Choosing Between Tivozanib and Lenvatinib/Everolimus in Third-Line RCC

Randy F. Sweis, MD (Moderator)

Assistant Professor of Medicine

Duchossois Center for Advanced Medicine - Hyde Park

UChicago Medicine

Chicago, IL

DISCUSSION QUESTIONS

• What factors influence decision to use tivozanib (Fotivda) for patients with metastatic renal cell carcinoma (RCC)?

RANDY F. SWEIS, MD: For those that [would] choose to use tivozanib, what factors influenced that? Are you familiar with the drug? Did you [review the] data? In which efficacy end points are you interested? Or is it the National Comprehensive Cancer Network [NCCN] guidelines? It’s a relatively new drug to the arsenal. I started using it last year a few times, and this year a few times. I’ve had some mixed responses with it, but I want to hear others’ thoughts.

MERAT KARBASIAN-ESFAHANI, MD: I’ve used this medication in a patient once. My patient was younger; the tolerance was good. The patient is still continuing with the treatment, so I am very eager to find out about the long-term efficacy data to further modify or mature my decision about subsequent administration of this medicine for other patients.

SWEIS: Do you remember what line of therapy that was?

KARBASIAN-ESFAHANI: The third line—the patient has received the immune checkpoint inhibitors ipilimumab [Yervoy] plus nivolumab [Opdivo], followed by cabozantinib [Cabometyx].

SWEIS: Great. I think sometimes when drugs like this come out, based on my experience, I use them sometimes in later lines than what the trial was to get a handle on them. Sometimes those patients have had a couple of TKIs [tyrosine kinase inhibitors] and IO [immunotherapy], but I have used it a couple of times earlier.

DISCUSSION QUESTIONS

• What has been your experience with lenvatinib (Lenvima) plus everolimus (Afinitor)?​ If you have not used it, please share your perceptions of this combination.​
• If you have used it for advanced or metastatic RCC, ​
  • In what line(s) of therapy?​
  • What’s your typical approach toward dosing? ​
  • What is the average duration of therapy, in your experience?​
  • What types of responses have you seen?

SWEIS: [Lenvatinib plus everolimus] is one of the other options. Lenvatinib plus everolimus comes up on the NCCN guidelines. Does anyone want to comment on that? When do people use lenvatinib plus everolimus?

STAN NABRINSKY, MD: I am currently using it in 2 patients and have used it on 2 patients before in much later lines of therapy. I emphasize lenvatinib as the base of the treatment, so adverse events [AEs] from everolimus are quite well defined, specifically stomatitis and that is a significant issue. Therefore, I am more lenient on withholding everolimus when there are AEs. But [for] lenvatinib, I typically stick with the 14 mg/day dose.¹ I use it in the third and fourth line, and patients don’t tolerate higher doses.

SWEIS: Do you start out with the 14 mg dose for most?

NABRINSKY: They try 18 mg, but after a week or so there are some gastrointestinal [GI] issues, and I easily reduce to 14 mg, and [approximately] 80% of the patients do well with 14 mg.

SWEIS: So you are starting with 18 mg with the assumption that they are probably going to drop pretty quickly. But you are not starting from day 1 on 14 mg? Some [physicians] do that.

NABRINSKY: No. I am trying to get more pills because it comes in 10 mg and 4 mg, so I am trying to get them 10 mg, 4 mg, and 4 mg, so there is some flexibility.

SWEIS: Have you seen responses?

NABRINSKY: Yes, I’ve seen responses in the third and fourth line.

SWEIS: What about AEs once you get to 14 mg [lenvatinib]? Do you think patients do OK?

NABRINSKY: I think they are doing OK, especially if you watch them real closely for stomatitis from [everolimus]. Another problem with [everolimus] is the high blood pressure, in my experience, more than with lenvatinib, and GI AEs when the 2 of them are given.

SWEIS: Have you used tivozanib at all?

NABRINSKY: I used it on 1 patient, and only because insurance requested it, and I was curious how it works. It didn’t work; on the first subsequent scan, the patient had progressed.

SWEIS: Did you get a sense of tolerability between lenvatinib plus everolimus and tivozanib? That’s a common question that comes up. Some feel that one is more tolerable than the other.

NABRINSKY: That’s where I rely on experts like you to tell how to sequence them because yes, it’s probably the only one with FDA approval for the third line in the clinical data, but so far [my] experience has been underwhelming.

SWEIS: [Are there] any other thoughts from anyone else?

TAN: Is anyone else impressed by the tail of the Kaplan-Meier curve [for progression-free survival] on that tivozanib trial [TIVO-3; NCT02627963]?² I am wondering if there is something that is inducing an immunogenic responses in a subset of patients. It would be interesting to see how this performs with immunotherapy in a frontline setting.

SWEIS: There is an ongoing second-line study [NCT04987203] that is nivolumab plus tivozanib versus tivozanib alone. At a minimum, even if that trial is negative, we will get a good readout in a modern cohort of patients of the performance of that drug as monotherapy in the second line. I am curious to see. I haven’t seen any recent updates on that, so I think it is still ongoing. We are not participating in it. The number of patients there is low, so I don’t want to overread into it, but we will see.

There is some thought with a lot of these TKIs that some of these tyrosine kinases can modulate the tumor microenvironment in a favorable way. I am not convinced of that yet. That’s a theoretical benefit, and I can also think of theoretical detriments to the immune response that could happen. Maybe they offset each other, or maybe neither is going on, but it’s just additive effects with the TKI. We will see.

_REFERENCES

_{1. Lenvima. Prescribing information. Eisai, Inc; 2022. Accessed April 14, 2023. https://bit.ly/3MRDWXg}

_{2. Pal SK, Escudier BJ, Atkins MB, et al. Final overall survival results from a phase 3 study to compare tivozanib to sorafenib as third- or fourth-line therapy in subjects with metastatic renal cell carcinoma. Eur Urol. 2020;78(6):783-785. doi:10.1016/j.eururo.2020.08.007}