Tivozanib for advanced – 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 (VEGF) receptors 1, 2 and 3, which are involved in . 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. for the first line treatment of metastatic renal cell carcinoma. Expected May 20111. • NICE technology appraisal in development. 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. (first-line), (first- and second- line), (second-line) and (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. -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 , 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 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 .

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 until death. Primary Progression free survival Long term safety. ORR at week 16; % of outcome (PFS). randomly assigned patients remaining progression free after 12 weeks treatment; safety. Secondary Overall survival (OS); OS; ORR; DR; PFS. PFS after randomisation; outcomes objective response rate overall PFS; (ORR); duration of ; response (DR); kidney- pharmacodynamics. specific symptoms using FKSI-DRSd and FACT- Ge; health related quality of life outcome measurements using EQ- 5Df instrument.; pharmacokinetics; safety. Key results - - Respectively for all patients, patients with CC component, patients undergone nephrectomy or both: ORR (%), 30.1, 23.9, 25.6, 35.8; median PFS (months), 11.7, 12.5, 13.4, 14.8.

PFS (months) respectively for patients: with or without CC component, 12.5 vs 6.7; with or without prior nephrectomy, 13.4 vs 7.2. For patients with CC component and prior nephrectomy, PFS for treatment naive and those who had prior treatment, 14.3 and 15.9 months respectively. Expected Study expected to Study expected to - reporting date complete December 2011. complete March 2012. Adverse - - Most common treatment effects (AEs) related AEs included combined hypertension (44.9%) and dysphonia (21.7%). Other AEs included diarrhoea (12.1%), asthenia (10.3%), fatigue (8.1%), stomatitis (4.4%) and hand- foot syndrome (4.0%).

dThe Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-Related Symptoms (FKSI- DRS) is used to assess patients' kidney cancer related symptoms. eFunctional Assessment of Cancer Therapy (FACT-G) is used to assess the functional status of patients with specific cancer diagnosis. fEQ-5D, a trade mark of EuroQol group is a standardised instrument to measure health outcome. 5 January 2011

Estimated cost and cost impact The cost of tivozanib is not yet known. The costs of comparable drugs for the treatment of patients with advanced RCC are as follows20, 28:

Drug Dose Period: 28 days Sunitinib (Sutent) 50mg for 4 weeks in a 6 week cycle £3,139 Pazopanib (Votrient) 800mg once daily £1,83020 Sorafenib (Nexavar) 400mg twice daily £2,980 Everolimus (Afinitor) 10mg once daily £2,772 Bevacizumab (Avastin) 10mg/kg once every 14 days4 £1,849g

Claimed or potential impact – speculative

Patients  Reduced mortality or increased Reduction in associated morbidity Quicker, earlier or more accurate length of survival or Improved quality of life for diagnosis or identification of patients and/or carers disease Other: None identified

Services Increased use Service organisation Staff requirements

Decreased use Other:  None identified

Costs Increased unit cost compared to Increased costs: more patients Increased costs: capital alternative coming for treatment investment needed New costs: additional treatment Savings:  Other: uncertain unit cost option. compared to alternative therapies.

Other issues  Clinical uncertainty or other research question identified: None identified Trials directly comparing tivozanib with sunitinib or pazopanib may be needed to determine the comparative efficacy and toxicity of tivozanib for the first line treatment of RCC.

References

1National Institute for Health and Clinical Excellence. Pazopanib for the first line treatment of metastatic renal cell carcinoma. Technology appraisal in development. Expected May 2011. 2National Institute for Health and Clinical Excellence. Everolimus for the treatment of advanced and/or metastatic renal cell carcinoma. Technology appraisal in development. Expected date of issue to be confirmed. 3National Institute for Health and Clinical Excellence. Pazopanib for the second line treatment of metastatic renal cell carcinoma. Technology appraisal in development. Suspended April 2010. 4National Institute for Health and Clinical Excellence. 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. Technology appraisal TA178. London: NICE; August 2009. 5National Institute for Health and Clinical Excellence. Sunitinib for the first-line treatment of advanced and/or metastatic renal cell carcinoma. Technology appraisal TA169. London: NICE; March 2009. 6National Institute for Health and Clinical Excellence. Improving outcomes in urological cancers – the manual. Guidance on cancer services N0138. London: NICE; September 2002. 7Ljungberg B, Hanbury DC, Kuczyk MA et al. Guidelines on renal cell carcinoma. European Association of urology. April 2010. Available at: http://www.uroweb.org/gls/pdf/Renal%20Cell%20Carcinoma%202010.pdf 8Cancer Care Ontario (CCO) Program in Evidence-Based Care (PEBC). Clinical practice guideline. The use of inhibitors of angiogenesis in patients with inoperable locally advanced or metastatic renal cell cancer: Guideline recommendations. April 2009

gCosting based on average adult bodyweight 76.9kg. 6 January 2011

9Cancer Care Ontario (CCO) Program in Evidence-Based Care (PEBC). Clinical practice guideline. Interferon- alfa in the treatment of patients with inoperable locally advanced or metastatic renal cell cancer: Guideline recommendations. May 2009 10National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: kidney cancer version 1. 2008. 11Peer Review Team - National Cancer Action Team. Revised urology cancer measures. London: National Cancer Action Team; November 2008. 12Cancer Care Ontario (CCO) Program in Evidence-Based Care (PEBC). Clinical practice guideline. Interleukin- 2 in the treatment of patients with unresectable or metastatic renal cell cancer. June 2006. 13NHS. Hospital episode statistics. NHS England 2009-2010 inpatient data. HES data 2010. www.hesonline.nhs.uk 14Conn JT, Hoyle M, Green C et al. Bevacizumab, sorafenib tosylate, sunitinib and temsirolimus for renal cell carcinoma: a systematic review and economic evaluation. Health Technology Assessment 2010; 14 (2). 15Chowdhury S and Choueiri TK. Recent advances in the systemic treatment of metastatic papillary renal cancer. Expert Reviews in Anticancer Therapy. 2009;9(3):373‐379. 16Cancer Research UK. Kidney cancer statistics - UK. http://info.cancerresearchuk.org/cancerstats/types/kidney/index.htm?script=true Accessed 30 November 2010. 17National Institute for Health and Clinical Excellence. Costing statement: 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. London: NICE; August 2009. 18Office for National Statistics. Mortality statistics-deaths registered in 2009. http://www.statistics.gov.uk/downloads/theme_health/dr2009/dr-09.pdf 19Cancer Research UK. CancerStats. http://info.cancerresearchuk.org/cancerstats/types/kidney/symptomsandtreatment/?a=5441 Accessed 30 November 2010. 20National Institute for Health and Clinical Excellence. Final appraisal determination - Pazopanib for the first line treatment of metastatic renal cell carcinoma. London: NICE; December 2010. 21British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; September 2010. 22 National Institute for Health and Clinical Excellence. Final appraisal determination-Everolimus for the second- line treatment of advanced renal cell carcinoma. London: NICE; November 2010. 23ClinicalTrials.gov. A Study to compare tivozanib (AV-951) to sorafenib in subjects with advanced renal cell carcinoma (TIVO-1). http://clinicaltrials.gov/ct2/show/NCT01030783? Accessed 30 November 2010. 24ClinicalTrials.gov. An extension treatment protocol for subjects who have participated in a phase 3 study of tivozanib versus sorafenib in renal cell carcinoma (Protocol AV-951-09-301). http://clinicaltrials.gov/ct2/show/NCT01076010? Accessed 30 November 2010. 25Bhargava P, Esteves B, Al-Adhami M et al. Updated activity and safety results of a phase II randomised discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2 and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC). Journal of Clinical Oncology 2009; 27 (suppl 15s; abstr 5032). 26Bhargava P, Esteves B, Al-Adhami M et al. Activity of tivozanib (AV-951) in patients with renal cell carcinoma (RCC): Subgroup analysis from a phase II randomised discontinuation trial (RDT). American Society of Clinical Oncology. 2010. 4599. Poster presentation. 27ClinicalTrials.gov. A study of tivozanib (AV-951), an oral VEGF inhibitor, in the treatment of renal cell carcinoma. http://clinicaltrials.gov/ct2/show/NCT00502307? Accessed 30 November 2010. 28British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; September 2010.

7 January 2011

The National Institute for Health Research National Horizon Scanning Centre Research Programme is funded by the Department of Health. The views expressed in this publication are not necessarily those of the NHS, the NIHR or the Department of Health

The National Horizon Scanning Centre, Department of Public Health and Epidemiology University of Birmingham, 90 Vincent Drive, Edgbaston, Birmingham, B15 2SP, England Tel: +44 (0)121 414 7831 Fax +44 (0)121 414 2269 www.haps.bham.ac.uk/publichealth/horizon

8