Dr. Hammers:
Welcome to Optimizing Patient Selection and Outcomes in Post IO Advanced Renal Cell Carcinoma, an ASCO Post Roundtable. I am Dr. Hans Hammers. I'm Professor of Medicine here at UT Southwestern, and I'm really excited to be joined by two of my colleagues, Dr. Qin and Dr. Harrison, who will introduce themselves. Dr. Qin?
Dr. Qin:
So great to be here. I'm Dr. Qin. I'm a medical oncologist focusing on genital urinary cancers here at UT Southwestern in Dallas.
Dr. Hammers:
And Dr. Harrison?
Dr. Harrison:
Hey, everyone, I'm Mike Harrison. I am a GU medical oncologist by training and Associate Professor of Medicine at the Duke Cancer Institute, and I'm really looking forward to the discussion today.
Dr. Hammers:
Outstanding. Thank you so much for your time. So our first case will focus on the treatment of renal cell carcinoma with disease progression after adjuvant therapy. This is obviously a space that is not well-defined, and so we will try to get some of the nuances maybe across that might be of interest to the audience.
So we'll start with case 1. Ms. L.P. is a 55-year-old woman. She was diagnosed with an incidental renal mass in March of 2022. She had a right radical nephrectomy in July revealing a stage III, grade 3 clear cell renal cell carcinoma with a roughly estimated risk of recurrence of around 50% over 5 years. She enrolled, actually at the time, on LITESPARK-022 in September of 2022. As the audience may have heard, at ASCO GU 2026, that trial read out as positive.
On this next slide, you can see that while we didn't unblind her, just for interest, so to say, you saw a significant drop in her hemoglobin, concentrations in the blue range is normal, and then it dropped on that particular trial. So she was certainly exposed to belzutifan. She did 1 year of pembrolizumab, 1 year of belzutifan 120 mg daily, and she completed therapy in September of 2023. On the next slide, you can see that in March of 2024, she had follow-up CT scans, which unfortunately revealed interval development of a dominant 1.4-cm right basilar nodule with a small increasing satellite of 0.6 cm. This was concerning for worsening intrathoracic metastatic disease, certainly very consistent with recurrent renal cell carcinoma.
So what are some of the consideration and goals when choosing the next line of therapy in this patient? What kind of treatment options would you potentially consider? So I would love to welcome or invite Dr. Qin and Dr. Harrison to give us their thoughts. Would they rechallenge, for example, with pembrolizumab at this stage? Would they go an IO/TKI doublet? Would they go for surgery or radiation? What are your thoughts and how do you think about those various treatment options in a space that unfortunately not very well defined?
Dr. Qin:
Happy to start. It's a really great case and really get to see that the patient was enrolled on LITESPARK-022, which read out positive recently.
I think the first question on my mind is the timing of the recurrence. So it looks like this patient had recurrence around the 6-month mark from what I could tell. And I think that's a very challenging timeframe for us to think about immunotherapy. We know that the receptor occupancy of immunotherapy, once we stop it, it's at least a couple of months. And so if we have a patient who progress within a few months of stopping immunotherapy, I'd be very worried about refractory disease. If it's been more than a year or so, I think it's very reasonable to think about rechallenge.
But it's the patients in between that can be a challenge when we think about are these patients going to respond to immunotherapy if we challenge? And so 6 months is right in the middle. And so, to me, I think it's reasonable to think about multiple options, whether we rechallenge with IO, either IO/IO or IO/TKI, single-agent TKI, I think are all potential options when I think about systemic therapy.
Dr. Harrison:
I'll just add this 6 to 12 months—and this patient is more close to around 6 months after trial progression—is very challenging. And so I think the way I would be thinking about this is, this patient has transitioned from localized disease to metastatic disease. And so what are our goals in that setting? My goal is always to talk with the patient first, but typically it's thinking about how can we put this patient into remission? And we know the first-line therapy for metastatic disease in RCC is one of the best chances to do that. Now this patient is, as you said, Hans, I mean, it's kind of a new type of a patient, and not only exposed to pembrolizumab, but also to belzutifan.
So I kind of have this checklist that I go down in my mind where I'm first considering what are the sites of disease, what's the burden of disease? And if they have oligometastatic disease, that's the patient I'm thinking about potentially things like SBRT and surgery or local therapies. When I think about the other options listed here, certainly if you're not going to do local therapy, so if you're thinking because of the timing, because of the sites of disease, maybe there's concern about nodules in other lobes of the lung or bilaterally and this patient isn't potentially a local therapy candidate, then you're thinking systemic therapy. I certainly think either pembrolizumab rechallenge or adding CTLA-4, that could be reasonable. There's some data for modest responses with salvage ipilimumab/nivolumab, for example.
And then I think a standard therapy for patients, a more standard therapy would be some type of a single agent TKI. I think the IO/TKI doublet is a little bit challenging with the CONTACT-O3 and TiNivo-2 data suggesting no benefit to continuing immunotherapy. But again, we're saying this patient is in that 6 to 12 month gray area.
So I think in summary, you could ask a lot of different oncologists and get a lot of different answers here, and maybe we should ask you some clarifying questions about the patient.
Dr. Hammers:
Sounds good. I think these are great discussions and you're absolutely correct, we don't really know very much, I would say, about this space. Although I would say, as you indicated, Dr. Harrison, continuing PD-1 after PD-1 progression has somewhat run into a wall, at least with the doublets that we have used before. So I would say, for me, who use a lot of dual immune checkpoints, there's always a sense that we may leave something on the table. If you look at the response rate to single-agent PD-1, they tend to be in the low 30% range; for nivolumab, ipilimumab, more in the 40% or 40%+ range. And so there is some thought that maybe we leave something on the table.
This was a young patient where we felt that maybe systemic therapy is important to prevent further recurrences. If this was a 70-, 80-year-old gentleman or woman who would like to avoid systemic therapy for a while, certainly stereotactic radiation could be a consideration if you want to spare them some from systemic therapy.
So with that in mind, and some of the experience that we had with nivolumab, ipilimumab after PD-1 progression, and if you look at three independent clinical trials, the answer is always roughly the same. We have roughly a 10%, 15% chance to potentially induce a remission there, and in some patient was actually very doable. And so we decided to rechallenge her with nivolumab, ipilimumab. She started that in April of 2024. She received all four induction doses with no major autoimmune adverse events. I would say that's one of the reassuring things. If somebody did well with PD-1 alone, certainly they can get some of the more CTLA-4–driven side effects such as the colitis, hepatitis, or hypophysitis. But in general terms, the patients who typically get these devastating side effects, we have weeded them out already. They did well with PD-1 for a year.
So she received all four induction doses. And then unfortunately in May of 2024, the previously seen pulmonary nerves were clearly decreasing in size compared to prior, but they remained enlarged. And then essentially down the road, you could see a resolution of multiple solid pulmonary nodules. You can see a little shadow left in the area that was previously more solid. And she completed essentially the entirety of two years, roughly. That's my practice of induction plus nivolumab subsequently as monotherapy.
And so, for me, I would say as clinical takeaways is that the truth is, the therapy space after adjuvant therapy is not well established. Personally, for me, if you didn't eradicate a cancer with 1 year of PD-1 inhibition, probably the rechallenge of PD-1 alone is probably not going to be that effective. There may be some exceptions of very long periods out, if you will. But in principle, immunotherapy can eradicate disease. So, if anything survives the assault in the PD-1 inventory space, probably rechallenge is going to be less active. That's my suspicion. We have to see what the data is. Receptor occupancy is around nine months plus, so it's a really complicated space.
Certainly TKIs, I would say with modern knowledge, is probably certainly always an option, but the quality of life can be an issue. I would love for those patients to have some data with, for example, belzutifan by itself. But even within the range of the TKIs, there are different options that could be considered. And certainly if the patient had any symptomatic disease, then we would probably think about that more in that particular setting.
So that was the rationale. It worked well in this case, but I think I would say patient education is important. You cannot promise them a 40% response rate. I think mentioning that it's roughly 10% to 15% chance, but in somebody who's young, 10% to 15% is not necessarily the lowest number they've ever heard. And we are just spoiled in renal cell carcinoma when we talk to patients about 40% to 70% of response rates. But 15% is in line with triple-negative breast cancer or other diseases, so I think it was not unreasonable in carefully selected patients.
Any other thoughts, Dr. Qin or Dr. Harrison, on this case?
Dr. Harrison:
Yeah, Hans. I was just going to say, I agree with you about the 10% to 15% response rate being reasonable in selected patients. I mean, I kind of will do a mental thought experiment where I think of what's the worst thing that could happen in 12 weeks of Ipilimumab/nivolumab induction. And certainly in the case you presented, the worst thing is those lung nodules would likely just grow. So certainly reasonable to take that chance. And like you said, you don't want to leave ipilimumab on the table, because once you go onto a TKI or it may be a HIF-2 inhibitor, you're probably not ever going to go back to the ipilimumab. So I definitely think that's a reasonable way of thinking about it.
Dr. Hammers:
Yeah. And even clinical trials in this space are very reasonable in carefully selected patients. So I think that's the recognition is that I think looking at the patient, individualizing therapy, and seeing what the goals truly are, I think is really important. Everything is about patient selection. And I think very similar about this patient, it's almost like with interleukin-2 where you want to select patients where it doesn't matter if they don't respond in the next 3 months. I think those are the patients you probably want to think about for this particular approach.
This brings us to the end of this case. So for the audience, please see the other segments for further discussion about this latest research in renal cell carcinoma or visit ascopost.com. Thank you very much.
