sign in sign up
<<
Home , Treatment of lung cancer

Sorafenib (Nexavar) for relapsed or refractory advanced non- small cell (NSCLC) – third or fourth line

December 2010

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

December 2010

Sorafenib (Nexavar) for relapsed or refractory advanced non- small cell lung cancer (NSCLC) – third or fourth line

Target group • NSCLC: predominantly non-squamous, advanced, relapsed/refractory – third or fourth line; after failure of 2 or 3 standard treatment regimens.

Technology description Sorafenib (BAY 43-9006, Nexavar) is one of a new series of raf signalling pathway inhibitors with raf kinase inhibitor activity. It has a dual action that targets serine/threonine and receptor tyrosine kinases, inhibiting (1) the raf cascade to prevent the downstream mediation of cell growth and proliferation, and (2) the VEGFR-2,3/PDGFR- βa signalling cascade to inhibit the activation of angiogenesis, thus acting on both tumour cell growth and tumour vasculature. Sorafenib is intended to treat advanced NSCLC (predominantly non-squamous) which is refractory to, or has relapsed after 2 or 3 standard treatment regimens. It is administered orally at 400mg twice daily in a 28 day cycle until disease progression or unacceptable toxicity.

Sorafenib is licensed and has received orphan designation in the EU for the treatment of advanced renal cell and hepatocellular carcinoma. It is in phase III clinical trials for the treatment of metastatic thyroid cancer. Sorafenib is also in phase II clinical trials for a variety of cancers, including acute myeloid leukaemia, gastric, head and neck, ovarian, metastatic colorectal and advanced breast cancer.

Innovation and/or advantages If licensed, sorafenib may provide a new treatment option for patients with advanced NSCLC, after failure of standard treatment regimes, where options are currently limited.

Developer Bayer Schering Pharma.

Availability, launch or marketing dates, and licensing plans In Phase III clinical trial.

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. monotherapy for the maintenance treatment of non-small cell lung cancer. Expected January 20111. • NICE technology appraisal in development. Erlotinib, in combination with for the maintenance treatment of non-squamous advanced or metastatic non-small cell lung cancer after previous containing . Suspended July 20102. • NICE technology appraisal. for the first line treatment of locally advanced or metastatic non-small cell lung cancer. 20103. • NICE technology appraisal. for the maintenance treatment of non-small- cell lung cancer. 20104. • NICE technology appraisal. Topotecan for the treatment of relapsed small cell lung cancer. 20095. a VEGFR: vascular endothelial growth factor receptor; PDGFR: platelet-derived growth factor receptor. 2 December 2010

• NICE technology appraisal. Pemetrexed for the first line treatment of non-small cell lung cancer. 20096. • NICE technology appraisal. Erlotinib for the treatment of non-small cell lung cancer. 20087. • NICE technology appraisal. Pemetrexed for the treatment of non-small-cell lung cancer.20078. • NICE clinical guideline. Lung cancer: the diagnosis and treatment of lung cancer. 2005. Update in progress, due March 20119. • American College of Chest Physicians. Diagnosis and management of lung cancer: ACCP guidelines (2nd Edition). 200710. 11 • SIGN. Management of patients with lung cancer. 2005 . • European Society for Medical (ESMO). Minimum clinical recommendations for the diagnosis, treatment and follow-up of non-small cell lung cancer. 200512. • Cancer Services Collaborative Improvement Partnership. Lung cancer service improvement guide. 200413.

Clinical need and burden of disease In the UK, lung cancer is the most common cause of cancer-related death in men and women. In 2007, there were 33,828 new cases of lung cancer in England and Wales14,15 (64 cases per 100,000 population) and around 30,300 deaths (55 deaths per 100,000 population) registered in 200816. In England and Wales lung cancer has a one-year survival rate of 25% and a five-year survival rate of 7%17. About 90% of lung cancer mortality among men and 80% among women is attributable to smoking11.

NSCLC accounts for approximately 80% of all lung cancers; the main types being , adenocarcinoma and large cell carcinoma18. Approximately 75% of newly diagnosed NSCLC patients have advanced (stage III or IV) disease in England and Wales (approximately 21,000 patients)19, which has a five-year survival rate of less than 1%20. An estimated 30% of patients with NSCLC receive first line chemotherapy; 30% to 50% of whom may also be suitable for second line treatment19. It is estimated that 20% of those receiving second line therapy will be suitable for a third or subsequent treatment.

Existing comparators and treatments There is currently no recommended pharmacological treatment available for patients with advanced NSCLC that is refractory to or has relapsed after first and second line treatment. The only treatment option for the majority of patients will be best supportive care, which aims to relieve symptoms, improve disease control, improve quality of life and increase survival9.

Efficacy and safety Trial MISSION, NCT00863746; sorafenib or placebo; phase III. Sponsor Bayer. Status Ongoing. Source of Trial registry21. information Location EU (inc UK), USA, Canada and other countries. Design Randomised, placebo-controlled. Participants and n=850 (planned); adults; NSCLC; predominantly non-squamous; advanced; schedule relapsed/refractory; treated with 2-3 prior standard regimens; Eastern Cooperative Oncology Group (ECOG) status 0-1; life expectancy ≥12 weeks. Randomised to sorafenib 400mg twice daily or placebo. 3 December 2010

Follow-up Active treatment until disease progression or unacceptable toxicity; follow-up every 3 weeks.

Primary Overall survival (OS). outcomes Secondary Progression free survival (PFS); disease control rate; overall response rate; time to outcomes progression; patient reported outcomes. Expected Study expected to complete May 2011. reporting date

Trial NCT00064350; sorafenib or placebo; NCT00101413; sorafenib; phase II. phase II. Sponsor Eastern Cooperative Oncology Group. Bayer. Status Ongoing and published in an abstract22. Published. Source of Trial registry23. Publication24, trial registry25. information Location USA. USA and Germany. Design Randomised, placebo-controlled. Non-randomised, uncontrolled. Participants and n=342 (97 randomised); adults; NSCLC; n=52; adults; NSCLC; predominantly schedule advanced; progressive disease; treated non-squamous; advanced; with at least 2 prior chemotherapy relapsed/refractory; measurable disease; regimens; >3 weeks since prior treated with 1-2 prior systemic or radiotherapy; no treatments; no prior treatment with concurrent treatment with biologic methyl ethyl ketone (MEK), farnesyl therapy or radiotherapy; ECOG status transferase, raf inhibitors or drugs 0-1. targeting VEGF/VEGFR; ongoing stable Received sorafenib 400mg twice daily corticosteroid treatment; ECOG status for 2 months in the absence of disease 0-2. progression or unacceptable toxicity. Received sorafenib 400mg twice daily. Patients with progressive disease (PD) Dose reduction to sorafenib 400mg once discontinued study; patients with daily and re-escalation to 400mg twice responding disease continue to receive daily permitted at discretion of the sorafenib; patients with stable disease investigator. (SD) randomised to sorafenib 400mg twice daily or placebo. Patients receiving placebo crossed over to sorafenib in case of disease progression within a year. Follow-up Active treatment period 1 year in the Active treatment until tumour absence of disease progression or progression or intolerable toxicity; unacceptable toxicity; follow-up every 3 median duration 68 days. months for 2 years, then every 6 months for 3 years. Primary SD; response after 2 months of Antitumour response, defined as outcomes treatment. proportion of patients achieving a complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumours (RECIST). Secondary Survival; PFS; response rate. Duration of response; PFS; duration of outcomes SD; OS; drug related toxicities. Key results Interim results for patients randomised No confirmed PRs or CRs reported; to placebo and sorafenib respectively: tumour shrinkage observed in 28.8%, median PFS (months), 1.9 vs 3.6, 27% of whom experienced unconfirmed p=0.01; reduction of ≥30% on at least one post- SD, 5% vs 29%, p=0.002; treatment measurement. PD, 37% vs 25%. 4 December 2010

SD reported in 58.5%; median SD duration 3.4 months (range, 0.9 to 13.1 months); SD rate similar in men (62%) and women (53%), and patients with squamous cell carcinoma (56%) or other histologies (60%). Median PFS 2.7 months (5.5 months in patients with SD); median OS 6.7 months. Expected Information not available. - reporting date Adverse effects Most common treatment-emergent AEs Drug related AEs reported in 90%, most (AEs) included rash/hand-foot syndrome commonly diarrhoea (40%), hand-foot (15%), fatigue (11%) and international skin reaction (37%), fatigue (27%) and normalized ratio (INR) abnormalities (25%). Serious AEs reported in (3%). 8%, including myocardial infarction, chest pain, hemoptysis, hypotension, headache and arterial hypertension. Two events of hyperuricemia and elevated lipase reported. Bleeding observed in 8% of patients.

Most common treatment-emergent AEs included fatigue (63.5%), diarrhoea (51.9%), cough (51.9%), and dyspnoea (48.1%). Rates of treatment-emergent AEs similar for patients with squamous or non-squamous cell histology.

Estimated cost and cost impact The cost of sorafenib if given at a dose of 400mg twice daily for 28 days would be around £2,98026.

Claimed or potential impact – speculative

Patients  Reduced mortality or increased  Reduction in associated Quicker, earlier or more accurate length of survival morbidity or Improved quality of diagnosis or identification of life for 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: option

Other issues  Clinical uncertainty or other research question identified: None identified Rapid introduction of new agents for NSCLC means that their relative efficacies and toxicities are not yet fully understood. 5 December 2010

References

1 National Institute for Health and Clinical Excellence. Erlotinib monotherapy for the maintenance treatment of non-small cell . Technology appraisal in development. Expected January 2011. 2 National Institute for Health and Clinical Excellence. Erlotinib, in combination with bevacizumab for the maintenance treatment of non-squamous advanced or metastatic non-small cell lung cancer after previous platinum containing chemotherapy. Suspended technology appraisal in development. July 2010. 3 National Institute for Health and Clinical Excellence. Gefitinib for the first line treatment of locally advanced or metastatic non-small cell lung cancer. Technology appraisal TA192. London: NICE; July 2010. 4 National Institute for Health and Clinical Excellence. Pemetrexed for the maintenance treatment of non-small- cell lung cancer. Technology appraisal TA190. London: NICE; June 2010. 5 National Institute for Health and Clinical Excellence. Topotecan for the treatment of relapsed small cell lung cancer. Technology appraisal TA184. London: NICE; November 2009. 6 National Institute for Health and Clinical Excellence. Pemetrexed for the first line treatment of non-small cell lung cancer. Technology appraisal TA181. London: NICE; September 2009. 7 National Institute for Health and Clinical Excellence. Erlotinib for the treatment of non-small cell lung cancer. Technology appraisal TA162. London: NICE; November 2008. 8 National Institute for Health and Clinical Excellence. Pemetrexed for the treatment of non-small cell lung cancer. Technology appraisal TA124. London: NICE; August 2007. 9 National Institute for Health and Clinical Excellence. Lung cancer: the diagnosis and treatment of lung cancer. Clinical guideline CG024. London: NICE; February 2005. 10 American College of Chest Physicians. Diagnosis and management of lung cancer: ACCP Evidence-based clinical practice guidelines (2nd Edition). Chest 2007; 132. 11 Scottish Intercollegiate Guidelines Network (SIGN). Management of patients with lung cancer. No.80. Edinburgh: SIGN; February 2005. 12 European Society for Medical Oncology (ESMO). Minimum clinical recommendations for the diagnosis, treatment and follow-up of non-small cell lung cancer (NSCLC). Annals of Oncology 2005; 16 (1): 128-129. 13 Cancer Services Collaborative Improvement partnership. Lung cancer service improvement guide. October 2004. http://www.ebc-indevelopment.co.uk/nhs/lung/index.html Accessed 7 July 2010. 14 Office for National Statistics. Cancer Statistics: Registrations Series MB1 No 38. http://www.statistics.gov.uk 15 Welsh Cancer Intelligence and Surveillance Unit. Cancer incidence in Wales, 2003-2007. http://www.wales.nhs.uk. 16 Office for National Statistics. Mortality statistics-deaths registered in 2008. http://www.statistics.gov.uk. 17 Cancer Research UK. http://info.cancerresearchuk.org/cancerstats/types/lung/survival/index.htm Accessed 7 July 2010. 18 Cancer Research UK. Cancer help UK. http://www.cancerhelp.org.uk/type/lung-cancer/about/types-of-lung- cancer Accessed 4 July 2010. 19 Liverpool Reviews and Implementation Group, ERG Report – Erlotinib for the treatment of relapsed non-small cell lung cancer. London: NICE; September 2006. 20 National Collaborating Centre for Acute Care. The diagnosis and treatment of lung cancer: methods, evidence and guidance. February 2005. 21 ClinicalTrials.gov. A 3rd/4th line placebo-controlled trial of sorafenib in patients with predominantly non squamous non-small cell lung cancer NSCLC. (MISSION). http://clinicaltrials.gov/ct2/show/NCT00863746? Accesssed 14 September 2010. 22 Schiller JH, Lee JW, Hanna N H et al. A randomized discontinuation phase II study of sorafenib versus placebo in patients with non-small cell lung cancer who have failed at least two prior chemotherapy regimens: E2501. Journal of Clinical Oncology 2008; 26(May 20 supplement: abstract 8014). 23 ClinicalTrials.gov. Sorafenib in treating patients with refractory non-small cell lung cancer. Accesssed 14 September 2010. 24 George R, Blumenschein Jr, Gatzemeier U et al. Phase II, multicentre, uncontrolled trial of single-agent sorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer. Journal of Clinical Oncology 2009:27(26):4274-4280. 25 ClinicalTrials.gov. BAY43-9006 - phase II study in non-small cell lung carcinoma (NSCLC). http://clinicaltrials.gov/ct2/show/NCT00101413? Accesssed 14 September 2010. 26 British Medical Association and Royal Pharmaceutical society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London: September 2010.

6 December 2010

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

7