Human kidney cross section. Photo courtesy: 2019 Fotolia
Human kidney cross section. Photo courtesy: 2019 Fotolia

A study led by researchers at City of Hope, a private, not-for-profit clinical research center, hospital and graduate medical school located in Duarte, California, demonstrated that Kidney cancer patients who had received two or three different treatments had improved chances of preventing cancer progression with an experimental drug called tivozanib (Fotivda®; AVEO Pharmaceuticals) compared to an alternative approved by the U.S. Food and Drug Administration (FDA).

Tivozanib is an oral, once-daily, vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI). It is designed to optimize VEGF blockade of all three VEGF receptors, while, at the same time, minimizing off-target toxicities, potentially resulting in improved efficacy and minimal dose modifications. [1][2]

In preclinical research, tivozanib significantly reduced regulatory T-cell production. And in a Phase II study in renal cell carcinoma (RCC) the investigational drug has demonstrated synergy in combination with nivolumab (Opdivo ; Bristol-Meyers Squibb/BMS), a human monoclonal antibody that blocks PD-1 and works as a checkpoint inhibitor, blocking a signal that prevents activation of T cells from attacking the cancer. [3][4].

“This agent has shown in clinical trials to be effective in delaying cancer growth beyond established standards for patients who have returning kidney cancer,” noted Sumanta Pal, MD, a medical oncologist at City of Hope and co-lead author of the new study.

“Although there are many options for patients with kidney cancer today, most are intended for first- and second-line therapy. We need a treatment that works for kidney cancer patients who have failed several lines of therapy,” Pal added.

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Published in The Lancet Oncology on December 3, 2019, the study is the first to show the benefit of tivozanib for patients with renal cell carcinoma, the most common form of kidney cancer, who had received two or more previous therapies, Pal said.

Although not yet approved in the United States, tivozanib has been approved by the European Medicines Agency for first-line treatment of adults with renal cell carcinoma. [1][5]

Trial
The multicenter phase III study randomly assigned 350 adult patients with metastatic renal cell carcinoma to receive either tivozanib or the FDA-approved sorafenib for a median of 19 months. This targeted therapy, a VEGFR inhibitor, hinders the growth of new blood vessels, the fuel source for tumors.

The patients had a median age of 63 and were based at 120 centers in 12 different countries. They had received at least one VEGFR inhibitor treatment in their previous two or three treatments. Yet, they had never received tivozanib or sorafenib (Nexavar®; Bayer).

At one year, progression-free survival was 28% with tivozanib compared to 11% with sorafenib. At the two-year mark, progression-free survival was 18% with tivozanib and 5% with sorafenib. The therapeutic benefit of tivozanib appeared to extend to patients who had received checkpoint inhibitors and those who were treated with two previous blood vessel growth inhibitors.

“[This trial] represents the first study to demonstrate a superior progression free survival (PFS) benefit versus an active comparator. It is the first Phase III study to investigate a predefined subpopulation of patients who received prior immunotherapy, the emerging standard of care for earlier lines of therapy,” explained Brian Rini, MD, Chief of Clinical Trials at Vanderbilt Ingram Cancer Center, principal investigator of the trial, and lead author of the publication.

“Data from this study reinforce that tivozanib has the potential to serve as an effective, tolerable therapy in the evolving RCC treatment landscape,” Rini added.

“City of Hope has a robust clinical trial program that often leads to practice-changing findings, and this is just one example of that,” Pal said.

“We are well known for working on investigational new drugs, and this is a late-stage study that is providing new options for patients with kidney cancer,” Pal concluded.

At the study’s end, 70 patients in the tivozanib group (40%) and 82 patients in the sorafenib group (47%) had received subsequent anti-cancer therapy, meaning their cancer had progressed.

AVEO Oncology plans to submit a new drug application (NDA) for tivozanib for the treatment of patients with relapsed/refractory renal cell carcinoma in the first quarter of 2020.

Clinical trial
A Study to Compare Tivozanib Hydrochloride to Sorafenib in Subjects With Refractory Advanced RCC – NCT02627963

Reference
[1] Summary of Product Characteristics (SmPC) Fotivda® (Tivozanib) August 2017. Online. Last accessed December 3, 2019.
[2] 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. J Clin Oncol. 2013;31(30):3791–3799. doi:10.1200/JCO.2012.47.4940
[3] Pawlowski N et al. AACR 2013. Poster 3971
[4] Barthelemy et al. ESMO 2018. Poster 878P
[5] Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncology 2019 (12) 3. DOI:https://doi.org/10.1016/S1470-2045(19)30735-1

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