A subgroup analysis of the phase 3 TiNivo-2 trial has revealed that tivozanib (Fotivda) monotherapy demonstrates comparable or superior efficacy to combination therapy with nivolumab (Opdivo) in patients with metastatic renal cell carcinoma (RCC) who have progressed on contemporary first-line immune checkpoint inhibitor-based regimens.
The analysis, presented at the 2025 ASCO Annual Meeting, examined outcomes in patients who received either ipilimumab plus nivolumab or a tyrosine kinase inhibitor (TKI) combined with an immune checkpoint inhibitor as frontline therapy before progressing to second-line treatment.
Efficacy Outcomes in Different Treatment Sequences
For patients who received frontline ipilimumab plus nivolumab, subsequent treatment with single-agent tivozanib (n = 37) resulted in a median progression-free survival of 9.20 months (95% CI, 4.50-not reached). In comparison, patients who received tivozanib plus nivolumab in the same setting (n = 33) experienced a median PFS of 9.33 months (95% CI, 7.26-15.34), with a hazard ratio of 1.05 (95% CI, 0.51-1.95; log-rank P = .8719).
Among patients who received first-line TKI plus ICI treatment, tivozanib monotherapy (n = 41) achieved a median PFS of 7.43 months (95% CI, 3.65-9.33) compared with 3.91 months (95% CI, 2.14-6.74) for those receiving tivozanib plus nivolumab (n = 42; HR, 1.20; 95% CI, 0.71-2.02; log-rank P = .5139).
Response Rates Favor Monotherapy Approach
The objective response rates further supported the efficacy of tivozanib monotherapy. Patients who received frontline ipilimumab/nivolumab and subsequently received tivozanib monotherapy achieved an ORR of 32.4% (95% CI, 18%-49.8%), while those receiving the combination therapy achieved 24.2% (95% CI, 11.1%-42.3%). No complete responses were observed in either arm.
In the TKI/ICI frontline subgroup, patients treated with subsequent tivozanib monotherapy achieved an ORR of 22% (95% CI, 10.6%-37.6%), compared with 9.5% (95% CI, 2.7%-22.6%) for the combination arm. Again, no complete responses were recorded in either treatment group.
Study Design and Patient Characteristics
TiNivo-2 was the first randomized phase 3 trial to examine the efficacy and safety of a PD-1 inhibitor-containing combination after disease progression during or following previous PD-1/PD-L1 inhibitor therapy. The open-label, multicenter study enrolled patients with locally advanced or metastatic RCC with a clear cell component who experienced radiographic disease progression during or following a minimum of 6 weeks of therapy with an ICI.
In the monotherapy arm, tivozanib was administered at 1.34 mg daily for the first 21 days of each 28-day cycle. The combination arm received tivozanib 0.89 mg plus intravenous nivolumab on day 1 of each 28-day cycle.
Clinical Implications for Treatment Sequencing
"There appeared to be no benefit [with] the addition of nivolumab to tivozanib in this context, akin to the results of the parent trial," noted Alexander Chehrazi-Raffle, MD, assistant professor in the Department of Medical Oncology & Therapeutics Research at City of Hope in Duarte, California.
The findings suggest that the combination of immunotherapy plus VEGF targeting is not superior to VEGF inhibition alone after patients have already progressed on an immunotherapy regimen. The analysis demonstrated that tivozanib can be considered as monotherapy at the 1.34 mg dose in the second-line setting.
Safety Considerations
The safety profile also favored the monotherapy approach, with more immune-related toxicity observed in patients who received nivolumab combination therapy. However, VEGF TKI-related side effects were not noticeably higher in the tivozanib monotherapy arm compared to the combination arm.
The study authors concluded that "tivozanib monotherapy at [a dose of] 1.34 mg daily showed activity in patients who previously received a contemporary first-line metastatic RCC regimen," providing evidence for its use as a viable second-line treatment option in the evolving landscape of RCC therapy.
