Tivozanib Shows Efficacy in Pretreated Metastatic RCC

“In this TiNivo-2 subgroup analysis, tivozanib monotherapy at [a dose of] 1.34 mg daily showed activity in patients who previously received a contemporary first-line metastatic RCC regimen,” according to the study authors.

Clinical activity was reported in patients with metastatic renal cell carcinoma (RCC) who received tivozanib (Fotivda) monotherapy following prior treatment with nivolumab (Opdivo) plus ipilimumab (Yervoy) or a tyrosine kinase inhibitor (TKI) plus an immune checkpoint inhibitor (ICI), according to subgroup analysis findings from the phase 3 TiNivo-2 trial (NCT04987203) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.¹

Patients who received tivozanib monotherapy following first-line TKI plus ICI treatment (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) among patients who received tivozanib plus nivolumab in the same setting (n = 42; HR, 1.20; 95% CI, 0.71-2.02; log-rank P = .5139).

Patients who received ipilimumab plus nivolumab in the frontline setting who went on to receive single-agent tivozanib (n = 37) experienced a median PFS of 9.20 months (95% CI, 4.50-not reached). Comparatively, 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), translating to an HR of 1.05 (95% CI, 0.51-1.95; log-rank P = .8719).

“There appeared to be no benefit [with] the addition of nivolumab to tivozanib in this context, akin to the results of the parent trial,” Alexander Chehrazi-Raffle, MD, and his coauthors wrote in a poster presentation of the data.

Chehrazi-Raffle is an assistant professor in the Department of Medical Oncology & Therapeutics Research at City of Hope in Duarte, California.

TiNivo-2 Subgroup Analysis: Background and Methods

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 first or second line of treatment.² Patients were also required to have recovered from adverse effects from prior therapy to grade 1 or baseline, have measurable disease per RECIST 1.1 criteria, and have an ECOG performance status of 0 or 1.

Eligible patients were randomly assigned 1:1 to receive tivozanib monotherapy or the agent in combination with nivolumab.¹ In the monotherapy arm, tivozanib was administered at a dose of 1.34 mg daily for the first 21 days of each 28-day cycle. In the combination arm, patients received tivozanib 0.89 mg plus intravenous nivolumab on day 1 of each 28-day cycle.

The primary end point was PFS.² Secondary end points included overall survival, objective response rate (ORR), duration of response, and safety.

The authors of the subgroup analysis noted that although TiNivo-2 did not meet its primary end point, clinically meaningful outcomes were reported with tivozanib as second- and third-line treatment following ICI therapy.¹ The objective of the subgroup analysis was to assess the efficacy of tivozanib as a second-line treatment option in the context of contemporary therapeutic sequencing. Outcomes were evaluated in patients who experienced disease progression following frontline therapy with either ipilimumab plus nivolumab or a VEGF TKI plus an ICI.

In the frontline ICI/TKI subgroup, the median ages were 64.3 years (SD, 10.27) and 66.0 years (SD, 8.44) among patients who went on to receive tivozanib or tivozanib plus nivolumab, respectively. Most patients in both arms had lung metastases (68.3% vs 64.3%). Prior ICI/TKI regimens consisted of avelumab (Bavencio) plus axitinib (Inlyta; 14.6% vs 9.5%), axitinib plus pembrolizumab (Keytruda; 53.7% vs 54.8%), cabozantinib (Cabometyx) plus nivolumab (19.5% vs 31.0%), and lenvatinib (Lenvima) plus pembrolizumab (12.2% vs 4.8%). Patients in both arms underwent prior complete (67.9% vs 43.5%), partial (17.9% vs 47.8%), other (14.3% vs 8.7%), or no (31.7% vs 45.2%) nephrectomy.

In the frontline ipilimumab/nivolumab subgroup, the median ages among patients who subsequently received tivozanib or tivozanib plus nivolumab were 59.6 years (SD, 9.62) and 62.1 years (SD, 12.25), respectively. Most patients in both arms were less than 65 years old (73.0% vs 57.6%), had lung metastases (81.1% vs 66.7%), had lymph node metastases (59.5% vs 57.6%), and underwent a prior complete nephrectomy (77.8% vs 73.3%).

Additional Subgroup Analysis Data

Additional findings from the subgroup analysis demonstrated that patients who received a TKI plus an ICI in the frontline achieved an ORR of 22% (95% CI, 10.6%-37.6%) after subsequent treatment with single-agent tivozanib. Patients who went on to receive tivozanib plus nivolumab after first-line TKI/ICI therapy experienced an ORR of 9.5% (95% CI, 2.7%-22.6%). There were no complete responses (CRs) in either arm.

Among patients who received frontline ipilimumab/nivolumab who went on to receive tivozanib monotherapy experienced an ORR of 32.4% (95% CI, 18%-49.8%). Patients who received tivozanib in combination with nivolumab after frontline ipilimumab/nivolumab achieved an ORR of 24.2% (95% CI, 11.1%-42.3%). No patients achieved a CR in either arm.

“In this TiNivo-2 subgroup analysis, tivozanib monotherapy at [a dose of] 1.34 mg daily showed activity in patients who previously received a contemporary first-line metastatic RCC regimen,” the study authors concluded.

Disclosures: Chehrazi-Raffle received honoraria from ASCO, EPG Health, Medical Oncology Association of Southern California, and OncLive/MJH Life Sciences. She has consulting or advisory roles with Aveo Inc, Eisai, Exelixis, and Seagen. She is also on the speakers' bureau of Exelixis and received research funding from the company. She received travel, accommodations, and expenses from Bayer.

References

1. 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
2. Study to compare tivozanib in combination with nivolumab to tivozanib monotherapy in subjects with renal cell carcinoma. ClinicalTrials.gov. Updated October 24, 2024. Accessed June 4, 2025. https://clinicaltrials.gov/study/NCT04987203