Treatment Options for Advanced Clear Cell RCC in the Second-Line and Beyond


Centering their discussion on the second-line setting, expert oncologists review mainstay second-line therapies for advanced clear cell RCC.


Thomas Powles, MD: We’re running out of time. Are there any final comments? Just a sentence from everyone, starting with you, Ben. Where do you think the next big chapter is, and what would you like to see next?

Benjamin Maughan, MD: I think the next big chapter is going to be defined by toxicity. As we are embarking on these combination treatments of 3 drugs, doing some sequence of them, the toxicities are really starting to become problematic…if you look at the adjuvant ipi-nivo [ipilimumab-nivolumab] study [CheckMate-914; NCT03138512], a large proportion of patients were not able to complete the therapy. If you look at COSMIC-313 [NCT03937219], there’s a significant increase in toxicity. Once you start looking at triplet therapy, that’s limiting our capacity to give the backbone of ipi-nivo; toxicity’s important. Ulka?

Ulka Nitin Vaishampayan, MD: I think improving the efficiency of our treatments—and for that we need biomarkers that will predict which treatment to choose and individualize which therapies—is the way of the future.

Thomas Powles, MD: I’m with you. Rana?

Rana McKay, MD: I agree. Biomarkers, and a way to implement biomarkers in a fashion that’s fast, cheap, and scalable. It’s amazing to see that 2 decades ago our patients were at 1 year survival, and now they’re at 4 years. We’ve made tremendous progress.

Thomas Powles, MD: Eric?

Eric Jonasch, MD: Biology. We are piling drugs on each other; we don’t know what’s happening in a micro-environment. For example, HIV-2 alpha; what does it do to a T-cell? What does it do to a myeloid-derived suppressor cell? We don’t know.

Thomas Powles, MD: We’ve transformed the disease; let’s work out why we’re doing it. Terrific. Thank you very much to the panel; thanks for your attention. I hope you enjoyed it. To our viewing audience, thank you for joining us; we hope you found the OncLive® peer discussion to be useful and valuable for treatment of patients with renal cell carcinoma. Thank you very much indeed. It looks like we’ve covered 2 big topics: first-line therapy, which takes a long time; and some of the uncertainty and excitement about adjuvant therapy. One of the things that I’m most confused about, and maybe Rana, you can start with this for me; we’d done a lot of trials with sequencing therapies back in the day, sunitinib vs sorafenib, second-line types. We haven’t done that much work post immune-combination therapy. We’re in this huge area of uncertainty. I’m involved in the ESMO [European Society for Medical Oncology] guidelines group, and we sit in a room, and we have all this frontline data. We spend hours on it, and then the second line, we’ve got level 3B evidence, you can give anything you want. Where are we in this second-line space? What data do we have to support us? I know there’s the METEOR trial [NCT01865747], there’s CheckMate 025 [NCT01668784], there’s len-eve [lenvatinib-everolimus] sorts of studies. How do you look at this from a patient perspective, and what treatment options do you think about for your patients?

Rana McKay, MD: Very good question. All the success of the frontline therapies has put us in a predicament in the second line because now our standard frontline is IO [immuno-oncology] combination strategies, and all of our standard second-line options were derived from the VEGF [vascular endothelial growth factor]-targeted era where people were progressing post VEGF, not necessarily post IOs. METEOR was a trial conducted post VEGF. There is great data for cabozantinib in the second-line space, but not necessarily patients who had received IO preceding. Similarly, with the axitinib data, the len-pem [lenvatinib-pembrolizumab], the len-eve [lenvatinib-everolimus] data, all done post VEGF-targeted therapy as opposed to post combinations. What we’re trying to do right now with the level of data that we have is scrapping together retrospective series. There are very limited prospective data to help guide: What is the appropriate strategy in patients that have had post-IO progression? It really is a predicament in the field, and I think it’s an area where we just need a ton of clinical trials to help better define what to do in the second-line space.

Thomas Powles, MD: Ben, I’m going to move to you to talk for a second about tivozanib; there’s N-TIVO, which is nivo [nivolumab] plus tivozanib vs tivozanib alone. Where are we with tivozanib? It’s not a drug that I’ve used a lot of because we had other drugs to use.

Benjamin Maughan, MD: Tivozanib is really, as much as you can call it, a pure VEGF inhibitor. It does have some activity at these other receptors, tyrosine kinases, but the binding affinity is very low for those. So, as much as we can describe it, it’s a pure VEGF inhibitor. Therefore, it has some of those classic complications that you see with VEGF therapy: wound-healing issues, hypertension. Overall, it seems to be a moderately well-tolerated therapy. If you look at the TIVO-3 [NCT02627963] data, comparing tivozanib to sorafenib, the proportion of patients who discontinued tivozanib is relatively low. Interestingly, the long-term follow-up data of that study shows that a reasonable proportion of patients receiving tivozanib in the third line or later continued on treatment; ie, they did not have disease progression extending out 12, 18, 24 months. The proportion was relatively low; it continues to drop over time. However, still out to 12 and 18 months, the proportion was in that 15% range. That demonstrates to be an impressive durability and efficacy of that medication. But, to Rana’s point, for the most part, these patients had progressed on VEGF therapy before, not the standard combination treatments of them.

Thomas Powles, MD: What’s your take on the lenvatinib-everolimus combination? Is it something that we should be using a lot of? Or is it something that just adds more toxicity, and we don’t really need it?

Ulka Nitin Vaishampayan, MD: It is an effective combination. The median PFS [progression-free survival] with lenvatinib and everolimus is about 14-15 months. It is very promising.

Thomas Powles, MD: In sunitinib refractory?

Ulka Nitin Vaishampayan, MD: Post VEGF-TKI, sunitinib, sorafenib, whatever what’s used. But the data that is backing that up is a phase 2 randomized trial. In summary, only about 50 patients on each arm. Despite that, I think it is a very useful regimen in the post-therapy, second, third-line setting. But it is a toxic regimen. The toxicities must be taken into account in a relatively sicker patient population who has progressed both front-line therapies.

Thomas Powles, MD: The thing that made me a bit nervous [was that] I didn’t think that arm and CLEAR study [NCT02811861] did super well. The PFS was quite good, [but] the OS [overall survival] wasn’t terrific. I thought, this isn’t something I need to give my patients. My current position is to give single-agent therapy rather than combination therapy. Rana, can you comment on whether we need to keep going with immune therapy?

Rana McKay, MD: I believe there are going to be a couple of clinical trials that are going to work to answer that question. There’s a CONTACT-03 trial [NCT04338269] that’s fully accrued that’s looking at the combination of cabozantinib-atezolizumab vs cabozantinib alone in the post-IO refractory setting. There’s a TiNivo-2 study [NCT04987203] as well, which is looking at tivozanib plus nivolumab vs tivozanib in the second line setting. The other question that I think some of these studies are going to answer is that progression post adjuvant. So, it’s allowing people who have received IO in the adjuvant setting to enroll in the context of those trials. I think what’s interesting about the CONTACT-03 study is that it’s also enrolling variant histology in addition to clear cell.

Transcript edited for clarity.

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