Prolonged Duration of Response With Tivozanib for RCC Revealed at Long-Term Follow-Up


Follow-up data from the phase 3 TIVO-3 trial that were reported at the 2021 ASCO Annual Meeting serve to further support the use of tivozanib versus standard-of-care sorafenib in patients with metastatic renal cell carcinoma who have failed on prior therapy.

The median duration of response (DOR) for patients with metastatic renal cell carcinoma (mRCC) treated with tivozanib (Fotivda) was more than double that of sorafenib (Nexavar)–treated patients on the phase 3 TIVO-3 trial, according to data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1

“Collectively, these data confirm and extend previous findings for tivozanib as an evidence-based treatment option for patients with relapsed and refractory RCC, including for patients whose disease has progressed after previous checkpoint inhibitor therapy,” the study authors concluded.

At the data cutoff for these analyses (January 15, 2021), the agent demonstrated clinically meaningful and statistically significant improvements in overall response rates (ORR) and duration of response (DOR), with similar overall survival (OS), compared with sorafenib.

Per investigator assessment, 41 (23%) patients in the tivozanib arm experienced a response to treatment, compared with 20 (11%) patients in the sorafenib arm. Similarly, the tivozanib group had a superior disease control rate compared with the sorafenib group (82% vs 69%, respectively), as well as a better partial response rate (23% vs 11%) and stable disease rate (59% vs 58%).

Median DOR was 20.3 months (95% CI, 9.8-29.9) with the potent and highly selective VEGFR TKI tivozanib, compared with 9.0 months with sorafenib (95% CI, 3.7-16.6). Moreover, 13 (7%) patients treated with tivozanib had continued ongoing responses at the time of data cutoff—32% of the response group—compared with 3 (2%) patients treated with sorafenib.

With the prolonged follow-up, tivozanib demonstrated superior OS, compared with sorafenib (HR, 0.91; 95% CI, 0.716-1.165; P = .47); however, this did not reach statistical significance.

“[A] statistically significant improvement in PFS and ORR had previously been shown and continues to improve with longer follow-up,” the study authors wrote. “OS relative to sorafenib continues to improve with longer follow-up.”

In the open-label, randomized-controlled phase 3 TIVO-3 trial (NCT02627963), investigators compared the efficacy and safety of tivozanib with sorafenib as a third- or fourth-line therapy in patients with metastatic RCC.2 In a poster presentation at the ASCO annual meeting, the study authors reported on the long-term durability of response based on an investigator assessment and updated OS in patients from the trial.

Between May 24, 2016, and August 14, 2017, investigators randomized patients 1:1 to receive treatment with either tivozanib at 1.5 mg orally once daily for 3 weeks on, and 1 week off in 4-week cycles (n = 175) or sorafenib at 400 mg orally twice daily continuously in 4-week cycles (n = 175) until progression or unacceptable toxicity.

Patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category (favorable, intermediate, or poor), and type of prior therapy (2 prior VEGFR TKIs, VEGFR TKI plus checkpoint inhibitor, or VEGFR TKI plus any other systemic agent). To be eligible for the trial, patients had to have advanced clear cell mRCC, progressed on 2 or 3 prior systemic therapies including 1 or more VEGFR TKIs, and an EGOG performance score of 0 or 1.

Progression-free survival (PFS) by independent review in the intention-to-treat population served as the primary end point. Secondary end points included OS, ORR, DOR, and safety.

Median follow-up was 19.0 months (IQR, 15.0-23.4).

The study authors noted that baseline patient demographics and disease characteristics were balanced and typical of those seen in patients with mRCC. Patients treated with tivozanib were a median age of 62 years (range, 34-88). The majority on the tivozanib arm were male (72%), had intermediate-risk disease (62%), received 2 prior systemic therapies (62%), including 2 VEGFR TKIs (45%).

The trial—published in Lancet Oncology—showed that median PFS was significantly longer in the tivozanib arm (5.6 months; 95% CI, 5.29-7.33), compared with the sorafenib arm (3.9 months; 95% CI, 3.71-5.55; HR, 0.73; 95% CI, 0.56-0.94; P = .016). In addition, ORR was 18% versus 8% (P = .02).

The most common grade 3/4 treatment-related adverse event (TRAE) in the tivozanib and sorafenib arms was hypertension (20% vs 14%, respectively). Serious TRAEs occurred in 19 (11%) patients treated with tivozanib and in 17 (10%) patients treated with sorafenib. No treatment-related deaths were reported.

As a result of the initial study results, in March 2021, the FDA approved tivozanib for adult patients with relapsed or refractory advanced RCC following 2 or more prior systemic therapies.3

“Tivozanib is a potent and highly selective vascular endothelial cell growth factor (VEGFR) tyrosine kinase inhibitor (TKI) with a long half-life that is an effective treatment option for patients with previously treated mRCC,” the study authors wrote, adding that the agent is approved in the EU for patients who are not previously treated with a VEGFR TKI or mTOR inhibitor.


1. 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; abstr 4546). doi:10.1200/JCO.2021.39.15_suppl.4546.

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.

3. FDA News Release. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. Published:March 10, 2021. Accessed June 4, 2021.

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