Horizon Scanning Centre January 2015

Rociletinib for advanced or recurrent non-small cell lung cancer with the EGFR T790M mutation

SUMMARY NIHR HSC ID: 8272

Rociletinib is intended to be used as a treatment option for patients with non- small cell lung cancer (NSCLC) with activating EGFR mutations that have progressed on prior EGFR-directed therapy as a result of the emergence of the This briefing is T790M secondary resistance mutation. Rociletinib is a novel oral, targeted, based on covalent (irreversible) mutant-selective EGFR tyrosine kinase inhibitor. It information selectively targets both initial activating EGFR mutations and the T790M resistance mutation whilst sparing the wild-type or normal EGFR. available at the time

of research and a In the UK, lung cancer is the most common cause of cancer-related death in limited literature men and women. NSCLC accounts for approximately 85% of lung cancer search. It is not cases and around 10-15% of people with NSCLC have EGFR positive disease. intended to be a In England and Wales, approximately 50% of patients with NSCLC present with definitive statement metastatic forms of the disease. The median survival rates of patients with on the safety, untreated metastatic NSCLC are 4-5 months, with a one year survival rate of efficacy or only 10%. effectiveness of the health technology Treatment for patients with NSCLC is determined by various factors such as the covered and should histological and genetic subtype of the tumour, disease stage, co-morbidity and not be used for performance status. Current guidelines recommend chemotherapy incorporating commercial a platinum drug as a first line therapy, with EGFR targeted agents as purposes or appropriate. Rociletinib is currently in one uncontrolled phase II clinical trial commissioning investigating its impact on response rate. This trial is expected to finish in 2017. without additional 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 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): advanced; mutant epidermal growth factor (EGFR) positive – progressed on prior EGFR-directed therapy due to T790M-mediated acquired drug resistance.

TECHNOLOGY

DESCRIPTION

Rociletinib (CO-1686; AVL 301; AVL-301; CNX-419) is a novel, oral, targeted, covalent (irreversible) mutant-selective EGFR tyrosine kinase inhibitor (TKI). It selectively targets both initial activating EGFR mutations and the T790M resistance mutation, while sparing the wild- type, or normal EGFR. In the phase II clinical trial, rociletinib was administered at 625mg oral twice daily on a continuous basis10.

Rociletinib is also in phase II development for EGFR positive advanced NSCLC in patients who have not previously received an EGFR inhibitor.

INNOVATION and/or ADVANTAGES

If licensed, rociletinib may offer a treatment option for patients with NSCLC with activating EGFR mutations who have progressed on prior EGFR-directed therapy as a result of the emergence of the T790M secondary mutation.

DEVELOPER

Clovis Oncology.

AVAILABILITY, LAUNCH OR MARKETING

In phase II clinical trials.

PATIENT GROUP

BACKGROUND

The majority of all lung cancer cases are non-small cell histology. There are three subtypes of NSCLC, namely squamous cell carcinoma, adenocarcinoma and large cell carcinoma1. The symptoms of NSCLC include haemoptysis, malaise, significant weight loss, dyspnoea and voice loss1. However, early stages of the disease are often asymptomatic and many cases will have metastasised by the time of diagnosis1. The main cause of lung cancer is smoking, which accounts for 80% of cases; however other risk factors include exposure to asbestos, arsenic, radon, and non-tobacco-related polycyclic aromatic hydrocarbons5. In addition, epidermal growth factor receptor (EGFR) mutations have been identified as oncogenic drivers of lung cancer; independent of smoking historya.

a Company information.

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NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • 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

Lung cancer is the second most diagnosed cancer in the UK; 34,899 people were diagnosed with lung cancer in England in 2011 (46.6 cases per 100,000 population)1. Approximately 50% of patients present with metastatic forms of the disease6. NSCLC accounts for approximately 85% of lung cancer cases1. An estimated 15% of patients that present with NSCLC will have EGFR-TK mutation positive disease13, and this rises to 35% of patients from Asian ethnic groupsb.

The median survival of patients with untreated metastatic NSCLC is only 4-5 months, with a one year survival rate of only 10%3. In 2012 there were 84,876 admissions for lung cancer (ICD-10 C34) in England resulting in 295,114 bed-days and 104,273 finished consultant episodes5. In 2013, 30,424 deaths from lung cancer were reported in England and Wales4.

The population likely to be eligible to receive treatment with rociletinib could not be estimated from routine available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE technology appraisal in development. Lung cancer (non-small cell, second line) – erlotinib and gefitinib (rev of TA162 and TA175) (ID620). Expected June 2014. • NICE technology appraisal in development. Nintedanib for treating previously treated metastatic non-small cell lung cancer (ID438). Expected May 2015. • NICE technology appraisal. Afatinib for the treating epidermal growth factor receptor mutation-positive locally advanced or metastatic non-small-cell lung cancer (TA310). April 2014. • NICE technology appraisal. Pemetrexed maintenance treatment following induction therapy with pemetrexed and cisplatin for non-squamous non-small-cell lung cancer (TA309). 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 the 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.

b Company information

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• 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. Systemic therapy for advanced non-small cell lung cancer. March 2013. • NICE quality standard. Quality standard for lung cancer (QS17). March 2012. • NICE interventional procedure guidance. Microwave ablation for treating primary lung cancer and metastases in the lung (IPG469). November 2013. • NICE interventional procedure guidance. Irreversible electroporation for treating primary lung cancer and metastases in the lung (IPG441). February 2013. • NICE interventional procedure guidance. Percutaneous radiofrequency ablation for primary or secondary lung cancers (IPG372). December 2010. • NICE interventional procedure guidance. Photodynamic therapy for localised inoperable endobronchial cancer (IPG137). November 2005. • NICE diagnostics guidance. EGFR-TK mutation testing in adults with locally advanced or metastatic non-small-cell lung cancer (DG9). August 2013.

Other Guidance

• Scottish Intercollegiate Guidelines Network. Management of lung cancer (SIGN 137). 20146. • European Society for Medical Oncology. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 20141. • American Society of Clinical Oncology. 2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non– Small-Cell Lung Cancer. 20117.

CURRENT TREATMENT OPTIONS

Treatment for patients with NSCLC is determined not only by the histological subtype and genetic subtype of the tumour, but also by disease stage, co-morbidity, and performance status. Chemotherapy for advanced disease can extend overall survival by several months compared to best supportive care and may improve quality of life, but it may not be appropriate for many patients with poor performance status8. Patients who smoke should be encouraged to cease, as cessation improves treatment outcomes1.

Current guidelines recommend that chemotherapy should be offered to patients with stage III or IV NSCLC and good performance status (WHO score of 0 or 1 or a Karnofsky score of 80-100)9. For advanced NSCLC, a combination of a single third-generation drug (docetaxel, gemcitabine, paclitaxel or vinorelbine) plus a platinum drug (either carboplatin or cisplatin) may be offered9.

As a first line treatment, the TKIs afatinib, erlotinib and gefitinib are the standard of care for EGFR positive metastatic NSCLC not previously treated with an EGFR-TK inhibitor9. Pemetrexed is also recommended as an option for maintenance treatment in people with locally advanced or metastatic NSCLC: with other than predominantly squamous cell histology if their disease has not progressed immediately following platinum-based chemotherapy in combination with gemcitabine, paclitaxel or docetaxel9. It is recommended that patients progressing after first-line chemotherapy be offered docetaxel or erlotinib as a second line treatment option9.

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EFFICACY and SAFETY

Trial TIGER-2; NCT02147990; rociletinib; TIGER-X, NCT01526928; rociletinib; phase II. phase I/II. Sponsor Clovis Oncology, Inc. Clovis Oncology, Inc. Status Ongoing Ongoing Source of Trial registry10, manufacturer15. Trial registry11, manufacturer14. information Location EU (excluding UK), USA, Canada and EU (excluding UK), USA, Canada and other countries. other countries. Design Non randomised, uncontrolled. Non-randomised, uncontrolled. Participants n=125 (planned); ≥18 years of age; n=605 (planned); ≥18 years of age; NSCLC; metastatic; EGFR mutation with NSCLC; metastatic; EGFR mutation with T790M resistance mutation. T790M resistance mutation.

For the phase II cohort: disease progression while on treatment with EGFR-TKI or following EGFR-TKI treatment.

Schedule Patients receive rociletinib 625mg, oral, In the phase II cohort, patients receive twice daily. rociletinib 500mg, 625mg or 750mg oral twice daily. Follow-up Treatment continued until investigator Not reported. determines it is no longer beneficial due to disease progression or unacceptable toxicity. Primary Objective response rate (ORR). For the phase II cohort, ORR. outcome/s Secondary Duration of response (DR); disease ORR; adverse events (AEs); OR; DCR. outcome/s control rate (DCR); progression free survival (PFS); overall survival (OS). Key results ORR 58%, PFS estimate exceeds 12 ORR 67%, DCR 89%. Median PFS months. estimated at 10.4 months. Adverse AEs reported include nausea, AEs reported include hyperglycaemia, effects (AEs) hyperglycaemia and impaired glucose diarrhoea, nausea, reduced appetite, tolerance(IGT), diarrhoea, vomiting, fatigue, muscle spasm and vomiting. decreased appetite, myalgia and prolonged QTc. Expected Not reported Not reported reporting date

ESTIMATED COST and IMPACT

COST

The cost of rociletinib is not yet known. The costs of selected comparators are listed below:

Drug Dose Cost12 Docetaxel 75mg/m2 on day 1 of a 21 day cycle £1,008.54 (total cost for one 21 day cycle)c Erlotinib 30 x 150mg tablets £1,631.53

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

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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; fewer chemotherapy visits, oral treatment option.

 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: uncertain treatment cost compared to  None identified existing treatment options.

Other Issues

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

REFERENCES

1 Peters S, Adjei AA, Gridelli C, et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2014 Annals of oncology, 23(suppl 7), vii56-vii64. 2 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 09 December 2015. 3 Green JA, Bates V, Greenhalgh J, Boland A, et al. First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No. CD010383. DOI: 10.1002/14651858.CD010383. 4 Cancer Research UK. Data Table: Cancer cases and rates by country in the UK 2011 http://publications.cancerresearchuk.org/cancerstats/statsincidence/dtinccountries.html. Accessed 09 December 2014. 5 Health & Social Care Information Centre. Hospital Episode Statistics for England. Inpatient statistics, 2012-13. www.hscic.gov.uk. 6 Scottish Intercollegiate Guidelines Network (SIGN). Management of lung cancer (SIGN publication no. 137). Edinburgh: SIGN; February 2014. 7 Azzoli C, Temin S, Aliff T et al. Focused update of 2009 American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non–small-cell lung cancer. Journal of Clinical Oncology 2011;29(28):3825-3831. 8 Spiro S, Rudd R, Souhami R, et al. Chemotherapy versus supportive care in advanced non-small cell lung cancer: improved survival without detriment to quality of life. Thorax 2004;59(10):828- 836. doi:10.1136/thx.2003.020164. 9 National Institute for Health and Clinical Excellence. Lung cancer: the diagnosis and treatment of lung cancer. Clinical guideline CG121. London: NICE; April 2011.

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10 ClinicalTrials.gov. Open Label Safety and Efficacy Study of Rociletinib (CO-1686) in Patients With T790M Positive NSCLC Who Have Failed One Previous EGFR-Directed TKI (TIGER-2). http://clinicaltrials.gov/ct2/show/NCT02147990. Accessed 08 December 2014. 11 ClinicalTrials.gov. Study to Evaluate Safety, Pharmacokinetics, and Efficacy of Rociletinib (CO- 1686) in Previously Treated Mutant Epidermal Growth Factor Receptor (EGFR) in Non-Small Cell Lung Cancer (NSCLC) Patient. http://clinicaltrials.gov/ct2/show/NCT01526928. Accessed 08 December 2014. 12 The Pharmaceutical Society. British National Formulary. BNF September 2014. https://www.medicinescomplete.com. Accessed 12 December 2014. 13 National Institute for Health and Clinical Excellence, Lung cancer (non-small cell, EGFR-TK mutation positive erlotinib (1st line): costing statement. Technology Appraisal (TA258), June 2012, http://www.nice.org.uk/guidance/ta258/chapter/5-implementation. Accessed 15 December 2014. 14 Soria J, Sequist L, Goldman J, Wakelee BH et al. Interim Phase II Results With The Irreversible Mutant Selective EGFR, EGFR inhibitor Rociletinib (CO-1686). 26th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, November 2014. Oral Presentation. http://www.clovisoncology.com/files/Rociletinib_ENA_2014_Soria_FINAL.pdf. 15 Sequist L, Soria J, Gadgeel S, Wakelee H et al. An Irreversible, Highly Selective Tyrosine Kinase Inhibitor of mutations of EGFR (Activating And T790M). ASCO annual conference. 2014. Oral Presentation. http://www.clovisoncology.com/files/CO1686_Oral_ASCO2014_FINAL.pdf.

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