Tivozanib Approval Adds to the Armamentarium in Relapsed/Refractory Advanced RCC

Brian I. Rini, MD

The FDA approval of tivozanib (Fotivda) has been a welcome addition to the armamentarium for patients with relapsed/refractory renal cell carcinoma (RCC), said Brian I. Rini, MD, who cited tolerability as a key characteristic of the VEGF inhibitor that may increase its utility in the clinic.

“Tolerability is the calling card of [tivozanib],” said Rini. “We always need more drugs in this disease, and we especially need drugs that are tolerated in a refractory setting. Patients [with refractory RCC] are not cured by VEGF-targeted monotherapy, so as patients progress through lines of therapy, the tolerance means a lot more. Patients know they are not getting cured. We start to ask ourselves: Are we helping patients more than we are hurting them?”

On March 10, 2021, the FDA approved tivozanib for the treatment of adult patients with relapsed/refractory advanced RCC following 2 or more prior systemic therapies.

The regulatory decision was based on findings from the phase 3 TIVO-3 trial, in which tivozanib significantly improved progression-free survival compared with sorafenib (Nexavar) in patients with highly relapsed/refractory metastatic disease. Overall survival was similar between arms (HR, 0.97; 95% CI, 0.75-1.24; P = .78).

In an interview with OncLive, Rini, a professor of medicine and the inaugural chief of Clinical Trials at Vanderbilt-Ingram Cancer Center, discussed the unique characteristics of tivozanib, how the FDA approval of the VEGF inhibitor is poised to further the advanced RCC paradigm, and the potential future utility of the agent.

OncLive: What about tivozanib’s mechanism of action distinguishes it from other available agents in RCC?

Rini: Tivozanib is a very potent and selective VEGF inhibitor. Several VEGF inhibitors are approved for [the treatment of patients with] kidney cancer; I’ve lost track of how many there are.

All [of the VEGF inhibitors] have [slightly] different [safety] profiles. There are those that are more selective, meaning they really just inhibit the VEGF receptor. Tivozanib and axitinib [Inlyta] are among [the more selective VEGF inhibitors]. At the other end of the spectrum, there are drugs that inhibit not only VEGF but a multitude of other targets. [The less specific] agents include more modern drugs, such as cabozantinib [Cabometyx] and lenvatinib [Lenvima], as well as sorafenib.

[Sorafenib] was the control arm of TIVO-3. It is an older drug and was the first TKI approved [in RCC].

There is probably some debate in the field over whether a more selective vs a less selective [VEGF inhibitor] is the right approach, [although] it is probably neither. More selective [VEGF inhibitors] definitely mean less adverse effects [AEs] because they have a cleaner profile. [The agent] isn’t hitting all of the other targets.

Whether there are efficacy advantages to some of the other targets is not well sorted out. However, if we just look at the TIVO-3 data, we have a selective inhibitor vs a less selective inhibitor showing advantages. At least in that setting, in that trial, and with [tivozanib and sorafenib], a more selective inhibitor [confers efficacy] advantages.

What type of patients comprised the population evaluated in the TIVO-3 trial?

In TIVO-3, patients were enrolled if they had 2 or more prior systemic therapies, including at least 1 prior VEGF TKI. Broadly speaking, [this was] a pretty typical refractory kidney cancer population. When the trial started, VEGF TKIs were standard. As [the trial] was accruing, immunotherapy became more standard. As a result, many patients also had prior immunotherapy. [TIVO-3] was basically a third- or fourth-line kidney cancer study.

What was noteworthy about the efficacy data from TIVO-3?

What is noteworthy about TIVO-3 is mostly the setting in which it was conducted, meaning there had never been a study specifically in third-line or later kidney cancer that had shown any advantages of one drug [vs] another. [Patients requiring third- or fourth-line therapy] is unfortunately a very common scenario in kidney cancer. Most patients will get multiple therapies because most of our therapies are not curative, although that is changing with immunotherapy. Patients get sequential palliative therapies, so many [patients] will make it to the third- and fourth-line [settings]. It is an important setting [in which] to do trials and show benefit for patients.

What AEs do clinicians need to be aware of when prescribing tivozanib?

Tivozanib is the best tolerated TKI [in patients with RCC]. That is the good news; it is really easy for patients to receive [tivozanib] and really easy for providers to give. [Tivozanib] [is associated with] typical VEGF [inhibitor] AEs, such as high blood pressure, dysphonia, [and other] on-target AEs. Some of the other typical AEs [observed with tivozanib], such as diarrhea and fatigue, are much less common [with tivozanib] compared with the multitargeted [VEGF inhibitors].

By now, 15 years into the approval of VEGF TKIs, most providers are fairly familiar with the [safety] profiles. As long as [providers] have given other TKIs, tivozanib will be, if anything, easier to give [vs other VEGF TKIs].

How is the approval of tivozanib going to affect the treatment algorithm?

It’s an interesting question. Right now, tivozanib is approved for patients [with RCC] who have received 2 or more prior systemic therapies. Commonly, we would give patients an immunotherapy-based doublet up front, such as ipilimumab [Yervoy] plus nivolumab [Opdivo] or an immunotherapy/VEGF TKI combination. After, cabozantinib is commonly a [second-line therapy] if the patient hasn’t gotten it already. My guess is that initially, tivozanib will be used very commonly in the third-, fourth-, and fifth-line settings. There are plenty of patients out there who have already gotten 2 to 4 prior agents, so [tivozanib] would certainly be a welcome option for them.

I have a feeling given [tivozanib’s] tolerance and activity that it could creep into earlier lines of therapy, even though it’s label [indicates its use] in the third- or fourth-line setting. [Tivozanib] is also being evaluated in other settings as well, but it will probably, on average, be a third-line drug.

Do you anticipate tivozanib will remain in the later-line settings as monotherapy or could it move into the frontline setting as monotherapy or in combination?

A large trial is being planned for tivozanib in combination with nivolumab. Initial cohort data from a French study [called TiNivo (NCT03136627) demonstrated early anti-cancer activity with that combination]. That [combination] is being looked at in an immunotherapy-refractory patient population. One of the main questions in kidney cancer is: Can patients have 2 shots at immunotherapy and, [therefore], potential cure as opposed to just one [shot] up front? That [question] is unanswered, but trials are ongoing, including the TiNivo-2 trial that is about to start.

I have a feeling there will be other investigator-initiated studies, perhaps looking at dosing or [moving tivozanib into] the neoadjuvant setting. After a drug is approved, the investigators can get their hands on it to look at the agent in other academic settings.

References

1. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. News release. FDA. Published March 10, 2021. Accessed April 27, 2021. https://bit.ly/3xtoFSH.
2. Rini BI, Pal SK, Escudier BJ, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21(1):95-104. doi:10.1016/S1470-2045(19)30735-1