Tivozanib Receives Full Approval for Treatment of Patients With Third-Line or Later RCC

Based on results of the phase 3 TIVO-3 trial in patients who have previously received at least 2 lines of therapy for renal cell carcinoma, the FDA granted approval to tivozanib for use in this patient population.

The FDA has granted approval to tivozanib (Fotivda) for the treatment of adult patients with relapsed or refractory renal cell carcinoma (RCC) following 2 or more prior lines of therapy.1

The new drug application for this indication was accepted back in June 2020 and was supported mainly by findings from the phase 3 TIVO-3 trial (NCT02627963). Patients receiving tivozanib on the trial were in a third or later line of therapy; outcomes were compared against another group of patients receiving standard-of-care sorafenib (Nexavar).2

“Today’s approval of Fotivda provides a new tool for treating patients with kidney cancer who have relapsed or become refractory to 2 or more prior systemic therapies,” Brian Rini, MD, chief of clinical trials at Vanderbilt Ingram Cancer Center and principal investigator of the TIVO-3 trial, said in a press release. “With advances in RCC treatment, patients are living longer, increasing the need for proven, well-tolerated treatment options in the relapsed or refractory setting. The TIVO-3 study is the first positive phase 3 study in patients with RCC who received 2 or more prior systemic therapies, and also the first phase 3 RCC study to include a predefined population of patients who have received prior immunotherapy, the current standard of care in earlier-line treatment. With this approval, I believe Fotivda represents an attractive intervention, and expect it to play a meaningful role in the evolving RCC treatment landscape.”

Final overall survival (OS) results from the trial were presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program. Although there was no significant OS benefit with the use of the experimental regimen (HR, 0.97; 95% CI, 0.75-1.24; P = .78), progression-free survival (PFS) was improved with tivozanib versus sorafenib.3

In the intention-to-treat population, there was a statistically significant benefit in the median PFS versus sorafenib, at 5.6 months versus 3.9 months, respectively (HR, 0.73; 95% CI, 0.56-0.94; P = .016). Additionally, those patients receiving prior treatment with checkpoint inhibitor therapy as well as a VEGF tyrosine kinase inhibitor (TKI) or 2 prior VEGF TKIs saw the greatest reduction in the risk of disease progression or death, with hazard ratios of 0.55 and 0.57, respectively.

Response rates were higher on the tivozanib arm at 18% (95% CI, 12.36%-24.19%) versus 8% (95% CI, 4.44%-13.06%) with sorafenib. All responses were comprised of partial responses. The disease control rate for each arm was 75% and 65%, respectively.

Treatment-related adverse events (AEs) were reported in 84% of patients on tivozanib versus 94% of patients randomized to sorafenib. The most common grade 3/4 AE was hypertension in 20% and 14%, respectively. Serious AEs were reported in 11% of patients on the tivozanib arm versus 10% on the sorafenib arm.

At the 2020 Genitourinary Cancers Symposium, tivozanib demonstrated a statistically significant increased quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) compared with sorafenib in the TIVO-3 trial. This was undertaken to quantify the net health benefits of tivozanib given the similar OS outcomes observed in the final analysis.4

The relative Q-TWiST benefit was defined as the mean absolute Q-TWiST difference divided by the sorafenib mean OS, with means of 15.04 months for tivozanib versus 12.78 months for sorafenib (= .0493).

“Relapsed or refractory RCC is a devastating disease for which patient outcomes can be limited due to the tradeoff between tolerability and efficacy,” said Dena Battle, president of KCCure. “The FDA approval of Fotivda represents an exciting, meaningful advancement by providing a new treatment option for this patient population.”

The recommended dose of tivozanib is 1.34 mg daily to be administered in 4-week cycles, with patients being treated on a 3-weeks-on/1-week-off basis until disease progression or unacceptable toxicity.

AVEO expects to have Fotivda available for patients in the United States by March 31, 2021.


1. AVEO Oncology announces U.S. FDA approval of Fotivda (tivozanib) for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma. News release. AVEO Oncology. March 10, 2021. Accessed March 10, 2021. https://aveooncology.gcs-web.com/node/14681/pdf

2. AVEO Oncology announces FDA acceptance for filing of a new drug application for tivozanib as a treatment of relapsed or refractory renal cell carcinoma. News release. AVEO Oncology. June 1, 2020. Accessed March 10, 2021. https://aveooncology.gcs-web.com/node/14681/pdf

3. Pal SK, Escudier B, Atkins MB, et al. TIVO-3: Final OS analysis of a phase III, randomized, controlled, multicenter, open-label study to compare tivozanib to sorafenib in subjects with metastatic renal cell carcinoma (RCC). J Clin Oncol. 2020;38(suppl 15):5062. doi:10.1200/JCO.2020.38.15_suppl.5062

4. Szarek M, Needle MN, Rini BI, et al. Q-TWiST analysis of tivozanib (T) versus sorafenib (S) in patients with advanced renal cell carcinoma (RCC) in the TIVO-3 study. J Clin Oncol. 2021;39(suppl 6):298. doi:10.1200/JCO.2021.39.6_suppl.298