Tivozanib third-line or fourth-line therapy improves PFS in metastatic renal cell carcinoma

Tivozanib as third-line or fourth-line therapy improves progression-free survival (PFS) compared with sorafenib in patients with metastatic renal cell carcinoma (mRCC) who have received ≥2 previous systemic treatments, according to results of the phase III, randomized, controlled TIVO-3 trial.

Over a median follow-up of 19.0 months, tivozanib demonstrated significantly improved independent radiologist review committee (IRC)–assessed PFS (median, 5.6 months vs 3.9 months; hazard ratio [HR], 0.73; 95 percent confidence interval [CI], 0.56 to 0.94; p=0.016) and investigator-assessed PFS (median, 6.0 months vs 5.4 months; HR, 6.2; 95 percent CI, 0.48 to 0.80; p=0.003) vs sorafenib. [Lancet Oncol 2019, doi: 10.1016/S1470-2045(19)30735-1].

Subgroup analyses of PFS by prognostic factors and previous therapy also showed benefit with tivozanib compared with sorafenib, particularly in patients with favourable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk (HR, 0.46; 95 percent CI, 0.25 to 0.85) and those who previously treated with a checkpoint inhibitor and a VEGFR tyrosine kinase inhibitor (TKI) (HR, 0.55; 95 percent CI, 0.32 to 0.94; p=0.028).

A higher rate of partial response was demonstrated with tivozanib than sorafenib (18 percent vs 8 percent) among patients with measurable disease at baseline. No significant difference was found in the proportion of patients with 1–year duration of response (ie, no disease progression on study) between the tivozanib and sorafenib groups (71 percent vs 46 percent; HR, 0.60; 95 percent CI, 0.22 to 1.61; p=0.33).

No significant difference in overall survival was demonstrated between tivozanib and sorafenib (median, 16.4 months vs 19.7 months; HR, 0.99; 95 percent CI, 0.76 to 1.29; p=0.95).

In the TIVO-3 trial, 350 patients older than 18 years (median age, 63 years) with metastatic RCC who had received ≥2 previous systemic treatments (including ≥1 previous treatment with a VEGFR inhibitor) were randomized (1:1) to receive either tivozanib 1.5 mg orally once daily or sorafenib 400 mg orally twice daily continuously. Disease progression was the most common reason for treatment discontinuation in both groups.

Tivozanib is a novel VEGFR TKI approved by the European Medicines Agency (EMA) for first-line treatment of adults with advanced RCC. [https://www.ema.europa.eu/en/documents/product-information/fotivda-epar-product-information_en.pdf] Whilst having a potent action on VEGFR, tivozanib’s half-life extends over 4–5 days, which minimizes off-target toxic effects, resulting in improved efficacy and a reduced need for dose interruptions and dose reductions compared with sorafenib. Similar benefits in PFS with tivozanib vs sorafenib have been reported previously in the phase III TIOV-1 trial on first-line treatment of metastatic RCC. [Clin Cancer Res 2011;17:7156-7163; Eur J Cancer 2018;94:87-94]

In the TIVO-3 trial, hypertension (20 percent for tivozanib vs 14 percent for sorafenib) was the most commonly reported grade 3/4 treatment-related adverse event. Serious treatment-related adverse events occurred in 11 percent and 10 percent of patients receiving tivozanib and sorafenib, respectively. No treatment-related deaths were reported.

“Results of TIVO-3 demonstrated a significant improvement in PFS with tivozanib vs sorafenib in patients with highly refractory advanced RCC. Tivozanib also had a favourable safety profile compared with other VEGFR TKIs. These results support tivozanib as a treatment option for patients with advanced RCC, including those who have progressed after previous immunotherapy,” the researchers concluded.