ASCO GU 2019: TIVO-3: A Phase III, Randomized, Controlled, Multicenter, Open-label Study to Compare Tivozanib to Sorafenib in Subjects with Refractory Advanced Renal Cell Carcinoma

San Francisco, CA ( Tivozanib is a selective oral VEGFR 1, 2, and 3 tyrosine kinase inhibitor which has been studied in numerous solid tumors including hepatocellular carcinoma, recurrent glioblastoma, and soft tissue sarcoma1-3. Tivozanib has also been studied in the first line setting for metastatic RCC in a large phase III trial with 517 patients, randomly assigned to tivozanib or sorafenib4.   In that study published in 2013, 260 patients were randomly assigned to tivozanib and 257 patients were assigned to sorafenib. 61% of patients who progressed on sorafenib crossed over to the tivozanib arm. In terms of overall survival, there was no significant difference between tivozanib compared with sorafenib (29.3 vs 28.8 months, HR 1.245, 95%CI 0.954-1.624, p=.105). This study compares tivozanib again to sorafenib, but in the refractory setting.

This is a phase III, open-label randomized study comparing sunitinib to tivozanib in patients with refractory RCC. Patients were classified into three groups: prior TKI treatment, prior immune checkpoint inhibitor treatment, and other. The primary endpoint was progression-free survival and second endpoints included overall survival, safety, objective response rates, and duration of response.

ASCO GU 2019 TIVO 3 study design

The baseline characteristics are shown below. The median age was 62 in tivozanib and 64 in the sorafenib arm. The majority of patients had intermediate or poor IMDC risk and the majority of patients were men. Most patients had two prior lines of therapy (62/59%), and most patients had two lines of TKI (45%/46%).

ASCO GU 2019 baseline pt characteristics ITT

In terms of efficacy, the objective response was 18% for tivozanib and 8% for sunitinib. Tivozanib demonstrated a statistically significant improvement in mPFS compared to sunitinib (7.3 months vs 5.1 months). Median overall survival was 16.4 months with tivozanib and 19.7 months with sorafenib (p=0.4). At this time, 34% of patients remain on tivozanib and 9% of patients remain on sorafenib.

ASCO GU 2019 Subsequent systemic therapy

In terms of safety, patients receiving tivozanib were less likely to require a dose reduction as compared with sunitinib (24%vs 38%) or dose interruption(48% vs 63%).55% of patients had a grade 3/4 severe adverse event on sorafenib and 44% on tivozanib. Most of the side effects were on target effects for tivozanib and off-target effects on sorafenib, per Dr. Rini.

For the third or fourth line of treatment of patients who had been previously treated with either two TKIs,TKI plus checkpoint inhibitor, or TKI + other therapy, tivozanib outperforms sunitinib in terms of progression-free survival and was well tolerated. It did not appear to matter if they were post-TKI, post checkpoint TKI, or post TKI other. The post-checkpoint inhibitor patient population is a growing population of patients with more and more patients are being treated with front line checkpoint inhibitors and will likely continue to grow as combination therapies with TKI+ checkpoint inhibitors gain front line approval in the future.

Presented by: Brian I. Rini, MD, FACP, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio

Written By: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

1. Lee SS, Miller A, Krishnamurthi SS, et al. Phase 1b/2 study of tivozanib in patients with advanced inoperable hepatocellular carcinoma. American Society of Clinical Oncology; 2018.
2. Kalpathy-Cramer J, Chandra V, Da X, et al. Phase II study of tivozanib, an oral VEGFR inhibitor, in patients with recurrent glioblastoma. Journal of neuro-oncology 2017;131:603-10.
3. Agulnik M, Costa R, Milhem M, et al. A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas. Annals of Oncology 2016;28:121-7.
4. Motzer RJ, Nosov D, Eisen T, et al. Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2013;31:3791-9.