Tivozanib for advanced renal cell carcinoma – first line January 2011 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research January 2011 Tivozanib for advanced renal cell carcinoma – first line Target group • Renal cell carcinoma (RCC): advanced – first line. Technology description Tivozanib (AV-951; KRN-951) is a selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3, which are involved in angiogenesis. Inhibition of VEGF driven angiogenesis has been demonstrated to reduce vascularisation of tumours, thereby suppressing tumour growth. Tivozanib is intended to substitute current therapies for the first line treatment of patients with advanced RCC. It is administered orally at 1.5mg once daily for 3 weeks in a 4 week cycle. Tivozanib is in phase I/II clinical trials for the treatment of breast cancer, gastrointestinal cancer and non-small cell lung cancer. Innovation and/or advantages If licensed, tivozanib will offer an additional first line treatment option for advanced RCC, a condition where current therapies offer relatively limited benefit. Developer AVEO Pharma Limited. Availability, launch or marketing dates, and licensing plans In phase III clinical trials. NHS or Government priority area This topic is relevant to the NHS Cancer Plan (2000) and Cancer Reform Strategy (2007). Relevant guidance • NICE technology appraisal in development. Pazopanib for the first line treatment of metastatic renal cell carcinoma. Expected May 20111. • NICE technology appraisal in development. Everolimus for the treatment of advanced and/or metastatic renal cell carcinoma. Expected date of issue to be confirmed2. • NICE technology appraisal in development. Pazopanib for the second line treatment of metastatic renal cell carcinoma. Suspended April 20103. • NICE technology appraisal. Bevacizumab (first-line), sorafenib (first- and second- line), sunitinib (second-line) and temsirolimus (first-line) for the treatment of advanced and/or metastatic renal cell carcinoma. 20094. • NICE technology appraisal. Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. 20095. • NICE guidance on cancer services. Improving outcomes in urological cancers – the manual. 20026. 7 • European Association of Urology. Guidelines on renal cell carcinoma. 2010 . • Cancer Care Ontario - program in evidence-based care. Clinical practice guideline. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. 20098. • Cancer Care Ontario - program in evidence-based care. Clinical practice guideline. Interferon-alfa in the treatment of patients with inoperable locally advanced or metastatic renal cell cancer: guideline recommendations. 20099. 2 January 2011 • National Comprehensive Cancer Network. Clinical practice guidelines in oncology: kidney cancer. 200810. • Peer Review Team - National Cancer Action Team. Revised urology cancer measures. 200811. • Cancer Care Ontario - program in evidence-based care. Clinical practice guideline. Interleukin-2 in the treatment of patients with unresectable or metastatic renal cell cancer. 200612. Clinical need and burden of disease RCC is the most common form of kidney cancer and accounts for around 3% of all adult cancers in the UK4. In England there were 16,306 admissions for kidney cancer (ICD C64-66, C68), resulting in 82,610 bed days and 19,241 finished consultant episodes in 2009-1013. In England and Wales, an estimated 90% of kidney cancers are RCCs14. Approximately 70-80% of all RCCs have a clear cell component15. RCC is nearly twice as common in men as in women, and most commonly affects adults aged 50-80 years4,16. In Europe, approximately 25% of cases of kidney cancer are attributable to obesity and 25% of cases in men are attributable to smoking7. Approximately 25% and 17% of patients present with advanced and/or metastatic disease (stage III or stage IV) respectively4, representing around 2,500 new patients per year17. In addition, an estimated 50% of patients who have curative resection for earlier stages will develop recurrent and/or metastatic disease4. The estimated five-year survival rate for RCC is 44%, which is reduced to 10% for metastatic disease4. In 2009, there were 3,317 deaths registered from kidney cancer (ICD C64-66, C68) in England and Wales18. Existing comparators and treatments Treatment of RCC is primarily surgical. The main objectives of medical intervention are to relieve physical symptoms and extend survival. Advanced and/or metastatic RCC is largely resistant to chemotherapy, radiotherapy and hormonal therapy. Until recently, the standard treatment was immunotherapy with interferon alpha (IFN-alpha), or less commonly interleukin-2 (IL-2)5. Not all patients are suitable for immunotherapy, which achieves overall response rates of 4-31%19, and is often associated with severe morbidity (physical and psychological side effects). In 2009, sunitinib (Sutent), a tyrosine kinase inhibitor, was recommended by NICE as a first line treatment for patients with advanced and/or metastatic RCC in whom immunotherapy would be suitable and who have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (typically mobile and can do light housework or office work)5. Pazopanib (Votrient) has recently received a positive NICE final appraisal determination (FAD) for the first line treatment of patients with advanced RCC who have not received prior cytokine therapy and have a ECOG performance status of 0-120. Other therapeutic options for the treatment of advanced or metastatic RCC that are licensed but not recommended by NICE include4,21,22: • Sunitinib (Sutent): second line therapy. • Sorafenib (Nexavar): first line therapy for patients unsuitable for cytokine therapy or second line therapy following cytokine failure. • Temsirolimus (Torisel): first line therapy in patients with >3 poor prognostic indicators. • Bevacizumab (Avastin): first line therapy in combination with IFN-alpha. • Everolimus (Afinitor): second line therapy after failure of VEGF targeted therapy. 3 January 2011 Efficacy and safety Trial TIVO-1, NCT01030783; NCT01076010; tivozanib NCT00502307; tivozanib or tivozanib or sorafenib; or sorafenib; phase III placebo; phase II. phase III. extension. Sponsor AVEO pharmaceuticals. AVEO pharmaceuticals. AVEO pharmaceuticals. Status Ongoing. Ongoing. Completed. Source of Trial registry23, Trial registry24, Abstract25,26, trial registry27, information manufacturer. manufacturer. manufacturer. Location EU (inc UK), USA, EU (inc UK), USA, India, Russia and Ukraine. Canada and other Canada and other countries. countries. Design Randomised, active- Extension study. Randomised, placebo- controlled. controlled. Participants n=500 (planned); adults; n=500 (planned); adults; n=272; adults; RCC; and schedule RCC; recurrent or RCC; recurrent or recurrent, metastatic or metastatic; CC component; metastatic; CC component; primary RCC not amendable undergone prior ECOG performance status to surgical intervention; nephrectomy; measurable 0-2; participated in trial measurable disease; received 0 disease as per RECISTa; NCT01030783; -1 prior systemic therapies; no received 0 -1 prior demonstrated disease prior treatment with VEGF- systemic therapiesb; no progression with sorafenib directed therapy; no active prior treatment with or clinical benefit and brain metastases; Karnofsky VEGF-directed therapy or acceptable tolerability with performance status ≥70%; life drug targeting mTORc tivozanib or sorafenib for expectancy ≥3 months. pathway; ECOG up to 2 years. Received tivozanib at 1.5mg performance status 0-1; Continued on the same once daily for 3 weeks in a 4 life expectancy ≥3 months; treatment as randomised in week cycle for 16 weeks. no active brain metastases. NCT01030783. Further treatment based on Randomised to tivozanib Participants who failed on tumour response. If <25% at 1.5mg once daily for 3 sorafenib in tumour change (growth or weeks of a 4 week cycle or NCT01030783 or during shrinkage) randomised to sorafenib at 400mg twice the extension study tivozanib at 1.5mg once daily daily in a 4 week cycle. crossed over to tivozanib. for 3 weeks of a 4 week cycle or placebo for 12 weeks; if ≥25% tumour shrinkage continued on tivozanib; and if ≥25% tumour growth discontinued treatment with tivozanib. Patients receiving placebo given the option to receive tivozanib after 12 weeks. Follow-up Patients with documented Active treatment until Active treatment period 12 stable disease or objective disease progression and/or weeks. Thereafter patients response receive treatment intolerable toxicities; with documented stable for up to 2 years. follow up until death. disease or objective response Thereafter they may enrol receive treatment until disease in a separate long-term progression and/or treatment protocol. unacceptable toxicities. Treatment continues until disease progression and/or unacceptable toxicities. aResponse Evaluation Criteria In Solid Tumors. bImmunotherapy including INF-alfa or IL-2 based therapy, chemotherapy, hormonal therapy or an investigational agent. cMammalian target of rapamycin. 4 January 2011 Follow up