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FormalPara Key Summary Points

As the treatment armamentarium for advanced renal cell carcinoma (aRCC) has expanded, the treatment decision-making process has become more complex.

Combinations of immuno-oncology (IO) agents and tyrosine kinase inhibitors [TKIs (IO-TKI)] and IO-IO combinations are now approved for either first- or second-line treatment of aRCC.

Considerations, such as those related to the patient, the disease, and the treatment efficacy and safety, are necessary when making treatment decisions.

Two case studies will be presented in this vodcast, thereby allowing for expert insight into the treatment decision-making process.

Digital Features

This article is published with digital features, including vodcast audio and a graphical abstract, to facilitate understanding of the article. To view digital features for this article, go to: https://doi.org/10.6084/m9.figshare.26819896.

Introduction (00:00–01:11)

Ulka Vaishampayan:

Welcome to this vodcast on understanding treatment decisions and management for patients with advanced renal cell carcinoma (aRCC) using hypothetical case studies. I’m doctor Ulka Vaishampayan. I’m a medical oncologist, focused on genitourinary (GU) cancers at University of Michigan in Ann Arbor. And with me is Doctor Benjamin Garmezy. Ben, you want to introduce yourself?

Ben Garmezy:

Hi, I’m Ben Garmezy. I’m a GU medical oncologist with Sarah Cannon Research Institute (SCRI) practicing at SCRI Oncology Partners in Nashville, Tennessee, and also tasked with helping lead the GU research program for SCRI.

Ulka Vaishampayan:

Right. So, starting with an overview of the topics to be covered—a brief overview of the treatment landscape of advanced RCC, we will talk about presentation of hypothetical case studies, including discussion of treatment approaches, therapy management, and management of adverse events. A review of clinical trials supporting the benefit of combination therapy in advanced RCC.

Advanced RCC and the Treatment Landscape (01:12–03:55)

Ulka Vaishampayan:

So, moving on to advanced RCC and the treatment landscape. Until 2005, the approved treatments for advanced RCC were interleukin 2 and interferon alpha, which were nonselective in their mechanism of action and produced response rates in only about 15% and 12% of the patients, respectively [1, 2].

In recent years, an unprecedented number of medical advances have revolutionized the systemic treatment of kidney cancer, especially for patients with advanced RCC. Combinations of immuno-oncology agents and tyrosine kinase inhibitors—TKIs, as they call them, and (immuno-oncology) IO–TKIs, so, which is immune-oncology immunotherapy along with tyrosine kinase inhibitors, and IO–IO combinations, which is two immune checkpoint therapy combinations, are now approved for either first- or second-line treatment of advanced RCC [2].

Ben Garmezy:

Yes, thank you. Axitinib plus pembrolizumab was the first vascular endothelial growth factor, or VEGF, IO–TKI combination approved for the first-line treatment of advanced RCC by the Food and Drug Administration (FDA) in 2019 [3], showing a sustained clinical benefit compared with the previous standard of care, which was sunitinib in that control arm [4].

Furthermore, axitinib and pembrolizumab is a recommended treatment in the guidelines of the National Comprehensive Cancer Network (NCCN), the European Association of Urology, and the European Society for Medical Oncology for first-line treatment of advanced RCC in all risk groups. However, there are additional options as well in front-line therapy for clear-cell RCC. Additional recommended immunotherapy combinations in the first line include the immunotherapy doublet with ipilimumab, an anti-CTLA-4 agent plus nivolumab, an anti-PD-1 agent, as well as two other IO–TKI combinations, cabozantinib plus nivolumab or lenvatinib plus pembrolizumab [1, 5,6,7].

Combinations such as nivolumab plus ipilimumab, nivolumab plus cabozantinib, avelumab plus axitinib, and lenvatinib plus pembrolizumab, have all received FDA approval [3] and will be discussed during the course of this podcast. This podcast will primarily report cases and management of front-line renal cell carcinoma with IO–TKI combination treatment, and we’ll touch on the immunotherapy doublet for a brief amount of time as well.

Ulka Vaishampayan:

We are going to be talking about this topic of discussion of treatment options in advanced renal cell carcinoma with two hypothetical cases.

Case Study 1 (03:56–21:16)

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.

Case Study 2 (21:17–32:13)

Ben Garmezy:

Okay. We’ll move on to case study 2. So, this is a 66-year-old female who presents with 6 weeks of painless hematuria. Past medical history includes hypertension, well-controlled on lisinopril, hyperlipidemia, and a hysterectomy. No family history of cancer.

Imaging reveals a 10.5 cm left renal mass and complete staging imaging is negative for spread of disease, and patient undergoes just left radical nephrectomy. There’s no extension into any major veins or perinephric tissues, and she is staged at pT2bN0 with histologic grade 3 disease. No adjuvant therapy is offered and she’s placed on surveillance.

She does well for 15 months until a new persistent cough develops that does not go away. A CT chest is ordered and three pulmonary lesions are found, the largest being 3.5 by 3.2 cm2. Additional staging imaging is concerning for recurrent disease in at least four lymph nodes in the abdomen, the largest measuring 3.8 cm. Upon review, it is determined that metastatectomy and radiation are not appropriate given the location of the disease and the amount of disease. Karnofsky performance status is 90. Labs are within normal limits, and the patient is determined to have IMDC favorable risk.

So, this is different than that first case where we had intermediate risk of disease. This is favorable-risk disease. Part of that being, right, because the disease didn’t show up for 18 months. So, it’s outside that 1-year window, which is a risk factor in the IMDC criteria. So that’s what differentiates this case; the favorable versus intermediate. What I would love for you to provide us some insight in, and some of that was in that case, is you decide that it’s not okay to provide radiation or a metastatectomy.

When are you considering a low-risk disease using radiation or doing surgery instead of providing systemic therapy? Are there any kind of cutoffs or criteria that you’re using?

Ulka Vaishampayan:

I think for the most part, how slow growing the disease is and how long it took for it to be metastatic. The other things that are clues is the location of the metastases. You know, pancreas, thyroid metastases tend to be very, very slow growing, spell for a prolonged course in the patient. And that’s why those might be areas where I would be more likely to consider surgical resection or local therapy. With lymph node metastases that cannot be adequately radiated, I think it is tough. And in an otherwise very healthy patient whose really long-term course is going to be dictated by the metastatic disease, I think systemic therapy now, we have evidence that it can allow long-term remission rates with, you know, 8 or 9 years’ follow-up where patients have prolonged survival with complete remission [16]. So, because of that long-term remission rate, I think systemic therapy would make sense in this patient.

Ben Garmezy:

I agree, most of my patients in favorable-risk disease are getting systemic therapy. We know there is that phase 2 data set out of MD Anderson that was published, I think it was in 2021, that suggests that you can safely radiate patients, watch them, and delay the time where they progressed and need systemic therapy [25]. So that’s reasonable in a patient with oligometastatic disease, something that’s easy to radiate, you know, maybe two or three lesions. But once you start talking about nodal disease and everything else, it just gets so much more difficult. And then when thinking about surgery, obviously that’s a whole different conversation. That’s at your GU tumor board if you have access to one. Is this an easy surgery? Is this not an easy surgery? But I feel like more often than not in these metastatic patients it’s harder to accomplish those goals, for the majority of patients. And then when thinking about systemic considerations, you know, we talked about in favorable-risk disease, what’s interesting about all of these IO–TKI combinations, as well as the immunotherapy doublet combination, that overall survival (OS) in these subset analyzes doesn’t actually beat single-agent TKI and sunitinib in this case, right? With all four of these trials that we’re talking about being with the control arm sunitinib.

So how do you decide whether to give a single-agent TKI, TKI monotherapy? Do you ever do that? Or do you always provide doublets to patients who are candidates for immunotherapy?

Ulka Vaishampayan:

Yeah, I think for the most part because of the possibility of long-term remission, we know about TKIs. We have used them for decades. And what we do know is that there is a very good response rate. There is a possibility of complete response, although small, about 5% or less. And that, long-term remissions, even after stopping therapy are exceedingly rare. So, because of that, finding I think it does make sense to at least offer to the right, otherwise healthy patient, who is a candidate for immune checkpoint therapy, the combination treatment.

Ben Garmezy:

Yeah, I completely agree. I only use single-agent TKI monotherapy in patients who are not candidates for immune therapy. And even in some patients that “have those risk factors [comorbidities]” like a mild rheumatoid arthritis or a mild, say, elbow psoriasis. Right, something like that, I try to give immunotherapy to those patients because it does provide that chance of durability. Now when we look at those curves, yes, they are somewhat overlapping between sunitinib and IO–TKI doublet. So, one can make the argument that TKI monotherapy is reasonable in favorable-risk patients. And I can’t say that that’s incorrect; right? But what I can say is we all think that there’s patients that are not being captured well by IMDC criteria that are going to be immune responsive, and that doesn’t always apply to the median or the average patient, but it applies to those subsets that we’re really trying to give a chance at durable remission, being alive 5, 10 years later, maybe even cured in a very, very small subset of patients. Right? So, for me, it’s hard to just look at lab values and say that we’re not going to give you an immunotherapy or a chance at immunotherapy. So that’s just my practice. It sounds like your practice is similar. And I know that most GU medical oncologists are providing doublets [IO–IO or IO–TKI] to their patients.

Now, in this patient with favorable risk though, you know we talked about hypertension a lot in the first case. We’ve talked about diarrhea. What we haven’t talked about so much as the hypothyroid and the hypothyroidism and how we determine if that’s from the IO or the TKI, or does it even matter? So, let’s say you have a patient with hypothyroidism. Are you pausing treatment or are you just providing agents to treat that hypothyroidism?

Ulka Vaishampayan:

Yeah. So, hypothyroidism is relatively easy to treat. You can just replace and start them on the thyroid replacement therapy and continue them on treatment. So that usually will not warrant a hold in the treatment. In fact, I monitor for that thyroid function about every 12 weeks or so, unless there are symptoms that are suggesting to me that this may be from hypothyroidism, severe fatigue, for instance, or of course, the hyperthyroidism based symptoms, again, fatigue, but, you know, the hypertachycardia and things like that can be clues of hyperthyroidism also. If the patient has hyperthyroidism, it may be considered to stop depending on how severe it is. But for the most part, if they have symptomatic hyperthyroidism, the recommendation would be to give them, beta blockers and continue or use methimazole, things like that, to reverse the hyperthyroidism. And then eventually, though, that patient is going to get hypothyroid and you will need to use thyroid supplement.

Ben Garmezy:

Yeah, I think that’s really good nuance there. So, hypothyroidism: very easy to treat. You don’t need to spend too much time discussing that. The hyperthyroidism is more challenging, perhaps more alarming, to a community medical oncologist that maybe doesn’t give, treats a lot of breast cancer, benign heme, that aren’t as familiar with these agents. What I would say is most of those patients with hyperthyroidism are not symptomatic, and it’s just a lab value, and you can just continue to treat through it, knowing that they’re going to burn out and become hypothyroid relatively soon. In this case, when I see signs of biochemical hyperthyroidism, I am just checking the thyroid labs more frequently with every cycle. Watching that happen, and also telling them that they are at risk and if they develop palpitations or any other of those symptoms of hyperthyroidism that they need to notify us immediately. Now, a patient with symptomatic hyperthyroidism, you absolutely need to hold therapy, manage the hyperthyroidism, wait for them to burn out, become hypothyroid before you resume. I think that was a very good distinction that you brought up here.

And it’s sometimes hard to tell. Is it from the TKI or from the immunotherapy; right? Because both of those can cause it, and I think the only thing is if you think it might be immunotherapy related, sometimes providing steroids to help with the management of that, is critical. Now in a symptomatic patient, and you’re not sure which one, I generally always provide immune suppression because those patients that are admitted in the hospital with bad cardiac issues, you don’t really have time to figure that out. Right?

So, we’ve, kind of talked a lot about these patients. We’ve talked about providing radiation and surgery and low risk disease. I think one thing that we haven’t talked about is sometimes surveillance is even appropriate in some favorable-risk patients who don’t want to intervene in their disease. Just watching them very closely, I scan them every 3 months, if that’s the case. Now, most of my patients are not on surveillance, but it is still reasonable. So I think with that, you know, is there anything else that you would like to add about this case discussion?

Ulka Vaishampayan:

I mean, I think the one thing I would say is for immune-related adverse events, we do find that immunosuppressive therapy is frequently delayed. So, for patients who have significant immune colitis or immune pneumonitis, they usually are hospitalized. Their symptoms are that severe. So, it is important to use, steroids in high doses right off the bat to try and reverse that toxicity. And then in a couple of days, if they’re not improving on steroids, consider switching to other immunosuppressive therapy like mycophenolate or infliximab.

Ben Garmezy:

Okay. So, we’ve done a good job discussing these two cases, I hope, right? I hope the listeners in and the watchers agree with that.

Safety and Efficacy Considerations (32:14–44:05)

Ben Garmezy:

Let’s now dig a little bit into the data. So, we’ve given you these kind of broad overviews of how we think about immunotherapy doublets and IO–TKI doublets. But let’s actually provide some numbers now. So, here are the results of the several phase 3 studies, all versus sunitinib, that demonstrated benefit of IO–TKI patients with advanced renal cell carcinoma. Remember this is talking about clear-cell biology.

KEYNOTE 426: 861 patients who were treatment-naive with advanced RCC were randomized between axitinib and pembrolizumab, versus the control arm, sunitinib. The latest analysis showed that after a median follow-up of 67.2 months, axitinib and pembro continued to show superior overall survival, progression free survival, objective response rate over sunitinib monotherapy. So, you know, really nice separation of the curves when you take a look at this [26].

CHEKMATE 214, very similar. Greater than 1000 patients with advanced RCC were randomized to nivolumab plus ipilimumab or sunitinib, in intermediate or high-risk disease. This is the immunotherapy doublet. After nearly 100 [~90] months of nivo plus ipi continued to improve overall survival compared to sunitinib. And again really nice, sustained separation of the curves [16]. Another thing that I would mention in stable risk disease, you actually did see a crossing over where ipi/nivo may be providing some benefit in some of those favorable-risk patients, which alludes to that conversation that we had earlier, that immunotherapy is relevant in favorable-risk disease [16].

The phase 3 CHECKMATE-9ER study looked at the nivolumab and cabozantinib versus sunitinib in 651 treatment-naive patients. After a median follow-up of 55.6 months nivolumab plus cabozantinib, significantly prolonged median progression free survival. Right? So 16.4 versus 8.4 months, as well as median overall survival, which was 46.5 versus 36.0 months, respectively [27].

In the CLEAR data set, after 4 years’ follow-up, the study confirmed that lenvatinib and pembrolizumab, compared with sunitinib, in the first-line treatment of patients with advanced RCC, median progression free survival of 23.9 months, the median overall survival at 53.7 months [28].

I think another thing that’s important here, though, is when you look at all of these combinations, let’s talk about CLEAR, CHECKMATE-9ER, and the KEYNOTE 426 study, that the hazard ratios for overall survival are all very similar—in the low 0.7s, which shows against the similar control arm that they’re all performing pretty similarly. I don’t think, you know, going and looking at the differences in the numbers is the most helpful thing because the difference in the balance of the patient population, knowing that in the CLEAR study, there are more patients with favorable-risk compared to poor risk. In the CHECKMATE-9ER study, there’s more patients with poor risk. Right? And then that KEYNOTE study is kind of in the middle [26,27,28]. So, knowing that there’s different patient populations, the hazard ratio is I think more important here because what it shows is consistency of IO–TKIs, which is when we say that if you’re going to select an IO–TKI, it’s not as important which one you select. The key is knowing how to manage that toxicity, feeling comfortable with dose reductions and modifications to keep your patient on therapy, and if you just get good with one of those front-line combinations, you’re going to serve your patient well. What do you take away from those major data sets with the IO–TKIs?

Ulka Vaishampayan:

Yeah, I think the one big thing is that the future is very hopeful for our patients with metastatic kidney cancer. You know, we have improved the response rates. We can offer a ton of hope with long-term remissions. Maybe down the road, we would actually have, patients with long enough follow-up to be considered curative regimens with this therapy in metastatic advanced renal cell carcinoma. The few things I would mention is that, you know, the bone and liver metastases patients can have tremendous morbidity from their cancer and also have limited survival. Those are things that are not captured in the IMDC criteria. So, keep those in mind when you’re considering the therapies, for your patients. And you do need a rapid response as well as potential for long-term remission in those patients.

The other thing I would mention is that all of these studies, even though, you know, the longest survival follow-up now, is like 8 or 9 years, I would caution that the survival follow-up is still immature and it’s evolving. So, stay tuned for future updates on each of these studies to tell us what the future brings and whether that tail-end on the curve continues to be sustained after longer follow-up.

The third thing I would mention is that treatment free interval is important to consider. You know, can you give the patient, limited duration of treatment? Most of the VEGF TKI and IO combinations stop the IO after 2 years, that was on the study. And if you can establish those patients’ remission after 2 years it may be worthwhile having that discussion and stopping the treatment and putting the patient on surveillance potentially. The VEGF TKI can be continued if the patient has continued response and tolerability of the regimen.

Ben Garmezy:

Yeah. Great. And I think it’s important to keep in mind, you know, the toxicity rates are higher versus sunitinib [1, 2]. So that discussion earlier about TKI monotherapy versus IO–TKI. However, we think it’s justified by the net benefit that these patients are getting with, you know, disease response and disease control. Thinking about IO–TKIs versus immunotherapy doublets. IO–TKIs having only a very low primary progressive disease rate of somewhere between 5% to 10% across those three IO–TKI combinations that we generally use that are NCCN-directed, knowing that the immunotherapy doublet is closer to 20% primary progressive disease [13,14,15]. So not quite double, but almost double versus some studies and even more than double versus other studies.

Right, so I think that’s something to keep in mind. Does your patient need a response? If they do, an IO–TKI is kind of critical—those patients with obviously liver disease and things like that. And thinking a little bit more about the therapies. Right, so IO–TKI combinations such as axitinib plus pembrolizumab are associated with adverse events such as diarrhea, palmar-plantar erythrodysesthesia, also known as hand foot syndrome, fatigue, hepatotoxicity, nausea. We’ve discussed how we manage some of those things. Rates of grade 3 or greater adverse events for axitinib and pembrolizumab versus sunitinib with hypertension in 22% versus 20%, elevated ALT at [approximately] 13 versus less than 3% for sunitinib alone. Diarrhea, 10% versus 5%. So, you can see some increases there. We’ve talked about managing those toxicities, and they’re all able to do if you’re monitoring your patients closely and effectively [4].

Ulka Vaishampayan:

So, we have discussed in detail with the presentation of these two cases, quite a bit of the nuances of considerations of different therapies, especially since there are five different combinations that are FDA approved in the front-line setting for advanced RCC. So, decisions have become complex due to expansion of therapeutic options, number of approved front-line therapies, combinations, and the absence of predictive biomarkers that will help us select therapies, specifically to an individual patient. So that makes it challenging to identify the optimal combination regimen and most of the time we have our clinical experience, adverse event management comfort level to go by when we pick a treatment regimen. Differentiation between IO- and TKI-related toxicity is vital to prevent delays in identifying and managing adverse events (AEs). Most common immune-related AEs are skin and GI system. About 30% of the patients experience skin, adverse reactions, so skin rashes, and 30 to 40% experience gastrointestinal adverse events, mainly immune colitis being the predominant one [29, 30].

Other immune-related AEs often occur in the first 3 months of treatment, but they can occur any time during the treatment and sometimes even after you have stopped the immune checkpoint therapy [31]. Management of mild AEs involves holding treatment until symptoms resolve. High-dose corticosteroids can be used for the treatment of moderate immune-related adverse events. And as I said, if the patient is not turning around, the toxicity is not improving quickly within the first couple of days, it may be important to switch to another immunosuppressive management. Treatment discontinuation is recommended if the patient has severe immune-related AEs that [do] not reverse rapidly or take a long time, to get reversed. And also depending on how significant the organ dysfunction is after that immune-related AE [32].

Ben Garmezy:

Yes. Thank you. Patients need to know of available treatment options, adverse events associated with treatments and treatment expectations. This will help avoid unnecessary dose reductions and/or interruptions. Because we do feel like that TKI dose can influence response. Involving patients in shared decision making can empower them and improve treatment adherence. And shared decision making is important, but the amount of information provided can sometimes be overwhelming, so it’s careful to provide your patients key nuggets of information that they really need to take away first. That will help you manage their symptoms. Many oncologists agree that if patients are rapidly progressing, they should be treated with a combination of an IO–TKI, whereas asymptomatic, younger, healthy, fit patients sometimes can be considered for immunotherapy doublets.

Metastatic renal cell carcinoma can present with a broad range of symptoms. The site of metastases was not included as a risk factor in RCC. However, liver, bone and brain metastases are likely to have a worse prognosis. Patients with these metastases usually need a combination of a VEGF TKI and immune therapy in order to develop that initial response. Brain metastases are first treated with local therapy, with surgery or radiation, or both, and then systemic therapy is started. Axitinib plus pembrolizumab represents one of several new standards of care in the treatment of advanced RCC. Adverse events must be effectively managed to help patients remain on their treatment and derive optimal clinical benefit. Thank you.

Closing Summary and Take-Home Points (44:06–46:40)

Ben Garmezy:

So, in summary multiple VEGF TKI and immune checkpoint therapy regimens are FDA approved in front-line metastatic renal cell carcinoma. Each of these regimens has shown superiority over sunitinib, but none of them have been compared. Nivo plus ipilimumab is FDA approved for intermediate and poor risk renal cell carcinoma, and shared therapeutic decision making must consider multiple factors in addition to IMDC risk criteria, such as disease location, how symptomatic is your patient when you’re making those decisions.

Ulka Vaishampayan:

And patient comorbidities clearly play a role. We gave you that example with the cardiac disease that our patient had. Also social and caregiver support is very important. You need to, be having the discussion with the caregivers along with the patients so they are informed, well informed about their side effects and what to expect and how to monitor the patient. Other patient concerns and overall therapy goals are important to discuss. And ultimately, it is a shared decision making with your patient about treatment choice.

So, take home points: it is important to be aware of the adverse events, have a balanced, detailed discussion with the patient and, about the nuances of immune checkpoint-based regimens or the IO–TKI regimen, and manage the patient carefully through the treatment, and monitor for both response as well as side effects.

The future does look bright for advanced RCC. We are clearly not curing everybody, and we have a number of novel therapies. So, I would make a final pitch that the only way we can improve therapy our current management in kidney cancer is through clinical trials. So, participation in clinical trials that have brought us all these advances remains a very important piece of the management of patients.

Ben Garmezy:

Yes, I think that’s a critical point. Clinical trials are essential to provide access to those patients. So always consider them in the front-line as well as in subsequent lines of therapy. And the final thing I would like to say is help patients help you. Give them criteria of when to call your clinic and have them bring a blood pressure cuff home.

Ulka N Vaishampayan:

Great. Thank you. Ben.

Ben Garmezy:

All right. Thanks everyone.