Tivozanib Shows Efficacy and Tolerability in Non-Clear Cell RCC


Retrospective analysis of a phase 2 trial indicated that tivozanib demonstrated efficacy and tolerability in the subset of patients who had non-clear cell histologies of renal cell carcinoma.

Tivozanib (Fotivda) showed efficacy and was well tolerated in patients with non-clear cell renal cell carcinoma (nccRCC), according to a retrospective subgroup analysis presented in a poster at the 2022 International Kidney Cancer Symposium: North America.1

The analysis of a phase 2 trial (NCT00502307) focusing on 46 patients with nccRCC histologies showed a best objective response rate (ORR) of 31.6% and a confirmed ORR of 21.1% with tivozanib. The median progression-free survival (PFS) was 6.7 months, which investigators considered comparable to other agents in this setting. Only 2 grade 4 treatment-related adverse events (TRAEs) were reported in this subgroup, with only 1 TRAE leading to discontinuation of tivozanib.

“Due to the rarity and poor molecular characterization of nccRCC, there is an underrepresentation in clinical trials evaluating patients with this type of RCC; because of this, patients are often treated with non-tailored therapies,” the investigators stated in their poster.

Tivozanib is an oral VEGF-receptor tyrosine kinase inhibitor approved for use in advanced RCC following at least 2 prior lines of systemic therapy based on the results of the phase 3 TIVO-3 trial (NCT02627963), which excluded patients with nccRCC histologies.2

However, this phase 2 discontinuation trial enrolled 272 patients including 46 (16.9%) who had nccRCC including papillary, chromophobe, collecting duct, and mixed or unclassified histologies. Patients with advanced RCC who had no prior VEGF-targeted therapy received open-label 1.5 mg of tivozanib orally once daily for 3 weeks followed by 1 week off for 4 cycles, totaling 16 weeks. Patients who had a 25% or greater tumor shrinkage continued treatment, whereas those who had a 25% or greater tumor growth stopped treatment.

Patients who had less than a 25% change in tumor size at 16 weeks were randomly assigned 1:1 to receive tivozanib or placebo in a double-blind fashion for 12 more weeks. Afterward, both groups could continue receiving tivozanib.

The primary end point was PFS as assessed by blinded radiological review per RECIST 1.1 criteria. Secondary end points included ORR, overall survival, and duration of response.

Of the 272 total patients, those with nccRCC subtypes included 11 patients with papillary disease, 2 with chromophobe, 2 with collecting duct, and 31 with mixed/unclassified subtypes. Only 26% of them had received prior systemic therapy, which was predominantly interferon therapy. Their ORR at 16 weeks was 15.2%. One patient with collecting duct subtype and 6 with mixed/unclassified subtype had a partial response (PR) at 16 weeks. Twenty-two patients, including patients with all 4 subtypes, had stable disease (SD) at 16 weeks and were randomly assigned to continue tivozanib or receive placebo, with 8 receiving placebo for the next 12 weeks.

Best ORR and confirmed ORR with tivozanib showed lower ORR for mixed/unclassified than all patients with nccRCC, though the number of patients was small. The best ORR for all nccRCC was 31.6% versus 22.6% only the mixed/unclassified subtype, whereas best confirmed ORR was 21.1% for all nccRCC versus 14.8% with mixed/unclassified.

Disease control rate (DCR) for all patients with nccRCC based on best unconfirmed response was 73.7%, 87.5% for the papillary subtype, 100.0% for the chromophobe subtype, 100.0% for the collecting duct subtype, and 66.7% for the mixed/unclassified subtype. The DCR did not count the 8 out of 46 patients who were assigned to receive placebo after 16 weeks.

The median time to best confirmed response was 23.2 weeks (mean, 26.7 weeks), and median time to best unconfirmed response was 19.1 weeks (mean, 27.2 weeks). There were 24 patients (52.2%) who experienced progression events during tivozanib treatment or follow-up for over 2 years.

In terms of safety and tolerability in the nccRCC subgroup, the most common TRAE of any grade was hypertension (46%, n = 21), followed by dysphonia (15%, n = 7), asthenia (13%, n = 6), diarrhea (11%, n = 5), fatigue (9%, n = 4), and rash (7%, n = 3). There were 2 grade 3 cases of hypertension and 1 each of asthenia and diarrhea. There was a single grade 4 duodenal ulcer hemorrhage and a grade 4 hyperbilirubinemia, and no reported grade 5 TRAEs. The single TRAE that led to treatment discontinuation was duodenal ulcer hemorrhage.

Investigators concluded that tivozanib had promising activity in nccRCC subtypes, especially considering that these patients have few effective treatment options compared with those with clear cell histology.

They stated that the results were comparable to the phase 2 ASPEN trial (NCT01108445) of everolimus (Afinitor) versus sunitinib (Sutent), which resulted in an ORR of 9% for everolimus and 18% for sunitinib, and a median PFS of 5.6 months for everolimus versus 8.3 months for sunitinib.3 Considering the low rate of grade 3 or higher TRAEs, tivozanib shows potential to be a viable treatment option in this population.


1. Barata P, Allman KD, Chehrazi-Raffle A, Anis-Alibozek A, Kasturi V, Pal SK. Activity of tivozanib in non-clear cell renal cell carcinoma (nccRCC): subgroup analysis from a phase 2 randomized discontinuation trial. Poster presented at: the International Kidney Cancer Symposium (IKCS): North America; November 4-5, 2022; Austin, TX. Abstract 35.

2. FDA approves tivozanib for relapsed or refractory advanced renal cell carcinoma. FDA. March 10, 2021. Accessed November 8, 2022. https://bit.ly/3tbKdSD

3. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol. 2016;17(3):378-388. doi:10.1016/S1470-2045(15)00515-X

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