Results from the second prespecified analysis of the TIVO-3 trial showed a hazard ratio for overall survival of 0.99 for tivozanib compared with sorafenib in patients with highly refractory metastatic renal cell carcinoma.
Sumanta K. Pal, MD
Results from the second prespecified analysis of the TIVO-3 trial showed a hazard ratio for overall survival (OS) of 0.99 for tivozanib (Fotivda) compared with sorafenib (Nexavar) in patients with highly refractory metastatic renal cell carcinoma (RCC), according to AVEO Oncology, the developer of tivozanib.1
The median OS was 16.4 months for tivozanib (95% CI, 13.4-22.2) and 19.7 months (95% CI, 15.0-24.2) for sorafenib (HR, 0.99; 95% CI, 0.76-1.29; P = .95). Regarding progression-free survival (PFS), at a median duration on study of 32.5 months, 20 patients remained progression free on the tivozanib arm compared with 2 patients on the sorafenib arm.
"The data from TIVO-3 are very compelling, particularly given the fact that patients in this study were heavily pretreated and many were exposed to prior checkpoint inhibitors," Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, said in a statement made to OncLive.
"The data really beg for future studies that explore combinations of tivozanib with immunotherapy. There has already been some data looking at the combination of tivozanib with nivolumab—this would be of particular interest. For those who have not used tivozanib, what sets it apart from other tyrosine kinase inhibitors is the exceptional safety profile. As one of the highest enrollers on the TIVO-3 trial, I have had patients who have been able to sustain dosing on tivozanib for extended periods without substantial toxicity."
In January 2019, the FDA recommended that Aveo Oncology should not submit a new drug application (NDA) for tivozanib with the preliminary OS data from the phase III TIVO-3 trial. The agency indicated that the initial data did not alleviate their concerns regarding a potential detriment in OS, which were outlined in a complete response letter issued in June 2013. The preliminary OS analysis showed a hazard ratio >1.
AVEO Oncology plans to discuss the updated OS data with the FDA and will provide an update regarding a potential submission of an NDA for tivozanib in RCC following these discussions. A potential regulatory submission would include data from TIVO-3 as well as the TIVO-1 trial, which evaluated tivozanib as a first-line therapy in patients with advanced RCC.
In the randomized, controlled, multi-center, open-label, phase III TIVO-3 study, investigators randomized 350 patients with highly refractory metastatic RCC who had failed ≥2 prior regimens, including VEGF-TKI treatment, 1:1 to receive either oral tivozanib or sorafenib. No cross over was permitted between arms.
To be eligible for enrollment on TIVO-3, patients with metastatic RCC must have failed 2 or 3 prior systemic therapies, one of which includes a VEGF TKI other than sorafenib or tivozanib; histologically or cytologically confirmed clear-cell RCC; measurable disease as assessed by RECIST v1.1 criteria; an ECOG performance status of 0 or 1; and a life expectancy of ≥3 months. Eligibility criteria also included patients who received checkpoint inhibitor therapy in earlier lines of therapy.
Those who received prior therapy with sorafenib or tivozanib; received more than 3 prior regimens for their metastatic disease; had central nervous system metastases, significant hematologic, gastrointestinal, thromboembolic, vascular, bleeding, or coagulation disorders; significant cardiovascular disease or serum chemistry abnormalities; inadequate recovery from any prior surgical procedure or a major surgery within 4 weeks prior to administration of the study drug; or a currently active second primary malignancy were excluded.
The primary endpoint was PFS; secondary endpoints were OS, objective response rate (ORR), and safety and tolerability.
For the second prespecified analysis, the data cutoff date was August 15, 2019, which was 2 years from the last patient enrolled and approximately 10 months from the data cutoff date for the first prespecified analysis. Between the two dates, 16 additional OS events were reported on the tivozanib arm and 28 on the sorafenib arm, which led to 114 OS events for tivozanib and 113 for sorafenib.
"These are the first data to demonstrate durable improvements in this highly refractory advanced kidney cancer population, including the post-immunotherapy setting, a predefined subset of the TIVO-3 trial," principal investigator Brian Rini, MD, professor of medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, director, Cleveland Clinic Genitourinary Cancer Program, said in a press release.
"The TIVO-3 study suggests the potential for tivozanib to serve as an important new treatment option for patients with advanced RCC. I look forward to seeing tivozanib studied further in the immunotherapy combination setting, and to continuing to explore its full potential in the evolving RCC treatment landscape," added Rini.
In November 2018, final results for the primary endpoint showed that the median PFS was 5.6 months and 3.9 months for tivozanib and sorafenib, respectively (HR, 0.73; P = .0165). The ORR was 18% with tivozanib and 8% with sorafenib (P = .02).2
The safety data that were also reported at this time showed that tivozanib was found to be generally well tolerated; grade ≥3 adverse events were consistent with previously observed findings in studies of the VEGF TKI. Thrombotic events were higher in the tivozanib arm, which was also similar to previously reported data. Additionally, the most common adverse event in the tivozanib arm was hypertension.
In August 2017, the European Commission approved tivozanib for the frontline treatment of adult patients with advanced RCC and for those with advanced RCC who are VEGFR- and mTOR-inhibitor naïve following disease progression after 1 prior treatment with cytokine therapy. The decision was based on findings from the phase III TIVO-1 trial, in which tivozanib reduced the risk of disease progression or death by over 20% compared with sorafenib in patients with advanced RCC who received up to 1 prior line of therapy, excluding targeted agents.3