Thanks. Let’s take a break from the case and talk about the CONTACT-03 [trial], which was presented today. One of the main questions in kidney cancer, now that many to most patients are getting IO [immunotherapy]-based doublets is, upon progression, this is a bit of a unique case, but let’s just take standard progression, if you will, while the patient’s still on immune therapy. What’s the next therapy, and does further immune therapy have benefit? I’ll describe it briefly, and then I’ll ask you each to give me your top level results. Were you surprised or not? Does it impact your practice?

CONTACT-03 [is a] large, randomized study [that] took IO refractory kidney cancer. About half the patients I think got ipilimumab [plus] nivolumab up front, half got more TKI [tyrosine kinase inhibitor] based than nivolumab monotherapy. There was a little bit of IO/TKI, but it accrued when those regimens were just getting approved and more in use. And patients were randomized to cabozantinib monotherapy, which we just said is certainly a standard, if not the standard, or cabozantinib plus atezolizumab. There have been it seems like 42 abstracts about cabozantinib [plus] atezolizumab and activity in various diseases including kidney cancer. A large, randomized phase 3, really well-done study.

Unfortunately, it was a negative trial. Response rates were equivalent in the arms at 40%, which is very high for a second-line setting, as you all realize. PFS [progression-free survival] was in the over 10-month range, I think it was 10.6, 10.8, something like that, for cabozantinib monotherapy. And then no survival difference, and you didn’t even need 

values because all the curves are entirely overlapping. Importantly, there was, not surprisingly, an excess of toxicity in the combination arm. I don’t remember the delta, I think a 10% or 20% difference in high-grade events or SAEs [serious adverse events] and 3 toxic deaths in the combination arm. Not only was it not as efficacious, it was more toxic. Bruno, maybe start with you.

 Your reaction to the data, are you surprised? Were you giving sequential IO before?

 I was aware of the data before ASCO [American Society of Clinical Oncology annual meeting] because there was a press release, some information that it was going to be negative. In clinical practice, we use it. I tend not to use it a lot. If they are having clear progression on IO, I tend to use a single-agent TKI already in my practice. But in a situation like this case that stopped the IO, I don’t know if….

Let’s take this case out of it, just more standard progression.

 But it is unfortunate because we know that the response, even though the data showed very good response, at least as a single agent, more than we would expect to see in the control arm. It is unfortunate because we know that these patients need better treatments in the second line. It makes me wonder whether in the third line, perhaps, it would be a positive study.

If there was more of a gap between IO….

 If you have more of a gap, exactly. You do a sequential [treatment] with the TKI only and then a third line of IO/TKI.

We don’t know. This study didn’t address that.

 Exactly. So at this point right now, I think it would be difficult to convince myself to continue IO/TKI in the second line, and to the payers also.

 I think the refractory setting is very different than the case we just discussed.

Let’s just take a general refractory setting.

 Exactly. This probably included people who progressed straight through these, and people who responded and then progressed, and I just believe those are different populations that weren’t parsed in the data. I think the short of it is cabozantinib is a really good drug in this space, and atezolizumab is probably a pretty weak drug.

Do you think the negative results are because atezolizumab is a PD-L1 inhibitor?

 I think it’s atezolizumab. I think there have been just so many….

So you don’t think it’s applicable necessarily to PD-L1 inhibitors? Do you think all of the negativity, so to speak, of this study could be related to it being atezolizumab?

 Not all of it, but I wouldn’t throw out this entire approach for all patients based on this study. I think if we looked at patients who responded and then progressed, or patients who had a gap or a stronger combination, we might do better.

But do you think it’s fair to say we shouldn’t be doing this until and unless we have data that it’s of benefit?

 A hundred percent, yes. Thank you for clarifying. You’re right. Yes, it’s a negative setting.

What do you think of the data and why did the cabozantinib monotherapy arm do so well?

 It did well because I think there is residual, these people had free PD-L1 on board still because of the fact that they had received a prior immunotherapy as their most recent therapy. And it’s true, the biological half-life is measured in months, so I think that’s part of the reason why cabozantinib did so well. I don’t think this study closes the door, I totally agree with Betsy, because of the fact that it was atezolizumab. If you want to test the hypothesis that continued PD-1 blockade is important, then you want to do that with the best possible agent, and this wasn’t that study. We obviously have the tivozanib [plus] nivolumab study that’s I guess completed accrual now, and we’re going to be waiting for a readout on that. There you have a very good PD-1 blocking agent. You have a TKI, and we’ll be able to answer that question I think with a little more certainty.

 I think it’s great that we have a large phase 3 trial in this setting. I think that was something we needed to have because the other trials that were mentioned today, like the HCRN [Hoosier Cancer Research Network] trial, the OMNIVORE study, using ipilimumab boost in different settings were small phase 2 studies or smaller numbers. So it’s nice to see, and I think it addressed a lot of what people do in real-life practice about using this and showing that there wasn’t a benefit. But I agree it is nuanced about the patient sitting in front of you in the clinic, like on Monday morning, who you see and what you actually do. And I agree with Betsy, the drug that was used, the PD-L1 inhibitor, is questionable about what it’s role is in kidney cancer. But it doesn’t mean that it’s not efficacious in general for everything. But I agree that compared to cabozantinib, it works, and it proved it again.

Yes, I guess my thoughts are, I agree mechanistically, PD-L1 inhibitors, at least in combination, if you look at the monotherapy data, it’s not that different, but in combination, it seems to not do well. I’m not sure I understand why, but I think it’s pretty clear now.

 In the adjuvant [setting]. The negative one was the atezolizumab one in both….

I think there’s a general sense PD-L1 inhibitors are not as active, and so the TiNivo-2 [trial] will at least potentially address that mechanistic question. Although I’m a little skeptical that that’s just it. I think the cabozantinib monotherapy is because of residual either drug and/or T-cell effect. I also think the patients who do really well with immune therapy, who are really immune responsive, aren’t on this trial, right? They’re still on therapy. So you’ve removed an immune-responsive subset, and guess what, you’re probably left with a subset enriched for angiogenic response, so to speak, and that might be one reason cabozantinib did so well. Negative trials can be really important and practice changing too, and as Stephanie said, it was important to do. I think it‘s really important, and TiNivo-2 is important. It won’t really impact my practice because I wasn’t doing this anyway, but I do think it’s important. Other comments about the refractory space, what’s your normal sequence, Betsy? Let’s say you’re giving IO/TKI up front, it sounds like cabozantinib second. Just for general refractory [disease].

 I think standard lenvatinib [plus] everolimus is still really good combination if you haven’t used lenvatinib already. Again, by the time you get to the third and fourth line, it’s kind of like, what have you used before? What did you choose? Like if you start with cabozantinib [plus] nivolumab, then that’s not available to you in the same way in the second line. I do think about these sequentially at the start, how it might pan out. And we use a lot of belzutifan, it’s in the NCCN [National Comprehensive Cancer Network] guidelines with a letter of medical necessity for patients who you feel have exhausted the benefit of TKIs or can’t get them for some reason, as well as IO, we turn to that often.

Belzutifan, a HIF inhibitor, of course we don’t yet have the definitive data. It’s not on label for sporadic kidney cancer, but it clearly has activity, is clearly combinable, and we’re going to find out over the next few years where it fits. Eric, is there anything you saw at ASCO, like mechanism-wise? We have a bunch of immune drugs, a bunch of antiangiogenic drugs, anything else that caught your eye at ASCO or just in general that you’re excited about in this refractory space?

 I think the question really is, if you have loss of immune response, why is it? And is there something you can do to the T cell, where maybe PD-1 blockade is necessary but not sufficient? So would it be LAG-3 inhibition, would it be an A2AR receptor inhibitor? Would it be other types of mechanistic approaches to basically reanimate the immune response? I think this is where we should be going over the next couple of years in renal cell carcinoma. It’s great that maybe there are going to be some new TKIs and things like that, but I think understanding why people lose response or don’t have response to immunotherapy, and what special sauce is needed to get that to happen, is where we should focus our energy.

Agreed. I love the phrase special sauce. And agreed, we need novel mechanisms, we don’t need another PD-1 inhibitor. I don’t think we need another VEGF/TKI. That’s frankly pretty boring, right? To get transformative to get cures, we need novel immune mechanisms.

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Switching their focus to relapsed/refractory advanced clear cell renal cell carcinoma, key opinion leaders review treatment options in this setting.

Relapsed/Refractory Clear Cell RCC: Novel Treatment Strategies

What would you do next for this patient? Let me throw out some options, but obviously you could do whatever. You could say, “Well, boy, I stopped pembrolizumab and something bad happened. Why don’t I just restart pembrolizumab?” Or [say,] “You know what? This patient has hepatic progression, that’s bad. And the consequences of further progression are bad. I’m going to switch therapy to, call it cabozantinib.” Or I’ll put cabozantinib [plus] atezolizumab in there as a teaser to talk about the CONTACT-03 [trial]. Stephanie, why don’t we start with you? What would you choose for this patient? New hepatic metastases, nice response to axitinib [plus] pembrolizumab, stopped pembrolizumab, and now you have some progression.

: This has been 2 and a half years post IO [immunotherapy], or a year and a half?

No, 2 and a half years post start of therapy.

 I do recognize the fact about IOs and what Dave Braun, [MD, PhD,] was saying about how many of the receptors are being taken up by the drug. At this point, you would assume that probably is not in their system anymore. For this patient, especially with sarcomatoid histology, I would want to restart their IO.

You’d be tempted to restart their IO and see what happens.

 It’s tempting, but again, I think the board answer and the community answer would be single-agent cabozantinib for this patient. But again, I think, what would happen if you were to give both? And do you need both? So maybe what you can do is you can start with cabozantinib, and you can layer in an IO if you’re not getting the response you need. But it’s a data-free zone, and I think both are reasonable strategies.

 I’ll share an anecdote. I had patient…with the same situation, having stopped the IO, and I restarted pembrolizumab and switched to lenvatinib. So gave lenvatinib [plus] pembrolizumab, and he did really well for quite some time on that. It scratches the itch of wanting to restart the IO because you stopped it, and maybe that was the culprit, but also bringing in your powerful liver metastasis combination.

: At tumor board, I was the only vote for that, but I tried it, and it worked.

 It was the only vote that mattered. Bruno, what do you think? What would you do here?

 The answer is, if you want to go to the guidelines, it would be cabozantinib as a single agent. However, the reason I’m saying this is because you may face insurance approval issues to restart immunotherapy. I’ve faced this situation before, but I would make a case that this patient needs to be reintroduced to the IO therapy. I would pick a different IO/TKI [tyrosine kinase inhibitor], I would be favoring the use of…some combination like cabozantinib [plus] nivolumab in this situation because I believe there is some role for IO. I would not pick ipilimumab because of the rheumatoid arthritis history, but definitely one of the PD-1 inhibitors I would reintroduce.

Comprehensive insight to treatment options available in the second-line setting of advanced clear cell renal cell carcinoma. 

Second-Line Treatment Armamentarium in Clear Cell RCC

We’re going to move on to the second-line therapy discussion. We’re going to talk about the CONTACT-03 trial [NCT04338269]. I think we’ll stick with the case since we have it in front of us. So I treated this patient with axitinib/pembrolizumab, had a nice PR [partial response] on the initial scans, maintained maybe some axitinib dose adjustments, etc. Actually got to the 2-year mark as [approximately 25%] of patients in KEYNOTE-426 [trial] did. I discontinued the pembrolizumab, which I do because that’s the way KEYNOTE-426 did it. Does anybody not discontinue IO [immuno-oncology] at 2 years? All the trials that have showed a survival benefit have discontinued at 2 years.

 I tend to continue it too. I’ve seen many cases in boards of patients recurring after the discontinuation.

They’ve continued TKI [tyrosine kinase inhibitor] and progressed?

 I do it because there’s no mechanistic rationale for discontinuing it…. Part of the reason why we’re perhaps seeing a collapse in the curves in the IO/TKI PFS [progression-free survival] is because of the fact that you’re discontinuing therapy. So it’s an unprovable statement, but generally speaking, I will continue it unless, of course, there’s toxicity. A lot of times there are patients who develop toxicity, and that will define what you give for how long.

I’ll disagree with you a little bit. I don’t think there’s been collapse of the overall survival curves. If you look at that [more complete] analysis, it’s not that patients are progressing and dying. That’s not what’s driving those curves coming together. It’s the [patients taking sunitinib] being rescued. So that was my first thought: “Oh boy, we had better not stop pembrolizumab at 2 years.” Again, the data are not perfect, and we haven’t looked into it completely. I don’t know the clear part of this, but I don’t think that it’s stopping pembrolizumab. I would argue mechanistically, that’s what immune therapy is supposed to do, right? You’re supposed to give it up front, generate an immune response, and then stop.

 If you have a complete response perhaps it makes more sense to me….. In this case it’s just pembrolizumab or PD-1. I would not stop.

 I’ll agree with you. I’ll say that ipilimumab is immune therapy that you stop after 4 cycles. We’re trusting that that is causing all these long-term benefits even though it stopped years ago. So I think the idea that you can stop IO does make mechanistic sense, at least in my mind. I will say I have some really lovely treatment-free survival scenarios with IO/TKI, where I’ve stopped both and they’re getting scans and they’re doing well. So most people have those stories related to their [patients taking] ipilimumab/nivolumab. But perhaps because I practice, I have a nice collection of those [instances].

 If the patient had a complete response, it would make sense to consider discontinuing, but if the patient still has disease on scans, like this patient who had a partial response not a CR [complete response], I will not stop it.

…. We’re not going to resolve this in this session, but it sounds as though there’s uncertainty…. I think there’s real uncertainty about continuing, and it’s just the way it was done in the trial.

 I mean, all trials nowadays are stopping. Is there a trial that’s actually in kidney cancer that’s making…

 Nivolumab did not. None of the nivolumab studies stopped. I don’t know about the…

 Cabozantinib/nivolumab stopped for the IO combination, the combination studies.

It’s a mixed bag. I didn’t want to go too far down that rabbit hole.

Focused discussion on the rationale behind discontinuing (or continuing) immunotherapy for patients with advanced clear cell renal cell carcinoma. 

Rationale Behind Discontinuing IO Therapy in Clear Cell RCC

…We talked about all the data first. Now we’re going to the case. I should just note, there were a number of abstracts at ASCO [American Society of Clinical Oncology Annual Meeting] about patients with bone metastasis and liver metastasis. We don’t have time to dive into them, but just for the audience, these are generally retrospective series and case series, but there are some data at ASCO to look at that might be relevant to practice. Now that we’ve laid out the data in our practice, let’s go to this patient case and then we’ll talk a little bit about management. Then we’re going to close [with discussing] the front line. I want to talk about any nivolumab data and then maybe just touch on triplets [therapy], which we already did a little bit.

A patient of mine, a 72-year-old man, comes in with some symptoms. Flank pain. [He] has a rheumatoid arthritis history. He is on low-dose methotrexate, don’t know much more about it at this point in time. But otherwise, a very active, healthy 72-year old. [He] was a fairly heavy smoker but quit upon diagnosis. You see the labs there, normal kidney function, normal to high hemoglobin. Then [he had a] CT scan with a kidney mass; what you’re actually seeing on this scan is the IVC [inferior vena cava] extension. Then [possibly we see] some small lung nodules, too small to characterize, maybe there’s a little something in the liver…. So definite kidney mass consistent with RCC [renal cell carcinoma] and vague other radiographic abnormalities and good performance status, as I mentioned. This patient is thought to have nonmetastatic disease. These radiographic abnormalities are not biopsied but are not worrisome enough. [The patient] undergoes right radical nephrectomy, tumor thrombectomy, has clear cell RCC with some sarcomatoid features, pathologic stage T3B, but otherwise, negative margins and negative nodes as is N0 [no cancer in nearby lymph nodes]. So again, we’re not going to talk about adjuvant therapy, but I can’t help myself. That was March 2019…. Let’s say adjuvant pembrolizumab, that’s why this patient didn’t get adjuvant therapy or one of the reasons, but your answer has to be yes or no, in the interest of time. Would you give this patient adjuvant pembrolizumab now? It’s grade 4 T3B…maybe upwards of 60% risk of recurrence, in a 72-year-old patient. [He] has this rheumatoid arthritis history on methotrexate. Yes or no, adjuvant pembrolizumab?

The patient says “Doc, you’re the expert. You know more about this than I do. I’ll would do whatever you say.”

 This patient has a very high risk; a lot of the future [is] concerning.

Yes. OK, good. We’re split here. Again, we’re not really talking about adjuvant therapy, but it was too juicy to pass up. But obviously, that history is relevant as we move to this. It’s going to be a frontline case. So, unfortunately, some of the small lung nodules progressed. There’s a new left lower lobe nodule. If you can see on this, there’s now a new left adrenal mass. Let’s say it’s biopsied and consistent with recurrent disease…. So it’s about a year after nephrectomy. Lab [results are] normal, still has good performance status, IMDC [International Metastatic RCC Database Consortium] favorable risk. It was just over a year ago, in part based on the timing of the scan, right? Just the way it happens, this is I guess [during the COVID-19 pandemic], right? So the scans were probably delayed a bit. We observed this patient in part because it was the middle of the pandemic or the first part, I should say. For that reason, and I think because he had low volume disease and favorable risk, we observed this patient initially, but then over the course of the next 6 months [the patient] had further progression. Pretend you don’t read the bottom of that slide, [the patient] has further progression requiring therapy…. Stephanie, we’ll start with you. So you have this [patient with an] ECOG performance status of 1; [the patient] does have rheumatoid arthritis, history on methotrexate but it is well controlled. You talk to the rheumatologist and they say, “It’s well-controlled and I have some other tricks up my sleeve if you need them. Favorable risk with low volume disease but growing, and we’re not going to observe or SBRT [stereotactic body radiation therapy] this patient.” Let’s take that off the table. What would you give this patient?

 I would say favorable risk. There’s been a big [discussion at ASCO] about is there really a need for immunotherapy or really going for favorable worse disease? You can just even do TKI [tyrosine kinase inhibitor] monotherapy for these patients. Being an older patient with really good performance status, I think either monotherapy would’ve been appropriate at this point or especially if they can’t utilize any SBRT…. I think it’s appropriate to do the combination. I don’t shy away from autoimmune disease, even though those patients were included on clinical trials, but a [patient with] well-controlled rheumatoid arthritis and a good rheumatologist….

 Correct. I would feel comfortable giving them either monotherapy with TKI and adding in…

Probably IO/TKI [immuno-oncology/tyrosine kinase inhibitor].

 The thing that worries me about this patient is you did say he had sarcomatoid features in his primary.

 Favorable risks aren’t created equal. This is an example, I think, of an individual who, although they are now starting to progress, they are “favorable risk,” but I’m concerned about the histology and I would give something containing a PD-1. I think you just work very closely with a rheumatologist in terms of managing whatever toxicities you arise. I would not give this patient ipilimumab [plus] nivolumab because…I think that would be a bridge too far from a toxicity perspective.

OK. I agree. I’m not trying to give ipilimumab to a patient with rheumatoid arthritis on methotrexate. I think that just, as you say, a bridge too far…. This was my patient, so I gave him axitinib [plus] pembrolizumab in part based on the timing of this. But before we go to back to the case, Dr Berg, what would you do?

 I would do axitinib [plus] pembrolizumab also. I think the reason I said no to adjuvant is because this was so likely to happen. He was so high risk for metastasis…. I think if you’re going to give IO, you’re going to give it once. They have rheumatoid arthritis, you’re going to learn what they have. Now’s the time to give it, not later. It’s unlikely that someone would go through therapy and never see an IO because of rheumatoid arthritis. So I think you bite the bullet at this point. And axitinib [plus] pembrolizumab for favorable risk is what I would do.

 I agree with the IO-TKI. IO-IO I would not give it, based on the history of rheumatoid arthritis. It sounds as though it’s well-controlled with the rheumatologist. I agree with the axitinib [plus] pembrolizumab choice. I would choose the same.

Centering discussion on a patient scenario of advanced clear cell renal cell carcinoma, panelists reflect on how they would approach selecting first-line therapy.

Eric A. Jonasch, MD, MD Anderson Cancer Center

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