Relapsed/Refractory Clear Cell RCC: Novel Treatment Strategies

EP: 1.Overview of First-Line Combination Therapy in Advanced Clear Cell RCC

EP: 2.Factors in Selecting First-Line Therapy for Patients With Advanced Clear Cell RCC

EP: 3.Advanced Clear Cell RCC: AE Profile of First-Line Combination Therapies

EP: 4.Dosing Strategies With First-Line Therapy in Advanced Clear Cell RCC

EP: 5.Selecting Therapy for a Real-World Patient With Clear Cell RCC

EP: 6.Rationale Behind Discontinuing IO Therapy in Clear Cell RCC

EP: 7.Second-Line Treatment Armamentarium in Clear Cell RCC

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EP: 8.Relapsed/Refractory Clear Cell RCC: Novel Treatment Strategies

EP: 9.Selecting Optimal Therapy for Advanced Non-Clear Cell RCC

EP: 10.Renal Cell Carcinoma: Future Evolutions in Care

EP: 11.Patient Profile Presentation: A 65-Year-Old Man with Advanced Clear Cell Renal Cell Carcinoma (RCC)

EP: 12.Available Treatment Options for Patients with Advanced RCC

EP: 13.Lenvatinib Plus Pembrolizumab for Firstline Treatment of Advanced RCC

EP: 14.Dosing Considerations for Combination Lenvatinib and Pembrolizumab in Patients with Advanced RCC

EP: 15.Managing Long-Term Toxicities of Combination Lenvatinib and Pembrolizumab in Advanced RCC

EP: 16.Key Takeaways in the Treatment of Advanced RCC From KCRS 2023

EP: 17.Future Perspectives in the Treatment of Advanced RCC

Transcript:

Brian I. Rini, MD: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 P 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.

Bruno R. Bastos, MD: Yes.

Brian I. Rini, MD: Your reaction to the data, are you surprised? Were you giving sequential IO before?

Bruno R. Bastos, MD: 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….

Brian I. Rini, MD:Let’s take this case out of it, just more standard progression.

Bruno R. Bastos, MD: 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.

Brian I. Rini, MD:If there was more of a gap between IO….

Bruno R. Bastos, MD: 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.

Brian I. Rini, MD:We don’t know. This study didn’t address that.

Bruno R. Bastos, MD: 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.

Brian I. Rini, MD:Agreed.

Elizabeth Plimack, MD, MS: I think the refractory setting is very different than the case we just discussed.

Brian I. Rini, MD:Let’s just take a general refractory setting.

Elizabeth Plimack, MD, MS: 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.

Brian I. Rini, MD:Do you think the negative results are because atezolizumab is a PD-L1 inhibitor?

Elizabeth Plimack, MD, MS: I think it’s atezolizumab. I think there have been just so many….

Brian I. Rini, MD:But it’s a PD-L1 inhibitor.

Elizabeth Plimack, MD, MS: …Places where other PD-1s have….

Brian I. Rini, MD: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?

Elizabeth Plimack, MD, MS: 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.

Brian I. Rini, MD: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?

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

Brian I. Rini, MD:What do you think of the data and why did the cabozantinib monotherapy arm do so well?

Eric Jonasch, MD: 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.

Brian I. Rini, MD:Stephanie, what do you think?

Stephanie A. Berg, DO: 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.

Brian I. Rini, MD: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.

Elizabeth Plimack, MD, MS: In the adjuvant [setting]. The negative one was the atezolizumab one in both….

Brian I. Rini, MD: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].

Elizabeth Plimack, MD, MS: 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.

Brian I. Rini, MD: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?

Eric Jonasch, MD: 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.

Brian I. Rini, MD: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.

Transcript edited for clarity.