Long-Term Follow-Up Confirms Tivozanib Monotherapy Efficacy in 2L/3L mRCC

Standard-dose tivozanib (Fotivda) monotherapy demonstrated durable efficacy in patients with metastatic renal cell carcinoma (mRCC) treated in the second-line and third-line settings, according to a post hoc, long-term follow-up analysis of the phase 3 TiNivo-2 trial (NCT04987203) presented during the 2026 Kidney Cancer Research Summit.¹

At a median follow-up of 28.5 months (95% CI, 27.0-30.6) for the standard-dose tivozanib arm, median progression-free survival (PFS) was 9.23 months (95% CI, 7.29-11.04) in second-line patients and 5.44 months (95% CI, 2.10-7.36) in third-line patients, and median overall survival (OS) was 23.52 months (95% CI, 18.33–not reached [NR]) in second-line patients and 22.70 months (95% CI, 11.79-NR) in third-line patients.

What was the design of TiNivo-2 and the long-term analysis?

TiNivo-2 randomly assigned patients with locally advanced or metastatic clear cell RCC who had progressed on 1 or 2 prior lines of therapy, including at least 1 immune checkpoint inhibitor (ICI), 1:1 to reduced-dose tivozanib at 0.89 mg once daily for 21 days on/7 days off plus nivolumab (Opdivo) at 480 mg intravenously once per cycle or standard-dose tivozanib at 1.34 mg once daily, same schedule) in 28-day cycles (N = 343).¹

The primary end point was PFS by independent radiologic review; secondary end points included OS, investigator-assessed PFS, objective response rate (ORR), duration of response, and safety.¹

In the primary analysis, at a median follow-up of 12.0 months (95% CI, 11.5-12.8) in the intent-to-treat (ITT) population, ICI rechallenge with tivozanib plus nivolumab was not beneficial and the combination arm did not meet its primary end point.²

This post hoc analysis, conducted after database closure on January 30, 2026, describes long-term outcomes with standard-dose tivozanib monotherapy— the trial's control arm—across the ITT, second-line, and third-line populations at a longer median follow-up of 27.8 months (95% CI, 26.8-28.9).¹ At the final database lock, 172 patients had been randomized to standard-dose tivozanib (171 treated) and 171 to tivozanib plus nivolumab (168 treated); after final results became available, 39 patients on the combination arm were eligible to transition to full-dose tivozanib monotherapy, though none did so.

The median duration of treatment was 7.36 months with standard-dose tivozanib and 6.28 months with tivozanib plus nivolumab.

What long-term efficacy outcomes were observed with standard-dose tivozanib?

The median PFS with standard-dose tivozanib was 7.43 months (95% CI, 5.52-9.23) in the ITT population. Compared with tivozanib plus nivolumab, PFS HRs were 0.95 (95% CI, 0.75-1.21; P = .69) in the ITT population, 1.11 (95% CI, 0.82-1.50; P = .49) in the second-line, and 0.74 (95% CI, 0.51-1.08; P = .11) in the third-line. Median OS with standard-dose tivozanib was 22.93 months (95% CI, 18.14-NR) in the ITT population, 23.52 months (95% CI, 18.33-NR) in the second-line, and 22.70 months (95% CI, 11.79-NR) in the third-line, with OS HRs vs tivozanib plus nivolumab of 0.95 (95% CI, 0.70-1.28; P = .74), 0.88 (95% CI, 0.60-1.30; P = .52), and 1.15 (95% CI, 0.73-1.83; P = .55), respectively.

Investigator-assessed, unconfirmed ORR by RECIST 1.1 criteria with standard-dose tivozanib was 20.4% (95% CI, 14.6%-27.2%) in the ITT population, 26.7% (95% CI, 18.5%-36.2%) in the second-line, and 10.5% (95% CI, 4.3%-20.4%) in the third-line. Across the ITT, second-line, and third-line populations, more patients receiving standard-dose tivozanib achieved a complete response or stable disease compared with those who received reduced-dose tivozanib as part of the combination arm.

What was the safety profile with long-term follow-up?

Among patients treated with standard-dose tivozanib monotherapy (n = 171) vs tivozanib plus nivolumab (n = 168), treatment-emergent adverse effects (TEAEs) of any grade occurred in 98.2% vs 97.6%, and grade 3 or higher TEAEs occurred in 64.9% of patients in both arms. Treatment-related TEAEs occurred in 86.0% vs 82.1% of patients, and death due to an adverse effect occurred in 2.9% vs 5.4%, with 1 death (0.6%) deemed related to study drug in the tivozanib monotherapy arm and none in the combination arm.

TEAEs led to treatment withdrawal in 21.1% vs 22.0% of patients, dose interruption in 57.9% vs 51.2%, and tivozanib dose reduction in 23.4% vs 11.9%. Hypertension was the most common any-grade and grade 3 or higher treatment-related adverse event, occurring at similar rates in both arms. Investigators reported that the type and frequency of adverse events with long-term tivozanib monotherapy indicated no new safety signals compared with the established safety profile of the tivozanib control arm in TiNivo-2.

Investigators concluded that this post hoc, long-term follow-up analysis of TiNivo-2 supports durable efficacy with standard-dose tivozanib monotherapy in patients with mRCC treated in the second- and third-line settings. The findings reinforce the primary analysis, in which ICI rechallenge with tivozanib plus nivolumab did not improve outcomes over tivozanib monotherapy and did not meet the trial's primary end point.¹,²

References

1. Motzer RJ, McGregor BA, Albiges L, et al. Final analysis of the TiNivo-2 phase 3 trial: long-term outcome of tivozanib (Tivo) in patients with metastatic renal cell carcinoma (mRCC). Presented at: Kidney Cancer Research Summit; July 23-24, 2026; Boston, MA.
2. Choueiri TK, Albiges L, Barthélémy P, et al. Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study. Lancet. 2024;404(10460):1309-1320. doi:10.1016/S0140-6736(24)01758-6