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.

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.

Sorafenib Versus Observation Following Radical Metastasectomy for Clear-cell Renal Cell Carcinoma: Results from the Phase 2 Randomized Open-label RESORT Study.

BACKGROUND: In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy. OBJECTIVE: To assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radical metastasectomy in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400 mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves. RESULTS AND LIMITATIONS: At a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20-not available [NA]) in the observation arm versus 21 mo (95% CI 11-NA) in the sorafenib arm (log-rank test p = 0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3 AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm. CONCLUSIONS: This prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy. PATIENT SUMMARY: This article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.

Role and relevance of quality indicators in the selection of first-line treatment of patients with metastatic renal cell carcinoma: a position paper of the MeetURO Group.

Tyrosine kinase inhibitors still play a very important role in the treatment of metastatic renal cell carcinoma despite a continuously changing scenario, in which immunotherapy and several combination-based approaches are also available. In this light, patient-reported outcomes and health-related quality of life are important factors in the selection of the best first-line treatment. This Review focuses on the existing evidence on patient-reported outcomes and health-related quality of life with several tyrosine kinase inhibitors (pazopanib, sunitinib, cabozantinib and tivozanib) used as first-line treatment for metastatic renal cell carcinoma.

TOKIO rationale and protocol: a phase II study to evaluate the activity and safety of third-line tyrosine kinase inhibitor after 2 tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma.

AIMS AND BACKGROUND: The introduction of agents targeting vascular endothelial growth factor has radically changed the approach to metastatic renal cell carcinoma (mRCC): sunitinib and pazopanib are now the standard first-line therapy in mRCC. At sunitinib failure, second-line axitinib or everolimus or sorafenib should be considered to improve the clinical outcome. No data are available for a third-line tyrosine kinase inhibitor (TKI) after 2 previous lines of therapy with TKIs. At pazopanib failure, no prospective data are available. STUDY DESIGN: The TOKIO study was designed to evaluate progression-free survival, safety, and efficacy of third-line therapy with TKI in 44 patients already treated with 2 previous lines of TKIs in 10 Italian centers, and relapsed from sunitinib-axitinib (group A) or pazopanib-sorafenib (group B). Standard treatment is sorafenib in group A and sunitinib in group B, administered until disease progression or unacceptable toxicity. Secondary endpoints include the evaluation of overall survival, safety, and quality of life.

Sunitinib, pazopanib or sorafenib for the treatment of patients with late relapsing metastatic renal cell carcinoma.

PURPOSE: Late recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outcome of patients treated with sorafenib, sunitinib and pazopanib for late relapsing renal cell carcinoma. MATERIALS AND METHODS: Data were collected from 21 Italian centers involved in the treatment of metastatic renal cell carcinoma. Late relapse was defined as more than 5 years after initial radical nephrectomy. RESULTS: A total of 2,490 patients were screened and 269 (11%) were included in the study. First line therapy was sunitinib in 190 patients (71%), sorafenib in 58 (21%) and pazopanib in 21 (8%). Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0-25.1), and 14.1 months for sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI 11.2-not reported). On multivariate analysis MSKCC score and metastases to lymph nodes, liver and brain were associated with worst overall survival, while pancreatic metastases were associated with longer survival. Furthermore, age, MSKCC score and brain metastases were associated with worst progression-free survival. CONCLUSIONS: Patients with late relapsing renal cell carcinoma seem to present a characteristic pattern of metastatic spread without showing significant differences in terms of progression-free survival among sorafenib, sunitinib and pazopanib.

Sequential Tyrosine Kinase Inhibitors (TKIs) in metastatic renal cell carcinoma: results from a large cohort of patients.

BACKGROUND: Only scanty data are available to evaluate the impact of sequential TKIs on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). This retrospective study investigated the efficacy of the sequence sorafenib-sunitinib (SO-SU) and vice versa (SU-SO) in a real-life scenario. PATIENTS AND METHODS: Median progression free-survival (PFS) and OS were evaluated. The correlation between PFS and OS was also assessed. RESULTS: In total, 104 patients received SO-SU and 21 (16.8%) SO-SU. No differences in PFS or OS were observed (PFS for SO-SU=26.1 months, and for SU-SO=20.0 months; OS=35.3 and 27.0 months, respectively). For both sequences, only a weakly-positive correlation between PFS and OS was observed. CONCLUSION: Our data support the use of the sequence of the two TKIs in a real-life setting. No strong evidence of a correlation between PFS and OS was observed.

Rationale and protocol of RESORT, a randomized, open-label, multicenter phase II study to evaluate the efficacy of sorafenib in patients with advanced renal cell carcinoma after radical resection of the metastases.

The introduction of targeted agents did not totally resolve the approach to the treatment of metastatic renal cell carcinoma (mRCC) because complete response is rarely achieved. Recent findings seem to indicate that metastasectomy may improve survival. The RESORT study was designed to evaluate the additional clinical benefit of metastasectomy followed by sorafenib in a population of mRCC patients. With the aim of evaluating time to recurrence, 132 patients with mRCC who underwent radical resection of metastases at the time of recurrence after nephrectomy will be randomized to receive either sorafenib or best supportive care. Targeted treatment will be administered for up to 52 weeks or discontinued in the case of disease recurrence or unacceptable toxicity. Patients will be followed for a period of 36 months.

Treatment of collecting duct carcinoma: current status and future perspectives.

BACKGROUND: Chemotherapy for collecting duct carcinoma (CDC) has demonstrated only limited efficacy in the advanced setting. The present study evaluated the activity of targeted therapies in metastatic CDC. PATIENTS AND METHODS: We evaluated a cohort of 384 consecutive patients with metastatic renal cell carcinoma (mRCC). The characteristics of patients with CDC were compared against those of the remaining cohort. All patients with CDC were treated with targeted therapies. RESULTS: Thirteen patients with advanced CDC were referred to our Center (incidence: 3.4% of all mRCC). Median age was 57 and 62 years in the CDC and non-CDC groups, respectively. The overall disease control in the CDC population was 23%, and median overall survival was 4 (95% confidence interval(CI)=2.4-5.6) months. Three patients obtained a satisfying response (disease control lasting 6-33 months). CONCLUSION: CDC has a poor prognosis compared to non-CDC renal cell carcinoma. Treatment for CDC represents a future challenge and targeted therapies may play a role in selected cases.

Rationale and protocol of SOAP: a phase II study to evaluate the efficacy of sorafenib as second-line treatment after pazopanib in patients with advanced renal cell carcinoma.

The introduction of agents targeting vascular endothelial grow factors has radically changed the approach to metastatic renal cell carcinoma; however, cure is not within definitive reach. In many cases, the tumor will progress several months after the start of first-line therapy and new lines of therapy are required. Pazopanib and sorafenib are two frequently used targeted agents, and no sound data are currently available for patients who relapsed after pazopanib. In this paper we illustrate the SOAP study, which was designed to evaluate the safety and efficacy of sorafenib in terms of progression free-survival in 44 patients treated in 10 Italian centers who had relapsed after first-line pazopanib. Standard treatment with sorafenib will be administered until disease progression or unacceptable toxicity. Secondary endpoints include the evaluation of overall survival, safety and quality of life. A subanalysis to evaluate toxicities as predictive factors has also been planned.

Is there a role for targeted therapies in the collecting ducts of Bellini carcinoma? Efficacy data from a retrospective analysis of 7 cases.

INTRODUCTION: Though uncommon, the collecting duct carcinoma (CDC) of Bellini is a very aggressive primary renal tumour occurring in less than 1% of all renal cell carcinoma (RCC) cases. This rare subtype was always excluded from the prospective trials with targeted therapies. Few data so far available concern the subgroup analyses from the expanded access programs with sorafenib and sunitinib, and from temsirolimus randomized study. PATIENTS AND METHODS: From December 2004 to May 2010, 333 patients with advanced RCC have been treated in our Institution with targeted therapies: of these, 7 (2.6%) were affected by CDC. General characteristics, symptoms, pathological features, treatments and patients' outcome were recorded. RESULTS: All patients affected by CDC received targeted agents as first-line therapy: more precisely, 4 patients were treated with sorafenib, 2 with temsirolimus and 1 with sunitinib. After progression 2 patients received a second-line treatment with sunitinib. No patients were alive at 5 years. Five patients developed early progression of disease with a very short 4-month survival, while 2 cases had a long-lasting disease control with an overall survival time accounting for 49 and 19 months, respectively. Treatment-related adverse events were manageable consisting of fatigue, diarrhoea, hand-foot syndrome, hypertension and anemia, the latter being the most frequent. No treatment discontinuations due to adverse event were needed. CONCLUSIONS: This investigation shows that targeted agents are safe, displaying some degree of activity in CDCs: therefore, they could be considered as an alternative in patients not eligible to chemotherapy regimens. Further studies including biomarkers as predictive factors of tumour biology and clinical features are required to improve the management of this challenging disease.

Renal cell cancer and sorafenib: skin toxicity and treatment outcome.

We describe the case of a young man with refractory renal cell carcinoma who achieved an objective response in a metastatic lesion after biotherapy with the multikinase inhibitor sorafenib and also developed a severe skin reaction. The patient had been previously treated with various combinations of immunochemotherapy without any clinical benefit. We performed a brief review of the literature where similar cases were documented with the use of various anti-EGFR agents. The hypothesis of the correlation of skin toxicity with disease response is not new, but in the absence of any strong evidence remains controversial.

Safety and activity of sorafenib in different histotypes of advanced renal cell carcinoma.

BACKGROUND: The aim of our study was to evaluate the efficacy and safety in unresectable or advanced renal carcinoma treated with sorafenib, in a situation closely similar to the everyday medical practice. PATIENTS AND METHODS: One hundred and thirty-six patients have been treated with 400 mg b.i.d. of sorafenib administered orally until disease progression or unacceptable toxicity. They were either previously untreated or relapsed after one or more previous treatments with systemic therapy. Most of them had clear cell renal carcinoma (RCC), but other histological types such as papillary, chromophobe, Bellini ducts, sarcomatoid and mixed forms were also represented. RESULTS: Overall disease control of 70.6% was achieved with 7.9% of partial remissions. Response was observed in the majority of patients with RCC, but also in some patients with non-clear cell RCC. Safety was acceptable, with the most common adverse events consisting of hand-foot skin reaction, cutaneous rash, diarrhoea, fatigue and hypertension. CONCLUSIONS: The results confirm previous ones reported in the literature concerning the efficacy and the safety of sorafenib as second-line treatment in patients with RCC. In addition, they disclose the hypothesis that sorafenib could be effective also in patients who underwent multiple previous treatments and in those with histology different from clear cells.