Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study.

BACKGROUND: Treatment for renal cell carcinoma has been revolutionised by inhibitors of VEGF receptor. Previous studies have suggested that treatment with a VEGF receptor (VEGFR) tyrosine kinase inhibitor might be effective in patients who had previous checkpoint inhibitor therapy. Therefore, TIVO-3 was designed to compare the efficacy and safety of tivozanib (a potent and selective VEGFR inhibitor) with those of sorafenib as third-line or fourth-line therapy in patients with metastatic renal cell carcinoma. METHODS: In this open-label, randomised, controlled trial done at 120 academic hospitals in 12 countries, we enrolled eligible patients older than 18 years with histologically or cytologically confirmed metastatic renal cell carcinoma and at least two previous systemic treatments (including at least one previous treatment with a VEGFR inhibitor), measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were excluded if they had received previous treatment with tivozanib or sorafenib. Patients were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk category and type of previous therapy and randomised (1:1) with a complete permuted block design (block size of four) to either tivozanib 1·5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily continuously. Investigators and patients were not masked to treatment. The primary endpoint was progression-free survival by independent review in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02627963. FINDINGS: Between May 24, 2016, and Aug 14, 2017, 350 patients were randomly assigned to receive tivozanib (175 patients) or sorafenib (175 patients). Median follow-up was 19·0 months (IQR 15·0-23·4). Median progression-free survival was significantly longer with tivozanib (5·6 months, 95% CI 5·29-7·33) than with sorafenib (3·9 months, 3·71-5·55; hazard ratio 0·73, 95% CI 0·56-0·94; p=0·016). The most common grade 3 or 4 treatment-related adverse event was hypertension (35 [20%] of 173 patients treated with tivozanib and 23 [14%] of 170 patients treated with sorafenib). Serious treatment-related adverse events occurred in 19 (11%) patients with tivozanib and in 17 (10%) patients with sorafenib. No treatment-related deaths were reported. INTERPRETATION: Our study showed that tivozanib as third-line or fourth-line therapy improved progression-free survival and was better tolerated compared with sorafenib in patients with metastatic renal cell carcinoma. FUNDING: AVEO Oncology.

Cessation of vascular endothelial growth factor-targeted therapy in patients with metastatic renal cell carcinoma: feasibility and clinical outcome.

BACKGROUND: The current treatment of metastatic renal cell carcinoma (mRCC) with vascular endothelial growth factor (VEGF)-targeted agents is continuous therapy until progression of disease (PD) or unacceptable toxicity. Chronic mild to moderate toxicity and risk of long-term toxicity ensue for some patients. It is hypothesized that patients with an initial response to treatment can maintain disease control off all therapy for a period of time. METHODS: A retrospective study of patients with mRCC who initiated VEGF-targeted therapy between January 2004 and December 2009 at The Cleveland Clinic Foundation, Cleveland, Ohio, or Institut Gustave-Roussy, Villejuif, France, was conducted. Patients had achieved RECIST (Response Evaluation Criteria in Solid Tumors)-defined stable disease or better on therapy, and were then taken off all therapy for reasons not including disease progression. Patient, disease, and therapy characteristics were recorded. The primary objective was progression-free survival (PFS), measured as the time from discontinuation of therapy to RECIST-defined PD. RESULTS: Forty patients were identified. After a median follow-up of 29.7 months (range, 4.2 to 84.7 months), 25 patients (63%) had PD off therapy (median PFS, 10.0 months; range, 1.4-27.2 months). Among these patients, 8 (32%) had progression in sites that were not previously involved with disease. Heng risk group (hazard ratio, 2.49; 95% confidence interval, 1.19-5.22; P = .011) and achievement of a complete response prior to discontinuing therapy (hazard ratio, 0.20; 95% confidence interval, 0.04-0.86; P = .025) were independent predictors of PFS in a multivariable Cox proportional hazards model. CONCLUSIONS: A select subset of mRCC patients achieving stable disease or better on VEGF-targeted therapy can be observed off all therapy. Further prospective investigation is warranted.

Q-TWiST Analysis of Tivozanib Versus Sorafenib in Patients With Advanced Renal Cell Carcinoma in the TIVO-3 Study.

BACKGROUND: In TIVO-3, tivozanib increased progression-free survival with no difference in overall survival relative to sorafenib as third- or fourth-line therapy in patients with metastatic renal cell carcinoma. We applied quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) methods to quantify the net health benefits of tivozanib, in the presence of similar survival, when compared with sorafenib. METHODS: The mean Q-TWiST was calculated by applying utility coefficients of 0.5, 1.0, and 0.5 to the 36-month restricted mean health states of time with toxicity (TOX), TWiST, and time after progression/relapse, respectively. The relative Q-TWiST gain was defined as the mean absolute Q-TWiST difference divided by the sorafenib mean overall survival. RESULTS: The mean TWiST was longer for tivozanib than for sorafenib, mean time after progression/relapse was shorter for tivozanib, with no difference in mean TOX. Mean Q-TWiST was 15.04 months and 12.78 months for tivozanib and sorafenib, respectively (P = .0493). The tivozanib relative gain was 11.2%. DISCUSSION: Tivozanib increased Q-TWiST relative to sorafenib, primarily through an increase in TWiST, which is generally considered to be the highest utility state. CONCLUSION: Q-TWiST may be considered an alternative patient-centered measure of benefit of tivozanib in as a third- or fourth-line therapy in patients with renal cell carcinoma. CLINICAL TRIAL INFORMATION: NCT02627963.

Final Overall Survival Results from a Phase 3 Study to Compare Tivozanib to Sorafenib as Third- or Fourth-line Therapy in Subjects with Metastatic Renal Cell Carcinoma.

Tivozanib is a potent and selective inhibitor of the VEGF receptor. In an open-label, randomized phase 3 trial, we compared tivozanib to sorafenib in patients with metastatic renal cell carcinoma (mRCC) who had received two or three prior therapies. We have previously reported that the study met its primary endpoint, demonstrating an improvement in progression-free survival with tivozanib versus sorafenib (5.6 mo vs 3.9 mo; hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.56-0.94; p=0.016). The current report reflects the final assessment of overall survival, showing no difference between treatment with tivozanib and sorafenib (HR 0.97, 95% CI 0.75-1.24). Given its activity and distinct tolerability profile, tivozanib represents a treatment option for patients with previously treated mRCC. PATIENT SUMMARY: We show that tivozanib, a targeted therapy, can delay tumor growth relative to an already approved targeted therapy (sorafenib) in patients with kidney cancer who have received two or three prior treatments. No difference in survival was observed.

Metastatic renal cell carcinoma treated with sunitinib: early evaluation of treatment response using dynamic contrast-enhanced ultrasonography.

PURPOSE: To determine the utility of dynamic contrast-enhanced ultrasonography (DCE-US) as a prognostic tool for metastatic renal cell carcinoma patients receiving sunitinib and to identify DCE-US parameters that correlate with early treatment response. EXPERIMENTAL DESIGN: Thirty-eight patients received 50 mg/d sunitinib on schedule 4/2 (4 weeks on followed by 2 weeks off treatment). After two cycles, response evaluation criteria in solid tumors were used to classify patients as responders or nonresponders. DCE-US evaluations were done before treatment and at day 15; variations between days 0 and 15 were calculated for seven DCE-US functional parameters and were compared for responders and nonresponders. The correlation between DCE-US parameters and disease-free survival (DFS) and overall survival (OS) was assessed. RESULTS: The ratio between DCE-US examinations at baseline and day 15 significantly correlated with response in five of the seven DCE-US parameters. Two DCE-US parameters (time to peak intensity and slope of the wash-in) were significantly associated with DFS; time to peak intensity was also significantly associated with OS. CONCLUSIONS: DCE-US is a useful tool for predicting the early efficacy of sunitinib in metastatic renal cell carcinoma patients. Robust correlations were observed between functional parameters and classic assessments, including DFS and OS.

Innovations and challenges in renal cancer: summary statement from the Third Cambridge Conference.

The Third Cambridge Conference on Innovations and Challenges in Renal Cancer, a symposium held in Cambridge, Massachusetts, June 27-28, 2008, and chaired by Michael B. Atkins, was convened to discuss the current state of knowledge in the field, critique new data, stimulate communication among those involved in basic and clinical research, and offer recommendations for further study. Four main topics were discussed: genetics and molecular biology of renal cell cancer, staging and prognosis, systemic therapy, and correlative science and biomarkers in stage IV disease. The conference format combined brief presentations with extended periods of discussion. The conclusions and recommendations are summarized in this paper and presented in more detail in the individual papers that follow.

Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma.

PURPOSE: Temsirolimus, an inhibitor of the mammalian target of rapamycin, has single-agent activity against advanced renal cell carcinoma (RCC). A recommended dose and safety profile for the combination of temsirolimus and interferon alfa (IFN) were determined in patients with advanced RCC. PATIENTS AND METHODS: Patients were enrolled onto a multicenter, ascending-dose study of temsirolimus (5, 10, 15, 20, or 25 mg) administered intravenously once a week combined with IFN (6 or 9 million units [MU]) administered subcutaneously three times per week. An expanded cohort was treated at the recommended dose to obtain additional safety and efficacy information. RESULTS: Seventy-one patients were entered to receive one of six dose levels. The recommended dose was temsirolimus 15 mg/IFN 6 MU based on dose-limiting toxicities of stomatitis, fatigue, and nausea/vomiting, which were observed at higher doses of temsirolimus and IFN. The most frequent grade 3 or 4 toxicities occurring in any cycle included leukopenia, hypophosphatemia, asthenia, anemia, and hypertriglyceridemia for all patients and those who received the recommended dose. Among patients who received the recommended dose (n = 39), 8% achieved partial response and 36% had stable disease for at least 24 weeks. Median progression-free survival for all patients in the study was 9.1 months. CONCLUSION: The combination of temsirolimus and IFN has an acceptable safety profile and displays antitumor activity in patients with advanced RCC. Temsirolimus 15 mg plus IFN 6 MU is the recommended dose for evaluation in a randomized phase III study.