Sequencing for Metastatic Clear Cell Renal Cell Carcinoma After Prior Therapy

Factors Favoring Tivozanib as Third-Line Therapy for Advanced RCC

During a Targeted Oncology case-based roundtable event, Saby George, MD, and participants discussed the role of tivozanib and other later-line options in patients with advanced renal cell carcinoma.


  • What factors influence use of tivozanib (Fotivda)?

TONY CHEUNG, MD: In the phase 3 study, were the patients allowed to cross over?

SABY GEORGE, MD: The original trial was TIVO-1 [NCT01030783], which allowed crossover.1 [TIVO-3; NCT02627963]…was not allowing crossover.

CHEUNG: Thank you.

GEORGE: TIVO-1 was largely done outside the United States and allowed for crossover because a lot of countries did not have subsequent-line treatments. What happened was patients [who received] sorafenib progressed. Even though the PFS [progression-free survival] was longer in the tivozanib arm, sorafenib patients crossing over to tivozanib affected the OS [overall survival] there. So that’s a problem they saw in that trial. But I don’t think [TIVO-3] is allowing for crossover.

SANTOSH KUMAR, MD: Tivozanib compared with the sorafenib; do you think that’s a good comparison for a disease that we have so many drugs for right now? I have not used sorafenib in my practice in 5 years, so I don’t know if it was a good comparison arm for this drug.

GEORGE: That’s a great point. Sorafenib was approved in 2005, based on a large, randomized phase 3 trial in the treatment-refractory setting in patients who had IL-2 [interleukin-2] or interferon.2 [Sorafenib was] approved in the treatment-refractory setting comparing with placebo. That was a default, [as] second-line treatment. A lot of second-line and third-line studies have been done with sorafenib as a comparator because there was no established second-line or third-line comparator before these trials were designed.

Now that we have more and more drugs coming through, [this has changed]. For lenvatinib [Lenvima] plus everolimus [Afinitor], 100% of the patients who were tested were purely second line.3 In the cabozantinib [Cabometyx] and nivolumab [Opdivo] trials, the METEOR [NCT01865747] and CheckMate 025 [NCT01668784] trials, 71% or 72% of them were in the second line, only [29% and 28%, respectively,] were in the third line.4,5

There’s no comparison there, so sorafenib became a default comparator in the third line because of its efficacy in the treatment-refractory setting. There are also some data showing that sorafenib works after sunitinib in the first line, so this is how it evolved over time. When the race was [on] to develop drugs in the first line for so long, now we have newer drugs, immune checkpoint inhibitors. A lot of them moved on to the first line now that we have combinations. Now we’re moving down the line with drugs which can be active after all those other drugs. In the third line, there are not much data but this is one way that trials were done. The FDA supported the use of sorafenib as a comparator, and that’s how this became the comparison. We do still use sorafenib in some situations, rarely.

ASHISH A. KHOT, MD: I think once the tivozanib/nivolumab trial comes out, we’ll know how good tivozanib is. It will [give] us much better comparison with other agents.

GEORGE: Absolutely. That trial [TiNivo-2; NCT04987203] is ongoing right now.

KHOT: Belzutifan [Welireg] with cabozantinib will also be a good option in the later-line settings, especially for heavily-pretreated patients, because it’s a different mechanism of action.

GEORGE: I agree with that.


  • How do you prevent, monitor, mitigate, and manage tyrosine kinase inhibitor [TKI]-associated toxicities?​
  • Please share your perspectives on the tolerability of tivozanib versus lenvatinib plus everolimus or other options you would strongly consider as third-line therapy for a patient like this. ​
  • How do you decide which drug to modify when using a combination regimen?​

GEORGE: How do you prevent, monitor, mitigate, or manage TKI-associated toxicities? Do you have staff dedicated for this? How do you approach TKI toxicities in your clinic?

RAMAN SOOD, MD: I make sure they come back on initiation of therapy [after] 2 weeks so they’re not out there 1 month struggling with it. We generally would call them some time [around] 1 week in to check in. [We have a] low threshold for withholding the dose if they are having adverse events [AEs], and then restart at a slightly lower dose, especially in the combination. I’ve not used tivozanib personally, so I cannot respond to that. But in the [other] TKIs, I tell them to come back [after] 2 weeks with close follow-up.

GEORGE: That’s great. You have to do the liver function tests and the [blood cell] count check and everything in the first couple weeks and then a couple more weeks until 6 weeks and then space it out every 6 weeks if they are safe. Fortunately, we have some dedicated nurses who are helping us with management and identification management of toxicities. Does anybody want to chime in about the tolerability of tivozanib versus lenvatinib/everolimus if you have used that?

DAVID BRAUN, MD, PHD:My personal experience is tivozanib being a much milder drug. In the patients I’ve had who have had difficulties on other TKIs, tivozanib has had a better shot of being tolerated. I think of lenvatinib/everolimus as a very potent regimen, and so…it’s always a question of when is the right time? I try to have that sweet spot where a patient needs it. If the patient is trudging along and has a little bit of progression and needs to switch therapies but it’s not [when] we need a response tomorrow, you have more flexibility. I think about toxicity a lot and tivozanib is a great option. If it’s something where someone needs a response [immediately] if they don’t respond to this line, [since] they might have terrible consequences, I think of lenvatinib/everolimus as something that, as long as the patient can tolerate it, is very potent. That’s how I think about the 2 [options].

GEORGE: That’s great. Does anybody want to comment on modifying the drug dosing or discontinuing the drug when you’re using a combination like lenvatinib and everolimus? Does anybody have experience with that? Have you thought of what’s causing the toxicity? How do you manage, or do you just stop the dose? How do you approach that practical question?

CHARLESSE PONDT HUANNOU, MD: I think it depends on what the AEs are. The AEs between the 2 can be quite different. Everolimus tends to be more mouth sores, etc. Lenvatinib tends to be myasthenia, fatigue, and those kinds of things. When it’s diarrhea I try to just control the diarrhea itself without stopping [treatment]. It’s hard to reduce everolimus, so I tend to reduce lenvatinib first based on the AE and then go from there.

GEORGE: That’s a great point. It becomes a problem when there are overlapping toxicities. There are common toxicities for both the drugs. A TKI/immune checkpoint inhibitor combination is one where you have to ponder.


1. Salgia NJ, Zengin ZB, Pal SK. Tivozanib in renal cell carcinoma: a new approach to previously treated disease. Ther Adv Med Oncol. 2020;12:1758835920923818. doi:10.1177/1758835920923818

2. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125-134. doi:10.1056/NEJMoa060655

3. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9

4. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814-1823. doi:10.1056/NEJMoa1510016

5. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665