Treatment for metastatic renal cell carcinoma (RCC) continues to change with evolving options, including targeted therapies and immunotherapy combinations. Sumanta K. Pal, MD, chair of the Kidney and Bladder Cancer Disease Team, codirector of the Kidney Cancer Program, and professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center moderated a virtual Case-Based Roundtable event. He highlighted different dosing regimens for lenvatinib (Lenvima), as well as data from tivozanib (Fotivda) trials evaluating efficacy in relapsed/refractory RCC.
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This article is part 2 of a 2-part series from a Case-Based Roundtable event.
Targeted Oncology: Can you discuss what Study 218 (NCT03173560) showed for patients with relapsed/refractory RCC?
Sumanta K. Pal, MD: This was a study I ran that looked at patients who had received a VEGF TKI [tyrosine kinase inhibitor] and possibly prior PD-1–based therapy. The goal of this trial was to see if you could mitigate the toxicity associated with lenvatinib and everolimus. I think that can be a tough regimen. The dose we usually give for refractory RCC is 18 mg, with 5 mg of everolimus. In this FDA mandated trial, we compared that to 14 mg and 5 mg, respectively. The primary end point of the study was to do a comparison of toxicities and response rate to see if they were equally efficacious.1
What I think is interesting—and this was shown in our final publication—is that it’s clear if you’re going with a higher dose of lenvatinib, you’re getting a little bit more bang for your buck. What is also interesting is, if you look at the frequency of toxicities associated with these agents, there’s not a meaningful difference between the 2 [dose levels]. You would think by coming down by a whole 4 mg of lenvatinib, you’d mitigate some of the toxicity signal with these regimens, but that doesn’t appear to be the case.
I think this is important because I see a lot of second opinions where physicians will start lenvatinib at a lower dose than what’s on label, and it may not necessarily be mitigating toxicity in the way that we think based on these data.
What are the data for using tivozanib monotherapy in the metastatic RCC space?
The pivotal TIVO-3 clinical trial [NCT02627963] was also a study I was involved with. One of the things I’d like to point out is that this study was not done in the era of checkpoint inhibitors or cabozantinib [Cabometyx]. This study compared tivozanib to sorafenib [Nexavar], and at the time, sorafenib was a very reasonable control arm. We didn’t have much else. But as this study evolved, we started to see more and more patients getting checkpoint inhibitors. Ultimately, this trial showed what I think is a pretty compelling signal for tivozanib over sorafenib. There was a tail on the Kaplan-Meier curve for progression-free survival [PFS].2 The response rate was better with tivozanib vs sorafenib, and this led to the approval of tivozanib in patients who received prior systemic treatment.3
Can you discuss the newer data with tivozanib combinations for this patient population?
At the 2024 European Society for Medical Oncology Congress, the TiNivo-2 study [NCT04987203] looked at combination of tivozanib and nivolumab [Opdivo] vs tivozanib monotherapy. There was a somewhat complicated dosing strategy for tivozanib. If you haven’t used it before, tivozanib is given at 1.34 mg orally on days 1 through 21 on the 28-day cycle. What’s interesting is that they did some phase 1 studies looking at tivozanib with nivolumab, and for some reason, that combination produced a very strong signal of hypertension. When the FDA gave comments around this study, they mandated that we use a lower dose of tivozanib of 0.89 mg with nivolumab. So it’s not necessarily a fully balanced comparison, but nonetheless, the goal of this study was to see whether, in patients who had received prior checkpoint inhibitors… there is any benefit in continuing the checkpoint inhibitor.4
One of the things the study highlights is that this is a contemporary population of patients. Most of the patients in the study, about two-thirds, had only received 1 prior line therapy. A checkpoint inhibitor was the most recent therapy for most of these patients, and about a third of patients had received no prior VEGF TKIs. You can assume that for the most part, those are patients who got nivolumab plus ipilimumab [Yervoy].
The patients who were entered onto this study had received prior nivolumab/ipilimumab or axitinib [Inlyta]/pembrolizumab [Keytruda]. Some had gotten nivolumab or cabozantinib in the second-line setting. But this was a good evaluation of second-line treatment by and large.
What was the result of the TiNivo-2 trial?
The key finding from the study was negative. There was no difference with a combination of tivozanib and nivolumab vs tivozanib in this in this setting. The Kaplan-Meier curves for PFS were fully overlapping. There was no subset of patients who benefited. You might think that perhaps a patient who has poor risk might benefit from the addition of further checkpoint inhibition, but we don’t see that the poor-risk category has that benefit. You might think that if patients receive more extensive prior targeted therapies, they might benefit more. That doesn’t appear to be the case.
But what I think this study is important for, despite being negative, is the benchmark for how tivozanib can perform when it’s administered as second-line therapy. There was a [median] PFS of 9.2 months when we use tivozanib as second-line therapy. I think this is fairly comparable in many respects to drugs like cabozantinib and others we started to use in the second line.
What other recent findings are relevant for tivozanib in patients with previously treated RCC?
There was a more recent analysis that my junior faculty member at City of Hope presented at American Society of Clinical Oncology in June.5 He had a terrific poster that gave a lot of important data for tivozanib in patients who had received either prior immunotherapy or prior targeted therapy and immunotherapy. What [he showed is] if your patient, for instance, had just gotten prior nivolumab/ipilimumab, the response rate with tivozanib is on the order of 32%, so a pretty respectable response rate. On the other hand, if your patient had received prior axitinib/pembrolizumab, or cabozantinib/nivolumab, the response rate dwindles down a little bit to 22% there, but still a reasonable response. I would say this is a compelling signal that tivozanib has good efficacy in these second-line settings.
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DISCLOSURES: Pal previously reported travel, accommodations, or expenses with CRISPR Therapeutics, Ipsen, and Exelixis.
References:
1. Pal SK, Puente J, Heng DYC, et al. Assessing the safety and efficacy of two starting doses of lenvatinib plus everolimus in patients with renal cell carcinoma: a randomized phase 2 trial. Eur Urol. 2022;82(3):283-292. doi:10.1016/j.eururo.2021.12.024
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
3. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. FDA. News release. Accessed August 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tivozanib-relapsed-or-refractory-advanced-renal-cell-carcinoma
4. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6
5. 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(suppl 16):4540. doi:10.1200/JCO.2025.43.16_suppl.4540