Oncologists Weigh Tivozanib Data in Pretreated Metastatic RCC

With multiple VEGFR-targeted therapies available after progression on immunotherapy-based regimens, oncologists continue to refine their approach to treatment sequencing in metastatic renal cell carcinoma (RCC). In a virtual Case-Based Roundtable event, Dillon Cockrell, MD, of Duke Cancer Institute, and Raji Shameem, MD, of Orlando Health Cancer Institute, led a discussion with oncologists from the South Atlantic and Southeast regions on the evolving role of tivozanib (Fotivda) in previously treated metastatic RCC.

This is the second part of a 2-part series. Read part 1.

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EVENT RECAP

The group reviewed data from the phase 3 TIVO-3 (NCT02627963) and TiNivo-2 (NCT04987203) trials.^1,2

DISCUSSION QUESTIONS

• From the TIVO-3 and TiNivo-2 data sets, what efficacy parameters appeal about tivozanib?
• What conclusions do you draw (eg, about tyrosine kinase inhibitor [TKI] dosing)?
• How important is proportion of patients who have received prior immune checkpoint inhibitors (ICIs) to you when weighing clinical trial data in your decision making?

Raji Shameem, MD: From TIVO-3 and TiNivo-2, is there anything that stands out to you? The combination [of tivozanib and nivolumab (Opdivo) did not outperform [single-agent tivozanib]…. Is there something that really surprised you?² Anything important—progression-free survival [PFS], response rate, durability, or the lines of therapy? Did anything from what we showed earlier strike out as important when you think about your treatment decisions?

George Robert Nahas, DO: You said the combination with regards to duration of response was not better?

Shameem: [In] TIVO-3…we have follow-up data looking at durability.¹ For TiNivo-2, focusing on the PFS [progression-free survival], and the depth of response that we tried to show, is that something that stuck out to you, the durability of TIVO-3?

Nahas: We usually think of durability of response in a setting of…these immunotherapies…because the immunotherapies [in] lung cancer [for example], we’re not used to seeing a tail end demonstrating some sort of immunological memory response, so to speak, so seeing that with other agents is important, almost from a molecular standpoint or microenvironmental standpoint, as I think it's important to explore.

Shameem: So the tail of the curve—I think that's something that strikes out too. And I just want to emphasize, those patients had prior TKI therapy; they were exposed, it's not like they never got it, but still, there's some who have that meaningful, durable benefit, so that’s an important point that you mentioned, the durability.

Nahas: Would you argue that that means that there's—maybe to extrapolate—possibly an immunological response as well?

Shameem: I can’t say. Only 26% got prior immune checkpoint inhibitor in that TIVO-3 trial,¹ but I definitely think that the drug is different. Every TKI is not the same, I kind of say that, but not sure about the immune reconstitution idea, but it's interesting for sure, seeing that tail of the curve.

Saritha Ravella, MD: I'm also wondering, if you are using lenvatinib [Lenvima] combinations in the second line, would you deliberately not pick that in the first line, although it is part of the NCCN options? That was one of the questions I had for you, [ Dr Shameem].

Shameem: I think that's a great question… Does your choice of second-line therapy dictate your frontline therapy? …Every patient and regimen is different, but I don't base that combination to dictate my frontline therapy. I'll say it that way, but every patient is individual. [Dr Ravella], for your practice, is that how you think?

Ravella: No…a lot of the studies you showed lenvatinib vs the second line, so I'm just thinking that we all know that every patient—assuming their performance status is intact, at least 2 or better—will not see every regimen, every line of therapy. I'm just saying, maybe we have to plan that way? That was a question that just popped in my mind while I was looking at the data.

Shameem: Does anyone feel the same way? That they have to plan their first line therapy based on what they're going to choose in second line, or they think the opposite?

Eugene Long, MD: I don't do that, because we may never get to the second line.

Shameem: That's true as well. Sometimes, your first shot is your only shot. That's fair. Based on that, do you have a favorite frontline therapy?

Long: I do. My patients either get ipilimumab [Yervoy] plus nivolumab upfront or pembrolizumab [Keytruda] plus lenvatinib, and what that means in practice is they get a couple doses of lenvatinib, and then they [often choose to discontinue lenvatinib], and then they're on pembrolizumab. After that, if that's what they got, it's cabozantinib [Cabometyx], and then after that tivozanib, and then belzutifan [Welireg].

Shameem: Dr Long, based on that small phase 2 trial, would that change your idea of what frontline would you think of using lenvatinib-everolimus [Afinitor] as a second line, like Dr Ravella?

Long: Patients [dislike the adverse events of] lenvatinib… I have 1 patient who's on it and it just doesn't bother her; she's been on for years. Everyone else, they lose their voice or they feel miserable, and they want to quit. And I find it a very difficult agent to get patients to adhere to.

Ravella: I had the same experience. Lenvatinib was hard, especially the high blood pressure and fatigue.

Long: And the thing about tivozanib is it's so tolerable in comparison. The patients just feel great.

Dillon Cockrell, MD: Dr Long, do you think that could be part of the reason why we see a tail on those curves with tivozanib, that patients are able to tolerate it and stay on it?

Long: They're absolutely still on the medicine. That is absolutely true. Whereas [with] lenvatinib, I just don't see any adherence to it at all. It requires dose reduction, and then they basically tell me they want to stop.

Shameem: That's a good point. Have you used them based on the data, looking at the second-line setting for TiNivo-2 monotherapy, 9.2 months PFS?² Does that make you consider tivozanib as a second-line option?

Long: Yes, I do, because a lot of times these patients are beat up, and so they don't want anything hard, and I found it to be a very tolerable agent.

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DISCLOSURES: Cockrell and Shameem have not previously disclosed any conflicts of interest.

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REFERENCES

1. Meza L, McDermott DF, Escudier B, et al. Tivozanib in patients with advanced renal cell carcinoma previously treated with axitinib: Subgroup analysis from TIVO-3. Oncologist. 2023;28(3):e167-e170. doi:10.1093/oncolo/oyac255

2. Chehrazi-Raffle A, Motzer RJ, Beckermann K, et al. Efficacy of second line (2L) treatment with tivozanib (Tivo) as monotherapy or with nivolumab (Nivo) in patients (pts) with metastatic renal cell carcinoma (mRCC) previously treated with an immune checkpoint inhibitor (ICI) combination of ipilimumab (Ipi)/Nivo or vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI)/ICI in the phase 3 TiNivo-2 study. J Clin Oncol. 2025;43(16_suppl):4540-4540. doi:10.1200/jco.2025.43.16_suppl.4540