Tivozanib Monotherapy May Serve as Effective Second-Line Option in Metastatic RCC

Alexander Chehrazi-Raffle, MD

Although the addition of nivolumab (Opdivo) to tivozanib (Fotivda) did not appear to provide greater benefit than tivozanib alone, the agent did exhibit meaningful activity as a monotherapy in patients with metastatic renal cell carcinoma (RCC) who had received contemporary first-line therapies, signaling its potential consideration as a viable option in the second-line setting, according to Alexander Chehrazi-Raffle, MD.

Findings from a subgroup analysis of the phase 3 TiNivo-2 trial (NCT04987203), which were presented during the 2025 ASCO Annual Meeting, showed that tivozanib monotherapy administered at 1.34 mg daily led to substantial reductions in tumor size were observed across the first-line immune checkpoint inhibitor/TKI and first-line ipilimumab (Yervoy)/nivolumab cohorts (n = 153), with 80% of patients achieving tumor shrinkage. Moreover, patients who received tivozanib monotherapy following a first-line TKI/immuno-oncology (IO) regimen (n = 41) achieved a median progression-free survival (PFS) of 7.43 months (95% CI, 3.65-9.33) compared with 3.91 months (95% CI, 2.14-6.74) with tivozanib plus nivolumab in the same setting (n = 42; HR, 1.20; 95% CI, 0.71-2.02; log-rank P = .5139).

“This [analysis] supports the idea that tivozanib should be considered in the second-line setting after progression on an IO combination in the first-line setting for metastatic RCC,” Chehrazi-Raffle, an assistant professor in the Department of Medical Oncology & Therapeutics Research at City of Hope, shared with OncLive®.

In the interview, Chehrazi-Raffle discussed the rationale for evaluating the efficacy of tivozanib as a second-line treatment option in the context of contemporary therapeutic sequencing, shared important efficacy findings from this subgroup analysis, and discussed the implications of using tivozanib monotherapy as a viable second-line therapy.

OncLive: What were the primary findings previously reported from TiNivo-2?

Chehrazi-Raffle: TiNivo-2 was a global, randomized phase 3 study that looked at the combination of tivozanib plus nivolumab vs tivozanib monotherapy in patients with metastatic RCC following exposure to immunotherapy. It was a trial that enrolled 343 patients globally, and was essentially a negative study because the primary end point of PFS was not improved with the combination of VEGF and immunotherapy compared with the VEGF monotherapy arm.

What was the rationale for conducting this subgroup analysis, and which patients were included?

Of the 343 patients in the phase 3 trial, there were a substantial number that received the treatments in unconventional settings that would be post adjuvant or in a clinical trial that had preceded the treatment. What this abstract was really hoping to do was to see what the patients who received the treatments in a conventional, contemporary setting would look like. In other words, patients who had received either nivolumab/ipilimumab for first-line metastatic RCC or patients who received a VEGF/IO combination as frontline therapy.

What did the subgroup analysis reveal about the efficacy of tivozanib alone and in combination with nivolumab for patients who progressed on first-line VEGF/IO or IO combinations?

In patients who had [received] prior nivolumab and ipilimumab, it wasn't too surprising that we saw categorically more robust responses for those who then went on to receive the tivozanib monotherapy. These were patients who had never received a VEGF combination before. When they were given the tivozanib in combination with nivolumab, they across the board, performed better than the patients who received some VEGF/IO combination in the first-line setting.

It was expected that we would see high responses in patients who received nivolumab and ipilimumab in the first-line setting. What was a bit surprising was that in patients who received prior VEGF/IO combinations, we still saw 17% of them have a 30% or greater reduction in tumor volume. This supports the idea that tivozanib at the higher dose of 1.34 mg is a very biologically active agent.

[The addition of nivolumab to tivozanib] mirrored the outcomes that we saw in the sister trial. The overall cohort showed equivocal results, and similar results were seen in this subgroup analysis.

Were any new safety signals observed?

Tivozanib is well-regarded as one of the better tolerated VEGF TKIs, and we saw similar toxicity profiles in both of the arms that we looked at. The most common adverse effect that was observed was hypertension, but more often than not, it was low grade and manageable.

What do these findings suggest about the potential role for tivozanib and other VEGF TKI/IO regimens more broadly, in second-line RCC?

Outcomes [from this analysis] were commensurate to the results that were seen in other trials such as [the phase 3] CONTACT-03 trial [NCT04338269] in which [the median] PFS was [10.6 vs 10.8] months [with atezolizumab (Tecentriq) plus cabozantinib (Cabometyx) vs cabozantinib alone]. In this subgroup analysis, we demonstrated that the median PFS was 9.2 months in patients [treated with ipilimumab and nivolumab] who then received tivozanib monotherapy. This was pretty much on par with other agents in this class.

We're going to continue to build out the subgroup analysis and dig into whether or not this should be considered to be a treatment added to the second-line setting for RCC.

Reference

Chehrazi-Raffle A, Motzer RJ, Beckermann K, et al. Efficacy of second line (2L) treatment with tivozanib (tivo) as monotherapy or with nivolumab (nivo) in patients (pts) with metastatic renal cell carcinoma (mRCC) previously treated with an immune checkpoint inhibitor (ICI) combination of ipilimumab (Ipi)/nivo or vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI)/ICI in the phase 3 TiNivo-2 study. J Clin Oncol. 2025;43(suppl 16):4540. doi:10.1200/JCO.2025.43.16_suppl.4540