乌鸦传媒

Although most frontline combination regimens for advanced and metastatic clear cell renal cell carcinoma (RCC) lead to responses, not all patients achieve durable responses, and the majority of patients develop resistance.

乌鸦传媒 brought together three expert leaders in the field -- moderator , from the Fox Chase Cancer Center in Philadelphia, is joined by , from the University of Texas MD Anderson Cancer Center in Houston, and , from the University of Texas Southwestern Medical Center in Dallas -- for a virtual roundtable discussion. This second of four exclusive episodes focuses on the management of clear cell RCC after frontline treatment.

Following is a transcript of their remarks:

Plimack: Aright, the next topic that we're going to cover is treatment after the frontline treatment. So you've selected your frontline treatment for your patient, doublet likely, IO [immunotherapy]/TKI [tyrosine kinase inhibitor] or IO/IO, and the patient has progressed let's say, and you're looking at the next-line treatment. So I'll start with you, Dr. Zhang. How do you think about next-line treatment for your patient and what are the things you take into account?

Zhang: Sure. It's a situation we come across quite often in clinic and oftentimes I'm thinking about how good a response did the patient have to frontline therapy, how long did it take for them to develop resistance, and is it 3 months their primary progressors or are they out a year or longer, and had an initial response. So those are the characteristics I think a lot about.

And then mechanism of action from frontline treatments and then how do we switch that out for second line or further. And at ASCO we had a pretty definitive randomized trial in this setting. So really excited to see CONTACT-03.

Plimack: Great. Dr. Shah?

Shah: Yeah, absolutely. I agree with everything Dr. Zhang said. The CONTACT-03 data was really helpful because this clinical question comes up all of the time. You have someone who's just progressed on either nivo-ipi [nivolumab (Opdivo)-ipilimumab (Yervoy)] or an IO/TKI, and our question for all of us every day in the clinic is, okay, do I start my next TKI and keep that IO on board or do I drop it? And so CONTACT-03 was perfect to answer that question.

These were patients who had their most proximal line of therapy was IO containing and they were randomized to cabozantinib [Cabometyx] versus cabozantinib-atezolizumab [Tecentriq]. And this was a negative study in terms of both PFS and OS. So the addition of atezo to cabozantinib post-IO progression did not seem to improve outcomes.

And actually the curves were strikingly parallel and the response rates were almost exact. So it really didn't seem to be adding much to the table. And the cabo responses were similar or better than historical data.

So that was actually really helpful, just as a practical point, where if you have somebody who's progressed on say, pembro-axi [pembrolizumab (Keytruda)-axitinib (Inlyta)] or nivo-ipi, to go into that second line, for most patients, you may not necessarily re-challenge that IO. Now, I say "may not" because what the CONTACT-03 trial didn't fully answer is for patients such as sarcomatoid patients where we know that IO therapy is really important biologically, so I don't want to paint it as an all-comers-type brush. But for the average patient, perhaps IO re-challenge isn't as relevant. I'll pause there.

Plimack: Yeah, I think I'm just reflecting on your comments. I think they're really salient. So, if you have, I'm sure we've all experienced this, a patient has a really nice, beautiful long-term response to immunotherapy and you finally have to admit that they've progressed -- first of all, that's a hard, hard switch because I think we have such high hopes for immune-containing doublets. But two, I'll have patients say, look, that worked for me. Can't I do another immunotherapy? And you don't want to say no.

So a lot of us had been doing that. I think we've been doing cabo-nivo post or axi-pembro post or whatever we didn't use before, we're trying that. And these data did give me at least pause in terms of doing that because there is higher expense and of course potential toxicity.

But the other thing you raised is the beautiful response rate for cabo single agent in this space. So it's almost a contemporary control arm in the appropriate setting of cabo. And so now I think we can quote that to our patients and it strengthens its position in the second line.

Zhang: Betsy, if I could add to that just for a moment. It's interesting to me that in that cabo control cohort there were about 30% of patients who'd received ipi-nivo. So no VEGF [vascular endothelial growth factor]-containing treatment in their frontline setting. And it really speaks to the fact that cabozantinib after initial immunotherapy combinations has activity. We saw single-cohort phase II data from at GU ASCO this year from Dr. Albiges.

But in this particular context, I think there is a group of patients who were progressing after prior IO/IO treatments, they may not have received prior VEGF-containing treatments. So this cohort of patients, they absolutely have good disease activity from cabozantinib monotherapy. But I think a part of it is that a control cohort did a bit better because they were not exactly mirroring the initial control cohort or the experimental cohort, I should say, of where cabozantinib got its label.

Plimack: Right. And also of course we're just in a new era compared to METEOR. I mean that feels like so long ago compared to how we understand these treatments, I think, honestly how we manage them. So I guess just a cautionary tale of interpreting data in new eras and how it might be different. But yeah.

Let's continue on this for a little bit longer. So after your cabo, right, let's say this is solidified in the post-doublet space, what regimens do you think about for the clear cell patient in your clinic? Dr. Zhang, we'll start with you.

Zhang: Well, I think [it] depends on what they receive frontline. So if they received a non-cabo-containing doublet in the frontline, then certainly I'm thinking cabozantinib in the second line. If they have received cabo-nivo, for example, in the frontline setting, then I'm thinking about lenvatinib [Lenvima] with everolimus for really robust patients or perhaps tivozanib [Fotivda] as a single agent. And maybe even axitinib as a single agent. But I think those are probably the treatments that we have with the most robust data in the refractory setting.

Plimack: Yeah, great. Dr. Shah, anything to add to that? What do you do in your clinic?

Shah: Yeah, absolutely. Pretty similar. Post-cabo, I've had actually excellent success with lenvatinib. It is what we call a dirtier TKI, so it hits more receptors and overcomes some of that post-TKI resistance. And so it is actually a fantastic salvage drug. And part of going back to the frontline discussion, it is such a good agent that sometimes post-lenvatinib, it's hard sometimes to salvage people. Whereas I know it will work well post-axi or post-cabo for many patients. So a lenvatinib-based strategy is definitely something I do in the later line.

I'll make a quick plug and this is evolving data, it is not standard of care. But there's a lot of excitement over the [hypoxia-inducible factor] HIF2α drugs. We have three trials with HIF2α agents at MD Anderson right now, so belzutifan [Welireg] and then other drugs with the same pathway.

And I have had some really incredible responses in heavily pretreated patients. And so right now belzutifan is only approved in syndromic VHL [Von Hippel-Lindau] patients. But there's clearly some activity in these clear cell patients and I'm very excited to see where this story evolves. Tolerability wise, it really gives patients a break from that TKI grind of diarrhea and fatigue and it's an active agent. So I'm excited to see where that story goes.

Plimack: Yeah, I would agree and shout out to Dr. Zhang's institution, UT Southwestern, where the drug was born. So pretty exciting to see that come out of an academic center. I will echo enthusiasm for that. I will say it is included in the NCCN [National Comprehensive Cancer Network] guidelines as an alternative therapy and I've been able to get it for some non-syndromic patients with a letter of medical necessity citing the guidelines. Of course, we're waiting larger trials to read out.

But all of the regimens that you mentioned are ones we use here too. Single-agent TKIs, tivozanib is a nice option to have, belzutifan if we can get it. And then lenvatinib, everolimus, kind of an oldie but goodie. But yes, great. Well, thank you.

Click here to watch the other videos from this ASCO roundtable series on renal cell carcinoma.

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