Horizon Scanning Centre November Enobosarm (Ostarine) for cachexia in patients with advanced non-small cell lung cancer first line

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1 Horizon Scanning Centre November 2012 Enobosarm (Ostarine) for cachexia in patients with advanced non-small cell lung cancer first line SUMMARY NIHR HSC ID: 5206 This briefing 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 or commissioning without additional information. Enobosarm (Ostarine) is intended to be used as first line therapy for the treatment of cachexia in patients with advanced non-small cell lung cancer (NSCLC) in combination with first line chemotherapy. If licensed, it would represent the first in a new class of drug for this patient group. Enobosarm is an oral, non-steroidal selective androgen receptor modulator (SARM). NSCLC accounts for approximately 80% of all lung cancers. Cachexia is common in patients with NSCLC and approximately 50% of patients with advanced NSCLC have severe muscle loss. Cachexia impairs quality of life and response to therapy, increasing the morbidity and mortality of cancer patients. The treatment approach for cachexia is multimodal and includes treatment of causes for decreased nutritional intake, evaluation of anti-neoplastic options to reduce the catabolic drive of cancer, nutritional therapy, use of corticosteroids and progestational agents, and non-drug treatment like nutritional counselling and physical training. Enobosarm is currently in two phase III clinical trials comparing its effect on physical function and lean body mass against placebo. This trial is expected to complete in second half of 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., University of Birmingham nihrhsc@contacts.bham.ac.uk Web:

2 TARGET GROUP Cachexia in patients with non-small cell lung cancer (NSCLC): advanced (stage III or IV) first line; in combination with first line chemotherapy. TECHNOLOGY DESCRIPTION Enobosarm (Ostarine; GTx-024; MK-2866) is an oral, non-steroidal selective androgen receptor modulator (SARM). SARMs bind to the testosterone receptor and have both agonist and antagonist activities, depending on the specific targeted tissues. Enobosarm is intended for the prevention and treatment of cachexia in patients with stage III or IV NSCLC and is administered orally at 3mg/day in combination with first line chemotherapy (dose used in clinical trials). Enobosarm is also in phase II clinical trials for the treatment of muscular atrophy associated with ageing (sarcopenia). INNOVATION and/or ADVANTAGES Enobosarm is tissue selective and may potentially have positive anabolic effects with fewer side effects and limited toxicity compared to existing pharmacological agents. If licensed, enobosarm would represent the first in a new class of drug for this patient group, where options are currently limited. DEVELOPER GTx, Inc. AVAILABILITY, LAUNCH OR MARKETING In phase III clinical trials. PATIENT GROUP BACKGROUND Cancer cachexia describes a multifactorial syndrome characterised by an ongoing loss of skeletal muscle, with or without loss of fat mass, in response to a malignant growth 1,2. The pathophysiology is characterised by a negative protein and energy balance which is driven by a variable combination of reduced food intake and abnormal metabolism 1. NHS or GOVERNMENT PRIORITY AREA This topic is relevant to Improving Outcomes: A Strategy for Cancer (2011).

3 CLINICAL NEED and BURDEN OF DISEASE In the UK, lung cancer is the most common cause of cancer related death in men and women 3. In England and Wales, there were 35,406 new cases of lung cancer (ICD C33-34) in 2009 (approximately 48 cases per 100,000 population in the UK) 4 and around 29,977 deaths were registered in 2010 (approximately 38 deaths per 100,000 population in the UK) 3,5. About 90% of lung cancer mortality among men and 80% among women is attributable to smoking 6. NSCLC accounts for approximately 80% of all lung cancers; the main types being squamous cell carcinoma, adenocarcinoma and large cell carcinoma 7,8. Approximately 75% of newly diagnosed NSCLC patients have advanced (stage III or IV) disease in England and Wales (approximately 24,536 patients), which has a five-year survival rate of less than 1% 7. An estimated 25% of patients with NSCLC receive first line chemotherapy 7. Cachexia is common in patients with NSCLC 9. At diagnosis, approximately 50% of patients with advanced NSCLC have severe muscle loss 9. Cachexia is present in nearly 100% of treated cancer patients at death and accounts for at least 20% of deaths in neoplastic patients 2. Cachexia impairs quality of life and response to therapy, increasing morbidity and mortality of cancer patients 2. PATIENT PATHWAY RELEVANT GUIDANCE NICE Guidance NICE technology appraisal in development. Cetuximab for the treatment of advanced non-small cell lung cancer (ID9). Expected date of issue to be confirmed 10. NICE technology appraisal in development. Erlotinib and gefitinib for the second line treatment of non-small-cell lung cancer (review of TA162 and TA175) (ID620). Expected July NICE technology appraisal in development. Crizotinib for the treatment of previously treated non-small cell lung cancer associated with an anaplastic lymphoma kinase fusion gene (ID499). Expected July NICE technology appraisal in development. Pemetrexed for maintenance treatment following induction therapy with pemetrexed and cisplatin for non-squamous non-smallcell lung cancer (ID489). Expected June 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 NICE technology appraisal. Erlotinib monotherapy for the maintenance treatment of nonsmall cell lung cancer (TA227). June NICE technology appraisal. Gefitinib for the first line treatment of locally advanced or metastatic non-small cell lung cancer (TA192). July NICE technology appraisal. Pemetrexed for the maintenance treatment of non-small cell lung cancer (TA190). June NICE technology appraisal. Pemetrexed for the first line treatment of non-small cell lung cancer (TA181). September NICE technology appraisal. Erlotinib for the treatment of non-small cell lung cancer (TA162). November NICE technology appraisal. Pemetrexed for the treatment of non-small cell lung cancer (TA124). August

4 NICE clinical guideline. The diagnosis and treatment of lung cancer (CG121). April NICE quality standard. Quality standard for lung cancer (QS17). March Other Guidance European Society for Medical Oncology (ESMO). Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up European Palliative Care Research Collaborative. Clinical practice guidelines on cancer cachexia in advanced cancer patients American College of Chest Physicians. Diagnosis and management of lung cancer: ACCP guidelines (2nd Edition) SIGN. Management of patients with lung cancer Cancer Services Collaborative Improvement Partnership. Lung cancer service improvement guide EXISTING COMPARATORS and TREATMENTS In patients with advanced NSCLC, the options for treating associated cachexia are limited. The approach is multimodal and includes 1 : treatment of secondary gastrointestinal symptoms and other causes for decreased nutritional intake. evaluation of anti-neoplastic options to reduce 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 cancer cachexia; however their use is not recommended by the recent European guideline for the treatment of cachexia in patients with advanced cancer 1. Prophylactic interventions such as nutritional counselling and physical training are also thought to be beneficial in delaying or preventing the development of cachexia in cancer patients 1. EFFICACY and SAFETY Trial POWER1, NCT , G300504; enobosarm vs placebo, both in combination with first line platinum plus taxane chemotherapy; phase III. POWER2, NCT , G300505; enobosarm vs placebo, both in combination with first line platinum plus non-taxane chemotherapy; phase III. Sponsor GTx, Inc. GTx, Inc. Status Ongoing. Ongoing. Source of Trial registry 27, manufacturer 28. Trial registry 29, manufacturer 28. information Location USA. USA. Design Randomised, placebo-controlled. Randomised, placebo-controlled.

5 Participants Schedule Follow-up Primary outcome/s Secondary outcome/s Expected reporting date n=300 (planned); aged 30 years; NSCLC; stage III or IV; BMI 32; weight <300 lbs (136 kg); chemotherapy naïve; planned first line chemotherapy - platinum plus paclitaxel or docetaxel; not on treatment with testosterone, other androgenic compounds or medication to increase appetite or treat unintentional weight loss; Eastern Cooperative Oncology Group (ECOG) score 1; life expectancy >6 months; baseline stair climb time 30 seconds. Randomised to enobosarm 3mg or placebo, both once daily in combination with first line platinum plus taxane chemotherapy. Active treatment for 5 months, follow-up up to 30 months. Physical function assessed by stair climb test at day 84 and lean body mass assessed by whole body composition dexa scan at day 84. Responders analysis defined as 10% improvement in physical function and no loss in lean body mass. Durability of treatment effect on physical function and lean body mass; overall survival; healthcare resource utilisation; adherence to chemotherapy and dose intensity; total body weight; quality of life assessed using FAACT-12 a, FACIT fatigue scale b, patient reported outcomes measurement information system (PROMIS) physical functioning, PROMIS emotional distress-depression and EQ- 5D-5L. Study completion date reported as second half of n=300 (planned); aged 30 years; NSCLC; stage III or IV; BMI 32; weight <300 lbs (136 kg); chemotherapy naïve; planned first line chemotherapy - platinum plus gemcitabine, vinorelbine or pemetrexed; not on treatment with testosterone, other androgenic compounds or medication to increase appetite or treat unintentional weight loss; ECOG score 1; life expectancy >6 months; baseline stair climb time 30 seconds. Randomised to enobosarm 3mg or placebo, both once daily in combination with first line platinum plus non-taxane chemotherapy. Active treatment for 5 months, follow-up up to 30 months Physical function assessed by stair climb test at day 84 and lean body mass assessed by whole body composition dexa scan at day 84. Responders analysis defined as 10% improvement in physical function and no loss in lean body mass. Durability of treatment effect on physical function and lean body mass; overall survival; healthcare resource utilisation; adherence to chemotherapy and dose intensity; total body weight; quality of life using FAACT-12, FACIT fatigue scale, Patient reported outcomes measurement information system (PROMIS) physical functioning, PROMIS emotional distressdepression and EQ-5D-5L. Study completion date reported as second half of Trial Sponsor Status Source of information Location Design Participants NCT , G200502; enobosarm vs placebo; phase II. GTx, Inc. Complete but unpublished. Trial registry 30, manufacturer. USA and Canada. Randomised, placebo-controlled. n=150; males >45 years, females confirmed as postmenopausal; stage II, III or IV NSCLC, stage II, III or IV colorectal cancer, non-hodgkin s lymphoma, chronic lymphocytic leukaemia or stage III or IV breast cancer; experienced 2% body weight loss from highest reported weight in 6 months prior to screening; chemotherapy naïve or between cycles of chemotherapy; not on treatment with testosterone, other androgenic compounds or medication to increase appetite or treat unintentional a Functional Assessment of Anorexia/Cachexia Therapy (FAACT)-12 questionnaire measures general aspects of quality of life as well as specific anorexia/cachexia-related concerns. b Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue measures an individual s level of fatigue during their usual daily activities over the past week.

6 weight loss; ECOG score 1; life expectancy >6 months. Schedule Follow-up Primary outcome/s Secondary outcome/s Key results Adverse effects (AEs) Randomised to enobosarm 1mg, 3mg or placebo, all once daily. Active treatment for 16 weeks. Lean body mass. Body weight, muscle function and total body fat mass. For enobosarm 3mg, 1mg and placebo respectively: Median change in lean body mass (range, p vs baseline), 1.0kg (-4.8 to 11.5, p=0.046), 1.5kg (-2.1 to 12.6, p=0.001), not reported (p=0.88); mean improvement in stair climb (p vs baseline), 22% (p<0.001), 18% (p=0.001), not reported (p=0.15); median change in time required to climb 12 stairs (range, p vs baseline), -0.5s (5.1 to -31.0, p=0.007), -0.86s (5.6 to -12.7, p=0.002), -0.1s (14.5 to -4.6, p=0.26); median change in stair climb power (range, p vs baseline), watts (-77.7 to 93.1, p=0.001), 14.3 watts ( to 110.0, p=0.001), 2.2 watts ( to 56.4, p=0.10). There were no significant differences in the secondary endpoints of absolute change or percentage change in handgrip strength from baseline to day 113. For placebo, enobosarm 1mg and enobosarm 3mg groups respectively: all AEs, 88.5%, 88.7%, 90.7%; treatment related AEs, 15.4%, 13.2%, 27.8% and serious AEs, 32.7%, 26.4%, 27.8%. Common AEs reported included: anaemia, nausea, diarrhoea, malignant neoplasm progression, vomiting, weight loss, cough, dyspnoea and dehydration. ESTIMATED COST and IMPACT COST The cost of enobosarm 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 Re-organisation of existing services Need for new services Other: None identified Impact on Costs Increased drug treatment costs Reduced drug treatment costs Other increase in costs: Other reduction in costs: Other: None identified

7 Other Issues Clinical uncertainty or other research question identified: It is not clear that the evidence base is being developed in the patients that have cachexia at presentation or develop it as part of the terminal phase of the illness. REFERENCES None identified 1 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, Patient.co.uk. Cachexia. Accessed 14 September Cancer research UK. Lung cancer mortality statistics. Accessed 14 September Cancer Research UK. Lung cancer - UK incidence statistics. Accessed 14 September Office for National Statistics. Mortality statistics: Deaths registered in 2010 (Series DR) Table Scottish Intercollegiate Guidelines Network. Management of patients with lung cancer. National clinical guideline 80. Edinburgh: SIGN; February 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 Cancer Research UK. Types of Lung Cancer. Accessed 14 September GTx Inc. enobosarm (Ostarine ; GTx-024). Accessed 14 September National Institute for Health and Clinical Excellence. Cetuximab for the treatment of advanced non-small cell lung cancer (ID 9). Technology appraisal in development. Publication date not yet confirmed. 11 National Institute for Health and Clinical Excellence. Erlotinib and gefitinib for the second line treatment of non-small-cell lung cancer (review of TA162 and TA175). Technology appraisal in development. Expected July National Institute for Health and Clinical Excellence. Crizotinib for the treatment of previously treated non-small cell lung cancer associated with an anaplastic lymphoma kinase fusion gene. Technology appraisal in development. Expected July National Institute for Health and Clinical Excellence. Pemetrexed for maintenance treatment following induction therapy with pemetrexed and cisplatin for non-squamous non-small-cell lung cancer. Technology appraisal in development. Expected June 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. London: NICE; June National Institute for Health and Clinical Excellence. Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer. Technology appraisal TA227. London: NICE; June 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 National Institute for Health and Clinical Excellence. Pemetrexed for the maintenance treatment of non-small cell lung cancer. Technology appraisal TA190. London: NICE; June 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 National Institute for Health and Clinical Excellence. Erlotinib for the treatment of non-small cell lung cancer. Technology appraisal TA162. London: NICE; November National Institute for Health and Clinical Excellence. Pemetrexed for the treatment of non-small cell lung cancer. Technology appraisal TA124. London: NICE; August 2007.

8 21 National Institute for Health and Clinical Excellence. The diagnosis and treatment of lung cancer. Clinical guideline CG121. London: NICE; April National Institute for Health and Clinical Excellence. Quality standard for lung cancer. Quality standard. QS17. London: NICE; March European Society for Medical Oncology. Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2010;21(5):v116- v 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; American College of Chest Physicians. Diagnosis and management of lung cancer: ACCP Evidence-based clinical practice guidelines (2nd Edition). Chest 2007;132(3): Cancer Services Collaborative Improvement partnership. Lung cancer service improvement guide. October Accessed 14 September ClinicalTrials.gov. Phase III study of the effect of GTx-024 on muscle wasting in patients with nonsmall cell lung cancer (NSCLC). Accessed 14 September GTx Inc. News Releases: GTx provides corporate update and reports 2011 financial results. Accessed 14 September ClinicalTrials.gov. Effect of GTx-024 on muscle wasting in patients with non-small cell lung cancer (NSCLC) on first line platinum. Accessed 14 September ClinicalTrials.gov. Study of GTx-024 on muscle wasting (cachexia) cancer. Accessed 14 September 2012.