Considering the Role of Tivozanib After Prior ICI-Based Therapy in RCC

The treatment landscape for advanced renal cell carcinoma (RCC) has evolved with the widespread use of immune checkpoint inhibitor (ICI)–based combinations in the frontline setting, creating new considerations for subsequent lines of therapy. In particular, clinicians must weigh efficacy, tolerability, prior treatment exposure, and whether continued ICI therapy provides additional benefit when selecting a second-line regimen.

In a virtual Case-Based Roundtable event, David Braun, MD, PhD, associate professor of Internal Medicine (Medical Oncology and Hematology) at Yale School of Medicine, and Jahan Aghalar, MD, medical oncologist/hematologist at New York Cancer & Blood Specialists/OneOncology, moderated a discussion with oncologists in the mid-Atlantic region, who evaluated data from the phase 3 TiNivo-2 (NCT04987203) and TIVO-3 (NCT02627963) trials and considered the role of tivozanib (Fotivda) in patients with advanced RCC following prior therapy.

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

DISCUSSION QUESTIONS

• What is your reaction to the efficacy data from the phase 3 TiNivo-2 study?
  • The combination arm?
  • The tivozanib monotherapy arm?
• Do you consider any of the results to be clinically meaningful, practice changing, or practice confirming?

David Braun, MD, PhD: I know the majority of people haven't used tivozanib before, and so just seeing these TiNivo-2 data, what is your reaction to it? Is it clinically meaningful? Does it reaffirm your practice, or is this something new for you?

Neal Shah, MD: I've seen some of the data before. Again, I haven't used the drug yet in clinical practice, but…I just look for what the first-line medication was mechanism-of-action–wise and then consider if the patient got dual immunotherapy [IO-IO], then potentially using [tivozanib] in the second line.

Joshua Kra, MD: I've prescribed [tivozanib]. Not as much in the second-line setting, more just in patients who have been through other therapies, but I’m becoming a little more comfortable with it. I think the data clearly show the [progression-free survival (PFS)] benefit, and as you mentioned, not really an overall survival [OS] benefit¹…and so I think it's just another very useful drug that we have available.

Braun: Great. Any other thoughts?

Eli Kirshner, MD: It’s a drug that I've never used and won't. I figure if it can't beat sunitinib [Sutent], what's the point?

Braun: Right. And that's the OS data that you're seeing for the TIVO-3 study?

Kirshner: Correct. In fact, I thought it should have been withdrawn from the market when it did not meet survival benefit.

Braun: Reasonable. I will say—this is sadly the case for RCC, and I think it's starting to change—but historically, very few drugs beat their comparators in terms of OS in the second-line setting. I mentioned a couple that did. But if we look at lenvatinib [Lenvima]-everolimus [Afinitor]—even though it was phase 2—there was no [statistically significant OS] benefit over everolimus alone.² But I think we look at belzutifan [Welireg], for instance, and belzutifan doesn't have a [statistically significant] OS benefit either.³ I think you highlight a real problem in the field.

Tina Mayer, MD: But I think [tivozanib] is more tolerable than sunitinib too… I haven't used it a ton because I use it in later lines, but when I've used it, sometimes I've had to dose-reduce, but it's reasonably well tolerated.

Yacoub Faroun, MD: I think it's a hard drug to use in my opinion. I had used it at 1.3 mg and then 0.89 mg. The patient [case you presented] is an optimal patient for clinical studies—60 years old—but our patients are in their 70s or 80s. I think fatigue and high blood pressure were significant in such patients.

Braun: You bring up the idea of hypertension. We didn't go over the adverse effects as much, but I think as you get more selective for [agents like] axitinib [Inlyta] and tivozanib, maybe the range of adverse effects is not as high. But certain effects like hypertension and proteinuria are certainly quite high with both of those drugs, tivozanib and axitinib.

Bhuvana Ramkumar, MD: I've used [tivozanib] a few times, and the patient is doing well. The first few months were hard for them. The patient had significant lung metastasis and was quite symptomatic, and he was struggling with the drug as well. I kept him at the 1.34 mg, and surprisingly, after 2 months, he started responding… he's actually 8 months into it. I used it post first-line cabozantinib [Cabometyx]-nivolumab [Opdivo].

Braun: That's great. It's less common these days to have these breaks with tyrosine kinase inhibitors [TKIs]; most of them are given continuously. This is one that has that break built in…for some people, that break can be helpful.

DISCUSSION QUESTIONS

• From TIVO-3 and TiNivo-2 datasets, what efficacy parameters appeal about tivozanib (eg, 5-year, long-term PFS, objective response rate, duration of response, line of therapy/setting)?
• How important is proportion of patients who have received prior ICI to you when weighing clinical trial data in your decision-making?

Ramkumar: I think the overall response rate and PFS [stand out], and especially for TiNivo-2, it clearly showed continuing an IO [nivolumab] didn't add any benefit.¹ In the second-line setting, I think we all look at the response rate and the adverse effect profile because [these patients] have already been treated and, as mentioned before, are beat up [from] prior TKI or IO-related [adverse] effects; on top of that, [they have] tumor burden, and then we are trying to challenge them again with another TKI. I think it's all those characteristics put together.

Braun: And then, how much does it matter for you how many of the patients on a trial had received prior immunotherapy? We see some trials that are more historic and none of them got immunotherapy. Some of them are kind of in between, like TiNivo-3, where a quarter of patients get immunotherapy, and then there are trials where everyone got prior immunotherapy. Are those data super important for you guys, or are they just more details?

Ramkumar: I think it's important because, in our clinical practice, most [patients] are going to receive a combination upfront; unless they cannot get an IO, they go on a single-agent TKI. So, I think for real-life [practice], it's important because we want to look back at the trial and see, are we treating the same population? I think majority of us are going to go for an IO-TKI combination.

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DISCLOSURES: Braun previously disclosed serving a consulting or advisory role for Bristol-Myers Squibb, Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, Insight Strategy, Schlesinger Associates, Exelixis, AVEO, Catenion, Cello Health, Aptitude Health, AbbVie, DLA Piper, Merck, Elephas Bio, CurIOS Therapeutics, Pfizer, Scholar Rock, Eisai, 2nd.MD, Compugen, Link Cell Therapies, Neomorph, Nimbus Therapeutics, Daiichi Sankyo, and Caris Life Sciences; and research funding from Exelixis and AstraZeneca.

Aghalar previously disclosed a consulting or advisory role for Bayer AG and Janssen Oncology, and serving on a speakers’ bureau for Janssen Oncology, Sanofi, and EMD Serono.

REFERENCES

1. 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

2. 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

3. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma. N Eng J Med. 2024;391(8):710-721. doi:10.1056/nejmoa2313906