Dr. Hammers:
Welcome to Optimizing Patient Selection Outcomes in Post-IO Advanced Renal Cell Carcinoma, an ASCO Post Roundtable. My name is Dr. Hans Hammers. I'm a medical oncologist and Professor of Medicine here at UT Southwestern in Dallas. And today I'm excited to be joined by two of my colleagues, Dr. Qin from UT Southwestern, Dr. Harrison from Duke. And I would like both to introduce themselves. Dr. Qin, would you please go ahead?
Dr. Qin:
Yes. So great to be here. I'm Dr. Qin, I'm a medical oncologist with focus on genitourinary cancers here at UT Southwestern, Dallas.
Dr. Hammers:
And Dr. Harrison?
Dr. Harrison:
Hey, everyone. I'm Mike Harrison, I'm a GU medical oncologist and Associate Professor of Medicine here at the Duke Cancer Institute in Durham, North Carolina, and I'm really excited for the discussion.
Dr. Hammers:
Outstanding. The second case will be presented by my colleague, Dr. Qin. So please take it away.
Dr. Qin:
Great. Thank you. So this case will focus on the treatment of advanced renal cell carcinoma with mild disease progression after immunotherapy combination.
So we have a 58-year-old man who presents the emergency room with fatigue and a protruding right neck vein. The patient does have some hypertension, sleep apnea at baseline, and was found to have renal cell carcinoma. He underwent right radical nephrectomy and had pT3N0 grade 2 disease.
Ten years later, the patient presented with some shortness of breath, and he was found to have a large infiltrative mediastinal mass with regional mass effect, as well as mediastinal hyaluronopathy and lesion in the pancreas.
Biopsy of the mediastinal mass is consistent with metastatic renal cell carcinoma. The patient was asymptomatic and elected to initiate ipilimumab and nivolumab. He subsequently developed weakness, fatigue, and headache. Workup did reveal hypophysitis with associated secondary adrenal insufficiency and hypothyroidism. The patient was started on hydrocortisone and levothyroxine with improvement in symptoms, and he was referred to endocrinology for co-management.
After four cycles of ipilimumab and nivolumab, the patient had restaging scans, which showed mild progression of the mediastinal disease. The patient remains asymptomatic.
So with a case like this, our first question is, what are the considerations when choosing next-line therapy after the patient has progressed on immunotherapy? What are some of the therapeutic options that you may present to the patient at this time?
Dr. Harrison:
Yeah. So I think generally a few key points for me are how symptomatic the patient is or not? In this case, it sounds like the patient is asymptomatic. I'm also thinking about the general pace and burden of disease, including sites of disease. So certainly places like endocrine organs, lymph nodes being more favorable.
And then in terms of progression, is it growth of existing lesions and how much vs new lesions, especially in new organ sites?
So this patient, again, being asymptomatic and having relatively mild growth in existing lesions would tend to fall on a more favorable prognosis I would think. And so, when you look at all the options, you're not necessarily having to use big guns or combinations automatically. Beyond that, I'm talking to them about what their goals of care and so on are.
Dr. Hammers:
Great. Yeah, I feel very similarly. I would say pace of progression, doubling time is something that we don't necessarily quantitate, but I think in the future ... To be honest with you, that's probably one of the most important things that I look at is are there any new lesions, any surprises? What's the doubling time? I wish we would get there at some point with modern radiomics to get that.
And if it's just smoldering disease progression, clearly immunotherapy didn't work for him despite having side effects, et cetera. Then the question is, what are we going to use? I mean, that's the beauty of the practice here in the United States. We essentially have a menu of treatment options that we can choose from, tailored to the patient. And so VEGF-TKIs, et cetera, different flavors we could pick from and choose depending on the aggressiveness of the disease that we are facing.
And in fact, it's expanding, I mean, the recent news at GU ASCO 2026 with doublet now beating even very aggressive TKI is quite exciting.
Dr. Qin:
So to ask a follow-up question, what patients would you consider TKI monotherapy vs choosing one of your doublets? Whether it's lenvatinib/everolimus or, as you've mentioned, LITESPARK-011. Potentially we'll have lenvatinib/belzutifan in the near future. So thinking about your patients, what cohort would you do doublet therapy and what cohort would you offer single-agent TKI at progression?
Dr. Harrison:
I guess, I would say when you're looking at the response rates, they're ranging from around 20% to 53%, ranging from tivozanib and axitinib being on the lower end of that. And then the combinations like lenvatinib/everolimus, and now lenvatinib/belzutifan being on the higher end of that. But the cost, if you will, is the toxicity of the doublet. So I really think you have to have either a high burden of disease or some kind of poor prognostic sites, or as Hans said earlier, rapid doubling time to justify the additional toxicity of the doublets, personally.
Dr. Hammers:
Yeah, I think very similarly. I think, to me, unfortunately, when immunotherapy doesn't work, at least with what's FDA approved, we really don't have any curative option and it's really primarily palliative. And the question is, how can we use these drugs without necessarily causing all kinds of side effects?
Certainly it's satisfying to see the tumor shrink. And I don't want to downplay the importance of seeing something work, quote unquote. But it's also about, do I want to give him hand-foot syndrome if this a physically active guy? Do we want to give him diarrhea nonstop in some of the combinations? Or do I want to give an agent that is much less likely to do either of the two, and it's mostly the classic on-target side effects such as hypertension and hoarseness of the voice, for example. So I think those are some of the considerations.
And I think it's a discussion with the patient. You could say, "Hey, this is roughly what I see. In this particular case, you didn't have the aggressiveness of the progression, you also had"—as Dr. Harrison mentioned—"a disease distribution that tends to be more favorable." So at the moment, let's say, endocrine organs are involved, tends to be more VEGF-driven tumors, tend to be less aggressive ones.
If you think about the patient had, if I remember correctly, he was diagnosed 10 years with a renal mass before eventually recurred. So these are all favorable risk factors if you will. Or complete the picture to maybe think about a tumor that's not moving fast and may in fact be actually quite sensitive to just VEGF inhibition by itself.
And I think all of us have had patients who can sometimes do well on these even more selective VEGF-TKIs, sometimes even range of years. So worth trying, I always call it testing biology. And I think that might not be unreasonable.
Dr. Qin:
Yeah, I think those are really all very great thoughts. And in fact, this patient did go on to TKI monotherapy because of those good prognosis biology. So the patient received tivozanib at full dose, of 1.34 mg PO daily, 3 weeks on, 1 week off.
So we touched a little bit on this already, the characteristics of the individual VEGF-TKIs. So in your practice, what characteristics are important when you're choosing this specific TKI for the patient, is it efficacy, side effect profile, is it other considerations?
Dr. Harrison:
I think beyond the efficacy considerations we discussed earlier, we didn't talk as much about the different profiles, but certainly tivozanib and axitinib have a more pure VEGF receptor inhibitory profile, and so could be better tolerated, at least in my experience. Than some of the more what I think of as extended spectrum TKIs like cabozantinib and lenvatinib. Where cabozantinib, you're having potentially more hand-foot syndrome, certainly lenvatinib, you're having other off-target side effects as well. So I think it's basically, like Hans said earlier, matching the risk of the disease with the risk of side effects and talking about the goals with the patient.
Dr. Hammers:
And the use of tivozanib may surprise some, because it's a relatively recent arrival to our VEGF-TKI armamentarium, was approved here in more pretreated patients. But we do have additional datasets. And I think to be honest with you, theoretically, it's actually an agent that I use more earlier than later simply because it is actually much more selective. And I think it's just a drug development pathway that this particular drug was on ended up where it was.
But I think we have additional data from the TiNivo-2 trials. One of the studies that showed us that PD-1 after PD-1 progression, at least for metastatic disease, doesn't seem to help. But we have dataset on patients who actually progressed on IO/IO and we treated them with tivozanib by itself, with a good response rate, good efficacy and good tolerability. And so I think we have a dataset that can inform us and would justify the use of tivozanib in selected patients.
Dr. Qin:
Yeah, I really agree. And toxicity is a major concern in terms of patients' quality of life. And I think warning patients early on about the potential toxicities, and managing them early as they develop, is also quite important in terms of keeping our patients on the right dose of drug.
We learned from TiNivo-2 and other studies that the dose of the drug when it comes to VEGF-TKIs are crucial. The higher the dose, and the more we can keep them close to the target, the better we'll be able to control the tumor. Great.
So with that, this patient did develop some hypertension with tivozanib. Tivozanib was held, blood pressure was managed, and patient was referred to cardio-oncology for co-management. And then tivozanib was restarted with close blood pressure monitoring.
So I think this also speaks to the multi-discipline care coordination that our patients really need in terms of our endocrinology, cardio-oncology, or other colleagues for co-management.
And so for this patient, restaging scan, digital response, patient remains on tivozanib at full dose. Tolerated treatment well without significant adverse events.
We have touched on this as well. But do we think the new data coming out of LITESPARK-011 will change your considerations in practice? I think we did touch on that combination therapies have higher efficacy, but potentially more toxicity. And so when we're choosing among the different options, looking at the disease characteristics, the biology, the prognosis, as well as patient preference will be very important.
Dr. Harrison:
I think the main takeaway for me is that you don't necessarily have to use the very most active therapy in the next line. It's easy to look, for example, and the LITESPARK-011 data is great, I mean, high response rate, 53%, 5% CRs, that may be important in a lot of patients, but it's not necessarily for every patient. So again, I think it's just matching the risk of disease with the risk of side effects and coming up with the right therapy for the right patient.
Dr. Qin:
So key takeaways from this case, front-line immunotherapy combinations can produce durable disease control, but primary progression and immune-related adverse events are of concern. And patient selection is key. VEGF-TKI post IO progression is a proven and active strategy. But I think the optimal choice remains to be defined and is a multifactorial decision. Immersion data, including LITESPARK-011 trial should further shape the therapeutic landscape for advanced RCC post-IO therapy.
Dr. Hammers:
Outstanding. Thank you so much for helping with this case.
This brings us to the end of this case. Please see the other segments for further discussion about the latest research in renal cell carcinoma. Or visit ascopost.com. Thank you very much.
