Final analysis of the TiNivo-2 phase 3 trial: Long-term outcome of tivozanib (Tivo) in patients with metastatic renal cell carcinoma (mRCC).

4555 Background: TiNivo-2 results showed that immune checkpoint inhibitor (ICI) rechallenge did not offer benefit to patients with mRCC, regardless of treatment sequencing ( Lancet , 2024; 404:1309). However, the data highlights activity for Tivo monotherapy in the post-ICI setting. Long term outcomes of the TiNivo-2 study are reported here. Methods: TiNivo-2 trial design and primary-endpoint results were previously reported: patients with mRCC were randomized to treatment with Tivo 0.89 mg once daily for 21/28 days plus Nivolumab (Nivo) at 480 mg every four weeks (Tivo/Nivo) or Tivo 1.34 mg once daily for 21/28 days. Here, long term progression free survival (PFS), overall survival (OS), and the safety profile are reported at final analysis. Results: At the data cutoff of 17 October 2025, 172 patients were randomized to Tivo (171 treated) and 171 patients were randomized to Tivo/Nivo (168 treated); median (m) follow up was 28.4 mo (95% CI 27.0-29.8) in Tivo versus 27.2 months (mo) (95% CI 26.1-28.5) in Tivo/Nivo. Survival outcomes and hazard ratios (HR) for the ITT population, 2L, and 3L populations are summarized in Table 1. In 2L, mPFS favored Tivo over Tivo/Nivo (9.23 mo [7.29, 11.04] vs 5.95 mo [5.42, 7.95]). Across subgroups, there were no differences in mOS. No new safety signals were observed with prolonged administration; the most common ≥ Grade 3 TEAE was hypertension occurring in 39 (22.8%) and 38 (22.6%) and of patients in the Tivo and Tivo/Nivo groups respectively. Other ≥ Grade 3 TEAEs included diarrhea (2.3% and 3.6%) and palmar-plantar erythrodysaesthesia (0.6% and 1.2%) in the Tivo and Tivo/Nivo groups respectively. Treatment Related SAEs occurred in 15 (8.8%) and 18 (10.7%) of patients in Tivo and Tivo/Nivo groups respectively. Conclusions: This final analysis of patients in the TiNivo-2 study highlights the sustained efficacy Tivo in mRCC with a consistent safety profile. Together, these findings support durable clinical benefit and tolerability of Tivo in the post-ICI treatment setting in RCC, an area of high unmet need (NCT04987203). Clinical trial information: NCT04987203 . Parameter By ITT 2L setting 3L setting Tivo (0.89mg) /Nivo (n=171) Tivo (1.34mg) (n=172) Tivo (0.89mg) /Nivo (n=111) Tivo (1.34mg)(n=105) Tivo (0.89mg) /Nivo (n=60) Tivo (1.34mg)(n=67) mPFS, months (95% CI) 5.72(4.37-7.43) 7.43(5.52-9.23) 5.95(5.42, 7.95) 9.23(7.29, 11.04) 5.45(3.15, 9.56) 5.44(2.10, 7.36) mPFS HR 0.96 (0.76, 1.21) 1.08 (0.80, 1.46) 0.77 (0.52, 1.15) mOS, months (95% CI) 23.85(19.71-NR) 22.93 (18.14-NR) 29.50(21.06, NR) 23.52(18.33, NR) 19.71(10.81, 31.90) 22.70(11.79, NR) mOS HR 0.95 (0.70, 1.28) 0.78 (0.53, 1.16) 1.13 (0.70, 1.81) NR, not reached.