because where we’re really talking is it’s a fraction of patients or proportion of patients who get more ipilimumab/nivolumab than IO/TKI. Really what we’re discussing is can we figure out who are the patients who will benefit from it? We can see that there in many different ways. The way I see it, there’s always a lower chance of you controlling disease with ipilimumab/nivolumab just based on the number of primary progressors than within IO/TKI, for example. I guess we are all users of ipilimumab/nivolumab, I think more or less we all use IO/TKI. I think if we have a way to know who are going to be the tail of the curves, then I think all of us would be using ipilimumab/nivolumab for that matter. But the thing is we don’t know that for a fact. I think where perhaps the disagreements probably practices we might have a larger fraction of patients getting IO/TKI for the reasons that Brian alluded to. We understand the side effect profile perhaps a little bit better. I mean we are very, very scared of significant immune-mediated adverse events. We use higher doses of high-dose steroids among other things and primary progressors are a little bit higher, etc. It’s not really looking for the median I think. Yes, the tail of the curve is not the median. Actually, we’re looking for a number that’s lower than the median or lower than 50%. But I agree with you in the sense that when we figure it out, who are going to be the patients that are going to be very close for us to say cure, that is the patient. If we know that, we’re going to be doing IO/IO upfront. I think we all agree IO/IO upfront is where it should be compared to later lines of therapy.

Dr. Atkins: I’ll just add to that, I’m glad to hear you say that, but I think we’ve tried to develop biomarkers by looking at IO/TKI, which is virtually impossible because we don’t know which component of the combination is actually responsible for the response. In order for us to determine who are the patients who are going to benefit from IO/IO or develop better IO combinations, we need to be giving IO first.

Dr. Zhang: If I could add, I think this is a great discussion. This is the exact point where precision oncology needs to come to kidney cancer. The exact point where patient selection upfront matters. Your trial, you’re too humble to talk about it, but your trial that is taking transcriptome signatures and directing therapy, I think is one step in that process. If we don’t do these types of trials where we select patients upfront for particular treatments, then we will never know.

I think kidney cancer, it’s great that we have all these treatments, but until we get to a lung cancer or breast cancer type of situation where we can find the right patients for the right treatments, we’re going to be lagging behind all of these other tumor types in terms of precision oncology. I’d wish that we do more molecular testing upfront; we think about resistance.

David Braun actually has a nice abstract here at ASCO where he’s looking at nivolumab resistance in a Hoosier cohort. I think that’s really important. Should we think about amplification chromosome 11, for example, as a marker of resistance and not select those patients for IO/IO and that would be a reason to use a VEGF IO? Or should we look at the inflammatory myeloid signature and send those patients to ipilimumab/nivolumab? I think these options are great options to have, but until we can get to optimal patient selection, we won’t catch up with the rest of solid tumor as we know it in 2023. I’m so excited about your trial OPTIC RCC, supported by DOD, and we’re very happy to participate.

Dr. Rini: I was just going to say we’re all, we all want biomarkers, right? In kidney cancer, we’ve talked about it, and we’ve talked about it, and we’ve talked about it, and it’s kind of just time to do it. I’d be interested in your take on this, Mike. My opinion about why it’s been so hard is that our treatment has been more strongly directed. We don’t have an EGFR mutation or HER2 mutation, which are tumor cell directed. We haven’t been able to cross that threshold of a clinically useful biomarker. PD-1 is unreliable and might enrich for response to ipilimumab/nivolumab, but we’re not really using it in practice. We’re going to keep having the same argument unless we find biomarkers. Because I have, my biases, you have yours, we’re going to talk about International Metastatic RCC Database Consortium (IMDC), which as Danny Heng, MD, himself will tell you was meant to be prognostic, not predictive, but we use it as predictive, which is silly.

Dr. Atkins: I was going to make the point about IMDC that it is prognostic, and I think there’s data to show that it’s prognostic even in pure immune therapy. But it’s only predictive for TKI therapy. Because we know the favorable-risk patients have more angiogenic-driven tumors. But for IO therapy to work, you need to have immune cells that recognize the tumor, and you need to have a normoxic tumor microenvironment. When you give IO/TKI, you produce hypoxia in the tumor microenvironment, particularly in the favorable-risk patients, which puts a drag on the immune response. There’s no reason why the fact that a tumor is more driven by VEGF should mean that there aren’t immune cells that recognize the tumor. There’s just no reason to try to use the IMDC model to be choosing therapy for when you’re giving a pure immune therapy.