Tivozanib Boosts RCC Treatment Portfolio

Daniel J. George, MD

The FDA's approval of tivozanib (Fotivda) adds an effective treatment option with a manageable safety profile for patients with relapsed or refractory renal cell carcinoma (RCC), according to Daniel J. George, MD.¹

In vitro cellular kinase assays showed that the tyrosine kinase inhibitor (TKI) inhibits the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3.² The agent was evaluated in the phase 3 TIVO-3 trial (NCT02627963), which compared tivozanib with sorafenib (Nexavar) in patients with refractory advanced RCC.

Efficacy data from the trial showed that the median progression-free survival (PFS) in the tivozanib group (n = 175) was 5.6 months (95% CI, 4.8-7.3) compared with 3.9 months (95% CI, 3.7-5.6) in the sorafenib group (n = 175). The objective response rate was 18% (95% CI, 12%-24%) in the tivozanib arm vs 8% (95% CI, 4%-13%) in the sorafenib arm.

In an interview with OncLive^®, George, director of genitourinary oncology at Duke University Cancer Institute (DCI), and cochair of DCI Center for Prostate & Urologic Cancers in Durham, North Carolina, discussed how tivozanib differs from other TKIs and its potential to fill an unmet need in the treatment of patients with RCC.

OncLive: Please provide an overview of the patient population in the TIVO-3 trial.

George: TIVO-3 examined a [population of patients with] refractory kidney cancer. These are patients with metastatic kidney cancer, clear cell type, who have already previously been treated with a TKI and an immunotherapy and were in either the third- or fourth-line setting of treatment. Patients could have had more than 1 of either of those regimens. Patients were randomized 1:1 to either sorafenib, an FDA-approved VEGF TKI used frequently in the refractory disease setting, or tivozanib, which had been approved in Europe based on a frontline study against sorafenib.

What was noteworthy about the efficacy data that led to the approval?

There were 2 noteworthy components to this trial. The first was that for the intention-to-treat population we saw a statistically significant improvement in the PFS associated with tivozanib vs sorafenib, which was approximately a 30% improvement in HR, delaying the time to disease progression. The second is that, in a prespecified subset analysis looking at patients who were immediately proceeded by an I/O [immuno-oncology] therapy, there was an even greater PFS benefit seen with the subsequent use of tivozanib vs sorafenib This suggests that this agent may be particularly useful in patients who are refractory to I/O agents, and it also suggests that this agent could work well in combination with I/O agents, which we’re seeing now as a standard of care in the frontline setting.

The last thing that’s interesting from both the Kaplan-Meier curves from this study is the tail of the curve. There are approximately 20% to 30% of patients who have a much more durable PFS associated with tivozanib than sorafenib. It seems as though there’s a subset of patients who appear to have VEGFdependent RCC, even in this refractory state. Tivozanib was a drug that most patients were able to tolerate at or near full dosage; that’s important in a refractory patient population. Many of these patients are refractory in part due to difficulty tolerating these agents and are at a point in their disease where they’re dealing with the symptoms of the disease as well as prior therapies. Tolerance becomes a critical and often differentiating factor in their survival.

Regarding safety, what do we know about tivozanib’s tolerability, and what adverse events should be taken into consideration when it is administered?

Even though we have several VEGF TKIs in the field, tivozanib has the greatest potency. It’s dosed at the lowest level of any VEGF TKI and it’s highly specific for the VEGF receptors. [Tivozanib] also has a relatively long half-life. There are biologic and toxicity ramifications of these features. Due to the VEGF specificity and high potency, we see an adverse effect profile that’s a little more narrowed around VEGF toxicities, including hypertension, diarrhea, fatigue, and dysphonia, in this refractory population. We’re also recognizing that blood pressure might need to be adjusted in this patient population.

It’s important to recognize that this toxicity is manageable. We’re able to dose this drug daily with a relatively long half-life. That’s important regarding toxicities that might be a bit more episodic, things such as nausea and diarrhea.

How does this approval advance the RCC treatment paradigm?

There’s a lot of progress being made in RCC in the frontline space with combinations of I/O therapy or I/O and TKI therapy. This suggests that for those patients who can tolerate those regimens, there’s a lot of benefit. However, most of those patients are still going to progress. When they progress, now having been exposed to multiple classes of drugs, it’s critical that there is tolerable therapy. What we’ve learned over the past 15 years in RCC is that the sequence of one TKI after another has been associated with a longer survival than switching to other classes or no therapy at all. Tivozanib fills an unmet need in the RCC space for patients who struggle to tolerate multitargeted VEGF TKIs that may be causing additional toxicity. It allows patients to potentially remain on treatment and to significantly delay the time to disease progression.

What are the next steps for tivozanib? 

It’s important to understand the unique features of this drug, to help educate clinicians about its differentiating characteristics, and [to encourage them] to use it in their patients in this disease setting. Also, it’s important that the [investigators] begins to revisit some the earlier disease settings that TKIs are being used in because we see a significant number of toxicities with those combinations and much of that is driven by the TKI of choice. Tivozanib needs to be able to generate data that show it is active in that combination setting. It is also tolerable in combination with I/O therapy, which will be an important future direction.

References

1. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. FDA. March 10, 2021. Accessed April 13, 2021. https://bit.ly/3xglNZ9
2. Tivozanib. Prescribing information. AVEO Pharmaceuticals Inc; 2021. Accessed April 13, 2021. https://bit.ly/32L8Ic5