Dr. Daniel George:
Hello and welcome to The ASCO Post Roundtable Series on New Approaches to Treatment Sequencing in Advanced Renal Cell Carcinoma. I'm Dr. Daniel George, Professor of Medicine, Surgery, and Urology at Duke Cancer Institute. And joining me today are two of my colleagues. Dr. Harrison?
Dr. Mike Harrison:
Hi everyone, I'm Mike Harrison. I'm an Associate Professor of Medicine at the Duke Cancer Institute
Dr. Daniel George:
And Dr. Fahey.
Dr. Catherine Fahey:
Hi, I am Dr. Catherine Fahey. I'm an Assistant Professor of Medicine at the University of North Carolina at Chapel Hill.
Dr. Daniel George:
Catherine and Mike, welcome both of you to this roundtable and let's jump right into our case here, if you will. So we're going to start with Mr. ST, a 51-year-old man who presents in June of 2013 with asymptomatic gross hematuria. He’s found to have a 12-cm right renal mass. He undergoes a nephrectomy, and pathology reveals a pT3a Nx Mx G2 clear cell carcinoma. So grade 2 clear cell carcinoma with stage III disease. This is before our data for adjuvant therapy. And so he's followed and for 5 years is disease-free until March of 2018, almost out of the woods, a CT scan shows a 1.1-cm right adrenal nodule and a enlarging 11-mm right middle lobe nodule and 10-mm right lower lobe lung nodule. So in truth, he had these lung nodules for a couple of years.
They were 3 to 5 mm and finally got up to the 1 cm or so range. And at that point he comes and is referred to see me. And so we have him undergo a VATS resection, which reveals clear cell carcinoma. We did genetic profiling on these tumors and he has the classic loss of VHL, but he also has PBRM1 and BAP1 loss mutations. So interesting kind of trifecta of genetic alterations, none of which are actionable. A follow-up CT scan a few months later shows an increase in the adrenal lesion and still some persistent subcentimeter lung nodules. And so he started on sunitinib. And in August he has a near complete response with his lung nodules and his adrenal nodule and the sunitinib is held. In December, he has a CT scan and 3 months off of sunitinib things are moving back.
He's got a lung nodule, but he's also got a recurrent now 7-mm right adrenal nodule. And so he undergoes radiation to that right adrenal nodule and we're following him again and the lung nodules are slowly increasing and we do another wedge resection and it takes out three more foci of renal cell carcinoma. So these little tiny lung nodules are real. We're just not quite clearing him. And by November 2023 now, he's got a new 2-cm left adrenal nodule. So stubborn little case here. Catherine, what do you think? First of all, his prognosis or goals of care, he's 50 years old at this point or 49, what would you tell him?
Dr. Catherine Fahey:
Yeah, I think this is a case where you've probably played the maximum amount of whack-a-mole that you can at this point. He had a great initial response to sunitinib and you've been able to manage things. You've gotten what, 3, 4 years of disease control, able to keep him off systemic therapy. So I think this is a time where you talk to him about, “I think your disease is declaring itself as it needs something systemic to try to manage it” and then just talk to him about what the expected toxicities are, what's important to him, and make a therapy plan together in that regard.
Dr. Daniel George:
That's great. That's great. And Mike, I mean, he's got a single adrenal nodule, but to Catherine's point, we know there's more disease in the lung, it's going to show up. We can use that adrenal nodule as a marker. Would you offer him, that or more focal tumor-directed therapy?
Dr. Mike Harrison:
Yeah, I mean, I don't necessarily think that more focal therapy is totally wrong, but I agree with Catherine that he's kind of declaring himself as having more systemic disease. So after I've done several kind of oligometastatic resections or treatments, and especially when they start to be within a few years or a year, I'm starting to think about systemic therapy and we're starting to get to your kind of goals of care and prognosis questions. I mean, we're starting to think that we can't probably cure the disease, but maybe it's indolent and slow growing and we can control it over time, still, over years. And so it's kind of balancing that aggressive approach with quality of life as well. You take out his other adrenal gland, then he is going to be on replacement therapy, which is not necessarily a big deal, but you start to get into those type of issues as well.
Dr. Daniel George:
And so you both mentioned systemic therapy, but you didn't tell me which one. So wow, this is 2023. Back in 2018, we were just early days with ipilimumab/nivolumab and it wasn't for the favorable-risk patients like him. So we did sunitinib. Now it's 2023, we have a lot more choices. What would you choose in this setting?
Dr. Catherine Fahey:
Yeah, I mean definitely an immunotherapy-containing regimen. I would probably think about an IO/TKI because he had such a great response to sunitinib in his first line with that near complete response. So I might lean that way for him. I'm curious what Mike and you, Dan, would say.
Dr. Mike Harrison:
Yeah, like Dan said, obviously we have the benefit now of having a lot longer follow-up with the ipilimumab/nivolumab CheckMate 214 data. I think I do think ipilimumab/nivolumab could be reasonable here. I mean, I kind of do a thought experiment where I think what's the worst that could happen in 12 weeks if I give him the ipilimumab/nivolumab? I mean obviously there's toxicity, but from a disease perspective, you're not worried that his disease is going to get out of control. And then realistically, if you don't give him ipilimumab now, you're not going to give him ipilimumab likely later. It is obviously possible. So I do think it's reasonable, but I don't know that there's a clear kind of right answer either way.
Dr. Daniel George:
No, I think that's exactly right, Mike. And if I were going to see this case now in 2025, I probably would do ipilimumab/nivolumab here, just along the lines of thinking that you mentioned. But that's because we have the long-term survival data for the favorable risk patients now looking like a 20% longer survival for ipilimumab/nivolumab long-term. We didn't have that a few years ago, so I actually proceeded with cabozantinib and nivolumab and right out of the gate, within the first 2 weeks, he had horrible abdominal cramping pain and had to immediately lower his dose of cabozantinib to 20 mg and then to 20 mg every other day. And so a very, very suboptimal dose of cabozantinib. And yet he still had decreases in his lung nodules and in that adrenal gland. Now at this point, he's shown some response, but he's having a difficult time tolerating the therapy. What are the goals of care at this point? I can tell you he's interested in getting off of therapy. What would you consider in terms of opportunities to get him off therapy?
Dr. Mike Harrison:
I guess I consider in these patients with kind of like I was saying earlier, indolent disease that we think we're going to be controlling over multiple years. And you know that realistically they're going to be on a TKI most of the rest of their life. I do consider intermittent therapy. So kind of minimizing disease burden and then holding it and having some kind of pre-established triggers to maybe restart therapy to try to maximize the patient's quality of life.
Dr. Daniel George:
Exactly, exactly. And that's what we do. We held his cabozantinib, we continued his nivolumab, but 3 months later he has a CT that shows some new right lung nodules. He's got increase in his left nodules, and now he's got a new 1-cm left paraspinal mass. I don't know if you can see it on this scan here. It is sort of this white, bright, hyper-enhancing area right in the middle of his psoas muscle of all spaces. So it's not biopsied, but with that characteristic hyper vascularity we are concerned about that. So he responded well to sunitinib. He didn't tolerate cabozantinib at all. Catherine, what are you thinking about this guy now in terms of systemic therapy?
Dr. Catherine Fahey:
Yeah, I think this is a patient I would probably think about belzutifan in. He doesn't have a pretty substantial disease burden. And one of the concerns with belzutifan is it's not quick in terms of its onset. So I'm not considering it for people who are rapidly progressing, but in someone who didn't really tolerate a TKI, I would think about belzutifan. And then I also think you can think about tivozanib in this area. It's been shown to be efficacious, this and this next line. And I think this is where you need to talk to him about how he would feel about trying another TKI. If that’s something that he's even willing to do with his poorly as cabozantinib went.
Dr. Daniel George:
And Mike, your thoughts?
Dr. Mike Harrison:
Yeah, I totally agree with what Catherine said. I mean, I think key points are that different TKIs are tolerated differently. I mean, different patients even have different side effects from the same TKIs. So tivozanib, axitinib are a little bit more narrow in their inhibitory profile, so maybe he tolerates those better. I think on the other hand, not mentioned so far was lenvatinib/everolimus, which is a textbook option here. But I guess I would be really worried about how he would tolerate that, and especially if he's prioritizing quality of life here.
Dr. Daniel George:
That's exactly right. And even though this guy's 51, he's lived with this disease 10 years, and these therapies have taken a toll on him. And so I actually started him on tivozanib and he's tolerated that pretty well. It's had a little bit of grade 1 toxicities, but manageable. And he's again, having a great response. His paraspinal lesions resolved, his lung nodules and adrenal gland are decreasing. And so I think when I think about the key takeaways on this case, you guys touched on this first, this is an indolent disease course and a low volume disease course. It's hard to cure, but it's no reason to panic and we can take slower approaches to managing a patient, and building in treatment breaks is a really important priority. This is not failure. This is simply a matter of balancing the quality of life, time off treatment vs time on treatment.
And that's sometimes really kind of a key goal when it comes to managing these kinds of cases. And Mike, you mentioned not all TKIs are the same, and tivozanib may have a little more specificity for the VEGF receptor pathway, maybe not as much off-target effects and maybe better tolerated in some patients. And certainly belzutifan is another option. Probably something we'll consider next if this becomes intolerable as well. And the patients can respond to sequential VEGF/TKI. So hopefully a lot of important lessons you can learn from these cases. This I think brings us to the end of this case, but please see the other segments for further discussion about the latest research in advanced renal cell carcinoma or visit ascopost.com. Thanks so much for your attention.
