Anamorelin for Anorexia-Cachexia in Advanced Non-Small Cell Lung Cancer

Horizon Scanning Centre November 2013

Anamorelin for anorexia-cachexia in advanced non-small cell lung cancer

SUMMARY NIHR HSC ID: 5342

Anamorelin is intended to be used for the treatment of anorexia-cachexia in advanced non-small cell lung cancer. If licensed, it will provide a new class of drug and an additional treatment option for this patient group, whose therapeutic options are currently limited. Anamorelin is a first-in-class, orally active ghrelin receptor agonist that binds and stimulates the growth hormone secretagogue receptor centrally, thereby mimicking the appetite-enhancing This briefing is and anabolic effects of ghrelin.

based on Cancer anorexia-cachexia is a multifactorial syndrome characterised by information involuntary weight loss, muscle atrophy and physiological changes, which available at the time leads to progressive functional impairment and a poor quality of life. It of research and a occurs in approximately 61% of non-small cell lung cancers and is limited literature accountable for around 20% of all cancer deaths. There are approximately search. It is not 32,500 new diagnoses of non-small cell lung cancer each year in England intended to be a and Wales, and around 30,000 deaths. definitive statement on the safety, Treatment options for treating anorexia-cachexia in non-small cell lung efficacy or cancer are limited. The approach is multimodal and may include: treatment effectiveness of the of secondary gastrointestinal symptoms, nutritional treatments, drug, and health technology non-drug treatments. Nutritional counselling and physical training may be covered and should beneficial in delaying or preventing the development of anorexia-cachexia. not be used for Anamorelin is currently in two phase III clinical trials comparing its effect on commercial lean body mass and muscle strength against treatment with placebo. One of purposes or these trials is expected to complete in Q1 2014. commissioning 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

• Anorexia-cachexia in non-small cell lung cancer (NSCLC): advanced (stage III or IV); unresectable.

TECHNOLOGY

DESCRIPTION

Anamorelin (ONO-7634; RC-1291) is a first-in-class, orally active ghrelin receptor agonist that binds and stimulates the growth hormone secretagogue receptor centrally, thereby mimicking the appetite-enhancing and anabolic effects of ghrelin. Anamorelin is administered orally at 100mg, once daily.

INNOVATION and/or ADVANTAGES

If licensed, anamorelin will provide a new class of drug and an additional treatment option for this patient group, whose therapeutic options are currently limited.

DEVELOPER

Helsinn.

AVAILABILITY, LAUNCH OR MARKETING

In phase III clinical trials.

PATIENT GROUP

BACKGROUND

Cancer anorexia-cachexia syndrome (CACS) is a multifactorial syndrome characterised by involuntary weight loss, muscle atrophy and physiological changes, which leads to progressive functional impairment1 and a poor quality of life2. It is associated with a poor performance status, reduced survival3 and an increased risk of treatment failure and toxicity4. Anorexia, the loss of appetite or desire to eat, is a common symptom in cachexia5, but anorexia alone does not explain the complex metabolic changes that occur during CACS, and cachexia may develop in the absence of anorexia3. Approximately 20% of cancer deaths are caused by the effects of CACS3,5.

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 most common cause of cancer-related death in the UK6. In 2010, there were 36,142 new cases of lung cancer in England and Wales (representing approximately 47 cases per 100,000 population)7, around 90%8 of whom (32,527) were NSCLC. In 2010,

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there were 29,914 lung cancer deaths registered in England and Wales6 (approximately 26,922 NSCLC). In England and Wales, one-year survival rates are estimated to be 29% for men and 33% for women, with five-year survival rates falling to 8% and 9%, respectively9. Around 5.5% of lung cancers are considered cured with currently available treatments10. An estimated 78% of newly diagnosed patients will have advanced (stage III or IV) disease11, and CACS occurs in approximately 61% of NSCLCs11. Advanced NSCLC is incurable12, with a five-year survival rate of less than 1%13. In 2011-12, there were 85,009 hospital admissions for cancer of the bronchus and lung (ICD-10 C34) in England, accounting for 104,814 finished consultant episodes and 302,720 bed days14.

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). Expected June 201415. • NICE technology appraisal in development. Afatinib for the treatment of EGFR mutation positive non-small cell lung cancer (ID556). Expected June 201416. • 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). December 201317.

• NICE technology appraisal. Crizotinib for previously treated non-small cell lung cancer associated with an anaplastic lymphoma kinase fusion gene (TA296). 201318. • 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 201219. • NICE technology appraisal. Erlotinib monotherapy for maintenance treatment of non- small cell lung cancer (TA227). June 201120. • NICE technology appraisal. Gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (TA192). July 201021. • NICE technology appraisal. Pemetrexed for the maintenance treatment of non-small cell lung cancer (TA190). June 201022. • NICE technology appraisal. Pemetrexed for the first-line treatment of non-small cell lung cancer (TA181). September 200923. • NICE technology appraisal. Erlotinib for the treatment of non-small cell lung cancer (TA162). November 200824. • NICE technology appraisal. Pemetrexed for the treatment of non-small cell lung cancer (TA124). August 200725.

• NICE clinical guideline. Lung cancer: the diagnosis and treatment of lung cancer (CG121). April 201110.

• NICE quality standard. Quality standard for lung cancer (QS17). March 201226.

Other Guidance

• National Comprehensive Cancer Network. The NCCN clinical practice guidelines in oncology. Non-small cell lung cancer. 201327.

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• European Society for Medical Oncology. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow- up. 201328. • European Society for Medical Oncology. Metastatic non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 201229. • European Palliative Care Research Collaborative. Clinical practice guidelines on cancer cachexia in advanced cancer patients. 201030. • American College of Chest Physicians. Diagnosis and management of lung cancer. ACCP guidelines (2nd edition). 200731. • Scottish Intercollegiate Guidelines Network. Management of patients with lung cancer (80). 200532.

EXISTING COMPARATORS and TREATMENTS

In patients with advanced NSCLC, the options for treating CACS are limited. The approach is multimodal and includes30: • treatment of secondary gastrointestinal symptoms and other causes for decreased nutritional intake. • evaluation of anti-neoplastic options to reduce the catabolic drive of cancer. • nutritional treatment – oral, enteral or parenteral nutrition therapy and use of supplements such as vitamins and minerals. • non-drug treatment – nutritional counselling or education, psychotherapeutic interventions and physical training. • drug treatment – short term use of corticosteroids (1-2 weeks) and progestational agents (megestrol and progestins). Other drugs like non-steroidal anti-inflammatory drugs, thalidomide and cytokine antagonists, cannabinioids, prokinetics and omega-3 fatty acids may be used to treat CACS; however their use is not recommended by the recent European guideline for the treatment of cachexia in patients with advanced cancer.

Prophylactic interventions such as nutritional counselling and physical training are also thought to be beneficial in delaying or preventing the development of CACS30.

EFFICACY and SAFETY

Trial ROMANA 1, NCT01387269, HT- ROMANA 2, NCT01387282, HT-ANAM- ANAM-301; anamorelin vs placebo; 302; anamorelin vs placebo; phase III. phase III. Sponsor Helsinn Therapeutics. Helsinn Therapeutics. Status Ongoing. Ongoing. 33 34 Source of Abstract , trial registry . Abstract33, trial registry35. information Location EU, USA, Canada and other countries. EU (incl UK), USA, Australia, Israel and Russia. Design Randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=477 (planned); aged ≥18 years; n=477 (planned); aged ≥18 years; NSCLC; NSCLC; stage III or IV; unresectable; stage III or IV; unresectable; involuntary involuntary weight loss of ≥5% body weight loss of ≥5% body weight within 6 weight within 6 months prior to months prior to screening or a screening screening or a screening body mass body mass index (BMI) <20kg/m2; ECOG index (BMI) <20kg/m2; ECOGa ≤2; life ≤2; life expectancy >4 months. expectancy >4 months. a Eastern Cooperative Oncology Group performance status.

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Schedule Randomised to anamorelin, oral, Randomised to anamorelin, oral, 100mg 100mg once daily; or placebo, once once daily; or placebo, once daily. daily. Follow-up Active treatment 12 weeks; 1 year Active treatment 12 weeks; follow-up not follow-up. reported.

Primary Lean body mass; muscle strength. Lean body mass; muscle strength. outcome/s Secondary Body weight; FACIT-Fb; FAACTc; Body weight; FACIT-F; FAACT; OS. outcome/s overall survival (OS) Expected Estimated primary completion date Q1 Not reported. reporting 2014. date

Trial ROMANA 3, NCT01395914, HT- NCT00622193, ST-ANAM-207; anamorelin ANAM-303; anamorelin vs placebo; vs placebo; phase II. phase III extension. Sponsor Helsinn Therapeutics. Helsinn Therapeutics. Status Ongoing. Complete. 37,38 39 Source of Abstract33, trial registry36. Abstract , trial registry . information Location EU, USA, Canada and other countries. USA and India. Design Non-randomised, placebo-controlled. Randomised, placebo-controlled. Participants n=300 (planned); completed trial n=226; aged 18-85 years; NSCLC; stage NCT01387269 (ROMANA 1) or IIIb or IV; eligible for treatment with NCT01387282 (ROMANA 2). paclitaxel and carboplatin with or without bevacizumab.

Schedule Participants will continue in same Randomised to anamorelin, oral, 100mg or treatment arm as randomised in 50mg once daily; or placebo, once daily. ROMANA 1 or ROMANA 2 trials. Follow-up Active treatment 12 weeks; follow-up Active treatment period 12 weeks; follow-up not reported. until death. Primary Safety and tolerability; adverse effects. Hand grip strength; body weight; safety outcome/s Secondary Body weight; muscle strength, FACIT- MDASId; biomarkers. outcome/s F; FAACT. Key results Not reported. For anamorelin 100mg, 50mg and placebo respectively: mean change in body weight (kg), +0.14 (p=0.005 vs placebo), -0.3, - 1.32; hand grip strength, mean difference between anamorelin 100mg and placebo, 0.58kg (not statistically significant); MDASI scores for anamorelin 100mg and placebo respectively (mean±SE change from baseline at week 12), total score, -8.6±4.58, -1.5±3.29; symptom domain score, - 6.7±2.98, -2.9±2.24; interference domain score, -1.9±1.99, 1.5±1.39. Adverse - AEs of anorexia, nausea and fatigue effects (AEs) reported in more placebo participants than those treated with anamorelin.

b Functional Assessment of Chronic Illness Therapy-Fatigue. c Functional Assessment of Anorexia/Cachexia Treatment. d MDASI – a multi-symptom patient-reported symptom assessment scale

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Expected Not reported. - reporting date

ESTIMATED COST and IMPACT

COST

The cost of anamorelin is not yet known.

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: possible, depending on degree of improved quality of life and patient independence.

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

 Other:  None identified

Impact on Costs

 Increased drug treatment costs: new  Reduced drug treatment costs therapeutic option.

 Other increase in costs:  Other reduction in costs: potential for a reduction in other health and social care costs depending on degree of improved quality of life and patient independence.

 Other:  None identified

Other Issues

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

REFERENCES

1 Wheelwright S, Darlington AS, Hopkinson JB et al. A systematic review of health related quality of life instruments in patients with cancer cachexia. Supportive Care in Cancer 2013;21:2625-2636. 2 Mantovani G, Madeddu C, Macciò A. Drugs in development for treatment of patients with cancer- related anorexia and cachexia syndrome. Drug Design, Development and Therapy 2013:7;645- 656. 3 Tisdale MJ. Cachexia in cancer patients. Nature Reviews. Cancer 2002;2(11):862-871. 4 Nicolini A, Ferrari P, Masoni MC et al. Malnutrition, anorexia and cachexia in cancer patients: a mini-review on pathogenesis and treatment. Biomedicine and Pharmacotherapy 2013; doi:10.1016/j.biopha.2013.08.005. 5 Del Ferraro C, Grant M, Koczywas M. Managemnt of anorexia-cachexia in late-stage lung cancer patients. Journal of Hospice & Palliative Nursing 2012;14(6):397-402.

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6 Cancer Research UK. Lung cancer mortality statistics. http://www.cancerresearchuk.org/cancer- info/cancerstats/types/lung/mortality/ Accessed 3 October 2013. 7 Cancer Research UK. Lung cancer incidence statistics. http://www.cancerresearchuk.org/cancer- info/cancerstats/types/lung/incidence/ Accessed 3 October 2013. 8 National Institute for Health and Care Excellence. Afatinib for the treatment of epidermal growth factor receptor mutation positive locally advanced or metastatic non-small cell lung cancer. Draft scope. London; NICE; April 2013. 9 Cancer Research UK. Lung cancer survival statistics. http://www.cancerresearchuk.org/cancer- info/cancerstats/types/lung/survival/ Accessed 3 October 2013. 10 National Institute for Health and Clinical Excellence. Lung cancer: the diagnosis and treatment of lung cancer. Full guideline. Clinical Guideline CG121. London: NICE; April 2011. 11 Granda-Cameron C, DeMille D, Lynch MP et al. An interdisciplinary approach to manage cancer cachexia. Clinical Journal of Oncology Nursing 2010;14(1):72-80. 12 National Institute for Health and Clinical Excellence. Costing statement: Erlotinib monotherapy for maintenance treatment of non-small cell lung cancer. London: NICE; June 2011. 13 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. 14 Health & Social Care Information Centre. Hospital episode statistics for England. Inpatient statistics, 2011-12. www.hscic.gov.uk 15 National Institute for Health and Care Excellence. Erlotinib and gefitinib for the treatment of non- small cell lung cancer that has progressed following prior chemotherapy (Review of TA162 and TA175). Technology appraisal in development (ID620). Expected June 2014. 16 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). Expected June 2014. 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). Expected December 2013. 18 National Institute for Health and Care Excellence. Crizotinib for previously treated non-small cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. Technology appraisal TA296. London: NICE; September 2013. 19 National Institute for Health and Clinical Excellence. Erlotinib for the first-line treatment of locally advanced or metastatic EGFR-TK mutation-positive non-small cell lung cancer. Technology appraisal (TA258). June 2012. 20 National Institute for Health and Clinical Excellence. Erlotinib monotherapy for maintenance treatment of non-small cell lung cancer. Technology appraisal (TA227). June 2011. 21 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). July 2010. 22 National Institute for Health and Clinical Excellence. Pemetrexed for the maintenance treatment of non-small cell lung cancer. Technology appraisal (TA190). June 2010. 23 National Institute for Health and Clinical Excellence. Pemetrexed for the first-line treatment of non-small cell lung cancer. Technology appraisal (TA181). September 2009. 24 National Institute for Health and Clinical Excellence. Erlotinib for the treatment of non-small cell lung cancer. Technology appraisal (TA162). November 2008. 25 National Institute for Health and Clinical Excellence. Pemtrexed for the treatment of non-small cell lung cancer. Technology appraisal (TA124). August 2007. 26 National Institute for Health and Clinical Excellence. Quality standard for lung cancer (QS17). March 2012. 27 National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. V.2.2013. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf Accessed 4 October 2013. 28 Vansteenkiste J, De Ruysscher D, Eberhardt WEE et al. Early and locally advanced non-small- cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow- up. Annals of Oncology 2013;24(supplement 6):vi89-vi98. 29 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. Annals of Oncology 2012;23(supplement 7):vii56-vii64.

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30 Radbruch L, Elsner F, Trottenberg P et al. Clinical practice guidelines on cancer cachexia in advanced cancer patients. Aachen, Department of Palliative Medicinen/European Palliative Care Research Collaborative; 2010. 31 American College of Chest Physicians. Diagnosis and management of lung cancer: ACCP Evidence-based clinical practice guidelines (2nd Edition). Chest 2007;132(3):744-746. 32 Scottish Intercollegiate Guidelines Network. Management of patients with lung cancer. National clinical guideline 80. Edinburgh: SIGN; February 2005. 33 Pickar Abernethy A, Temel JS; Curnow D et al. Phase III clinical trials with anamorelin HCI, a novel oral treatment for NSCLC cachexia. Journal of Clinical Oncology 2013;31:(suppl: abstract TPS9649). 34 ClinicalTrials.gov. Safety and efficacy of anamorelin HCI in patients with non-small cell lung cancer-cachexia (ROMANA 1). http://clinicaltrials.gov/ct2/show/NCT01387269?term=anamorelin&rank=2 Accessed 23 October 2013. 35 ClinicalTrials.gov. Safety and efficacy of anamorelin HCI in patients with non-small cell lung cancer-cachexia (ROMANA 2). http://clinicaltrials.gov/ct2/show?term=anamorelin&rank=1 Accessed 23 October 2013. 36 ClinicalTrials.gov. Anamorelin HCI in the treatment of non-small cell lung cancer-cachexia (NSCLC-C): an extension study (ROMANA 3). http://clinicaltrials.gov/ct2/show/study?term=anamorelin&rank=3 Accessed 23 October 2013. 37 Temel JS, Bondarde SA, Jain MM et al. Evaluation of quality of life from a phase II study of anamorelin HC1 in NSCLC patients. Journal of Clinical Oncology 2013; (suppl 31; abstr 42). 38 Temel J, Bondarde S, Jain M et al. Efficacy and safety of anamorelin in HC1 in NSCLC patients: results from a randomized, double-blind, placebo controlled, multicentre phase II study. European Cancer Congress. September 2013. Abstract 1308. Poster. 39 ClinicalTrials.gov. Dose range study of anamorelin in patients with non-small cell lung cancer. http://clinicaltrials.gov/ct2/show/study?term=anamorelin&rank=4&show_locs=Y Accessed 23 October 2013.