Longer-Term Follow-Up on Frontline IO and TKI Studies and Impacts to Treatment Selection

A roundtable discussion, moderated by Brian Rini, MD, discussed the latest data from the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024 in clear and non-clear cell RCC. Dr. Rini was joined by David McDermott, MD; Elizabeth Plimack, MD; and Martin Voss, MD.

In the next segment of the roundtable series, Dr. Voss compares IO/IO and TKI/IO treatment options, as well as toxicity considerations.

Watch the next segment in this series.

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Dr. Rini: Martin, didn’t mean to ignore you there. We’ll give you the final word of what you think. Any ASCO [GU] data significantly impact your practice and where do you stand on this debate?

Dr. Voss: Yeah, it’s good. Like Betsy said, it’s good to see these analyses and the data being put to use, remembering that a lot of patients committed to these trials and a lot of work went on on part of the study teams and continues to. We’re still all logging data for these trials. I think it is important that we keep looking at this data and making sure that it can shape decision making. I would say there was no surprises here. I think it is good that we’ve now seen data north of 4 years for all the pivotal trials that we need to consider when we make decisions in the clinics, and I think the theme has been the same. We see that group of patients who clearly benefited from CTLA-4 PD-1 inhibition continue to benefit. I think the most impressive part of that was duration of response data that was seen for those patients who are still being followed, anyway, for those responders that are still being tracked, 50% of them are still in response north of 7 years of follow-up.

I think that is important and I think that does help with decision and with discussions in clinic because what I usually tell patients is I can’t predict how they’re going to do, but I can reference some examples and I can tell them now that patients that we studied in similar scenarios on a clinical trial and those who did have a response, which isn’t everyone, had a very high chance of holding onto that response not only for months, but for years. The other thing that I was very happy to see and have been pleased to see for the BMS data set is that we see toxicity data and how it evolves over time. We’ve seen that for ipilimumab/nivolumab before and it’s one of my frustrations for all the TKI/IO data sets. We see that tornado plot again and again and it’s not going to change because it won’t change.

Even if it did change to some nuances, to the highest grade toxicity per patient, doesn’t really help think through what happens to patients over time, and that’s what we really care about. We care about keeping patients on the same regimen for a long time, the good and the bad, the chronicity of toxicity and the duration of their response. I think it would be very helpful if we could see some prospective assessment of what happens with the TKI toxicity over time, what happens with IO toxicity once patients come off after 2 years of pembrolizumab, for instance, and maybe I’m just missing it, but I don’t think we’re seeing the data, although that data is being collected and there’s still lots of data entry happening on some of these trials.

Dr. Rini: Yeah, I agree with you. I think I certainly, we’ve all treated patients with TKIs for years, individual patients, let alone collectively. As patients get years out, I tend to give less and less TKI, either stop it entirely or give very generous breaks. But to your point, we don’t have even toxicity data, let alone quality of life data, etc. We just have our collective experience. My experience, anyway, by the time patients get years out, clearly they’re tolerating it reasonably well, otherwise they wouldn’t be there. I’m so liberal with breaks and I certainly have patients where I’ve stopped it.

When patients get to that 2-year point of IO, I generally stop and I also have a discussion about stopping the TKI, and it’s hit or miss. Some patients say, yeah, great doc, I’d love to, and other patients are tied not inappropriately to this drug that they think is keeping them alive, and they’re not wrong. I think that’s a different discussion. But you’re right, we don’t have granular reporting because to Betsy’s earlier point, we didn’t really plan for success I think in these trials and have faithful data collection and second therapies and long-term toxicity and all that stuff that now we’re clamoring for the data, but it doesn’t exist as much as we would want. Martin, just maybe to follow up with you, what is your approach, your general approach then? Clear cell patient walks in, they see you in clinic.

Dr. Voss: The first decision for any of us I think is between IO/IO and IO/TKI, if they are in need of systemic therapy, some patients are not. But if they are in need of it, I do look at the pace of disease, and I think Betsy mentioned this before and the kinetics, my concerns of how quickly they are getting worse clinically and can they afford the room that we may need with a higher upfront failure rate with an IO doublet that then might necessitate second-line therapy. If a patient has intermediate/poor-risk disease, low volume, asymptomatic, I continue to be very encouraged by the long-term data for ipilimumab/nivolumab, and I consider that certainly for any patients who have a higher pace of disease and I am concerned that they’re getting worse quickly, I need something that has a low failure rate, and that we’ve seen now with the TKI/IO combinations and can rely upon that.

Dr. Rini:  Yeah. I think that’s probably the one area that people do agree on is that higher volume, higher pace. Now, we all might define that differently. I think you know when you see it, but if you ask me to quantify it, I might struggle to say, well, it’s this much disease or that much disease.

Speaking of, we did see some data that Victor Grünwald presented from the CLEAR study, the lenvatinib/pembrolizumab, about baseline tumor burden and association with outcome. If I remember correctly, really the one thing that struck me was the chance of a CR went down with higher tumor burdens, not surprisingly. I don’t think he broke it down into primary in place or not, but I assume a lot of those patients would’ve primary in place. Does anything about that dataset for any of you impact the way you think or is it sort of, yeah, that’s what we thought?

Dr. Voss: I think it reaffirms things yet again, and I think I would look at the other end of the spectrum looking at these 4 subgroups. He broke things down by separating all the patients into quartiles by sum of target lesions as an estimate of volume of disease. We know there’s all kinds of issues with RECIST assessment, but I think what was helpful to see is that even in the group with the biggest burden of disease, the failure rate, the PD rate, remained low. You may not have significant shrinkage. The CR rate goes down, which makes sense from a common sense perspective. It’s just harder to bring that down to zero. But that does not mean that you can’t control the disease. I think the overall ability to control disease was quite good, under 10%, even in that largest volume group of patients. I think that’s reassuring for that regimen.

Dr. Rini: Yeah, agreed. Some of this of course has to do with RECIST categories are based on percentage, not absolute change in the absence of new lesions, so I guess it would’ve been nice to see that. It might be harder to progress if you have high volume because it’s 20% of a higher baseline, so it works a lot of ways, but I agree. It’s very interesting data. To me, it fits what we think. I’m not sure it impacts my practice too much.