Long-Term Durability Favors Tivozanib Vs Other TKI in Recurrent mRCC

Commentary
Article

During a Case-Based Roundtable® event, Sumanta Kumar Pal, MD, discussed long-term outcomes of the TIVO-3 trial in patients with metastatic clear cell renal cell carcinoma in the first article of a 2-part series.

Sumanta Pal MD

Sumanta Kumar Pal, MD

Codirector, Kidney Cancer Program

Chair, Kidney and Bladder Cancer Disease Team

Professor, Department of Medical Oncology & Therapeutics Research

City of Hope

Duarte, CA

Targeted Oncology: What is the significance of the TIVO-3 study (NCT02627963) in patients with recurrent metastatic clear cell renal cell carcinoma (RCC)?

SUMANTA KUMAR PAL, MD: This is the phase 3 clinical trial that ultimately led to the approval of tivozanib [Fotivda] and you can bear in mind the eligibility criteria. I interpret this fairly loosely, but this included patients [whose disease failed to respond to] 2 or 3 prior regimens, including at least 1 VEGF-TKI [tyrosine kinase inhibitor]. In the era in which the study was done, patients were typically getting sunitinib [Sutent] followed by pazopanib [Votrient], [or] sunitinib followed by everolimus [Afinitor]. When we were enrolling to this trial—this is a study that I enrolled pretty heavily to—we were just starting to see patients get second-line nivolumab [Opdivo] at that point. This wasn’t in an era when patients were getting axitinib [Inlyta] plus pembrolizumab [Keytruda] upfront, or cabozantinib [Cabozantinib] and nivolumab upfront. This was done well before that.

In this study, patients had to at least received 1 VEGF-TKI, and I want to emphasize the stratification factors.… We looked further at subsets based on TKI followed by PD-1 [inhibitor], TKI to TKI, or TKI followed by other regimens.

Patients in the study were [randomly assigned] to tivozanib vs sorafenib [Nexavar]. For those that haven’t used tivozanib before, this is a drug that follows…the dose interruption schedule that we had with sunitinib where patients are on for 3 weeks, off for 1 week. The dose you get in your electronic medical records looks different from [this trial]. It’s not 1.5 mg, but rather 1.34 mg. That’s just a formulation issue.

What were the key efficacy outcomes of the RCC population in this trial?

There are data [the other investigators and] I published a couple of years ago that updated some of the initial results from TIVO-3.1 The primary end point of the study was progression-free survival [PFS], and the primary end point was met. When you look at the data, PFS with sorafenib was 3.9 months. PFS with tivozanib was 5.6 months. But…this is the important element of the dataset: as time goes on, one of the things I’m appreciating is that tivozanib splays apart from sorafenib. Over the course of time, we run into the subset of patients who derive substantial benefit from tivozanib [2-year PFS rate: 18% with tivozanib vs 5% with sorafenib].2

I have a patients who received tivozanib therapy for 3.5 to 4 years after being enrolled. This is a patient who had received prior sunitinib, prior nivolumab, and prior axitinib. This patient was on therapy for several years. It’s not the majority of patients in the study, but there’s at least a proportion who remain on therapy out to the 3- and 4-year mark [12.3% PFS rate at 3 years, 7.6% at 4 years].3 I think that this is quite interesting, and we’re in the process of updating some of the data from this trial as we speak.

[The investigators] broke out the cohort of patients who had received prior checkpoint inhibitors. This is an important subset because at the time we didn’t have patients [receiving] axitinib/pembrolizumab [or] cabozantinib/nivolumab enrolling on this. This is the subset of patients who went from sunitinib to nivolumab or pazopanib to nivolumab, and then went on to therapy with tivozanib. In the Kaplan-Meier curves, there was even more of a tail on the curve and more patients who are deriving protracted benefit.3,4

Patients will ask in the clinic, “If I get therapy with tivozanib, what is my chance for response?” The overall response rate in this study was 23% with tivozanib vs 11% with sorafenib.5 True to the form of these Kaplan-Meier curves, if you do get a response with tivozanib, it tends to be fairly long-lasting. These patients responded for a median of 20 months on the trial, which is impressive in the third- and fourth-line setting where the study was conducted.3

What treatment-related toxicities of grade 3 or higher were observed with tivozanib compared with sorafenib?

When you look at tivozanib vs sorafenib, which is a drug that we all have experience with from patients with hepatocellular carcinoma, there seemed to be less diarrhea [2% vs 9%, respectively], less in the way of fatigue [4% vs 5%], and less in the way of hand-foot syndrome [1% vs 10%].6 One thing that there is a bit more of and something we need to be cautious of with tivozanib is hypertension [20% vs 14% with sorafenib], but in general, the tolerability profile seemed to be better with this regimen relative to sorafenib.

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. Rini BI, Pal SK, Escudier B, et al. TIVO-3: Tivozanib in patients with advanced renal cell carcinoma (aRCC) who have progressed after treatment with axitinib. J Clin Oncol. 2021;39(suppl_6):278. doi:10.1200/JCO.2021.39.6_suppl.27

3. Atkins MB, Verzoni E, Escudier BJ, et al. Long-term PFS from TIVO-3: Tivozanib (TIVO) vs sorafenib (SOR) in relapsed/refractory (R/R) advanced RCC. J Clin Oncol. 2022;40(­suppl_6):362. doi:10.1200/JCO.2022.40.6_suppl.362

4. Rini BI, Pal SK, Escudier B, et al. TIVO-3: A phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC). J Clin Oncol. 2019;37(suppl 7):541. doi:10.1200/JCO.2019.37.7_suppl.541

5. Verzoni E, Escudier B, Hutson TE, et al. TIVO-3: Durability of response and updated overall survival of tivozanib versus sorafenib in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2021;39(suppl_15):4546. doi:10.1200/JCO.2021.39.15_suppl.4546

6. Beckermann KE, Asnis-Alibozek AG, Atkins MB, et al. Long-term survival in patients with relapsed/refractory advanced renal cell carcinoma treated with tivozanib: analysis of the phase III TIVO-3 trial. Oncologist. 2024;29(3):254-262. doi:10.1093/oncolo/oyad348

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