Ulka Vaishampayan:

Starting with the first case, this is a 68-year-old man who presents with flank pain, dyspnea, and cough. Past medical history includes hypertension and angina that occurred about 18 months ago. Patient had cardiac ischemia at the time, and he had a cardiac cath (catheterization) and angioplasty, and two stents were placed. The patient feels well now and has not had angina since, and there is no history of arrhythmia. Nonsmoker, uses alcohol occasionally, no relevant family history of cancer. Currently he is taking statin, lisinopril, and irbesartan for hypertension and is on aspirin and Plavix [clopidogrel].

Chest X-ray shows multiple bilateral lung nodules, the largest being about 1.8 cm. Computed tomography (CT) confirms these bilateral lung lesions. It also shows hilar lymphadenopathy of about 3 cm and right renal mass of about 8 cm. His Karnofsky performance score is 80% and hemoglobin, complete blood count, and calcium are all normal. Image-guided biopsy of the lung mass shows clear-cell histology, consistent with metastatic renal cell carcinoma. The patient has intermediate risk RCC, per the International Metastatic Disease Consortium or IMDC criteria. One risk factor that is noted makes him intermediate risk, and that one risk factor is synchronous metastatic disease with primary renal cancer.

So, Ben, can you discuss some of the points and the clinical factors about this patient that would influence your determination of treatment options?

Ben Garmezy:

I think you set the stage really well for this case. This is an intermediate risk by the IMDC, and I know that there’s a lot of controversy in some of the GU medical oncology community about how much should we be relying on IMDC or (Memorial Sloan-Kettering Cancer Center) MSKCC risk stratification for selecting therapy, knowing that the immunotherapy doublet is approved in intermediate and poor risk, as far as guideline directed therapy, though you could get it for a favorable-risk patient if you wanted. It is listed in the NCCN as another recommended option. And also knowing that the IO–TKI combinations—there’s three that are recommended; we’ve discussed earlier, to abbreviate: pembro–axi, cabo–nivo and pembro–lenvatinib, for these patients [1, 5]. So, in this case you have intermediate risk and you could use all four. Now, how I like to think about this is the IO–TKIs are more similar than different. And then the immunotherapy doublet is kind of separate from those options. How do we pick the right IO–TKI combination? Again, there’s never the right choice or the wrong choice, and they are all reasonable and they all have slightly different utility.

This patient has known cardiac ischemia, has had a history of hypertension on two antihypertensive medications, on a statin for, you know, assuming the hyperlipidemia, or coronary artery disease (CAD) going on Plavix. So, this patient does have cardiac risk. Now all of those TKIs that we use can have increased cardiac risk for our patients, whether that’s changes in arrhythmia, changes in actually the healing based on taking away that VEGF can actually cause the way the arteries in the heart actually remodel [8]. So, there are some increased cardiac risk factors. That being said, most of our patients in clinic have cardiac risk factors and go safely on IO–TKI combinations. So, I think it would be reasonable.

When I think about setting that stage, I’ll toss it back to you and say, when would you use an IO–IO combination? Would you consider that for this patient with intermediate risk? Or would you think an IO–TKI doublet would be more reasonable?

Ulka Vaishampayan:

I think the IO–IO combination of ipilimumab and nivolumab may be a little bit too toxic potentially, for this patient [in terms of immune-related toxicity]. This patient already has somewhat limited reserve because of the cardiac issue that is relatively recent, 18 months ago, he is still on anticoagulation, he had recent stents. So, I would be a little bit nervous about doing combination ipilimumab and nivolumab. The other thing is his disease does not appear to be terribly bulky and, you know, requiring immediate type of symptomatic based management.

But, based on just my concern about the immune-related adverse events and the patient not having adequate reserve to tolerate those, which clearly increase in incidence and severity with the IO–IO combination [9], I would prefer to go with IO–TKI combination. Again, which IO–TKI? That is, a tough question; each of them, as we know, none of them have been compared to each other, all of them have been only compared to sunitinib, which was the default treatment at the time. I would consider that because this patient has hypertension and cardiac disease, which, TKIs clearly have been shown to aggravate or worsen at times [8], I would prefer an agent with a relatively short half-life like, axitinib, because it allows us to reverse the toxicity relatively quickly rather than a longer acting agent in this case [10, 11].

Ben Garmezy:

Yeah, I think that’s a good point. So, you know, I use all three IO–TKI combinations in my clinic, and I use them a little differently. I think axitinib does have that benefit of the short half-life [10, 11]. So in those patients where you think you might run into trouble with the VEGF toxicity, axitinib is nice because you can turn it off fairly quickly by holding it and then sometimes even be able to hold off on giving high-dose steroids, if you’re unsure if it’s an immunotherapy toxicity or a VEGF–TKI based toxicity. That is the 1 benefit of axitinib, knowing that cabozantinib and lenvatinib have much longer half-lives [10, 11].

That being said, there’s also some difference in the toxicity profiles when you think about the VEGF selectivity of these three agents, axitinib is more VEGF-selective compared to cabozantinib and lenvatinib, which are slightly more multi tyrosine kinase inhibitors in the sense that they hit more of platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), the TAM (TYRO3, AXL, MER) kinase receptors [12]. That doesn’t change the toxicity profile [even] a little bit. Perhaps you get a little bit more of the palmar–plantar erythrodysesthesia (PPE) and some of the gastrointestinal (GI) side effects with some of those other agents compared to axitinib [13,14,15]. Axitinib does have a slightly more clean profile,Footnote 1 though you can also see elevated liver function tests (LFTs), obviously see a lot of hypertension and fatigue with all of these drugs.

So, those are things to keep in mind. And, I think, when we start talking about how are we going to mitigate cardiac risk in this patient with known cardiac risk factors and safely select a TKI, I think sending a patient home with a home blood pressure cuff, telling them to pick it up from their local drugstore, their local pharmacy, so that they can help be a partner in the mitigation of that risk instead of relying on seeing them in clinicFootnote 2—in our busy clinics, wondering what’s white coat hypertension and what’s real hypertension, I think it’s easy to have everyone you start, go home with those blood pressure cuffs. And when starting to think about, we’ve been talking about the IO–TKIs, you’ve given some reasons why maybe you wouldn’t want to give ipilimumab in this patient.

I think when I give an immunotherapy doublet, it’s more in patients with sarcomatoid biology. Those patients that are kind of, that you feel are going to need that ipilimumab so sarcomatoid, rhabdoid features are features that we know are more immune-sensitive relative to the VEGF sensitivity. I think it’s critical to offer those patients immunotherapy doublet. I think otherwise, you know, we hear this conversation about ipilimumab and nivolumab perhaps increasing durability of a response. But you do sacrifice that initial response rate. Now, what I think we don’t know for sure yet is how much that ipilimumab is still adding. Obviously that data set that got approved with 8-year follow-up, that Doctor Tannir presented at GU ASCO in 2024, it was exciting to see continued durability in a large patient subset [16]. So, there’s definitely a role in some patients for ipilimumab. What we don’t know is who are those patients in that subset. So, I think it’s still harder to figure that out I think sarcomatoid biology is probably one of those important factors. I also think there’s more data coming about the role of ipilimumab on studies currently out there like CheckMate-8Y8 (NCT03873402) [17]. So, we’ll learn more about when we should probably be giving ipilimumab versus, not giving ipilimumab in the near future.

I think another question that comes up in a patient like this: metastatic disease, but a very large, you know, renal tumor, when would you consider cytoreductive nephrectomy? Would you ever consider it? Would you do it prior to systemic therapy, after a nice response? How do you think about that?

Ulka Vaishampayan:

I think, cytoreductive nephrectomy and the sequence of it has really changed over the times. So initially, in the era of cytokine therapy, cytoreductive nephrectomy showed improvement in overall survival as compared to not doing the nephrectomy and just putting the patient on, systemic therapy. At that time, the systemic therapy was interferon alpha, which has like a [low] response rate [18, 19]. So, we had very limited systemic therapy options at that time. Now the study, a randomized trial called CARMENA, sort of changed that paradigm, and this was a study in the context of sunitinib therapy, where patients were randomized to upfront nephrectomy versus just going on systemic therapy with sunitinib. That study actually showed that there was not any survival benefit; in fact, 20% of the patients did not get to the systemic therapy that they really needed [19, 20]. So, because of that, upfront cytoreductive nephrectomy should not be considered in majority of the synchronous, metastatic disease patients. I think if they have majorly symptomatic disease, significant hematuria that you cannot quite control, or major pain for a resectable tumor, then those may be areas where you could consider also very, you know, limited metastatic disease where you can resect it, for instance, if the same side adrenal gland has a mass that is involved with cancer and that’s the only site of metastases you could consider upfront cytoreductive nephrectomy or a solitary metastases elsewhere too, that is resectable. So, for the most part, I would say right now in immune checkpoint therapy, and as our systemic therapy is getting better and better over the years, it seems like upfront cytoreductive nephrectomy should not be done.

There is a clinical trial SWOG 1931 or the PROBE trial that is currently exploring the role of cytoreductive nephrectomy in the setting of immune checkpoint-based combination therapy [19, 21]. So, consideration of that trial, but everyone ideally should go on systemic therapy first at about 12–16 weeks. You start looking at, depending on their response and benefit from the therapy, you can start considering cytoreductive nephrectomy.

Ben Garmezy:

Yeah, I think that’s very helpful. That’s kind of what we’re doing in the community out here in Tennessee, right? So, I’m in a community-based practice, working with community-based urologists outside of my practice, kind of a real-world experience. And we like to get patients started on therapy unless they’re symptomatic as you mentioned. Hematuria that’s not resolving is another big one, another big reason to do a cytoreductive nephrectomy. But, you know, we’re looking at that 6–9-month mark. Does a patient have a complete (CR) or a near CR, that kind of 80% threshold of reduction of all the metastatic disease outside the primary? Those patients are then being considered for a cytoreductive nephrectomy in our clinic.

Now, is that the right way to be doing it? We’re not sure, but that is how we’re doing it currently. And of course, we await more data to better, you know, hone our skills in our practice on how to manage these patients.

Ulka Vaishampayan:

Yeah.

Ben Garmezy:

Yeah. Great.

Ulka Vaishampayan:

So, we talked about adverse events you did mention and that’s an excellent idea that people should use is monitoring the blood pressure and having patients do daily monitoring, etc. What other adverse events are you looking at and how are you following for them?

Ben Garmezy:

I mean, I think the big one is, management of the GI toxicity, right? So those aren’t that hard to manage. Right, because they don’t always—the only one that’s harder is the diarrhea because that can be overlapping with the immunotherapy and the VEGF–TKI. So, thinking about sending everyone home with Imodium [loperamide]. It’s describing how they use it, you know, the bottle is confusing and it also, you know, isn’t as much as they often need sometimes for VEGF–TKI. Now when is that point to start thinking about—is diarrhea immune-related? So, I tell my patients use Imodium this way: take two in the morning, take one every few hours after that, but I want to know if you’re having more than five stools, right. So, if you’re having four or less, then you can manage that at home, even if that’s a smoldering immune-related diarrhea. We’ll catch that in clinic. We’ll see how it’s going. But if they start having five, that’s when I need to know about it. That’s when I need to start tracking it. And that is not a number that is dogmatic in practice. That’s a number that’s worked for me in my clinic. I feel like everyone’s patient population is a little bit different.

Now, let’s say you have a patient with a smoldering rheumatoid arthritis or some kind of mild immune risk factor we should say. Well, those patients are going to watch even more closely, because what we know from the literature is, while you can have an exacerbation of that, whatever that immune-[risk] is, so, if you have a mild psoriasis, skin disease or a mild rheumatoid arthritis, arthritic disease [22]. You can also more likely get an immune-related toxicity in a separate organ. So, those patients are going to need a little bit more, close monitoring. I don’t know. Do you have any other thoughts to add to that about how you proactively manage the toxicity?

Ulka Vaishampayan:

No, I think pretty much similar to what you’re doing management wise. But I would say that usually I hold both agents, depending on, you know, how severe it is and if it’s not quickly controlled with whatever antimotility agent you’re using. I think I hold both therapies and then sort it out because the TKI based toxicity will reverse relatively quickly once you hold it, the immune-related toxicity will not. And the same principle, I guess I use for transaminitis, which is another common finding where the liver enzymes start going up with combinations of TKI and IO [23, 24]. Again, you know, if it starts improving quickly, that’s TKI related. If it’s not, then it’s time to use steroids and immunosuppression. The other thing to remember is for TKI-based toxicities, you know, if they are severe enough and to rechallenge the patient, it is very easy to alleviate the toxicity with lowering the dose. Not so for immune checkpoint therapy obviously. So there, the rechallenge, you would have to wait and make sure the patient has improved and stabilized appropriately. And if that happened quickly enough, the steroid therapy turned them around relatively quickly, you can consider a rechallenge gradually.

And then I guess the last thing that we need to address is how do you monitor for treatment response?

Ben Garmezy:

Generally, it’s simple for me. It’s scans and I’m generally doing it every 3 months. Now if patients have been stable for a very long time, say they’re now on, you know, immunotherapy for over a year and a half or so, I’ll start decreasing the interval of the scans. But generally, at first it’s everything.

Ulka Vaishampayan:

I agree with you that’s pretty similar. And sometimes if they start off with major symptomatic disease just resolution of the symptoms, or improvement in the symptoms will give you a clinical clue that the patient is improving.

Ben Garmezy:

Yeah. Absolutely.