Horizon Scanning Centre July 2013

Onartuzumab for metastatic Met positive non-small cell

SUMMARY NIHR HSC ID: 3495

Onartuzumab is a first-in-class monoclonal monovalent antibody designed to inhibit Met signalling in cancer cells by binding to the extracellular domain of Met – thereby blocking hepatocyte (HGF)-mediated activation. Overexpression of the Met receptor is associated with poor survival and resistance to in non-small cell lung cancer (NSCLC). Onartuzumab is intended as second line treatment of stage III or IV Met-positive NSCLC. It is administered by intravenous (IV) infusion at 15mg/Kg once every 3 weeks in combination with erlotinib 150mg oral once daily until disease progression. This briefing is

based on NSCLC is the most common type of lung cancer accounting for information approximately 85-90% of lung cancers in the UK. NSCLCs are further available at the time differentiated into three main histological subgroups: squamous cell of research and a carcinoma, adenocarcinoma, and large cell carcinoma. limited literature search. It is not In stage IIIB NSCLC, the tumour may be any size and has spread to lymph intended to be a nodes above the clavicle or in the opposite side of the chest from the tumour; definitive statement and/or to any of the organs in the thoracic cavity. Stage IV NSCLC may have on the safety, spread to lymph nodes and has spread to another lobe of the lungs or to efficacy or other parts of the body, such as the brain, liver, adrenal glands, kidneys, or effectiveness of the bone. health technology covered and should The company estimate that around half of all advanced NSCLC tumours not be used for overexpress Met, which is associated with a poor outcome in many cancers, commercial including NSCLC. In England and Wales, approximately 78% of newly purposes or diagnosed NSCLC patients have advanced (stage III or IV) disease that is commissioning incurable at outset. Lung cancer is the second most common cancer in the without additional UK with around 42,000 new diagnoses in 2010, and 34,900 deaths. information. Onartuzumab in combination with erlotinib is currently undergoing a phase III clinical trial assessing its effect on overall survival compared with erlotinib treatment alone.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Centre, University of Birmingham Email: [email protected] Web: http://www.hsc.nihr.ac.uk NIHR Horizon Scanning Centre

TARGET GROUP

• Non-small cell lung cancer (NSCLC); Met-positive; relapsed stage IIIB or IV metastatic – second line after failure of prior ; in combination with erlotinib.

TECHNOLOGY

DESCRIPTION

Onartuzumab (hOA-5D5.v2; MetMAb; OA 5D5; PRO143966; RG 3638; RO 5490258) is a first-in-class monoclonal monovalent antibody designed to inhibit Met signalling in cancer cells by binding to the extracellular domain of Met – thereby blocking (HGF)-mediated activation. Overexpression of the Met receptor is associated with poor survival and resistance to erlotinib in NSCLC. Onartuzumab is intended as second line treatment of stage III or IV Met-positive NSCLC. It is administered by intravenous (IV) infusion at 15mg/Kg once every 3 weeks in combination with erlotinib 150mg oral once daily until disease progression.

Onartuzumab is also currently in late stage development for the following indications: Phase III • Gastroesophageal cancer; metastatic; HER2 negative; Met positive • NSCLC; EFGR positive – first line; in combination with erlotinib (planned) Phase II • NSCLC; non-squamous – first line • NSCLC; squamous – first line • Breast cancer; metastatic; triple negative – first/second line • Colorectal cancer; metastatic – first line • Glioblastoma multiforme; recurrent • Hepatocellular carcinoma; advanced (planned)

COMPANION DIAGNOSTIC

Roche is working with its subsidiary – Ventana Medical Systems – to develop and commercialise a companion diagnostic assay used to determine c-MET expression in NSCLC tumours. This assay will be used to select patients for the pivotal phase III study and the company plan to launch the validated companion diagnostic in concurrence with onartuzumab.

INNOVATION and/or ADVANTAGES

The company claim that onartuzumab utilises a novel target for its action and if licensed, may be used as an adjunct to existing treatment options in order to improve their efficacy in this patient group.

DEVELOPER

Roche Products Ltd.

2 NIHR Horizon Scanning Centre

AVAILABILITY, LAUNCH OR MARKETING

Currently in phase III clinical trials.

PATIENT GROUP

BACKGROUND

NSCLC is the most common type of lung cancer accounting for approximately 85-90% of lung cancers in the UK1. NSCLCs are further differentiated into three main histological subgroups2,3,4: • Squamous cell carcinoma (33%) – this is the most common type of lung cancer. It develops in the respiratory epithelium and is often caused by smoking. • Adenocarcinoma (25%) – develops from the cells that produce mucus in the lining of the airways (goblet cells). • Large cell carcinoma (4%).

In addition, approximately 36% of patients are listed as being NSCLC ‘not otherwise specified’ (NOS), 1% as carcinoma in situ and 1% as bronchioloalveolar. The relative proportions of these subgroups vary over time, by population and by stage of disease. The different types of NSCLC are grouped together because they behave in a similar way and respond to treatment in a different way to small cell lung cancer (SCLC)2. It is often difficult to distinguish the type of NSCLC if only a few cells are taken during a biopsy or the cells are undifferentiated (called undifferentiated NSCLC)2,3. However, the histological confirmation rate is estimated to be approximately 75%a. In stage IIIB NSCLC, the tumour may be any size, but it will have spread to lymph nodes above the clavicle or in the opposite side of the chest from the tumour, and/or to any of the organs in the thoracic cavity5. Stage IV NSCLC has spread to lymph nodes and another lobe of the lungs, or to other parts of the body (metastases), such as the brain, liver, adrenal glands, kidneys, or bone5.

The symptoms of lung cancer may include: a continuing cough, or change in a long-standing cough, dyspnoea and wheeze, haemoptysis, chest or shoulder pain, weight loss, a persistent chest infection, a hoarse voice, a dull ache or sharp pain on coughing/taking a deep breath, difficulty swallowing, fatigue and lethargy, finger clubbing, and swelling of lymph nodes in the neck area2,3.

The company estimate that around half of all advanced NSCLC tumours overexpress Met. Upon initial diagnosis of NSCLC, Met gene amplification is uncommon; however, acquired Met amplification has been noted in up to 20% of epidermal (EGFR) mutated tumours that have been pre-treated with an EGFR inhibitor (TKI)6 such as erlotinib. Met activation is associated with a poor outcome in many cancers, including NSCLC, and is a mechanism of resistance to EGFR inhibition7.

Smoking is the main cause of lung cancer, responsible for 80% of cases. There are several other known risk factors including exposure to asbestos, arsenic, radon, and non-tobacco- related polycyclic aromatic hydrocarbons8.

a Expert clinical opinion.

3 NIHR Horizon Scanning Centre

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: Improving Outcomes: A Strategy for Cancer (2011).

CLINICAL NEED and BURDEN OF DISEASE

Lung cancer is the second most common cancer in the UK with around 42,000 new diagnoses in 2010, and 34,900 deaths9. According to the National Lung Cancer Audit 2010 (an audit of data from hospital trusts and/or hospital sites within England that treat patients with lung cancer, amalgamated with data from other parts of the UK to produce a report on the national standards of care in England and Wales), there were 26,731 cases of NSCLC in England and Wales10. Of these, 14,629 patients had stage IIIB or IV disease10. In England and Wales during 2010 approximately 4,200 patients with advanced NSCLC received chemotherapy10 and around 30-40% of these patients receive second-line therapy5. In 2011- 12, there were 85,009 hospital admissions for lung cancer11, of which approximately 74,400 are thought to be due to NSCLC. For patients presenting with NSCLC stage IIIB, the 5-year survival rate is around 7 to 9% whilst for patients presenting with NSCLC stage IV, the 5- year survival rate varies from 2 to 13%4.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. for the treatment of advanced non-small cell lung cancer (ID9). Suspended September 201212. • NICE technology appraisal in development. Lung cancer (non-small cell, second line) – erlotinib and (rev of TA162 and TA175) (ID620). Expected June 201413. • NICE technology appraisal in development. for the treatment of EGFR mutation positive non-small cell lung cancer (ID556). Expected March 201414. • NICE technology appraisal in development. (EGFR-TK) mutation testing in adults with locally advanced or metastatic non- small cell lung cancer. Expected September 201315. • NICE technology appraisal in development. for the treatment of previously treated non-small cell lung cancer associated with anaplastic lymphoma kinase fusion gene. (ID499). Expected July 201316. • NICE technology appraisal in development. Pemetrexed for maintenance treatment following induction therapy with pemetrexed and cisplatin for non-squamous non-small- cell lung cancer. (ID489). Expected July 201317.

• NICE technology appraisal. Erlotinib for the first line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small cell lung cancer (TA258). June 201218. • NICE technology appraisal. Erlotinib monotherapy for the maintenance treatment of non- small cell lung cancer. (TA227). June 201119. • NICE technology appraisal. Gefitinib for the first line treatment of locally advanced or metastatic non-small cell lung cancer. (TA192). July 201020. • NICE technology appraisal. Pemetrexed for the maintenance treatment of non-small cell lung cancer. (TA190). June 201021. • NICE technology appraisal. Pemetrexed for the first line treatment of non-small cell lung cancer. (TA181). September 200922.

4 NIHR Horizon Scanning Centre

• NICE technology appraisal. Erlotinib for the treatment of non-small cell lung cancer. (TA162). November 200823. • NICE technology appraisal. Pemetrexed for the treatment of non-small cell lung cancer. (TA124). August 200724.

• NICE clinical guideline. Lung cancer: the diagnosis and treatment of lung cancer. (CG121). April 201125. • NICE quality standard. Systemic therapy for advanced non-small cell lung cancer. March 201326. • NICE quality standard. Quality standard for lung cancer. (QS17). March 201227.

Other Guidance

• American College of Chest Physicians. Diagnosis and management of lung cancer: ACCP guidelines (3rd edition). 201328. • Liverpool Reviews and Implementation Group (LRiG). Erlotinib and gefitinib for treating non-small cell lung cancer that has progressed following prior chemotherapy (review of NICE technology appraisals 162 and 175. 20134. • European Society for Medical Oncology (ESMO). Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 20128. • ESMO. Early stage and locally advanced (non-metastatic) non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 201029. • SIGN. Management of patients with lung cancer. 200530. • Cancer Services Collaborative Improvement Partnership. Lung cancer service improvement guide. 200431.

EXISTING COMPARATORS and TREATMENTS

Treatment of relapsed or metastatic NSCLC after failure of prior chemotherapy aims to improve disease control, improve quality of life and increase survival. Current second line treatment options include8,23,24,25,30,32:

• Docetaxel monotherapy – when cancer has relapsed after previous chemotherapy. • Erlotinib monotherapy– is recommended as an alternative to docetaxel for patients who have already progressed despite chemotherapy regimen. • Pemetrexed – for a non-squamous histology only (not recommended by NICE for the treatment of locally advanced or metastatic NSCLC in people who have had prior chemotherapy).

• EGFR TKI (e.g. erlotinib or gefitinib) – patients with a tumour bearing an activating (sensitizing) EGFR mutation should receive an EGFR TKI as second-line therapy, if not received previously (gefitinib is not recommended by NICE).

EFFICACY and SAFETY

Trial MetLung, NCT01456325; onartuzumab vs placebo; phase III. Sponsor Roche. Status Ongoing. Source of Trial registry33, manufacturer. information Location EU (incl UK), USA, Canada and other countries. Design Randomised, placebo-controlled.

5 NIHR Horizon Scanning Centre

Participants n=490 (planned); aged ≥18 years; incurable stage IIIb/IV NSCLC; Met-positive; ECOGb performance status 0-1; prior treatment with ≥1 platinum based line of treatment; no more than 1 additional line of chemotherapy; last dose administered ≥21 days prior to day 1; tissue sample available for diagnostic testing; not exposed to an EFGR inhibitor ≥30 days. Schedule Randomised to onartuzumab 15mg/kg IV once every 3 weeks with erlotinib 150mg oral once daily until disease progression; or placebo IV once every 3 weeks with erlotinib 150mg oral once daily until disease progression. Follow-up Active treatment until disease progression. Primary Overall survival. outcome/s Secondary Progression-free survival; overall response rate; safety. Quality of life measurement outcome/s included but not specified by company. Expected Estimated study completion date December 2015. reporting date

ESTIMATED COST and IMPACT

COST

The cost of onartuzumab is not yet known. The cost of testing for Met expression will also have to be considered as part of the overall cost of onartuzumabc. The cost of a 150mg 30 tablet pack of erlotinib is £1631.5334.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other:  No impact identified

Impact on Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services: requirement for biopsy and Met testing.

 Other:  None identified

Impact on Costs

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs: additional costs for IV  Other reduction in costs: administration in clinic and additional costs associated with Met testing (including biopsy) and the possible requirement for re-testinge.

 Other:  None identified

b ECOG (Eastern Cooperative Oncology Group) performance status: a 6 point performance scale used by clinicians to assess disease progression. c Expert clinical opinion.

6 NIHR Horizon Scanning Centre

Other Issues

 Clinical uncertainty or other research question  None identified identified:

REFERENCES

1 National Institute for Health and Clinical Excellence. Cetuximab for the first-line treatment of advanced and/or metastatic non-small cell lung cancer final scope. London: NICE; August 2011. 2 Cancer Research UK. About cancer: lung cancer. http://www.cancerresearchuk.org/cancer- help/type/lung-cancer/ Accessed 12 June 2013. 3 Macmillan Cancer Support. Cancer information: cancer types. Lung cancer. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Lung/Lungcancer.aspx Accessed 12 June 2013. 4 Liverpool Reviews and Implementation Group. Erlotinib and gefitinib for treating non-small cell lung cancer that has progressed following prior chemotherapy (review of NICE technology appraisals 162 and 175. University of Liverpool; March 2013. 5 National Institute for Health and Clinical Excellence. Final scope for the appraisal of erlotinib monotherapy for the maintenance treatment of advanced or metastatic non-small cell lung cancer. London: NICE; November 2009. 6 Carter CA and Giaccone G. Treatment of non small cell lung cancer: overcoming the resistance to EGFR inhibitors. Current Opinion in Oncology 2012;24(2):123-129. 7 Spigel DR, Ervin TJ, Ramlau R, et al. Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. Journal of Clinical Oncology 2011;29:(suppl; abstr 7505). http://meeting.ascopubs.org/cgi/content/abstract/29/15_suppl/7505?sid=0ce Accessed 16 July 2013. 8 Peters S, Adjei AA, Gridelli C et al. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2012:23(7):vii56–vii64. 9 CancerResearchUK. Lung cancer key facts. http://www.cancerresearchuk.org/cancer- info/cancerstats/keyfacts/lung-cancer/ Accessed 21 March 2013. 10 Health and Social Care Information Centre. National lung cancer audit: 2011 patient cohort. December 2012. http://www.hscic.gov.uk/searchcatalogue?productid=10043&q=title%3a%22Lung+cancer%22&inf otype=0%2fAudit&sort=Relevance&size=10&page=1#top 11 NHS Hospital episode statistics. NHS England 2011-12 HES data. 2013. www.hesonline.nhs.uk 12 National Institute for Health and Care Excellence. Cetuximab for the treatment of advanced non- small cell lung cancer. Technology appraisal in development suspended ID9. London: NICE; September 2012. 13 National Institute for Health and Care Excellence. Lung cancer (non-small cell, second line) – erlotinib and gefitinib (rev of TA162 and TA175) Technology appraisal in development ID620. London: NICE; expected June 2014. 14 National Institute for Health and Care Excellence. Afatinib for the treatment of EGFR mutation positive non-small cell lung cancer. Technology appraisal in development ID556. London: NICE; expected March 2014. 15 National Institute for Health and Care Excellence. Epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation testing in adults with locally advanced or metastatic non-small cell lung cancer. Technology appraisal in development. London: NICE; expected September 2013. 16 National Institute for Health and Care Excellence. Crizotinib for the treatment of previously treated non-small cell lung cancer associated with anaplastic lymphoma kinase fusion gene. Technology appraisal in development ID499. London: NICE; expected July 2013. 17 National Institute for Health and Care Excellence. Pemetrexed for maintenance treatment following induction therapy with pemetrexed and cisplatin for non-squamous non-small-cell lung cancer. Technology appraisal in development ID489. London: NICE; expected July 2013. 18 National Institute for Health and Care Excellence. Erlotinib for the first line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small cell lung cancer. Technology appraisal TA258. London: NICE; June 2012.

7 NIHR Horizon Scanning Centre

19 National Institute for Health and Care Excellence. Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer. Technology appraisal TA227. London: NICE; June 2011. 20 National Institute for Health and Care Excellence. Gefitinib for the first line treatment of locally advanced or metastatic non-small cell lung cancer. Technology appraisal 192. London: NICE; July 2010. 21 National Institute for Health and Care Excellence. Pemetrexed for the maintenance treatment of non-small cell lung cancer. Technology appraisal TA190. London: NICE; June 2010. 22 National Institute for Health and Care Excellence. Pemetrexed for the first line treatment of non- small cell lung cancer. Technology appraisal TA181. London: NICE; September 2009. 23 National Institute for Health and Care Excellence. Erlotinib for the treatment of non-small cell lung cancer. Technology appraisal TA162. London: NICE; November 2008. 24 National Institute for Health and Care Excellence. Pemetrexed for the treatment of non-small cell lung cancer. Technology appraisal TA124. London: NICE; August 2007. 25 National Institute for Health and Care Excellence. Lung cancer: the diagnosis and treatment of lung cancer. Clinical guideline CG121. London: NICE; April 2011. 26 National Institute for Health and Care Excellence. Systemic therapy for advanced non-small cell lung cancer. Quality standard. London: NICE; March 2013. 27 National Institute for Health and Care Excellence. Quality standard for lung cancer. Quality standard QS17. London: NICE; March 2012. 28 American College of Chest Physicians. Diagnosis and management of lung cancer, 3rd ed: ACCP Evidence-based clinical practice guidelines. Chest 2013;143:(5_suppl). 29 Crino L, Weder W, van Meerbeeck J et al. Early stage and locally advanced (non-metastatic) non- small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21(suppl 5):v103-v115. 30 Scottish Intercollegiate Guidelines Network (SIGN). Management of patients with lung cancer. No.80. Edinburgh: SIGN; February 2005. 31 Cancer Services Collaborative Improvement partnership. Lung cancer service improvement guide. October 2004. http://www.ebc-indevelopment.co.uk/nhs/lung/index.html Accessed12 June 2013. 32 National Institute for Health and Care Excellence. NICE Pathways: Treatment for non-small cell lung cancer. London: NICE; March 2012. http://pathways.nice.org.uk/pathways/lung- cancer#path=view%3A/pathways/lung-cancer/treatment-for-non-small-cell-lung- cancer.xml&content=close Accessed 13 June 2013. 33 Clinicaltrials.gov. A study of onartuzumab (MetMAb) in combination with Tarceva (erlotinib) in patients with Met diagnostic-positive non-small cell lung cancer who have received chemotherapy for advanced or metastatic disease (MetLung). http://clinicaltrials.gov/ct2/show/NCT01456325?term=NCT01456325&rank=1 Accessed 13 June 2013. 34 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BNF 64. London: BMJ Group and RPS Publishing, March – September 2013.

8