For EGFR Positive, Advanced Or Metastatic Non-Small Cell Lung Cancer

Horizon Scanning Research July 2015 & Intelligence Centre

Bevacizumab (Avastin) with erlotinib (Tarceva) for EGFR positive, advanced or metastatic non-small cell lung cancer – first line

SUMMARY NIHR HSRIC ID: 2920

This briefing is based on information Bevacizumab (Avastin) with erlotinib (Tarceva) is intended to be used as a first line treatment option for patients with epidermal growth factor receptor available at the time (EGFR) positive, advanced or metastatic non-small cell lung cancer of research and a (NSCLC). Bevacizumab is a humanised immunoglobulin (IgG1) monoclonal limited literature antibody that acts as a vascular endothelial growth factor antagonist and search. It is not erlotinib is an orally active inhibitor of the EGFR tyrosine kinase. intended to be a definitive statement In the UK, lung cancer is the second most common diagnosed cancer after on the safety, breast cancer, but it is the most common cause of cancer deaths, accounting efficacy or for more than 1 in 5 cancer deaths. Over 33,000 new cases of lung cancer effectiveness of the are diagnosed each year in England, 80% of these are thought to be health technology NSCLC, and 78% are anticipated to be advanced and/or metastatic at covered and should diagnosis. Approximately 15% of NSCLC is evaluated as EGFR positive. not be used for commercial European Society for Medical Oncology guidelines recommend that patients purposes or with NSCLC be tested for EGFR mutations before initiation of first line commissioning treatment. Bevacizumab and erlotinib are in phase II clinical trial, comparing without additional their effect on overall survival against treatment with erlotinib monotherapy. information.

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 Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Non-small cell lung cancer (NSCLC): advanced or metastatic; EGFR mutation positive – first line.

TECHNOLOGY

DESCRIPTION

Bevacizumab (Avastin) is a humanised immunoglobulin (IgG1) monoclonal antibody that acts as a vascular endothelial growth factor (VEGF) antagonist. Bevacizumab binds to VEGF, the key driver of vasculogenesis and angiogenesis, and thereby inhibits the binding of VEGF to its receptors, Flt1 (VEGFR-1) and KDR (VEGFR-2), on the surface of endothelial cells. Neutralising the biological activity of VEGF causes regression of the vascularisation of tumours, normalises remaining tumour vasculature and inhibits the formation of new tumour vasculature, thereby inhibiting tumour growth. Erlotinib (Tarceva) is an orally active inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. Mutations that lead to EGFR overexpression (upregulation) or over activity may lead to uncontrolled cell division and are associated with a number of cancers, including NSCLC. In phase II clinical trials, erlotinib was administered orally at 150mg daily in combination with bevacizumab administered via intravenous (IV) infusion at 15mg/kg every three weeks, both continued until disease progression or unacceptable toxicity1.

Bevacizumab, in addition to platinum based chemotherapy is currently licensed for the first line treatment of adults with unresectable advanced, metastatic or recurrent NSCLC with other than predominantly squamous cell histology. It is also licensed for the treatment of colorectal carcinoma, breast cancer, renal cell cancer, cervical cancer and epithelial ovarian, fallopian tube or peritoneal cancer. Erlotinib is currently licensed for the first line treatment of patients with locally advanced or NSCLC with EGFR activating mutations; for the maintenance treatment of patients with locally advanced or metastatic NSCLC with EGFR activating mutations; and for the maintenance treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen. It is also licensed for the treatment of pancreatic cancer. Bevacizumab is currently in phase III trials for breast cancer, glioblastoma, head and neck cancer, ovarian cancer and renal cancer. Erlotinib is also in phase III trials for ependymoma in children and for head and neck cancer.

INNOVATION and/or ADVANTAGES

If licensed, bevacizumab with erlotinib will offer an additional treatment option for patients with advanced EGFR positive NSCLC.

DEVELOPER

Roche Products Ltd.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials

2 Horizon Scanning Research & Intelligence Centre

PATIENT GROUP

BACKGROUND

Approximately 85-90% of all lung cancers are of the non-small cell type; NSCLC can be further classified into three histological sub-types, namely large-cell undifferentiated carcinoma, squamous cell carcinoma, and adenocarcinoma2. The symptoms of NSCLC include haemoptysis, malaise, significant weight loss, dyspnoea and voice loss3. Smoking is the main cause of lung cancer, responsible for in excess of 80% of cases; other known risk factors include exposure to asbestos, arsenic, radon, and non-tobacco-related polycyclic aromatic hydrocarbons4.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • Improving Outcomes: A Strategy for Cancer (2011). • NHS England. 2013/14 NHS Standard Contract for Cancer: Chemotherapy (Adult). B15/S/a. • NHS England. 2013/14 NHS Standard Contract for Cancer: Radiotherapy (All Ages). B01/S/a.

CLINICAL NEED and BURDEN OF DISEASE

In the UK, lung cancer is the second most common diagnosed cancer after breast cancer, but it is the most common cause of cancer death, accounting for more than 1 in 5 cancer deaths5. In England there were 34,889 cases of lung cancer in 2011 (representing 46.6 cases per 100,000 population) (ICD-10 C33-C34)6. Incidence of lung cancer is higher in lower socioeconomic groups, and survival is poorer in these groups compared to higher socioeconomic groups7. The majority of lung cancers are diagnosed in the later stages of the disease, with 21% presenting with locally and regionally advanced disease (stage IIIB) and 48% presenting with metastases (stage IV)2. For people presenting with NSCLC stage IIIB disease, the 5-year survival rate is around 7 to 9%; for people presenting with NSCLC stage IV the 5-year survival rate varies from 2 to 13%2. Median survival for patients with stage IV disease NSCLC treated with platinum-based therapy is 8 to 12 months8,9.

Over 33,000 new diagnoses of lung cancer are made each year in England10. Of these, 80% are thought to be NSCLC and 78% are anticipated to be advanced and/or metastatic at diagnosis2. Approximately 15% of NSCLC is evaluated as EGFR positive10. Expert personal communication suggests that the average survival for patients with EGFR positive tumours is 2-3 yearsa.

In 2013-14, there were 88,350 hospital admissions in England due to lung cancer (ICD-10 C34), accounting for 108,216 finished consultant episodes and 282,717 bed days11. In 2013, there were 60,848 deaths from lung cancer registered in England and Wales12.

a Expert personal communication.

3 Horizon Scanning Research & Intelligence Centre

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Erlotinib and gefitinib for the treatment of non-small cell lung cancer that has progressed following prior chemotherapy (review of TA162 and TA175) (ID620). Expected date of issue to be confirmed. • NICE technology appraisal in development. Ceritinib for previously treated anaplastic lymphoma kinase-positive non-small cell lung cancer (ID729). Expected January 2016. • NICE technology appraisal in development. Nintedanib for treating previously treated metastatic non-small cell lung cancer (ID438). Expected July 2015. • NICE technology appraisal. Pemetrexed for maintenance treatment following induction therapy with pemetrexed and cisplatin for non-squamous non-small cell lung cancer (TA309). April 2014. • NICE technology appraisal. Afatinib for treating epidermal growth factor receptor mutation-positive locally advanced or metastatic non-small cell lung cancer (TA310). April 2014. • NICE technology appraisal. Crizotinib for previously treated non-small cell lung cancer associated with an anaplastic lymphoma kinase fusion gene (TA296). September 2013. • 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 2012. • NICE technology appraisal. Erlotinib monotherapy for maintenance treatment of non- small cell lung cancer (TA227). June 2011. • NICE technology appraisal. Gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (TA192). July 2010. • NICE technology appraisal. Pemetrexed for the maintenance treatment of non-small cell lung cancer (TA190). June 2010. • NICE technology appraisal. Pemetrexed for the first-line treatment of non-small cell lung cancer (TA181). September 2009. • NICE technology appraisal. Erlotinib for the treatment of non-small cell lung cancer (TA162). November 2008. • NICE technology appraisal. Pemetrexed for the treatment of non-small cell lung cancer (TA124). August 2007.

• NICE clinical guideline. Lung cancer: the diagnosis and treatment of lung cancer (CG121). April 2011.

• NICE quality standard. Quality standard for lung cancer (QS17). March 2012.

Other Guidance

• European Society for Medical Oncology. Metastatic non-small cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 20144. • Scottish Intercollegiate Guidelines Network. Management of lung cancer (137). 201413.

CURRENT TREATMENT OPTIONS

The aim of treatment for locally advanced or metastatic NSCLC is to prolong survival, improve quality of life, and control disease-related symptoms14. Treatment strategies should take into account the tumour histology and molecular pathology, as well as the patient’s age,

4 Horizon Scanning Research & Intelligence Centre

performance status, comorbidities, and preferences4. Patients who smoke should be encouraged to cease, as cessation improves treatment outcomes4.

European Society for Medical Oncology guidelines recommend that patients with NSCLC should be tested for EGFR mutations before initiation of first line treatment4. In patients with activating EGFR mutations (except EGFR wild-type mutations), EGFR-tyrosine kinase inhibitor (TKI) therapy should be considered as front-line therapy4. Erlotinib and gefitinib are options for patients with epidermal growth factor receptor tyrosine kinase (EGFR-TK) positive metastatic NSCLC15. Afatinib is also an option for EGFR-TK positive metastatic NSCLC not previously treated with another EGFR-TKI15.

EFFICACY and SAFETY

Trial J025567, JapicCTI-111390; erlotinib vs BELIEF, NCT01562028; bevacizumab erlotinib and bevacizumab; phase II. and erlotinib; phase II. Sponsor Chugai Pharmaceutical Co Ltd. European Thoracic Oncology Platform. Status Completed. Ongoing. 16 Source of Trial registry1. Trial registry . information Location Japan. EU (inc UK). Design Randomised. Non-randomised. Participants n=154; aged ≥ 20 years; histologically or n=110 (planned); aged ≥18 years; ECOG cytologically (excluding sputum cytology) performance status 0-2; pathological confirmed stage IIIB/IV or postoperative diagnosis of predominantly non- recurrent non-squamous NSCLC with squamous NSCLC; TNM version 7 stage activating EGFR mutation; Eastern IV disease including M1a (malignant Cooperative Oncology Group (ECOG) effusion) or M1b (distant metastasis), or performance status 0 or 1; no previous locally advanced disease not amenable chemotherapy for advanced disease. to curative treatment (including progression after radiochemotherapy for stage III disease); measurable evaluable disease according to RECIST 1.1 criteria; centrally confirmed EGFR mutation. Schedule Randomised to erlotinib 150mg orally Participants received erlotinib 150mg once daily or erlotinib 150mg orally once orally daily, plus bevacizumab 15mg/kg daily plus bevacizumab 15mg/kg IV every IV every three weeks. three weeks. Follow-up Active treatment until disease progression Active treatment until disease or unacceptable toxicity. progression. Primary Progression free survival (PFS). PFS. outcome/s Secondary PFS, tumour response according to Time to treatment failure; Overall survival outcome/s RECIST 1.1; quality of life, symptom (OS); objective response (toxicity, improvement measured by the FACT-1 disease control, duration of response). scale and safety profile. Key results Median PFS was 16 months with erlotinib - plus bevacizumab and 9.7 months with erlotinib alone. Adverse For erlotinib and bevacizumab vs erlotinib - effects (AEs) only, respectively: rash, 25% vs 19%, hypertension 45% vs 10%, proteinuria 6% vs 0%. Expected - Study completion date reported as reporting October 2016. date

5 Horizon Scanning Research & Intelligence Centre

ESTIMATED COST and IMPACT

COST

Drug Dose Cost17 Bevacizumab 15mg/kg £2334.12b Erlotinib 150mg daily £1631.53 for a pack of 30 x 150mg tablets

IMPACT - SPECULATIVE

Impact on Patients and Carers

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

 Other:  No impact identified

Impact on Health and Social Care Services

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

 Re-organisation of existing services  Need for new services

 Other:  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs

 Other increase in costs:  Other reduction in costs:

 Other:  None identified

Other Issues

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

REFERENCES

1 T Seto, T Kato, M Nshio, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncology 2014;15(11):1236-1244. 2 NICE technology appraisal in development. Nintedanib for treating previously treated metastatic non-small cell lung cancer (ID438). Final scope. London: NICE; July 2014. 3 National Cancer Institute. General information about non-small cell lung cancer (NSCLC). www.cancer.gov/cancertopics/pdq/treatment/non-small-cell- lung/healthprofessional/page1#Section_48499 Accessed 16 June 2015. 4 Reck M, Popat S, Reinmuth N et al. Metastatic non-small cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2014;25(suppl 3):iii27-iii39. 5 Cancer Research UK. Lung Cancer. November 2014. http://publications.cancerresearchuk.org/downloads/Product/CS_KF_LUNG.pdf 6 Cancer Research UK. Data Table: Cancer cases and rates by country in the UK 2011. publications.cancerresearchuk.org/cancerstats/statsincidence/dtinccountries.html Accessed 16 June 2015

b Based on an average body surface area of 1.88m2, assumes wastage.

6 Horizon Scanning Research & Intelligence Centre

7 Scottish Intercollegiate Guidelines Network (SIGN). Management of lung cancer (SIGN publication no. 137). Edinburgh: SIGN; February 2014. 8 Reinmuth N, Payer N, Muley T et al. Treatment and outcome of patients with metastatic NSCLC: a retrospective institution analysis of 493 patients. Respiratory Research 2013;14(1):139. 9 NIHR Horizon Scanning Centre. Ramucirumab (Cyramza) in combination with docetaxel for locally advanced or metastatic non-small cell lung cancer – second line. University of Birmingham, November 2014. www.hsc.nihr.ac.uk/ 10 National Institute of Health and Clinical Excellence. NICE technology appraisal costing statement. 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. 11 Health and Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2013-14. www.hscic.gov.uk 12 Office for National Statistics. Deaths registered in England and Wales (series DR) - 2013. www.ons.gov.uk 13 Scottish Intercollegiate Guidelines Network. Management of lung cancer. National clinical guideline 137. Edinburgh: SIGN; February 2014. 14 National Cancer Institute. Stage IV NSCLC Treatment. http://www.cancer.gov/cancertopics/pdq/treatment/non-small-cell-lung/healthprofessional/page11 Accessed 20 March 2015. 15 National Institute for Health and Care Excellence. NICE Pathways. Treatment for non-small-cell lung cancer. http://pathways.nice.org.uk/pathways/lung-cancer Accessed 20 March 2015. 16 ClinicalTrials.gov. An open-label phase II trial of erlotinib and bevacizumab with advanced non- small cell lung cancer and activating EGFR mutations. https://clinicaltrials.gov/ct2/show/NCT01562028?term=NCT01562028&rank=1 Accessed 17 June 2015. 17 Joint Formulary Committee. British National Formulary. BNF June 2015. www.medicinescomplete.com Accessed 17 June 2015.