Roundtable Discussion: Integrating New Approaches for Advanced Relapsed/Refractory RCC Into Practice

Sumanta Kumar Pal, MD (Comoderator)

Clinical Professor, Department of Medical Oncology & Therapeutics Research

Codirector, Kidney Cancer Program

City of Hope

Duarte, CA

David I. Quinn, MD, MBBS, PhD (Comoderator)

Associate Professor of Medicine

Section Head, Genitourinary Oncology

Division of Cancer Medicine and Blood Diseases

Keck School of Medicine

University of Southern California

Los Angeles, CA

PAL: What factors would you consider in deciding upon frontline therapy in this patient [with RCC]?

QUINN: I tend to automatically do the Motzer criteria and also the IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] just to see where my patient lies. What I am interested in there is [whether] the patient has favorable, intermediate, or poor risk, because that will tend to dictate what different sorts of therapy and what kind of combination [I want to use]. I’m going to give [a combination] to everybody with intermediate or poor risk who is fit enough; not everyone is. In the favorable risk, it is complicated. There are some patients [for whom,] if it is [caught] early, I might be thinking I can watch, but I am interested in what other people have to say.

PAL: What do you think of for this patient who has an indolent pattern of growth over a long period of time?

MAR: I use the IMDC criteria with knowledge that it is not perfect. There are other factors that I think are not included; for example, the molecular characteristics of the tumor, patient comorbidities, and their volume of disease. Also, what do I think is their ability to tolerate any given tyrosine kinase inhibitor [TKI]. Do I want to use a narrower TKI or a broader TKI? All of that plays into the decision. Also, the rate of growth and the rate of change on the scans influence how aggressive I want to be upfront with these patients.

PAL: How do you decide between axitinib/pembrolizumab, cabozantinib/nivolumab, or lenvatinib/pembrolizumab for a favorable-risk patient? I assume we would not necessarily be discussing nivolumab/ipilimumab [Yervoy] or would you?

MAR: I do not use ipilimumab/nivolumab that much unless there is clear sarcomatoid differentiation to the tumor. I like the combination therapy with immunotherapy [IO] and TKI because of the different mechanisms of action, because not all tumors are immunologically hot. I usually go to pembrolizumab/lenvatinib, nivolumab/cabozantinib, or axitinib/ pembrolizumab. If I want to minimize the toxicity, and the patient has a lower tumor volume and slower rate of growth or comorbidities or they are older, I use a narrower TKI like axitinib, so that is my go-to. If somebody is younger and more fit, if they have a lot of tumor volume, [and/or] they are symptomatic, I want to use the broader TKI like cabozantinib or lenvatinib, for example.

CHEN: There is a lot of clinical judgment [when it comes to the] broader spectrum of TKI vs the narrower focus of TKI. I am not so sure there is a previous study, but theoretically, I think that makes sense. What is challenging to us is you now have so many good combinations, and there are no head-to-head comparisons. So it is going to [involve] quite a bit of clinical judgment.

PAL: I moved primarily to using cabozantinib/nivolumab up front. I have been impressed by the tolerability of cabozantinib at the 40-mg dose. We are all using cabozantinib at 60 mg [for] second-, third-, and fourth-line therapy; that could be a bit of a challenge, as Dr Mar had mentioned, with older, more frail patients but I have moved to using cabozantinib/ nivolumab almost across the board in the front line because I found that 40-mg dose could be well tolerated.

I have used a lot of lenvatinib and I have been troubled by the toxicities associated with 18 mg in the second-line setting. Lenvatinib plus pembrolizumab in the frontline setting, similar to other histologies, is being dosed at 20 mg, which is a bit of a challenge, particularly if you want to keep patients on long term.

That is reflected in the trial data—about 60% of patients had treatment discontinuations [with lenvatinib/pembrolizumab vs 81.2% with sunitinib].¹ You are not seeing a lot of differences in terms of quality of life with that vs sunitinib in the CLEAR study [NCT02811861]. Cabozantinib/ nivolumab tends to be my go-to across the board for front line [therapy] these days.

QUINN: I am splitting between. If I have an intermediate-or poor-risk patient, I still give them nivolumab/ipilimumab most of the time. Cabozantinib/nivolumab for an older patient or for a good-risk patient is extremely well tolerated with that 40-mg cabozantinib dose. We know nivolumab on its own is pretty well tolerated in these patients. So it is interesting. I was surprised when I started using the combination of cabozantinib 40 mg with nivolumab, [which was] also well tolerated.

PAL: I had the same experience even with my older patients—not a lot of hand-foot [syndrome] and the diarrhea is pretty manageable. You are not rushing back for dose reductions like you were with 60 mg.

AMBIKA: I have been using a lot of axitinib/pembrolizumab, but after [the findings from the] CheckMate 9ER trial [NCT03141177], I started using cabozantinib/ nivolumab. Like you said, so far things are going well. Toxicity wise, I think 40 mg is definitely better tolerated, but only a few months ago I was using more axitinib/ pembrolizumab because of the familiarity with the regimen.

PAL: That makes sense.

PAL: I think this is a pretty unusual scenario. Especially if you are looking at your own scans, you are going to probably catch pneumonitis way ahead of its manifesting with grade 3 disease or what have you, so I think that is one peculiarity around this space. I am sure most of you would agree in practice.

What factors would you use to align second-line therapy in this setting? This patient has progressed on therapy with axitinib but in the context of prior axitinib with pembrolizumab, getting pneumonitis with pembrolizumab, and now you are looking around for second-line options.

He has back pain, central bony metastases, and so forth. What are your thoughts in terms of further workup here? More importantly, how would you walk through second-line treatment?

MAR: My second-line approach is, if I have not used cabozantinib up front, I am going to use it in the second–line. That is my go-to second line drug unless I use it up front. Also, if I have used it, I would probably go to an everolimus/lenvatinib combination.

PAL: Have you had any experience with tivozanib [Fotivda] yet?

MAR: I have used it a lot since it has been approved. We also had a trial with it. I generally do not use it this early on unless somebody is really on the frail side and I do not think they can tolerate cabozantinib or lenvatinib. So for me that is more of a third- or fourth-line drug.

PAL: I think that is reasonable. Dr Mar mentioned she is primarily going to use cabozantinib in this setting. That mirrors my practice in a patient like this, [who has] new bone metastases and has not been exposed to cabozantinib, and generally [we are] going to [use] that second. Dr Mar has mentioned maybe lenvatinib/everolimus or potentially tivozanib as salvage therapy beyond that.

QUINN: I think our data are consistently favoring cabozantinib in patients with bone metastases across the randomized studies we do, whether it is alone or in combinations. That is a good choice. It is an interesting discussion about what is second, if they already had cabozantinib and have bone metastases, [regarding] what you do. I do not think we know the answer to that question. I think that they are equivalent.

I am now treating patients who are multiple lines through with tivozanib, which has become available because of tolerability. [Tivozanib] is good and I think you get responses that are probably just as good even in those patients with difficult disease.

PAL: Yes, I am perfectly aligned with you here. That is precisely the way that I think through in cases like this.

VORA: With the advent of cabozantinib in kidney cancer, I definitely would consider that in this patient if they have not seen it already.

VORA: The question I have for you is, given that history of pneumonitis that you saw with pembrolizumab, where do you stand on rechallenging with immune checkpoint inhibitors [ICIs] in patients like this?

PAL: I do not think most of us in practice are going to let pneumonitis get to grade 3, right? We recognize it pretty readily before it appears and, in these days, you have to be concerned about COVID-19 overlapping in its presentation with ICI-related pneumonitis. But if the patient did have any grade 3 toxicity— whether it is pneumonitis or hepatotoxicity, colitis, etc—outside of thyroiditis, which is easy to manage, I would probably say that I would not give an ICI another go.

QUINN: I think with a single-agent ICI and TKI, pneumonitis is relatively uncommon, and I have not seen grade 3 pneumonitis in…years. So going back to the patient with another ICI would be a little bit of a push. We do need some data on that, and we are going to get some in the cabozantinib and atezolizumab [Tecentriq]-type trials that have been done, the COSMIC trials. That will teach us about what the second toxicity is. If you look at those trials, the patients with a grade 3 pneumonitis would be excluded. More often than not, you see a bit of grade 1 and they are OK with steroids and you are rechallenging them. I think it is an interesting question. We do not know the pros and cons of that second set of treatments until we try. I have seen a number of patients that have been given nivolumab/ipilimumab later. The addition of ipilimumab to nivolumab as an adjunct [treatment] in a couple of trials we saw last year didn’t suggest there was a lot to be gained with that, so I think that might become a little less common.

PAL: I agree with you there. We are learning more and more with ipilimumab [that] if you are going to use it, you have to use it up front to get that bang. Otherwise, it is probably not doing a lot.

PAL: When you are getting to third-line treatment, what factors are you looking at in a patient like this to align with therapy?

ALI BAGHIAN: With the previous toxicity, pneumonitis is one reason to steer away from IO. The nature of response after therapy may play a pretty important role. If he is progressing on axitinib, is he developing resistance to the pathway? In my experience, if my patients are sensitive to either IO or TKI treatment, that is where it affects my third-line approach.

PAL: Dr Khattab, are you getting into palliative mode with that patient? Are you still thinking about maximizing efficacy? What is on your mind there?

KHATTAB: After the second line, you probably are just thinking about keeping him comfortable more than anything else. In your third line, you can use lenvatinib/ everolimus, which can get you decent outcomes. Beyond that I do not think it makes any difference what you do.

BAGHIAN: Are you frequently doing any profiling on these patients. Is there any utility to do that with RCC?

PAL: I am. I do it to catch the outliers. I published a series on patients a couple of years back with ALK mutations with RCC. We treated 3 patients with ALK translocations with alectinib [Alecensa] and had beautiful responses to therapy. You do that to find the needle in the haystack. You might find an alteration in core pathway that seems to pop up on almost every FoundationOne report that I get, and [with] kidney cancer specifically you see that in about 4% of patients.

If they identify a core pathway alteration, that might… push me toward using lenvatinib/everolimus a little bit earlier in the sequencing, but in a scenario like the one we discussed, the patient has been beat up. He has an ECOG performance status of 1, bone metastases, etc. I would still be leaning toward tivozanib in this scenario based on the quality-of-life consideration.

QUINN: I tend to do the profiles looking for that group of patients that might exquisitely respond to an mTOR inhibitor. In this patient, let’s say we profiled him and we got an next-generation sequnecing [NGS] back and he had an alteration. Would I go to lenvatinib/everolimus? I think it is a good choice for efficacy.

Where I have the problems is 2-fold. One is managing the toxicity of lenvatinib, at least in combination with the everolimus. The other is the dose of lenvatinib. I think 20 mg is a very high dose and if you look at the CLEAR study, where 1 of the arms was lenvatinib/everolimus in the first line, the progression-free survival was better than [with] sunitinib but there was no overall survival advantage over [the sunitinib regimen].¹ There was with lenvatinib/pembrolizumab, but the toxicity was worse than sunitinib for that combination. So if there was a TOR mutation, I might go for everolimus on its own. The other issue for this patient [is that] he is young and he has not had a durable response to the prior VEGF-TKIs, so that makes me wonder how he will do. Tivozanib is a good choice because you can get prolonged VEGF blockade with a good adverse event spectrum provided you control that.

PAL: I really like that point around everolimus monotherapy if they have a TOR mutation. I am always tossing in lenvatinib with it but it makes perfect sense [not to]. Also, how do you know what they are responding to if you give them both? I like that idea.

AMBIKA: If somebody progressed through nivolumab/ cabozantinib, do you have a go-to regimen? Do you go directly to tivozanib?

PAL: In my practice, if I had a patient that progressed on cabozantinib plus IO up front, I have no reservations about using tivozanib in those patients who are a bit frailer as second-line treatment. In my mind, they technically had been exposed to 2 treatments previously with IO and cabozantinib. If they are particularly frail, I do not know if they are going to hold up with lenvatinib/everolimus.

I would say that tivozanib would probably be my go-to in a frail patient. If the patient is robust, I am going to go with lenvatinib/everolimus and I will save tivozanib as third-line treatment or fourth line.

QUINN: The other consideration is they have not seen axitinib, that is also an option. I think you can play around with it. When we started in this field, we did not have much. Now some of these drugs can produce very long, durable, stable disease and responses, especially in a young patient of 54 years.

AMBIKA: We are seeing more and more brain metastases developing along the course. Cabozantinib has some central nervous system [CNS] activity, but in general if they have CNS-predominant disease, does it affect your choice? Does tivozanib have much activity for that?

PAL: Cabozantinib is definitely my go-to in that particular setting. I think that with second- and third-line therapy and so forth, it is hard for me to use brain metastases as a distinguishing factor beyond cabozantinib. I do think that brain metastases unfortunately coalesce with the poor performance status population, so it aligns with using an agent like tivozanib as a better-tolerated palliative regimen.

MAR: Is there ever a scenario where you would you use bevacizumab [Avastin] plus IO or on its own in these patients?

PAL: There was a time when I was using a lot of bevacizumab as my sixth- and seventh-line option, but now that we have so many different TKIs in this context, I have fallen away from that. I was a big proponent for bevacizumab/atezolizumab and when those data initially came out, I thought that regimen was very attractive and very well tolerated. But [because] none of the bevacizumab- IO combinations have panned out in RCC—I realize it’s different with hepatocellular and other diseases—I have shied away from using it. So I would sequence that perhaps a little later.

QUINN: I think bevacizumab is great for tolerability provided you control the blood pressure and you do not get a clot, which is very unusual. Patients do well on it. I know some people who would use it up front. I give it to patients because they tolerate it well. It was infusion that was covered by most insurance without a copay, but I think we have more active agents. There are some things to look at; [for example], getting an elevated activity of the immune system with bevacizumab is something we have to reevaluate at some stage, hopefully, in the not too distant [future].

CHEN: Does anyone use focus palliative radiation in conjunction [with therapy] in selected cases, such as brain metastases? Would you need to stop ICI or TKI during the radiation?

PAL: I feel very comfortable continuing radiotherapy to the brain during ICI. During TKI, I do not feel comfortable doing the 2 in concert. I would treat the brain, wait for a week or 2, and then begin TKI therapy. There is too much risk of hemorrhage when you do the 2 concurrently.

QUINN: I tend to give a bit of a break because they are also on dexamethasone. I found that blood pressure goes up but you have the issue of trying to control hypertension while you are radiating a probable mass in the head. With stereotactic body radiation therapy, stereotactic radiation is the radiation of choice, and it is a brief time period. It is not even a 10-day period most of the time. So from that perspective, they are not off [therapy] for very long.

PAL: We are doing a lot of it for oligoprogressive disease. It is a great way to salvage 1 or 2 sites and keep the patient on the same TKI.

PAL: Using tivozanib in the salvage setting I think is a good choice. Your patients have been exposed to cabozantinib if they have been exposed to IO. You think about lenvatinib/ everolimus but I would say more than likely I think about tivozanib [if] they are in palliative mode and if you are thinking about an option for a patient not able to tolerate the spectrum of toxicity we see with lenvatinib/everolimus.

_REFERENCE

_{1. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716}