Further study of tivozanib is warranted to provide additional insights into the utility of tivozanib for the treatment of patients with metastatic renal cell carcinoma.
—Robert J. Motzer, MD
The investigational agent tivozanib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3. In a phase III trial reported in the Journal of Clinical Oncology by Robert J. Motzer, MD, of Memorial Sloan-Kettering Cancer Center (MSKCC), and colleagues, tivozanib was found to improve progression-free survival but not overall survival and to exhibit a different toxicity profile when compared with sorafenib (Nexavar) as a first targeted therapy in patients with metastatic renal cell carcinoma.1
In this open-label trial, 517 patients with metastatic renal cell carcinoma with a clear cell component, prior nephrectomy, measurable disease, and no or only one prior therapy for metastatic renal cell carcinoma were randomly assigned to receive tivozanib at 1.5 mg/d for 3 weeks followed by 1 week off (n = 260) or sorafenib at 400 mg/d continuously. Prior VEGF-targeted therapy and mTOR inhibitors were not permitted.
Hypertension for tivozanib and skin toxicity for sorafenib were managed according to specific guidelines. The primary endpoint was progression-free survival on independent review.
Patients in the tivozanib and sorafenib groups were generally well matched for age (median, 59 years in both), sex (71% and 74% male), race/ethnicity (96% and 97% white), time from diagnosis to study entry (≥ 1 year in 53% in both), most common sites of metastases (eg, lung in 82% and 79%, lymph nodes in 70% and 65%), number of involved organs (1 in 29% and 34%, > 2 in 33% and 25%), and MSKCC prognostic group (favorable in 27% and 34%, intermediate in 67% and 62%). A greater proportion of sorafenib patients had better Eastern Cooperative Oncology Group (ECOG) performance status (0 in 54% vs 45%, P = .035).
Seventy percent of patients in both groups had received no prior systemic treatment for metastatic disease, and 30% of both had received one prior treatment, with the predominant therapy (> 90% of patients) being interferon alfa. Prior adjuvant therapy had been given to 9% of patients in both groups. In total, 457 patients were from Central/Eastern Europe, 40 from North America/Western Europe, and 20 from South America/Asia.
Prolonged Progression-Free Survival
Patients received tivozanib for a median duration of 12.0 months and sorafenib for 9.5 months at the data cutoff. Median progression-free survival was 11.9 months in the tivozanib group vs 9.1 months in the sorafenib group (hazard ratio [HR] = 0.797, P = .042).
Prespecified progression-free survival subgroup analyses based on baseline characteristics showed a consistent advantage with tivozanib treatment across subgroups. Significant advantages were observed among patients who were treatment-naive for metastatic disease (median, 12.7 vs 9.1 months, HR = 0.756, P = .037), patients with ECOG performance status of 0 (14.8 vs 9.1 months, HR = 0.617, P = .004), and those in the MSKCC favorable prognostic group (16.7 vs 10.8, HR = 0.590, P = .018).
Hazard ratios also significantly favored tivozanib among the 40 patients from North America/Western Europe and the 274 patients enrolled at ≥ 1 year from time of diagnosis.
Overall response rates were 33.1% vs 23.3% (P = .014). A trend toward greater overall survival was observed for the sorafenib group (median, 28.8 vs 29.3 months, HR = 1.245, P = .105).
A greater proportion of patients in the sorafenib group received subsequent therapy (65% vs 26%) including a next-line targeted therapy for renal cell carcinoma (63% vs 13%), with nearly all of the sorafenib patients receiving tivozanib (156 of 162, 61% of entire group) as part of a companion protocol that allowed crossover at progression.
Subsequent therapies in the tivozanib group included VEGFR inhibitors (7%), mTOR inhibitors (6%), cytokines (5%), and radiotherapy (5%). Subsequent therapies apart from tivozanib in the sorafenib group included mTOR inhibitors (2%), cytokines (1%), and radiotherapy (1%).
By region, next-line therapy was received by 23% of tivozanib patients and 64% of sorafenib patients from Central/Eastern Europe, 59% and 78% of those from North America/Western Europe, and 33% and 82% of those from the rest of the world. In patients from North America/Western Europe, which had the greatest proportion of tivozanib patients receiving subsequent therapies, there was a trend toward increased overall survival in the tivozanib group (HR = 0.503, P = .195).
Adverse events of any grade that were more common with tivozanib were hypertension (44% vs 34%) and dysphonia (21% vs 5%), and those more common with sorafenib were hand-foot skin reaction (54% vs 14%) and diarrhea (33% vs 23%). The most common grade 3 or 4 adverse events were hypertension (27%) and increased lipase (11%) in the tivozanib group and hypophosphatemia (26%), increased lipase (24%), hypertension (18%), and palmar-plantar erythrodysesthesia (17%) in the sorafenib group. Of deaths occurring within 30 days of the last dose of study drug, 13 in the tivozanib group and 12 in the sorafenib group were considered related to causes other than progressive disease.
Dose reduction due to adverse events occurred in 14% of tivozanib patients and 43% of sorafenib patients (P < .001), treatment interruptions occurred in 19% and 36% (P < .001), and discontinuation due to treatment-related adverse events occurred in 4% and 5%. Dose reductions were most commonly due to hand-foot syndrome (2% vs 18%), diarrhea (1% vs 5%), and hypertension (2% vs 4%). Mean relative dose intensities of tivozanib and sorafenib were 94% and 80%.
Assessment of health-related quality of life showed no clinically meaningful changes from baseline in either group over the first 12 months of treatment.
Dr. Motzer told The ASCO Post, “Tivozanib improved progression-free survival but not overall survival in patients with metastatic renal cell carcinoma. Further study of tivozanib is warranted to provide additional insights into the utility of tivozanib for the treatment of patients with metastatic renal cell carcinoma.” ■
Disclosure: The study was supported by AVEO Oncology and Astellas. For full disclosures of the study authors, visit jco.ascopubs.org.
1. 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. September 9, 2013.