Enobosarm (Ostarine) for Cachexia in Patients with Advanced Non-Small Cell Lung Cancer

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

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 This briefing is (NSCLC) in combination with first line chemotherapy. If licensed, it would based on represent the first in a new class of drug for this patient group. Enobosarm is an oral, non-steroidal selective androgen receptor modulator (SARM). information

available at the time NSCLC accounts for approximately 80% of all lung cancers. Cachexia is of research and a common in patients with NSCLC and approximately 50% of patients with limited literature advanced NSCLC have severe muscle loss. Cachexia impairs quality of life search. It is not and response to therapy, increasing the morbidity and mortality of cancer intended to be a patients. definitive statement on the safety, The treatment approach for cachexia is multimodal and includes treatment of efficacy or causes for decreased nutritional intake, evaluation of anti-neoplastic options effectiveness of the to reduce the catabolic drive of cancer, nutritional therapy, use of health technology corticosteroids and progestational agents, and non-drug treatment like covered and should nutritional counselling and physical training. Enobosarm is currently in two not be used for phase III clinical trials comparing its effect on physical function and lean body commercial mass against placebo. This trial is expected to complete in second half of purposes or 2013. 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

 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 growth1,2. The pathophysiology is characterised by a negative protein and energy balance which is driven by a variable combination of reduced food intake and abnormal metabolism1.

NHS or GOVERNMENT PRIORITY AREA

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

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CLINICAL NEED and BURDEN OF DISEASE

In the UK, lung cancer is the most common cause of cancer related death in men and women3. 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 smoking6. NSCLC accounts for approximately 80% of all lung cancers; the main types being squamous cell carcinoma, adenocarcinoma and large cell carcinoma7,8. 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 chemotherapy7.

Cachexia is common in patients with NSCLC9. At diagnosis, approximately 50% of patients with advanced NSCLC have severe muscle loss9. Cachexia is present in nearly 100% of treated cancer patients at death and accounts for at least 20% of deaths in neoplastic patients2. Cachexia impairs quality of life and response to therapy, increasing morbidity and mortality of cancer patients2.

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 confirmed10.  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 201411.  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 201312.  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 June 201213.  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 201214.  NICE technology appraisal. Erlotinib monotherapy for the maintenance treatment of non- small cell lung cancer (TA227). June 201115.  NICE technology appraisal. Gefitinib for the first line treatment of locally advanced or metastatic non-small cell lung cancer (TA192). July 201016.  NICE technology appraisal. Pemetrexed for the maintenance treatment of non-small cell lung cancer (TA190). June 201017.  NICE technology appraisal. Pemetrexed for the first line treatment of non-small cell lung cancer (TA181). September 200918.  NICE technology appraisal. Erlotinib for the treatment of non-small cell lung cancer (TA162). November 200819.  NICE technology appraisal. Pemetrexed for the treatment of non-small cell lung cancer (TA124). August 200720.

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 NICE clinical guideline. The diagnosis and treatment of lung cancer (CG121). April 201121.  NICE quality standard. Quality standard for lung cancer (QS17). March 201222.

Other Guidance

 European Society for Medical Oncology (ESMO). Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. 201023.  European Palliative Care Research Collaborative. Clinical practice guidelines on cancer cachexia in advanced cancer patients. 201024.  American College of Chest Physicians. Diagnosis and management of lung cancer: ACCP guidelines (2nd Edition). 200725.  SIGN. Management of patients with lung cancer. 20056.  Cancer Services Collaborative Improvement Partnership. Lung cancer service improvement guide. 200426.

EXISTING COMPARATORS and TREATMENTS

In patients with advanced NSCLC, the options for treating associated cachexia are limited. The approach is multimodal and includes1:  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 cancer1.

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 patients1.

EFFICACY and SAFETY

Trial POWER1, NCT01355484, G300504; POWER2, NCT01355497, G300505; enobosarm vs placebo, both in enobosarm vs placebo, both in combination with first line platinum plus combination with first line platinum plus taxane chemotherapy; phase III. non-taxane chemotherapy; phase III. Sponsor GTx, Inc. GTx, Inc. Status Ongoing. Ongoing. 27 28 Source of Trial registry , manufacturer . Trial registry29, manufacturer28. information Location USA. USA. Design Randomised, placebo-controlled. Randomised, placebo-controlled.

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Participants n=300 (planned); aged ≥30 years; n=300 (planned); aged ≥30 years; NSCLC; stage III or IV; BMI ≤32; weight NSCLC; stage III or IV; BMI ≤32; weight <300 lbs (136 kg); chemotherapy naïve; <300 lbs (136 kg); chemotherapy naïve; planned first line chemotherapy - planned first line chemotherapy - platinum plus paclitaxel or docetaxel; not platinum plus gemcitabine, vinorelbine or on treatment with testosterone, other pemetrexed; not on treatment with androgenic compounds or medication to testosterone, other androgenic increase appetite or treat unintentional compounds or medication to increase weight loss; Eastern Cooperative appetite or treat unintentional weight loss; Oncology Group (ECOG) score ≤1; life ECOG score ≤1; life expectancy >6 expectancy >6 months; baseline stair months; baseline stair climb time ≤30 climb time ≤30 seconds. seconds. Schedule Randomised to enobosarm 3mg or Randomised to enobosarm 3mg or placebo, both once daily in combination placebo, both once daily in combination with first line platinum plus taxane with first line platinum plus non-taxane chemotherapy. chemotherapy. Follow-up Active treatment for 5 months, follow-up Active treatment for 5 months, follow-up up to 30 months. up to 30 months Primary Physical function assessed by stair climb Physical function assessed by stair climb outcome/s test at day 84 and lean body mass test at day 84 and lean body mass assessed by whole body composition assessed by whole body composition dexa scan at day 84. Responders dexa scan at day 84. Responders analysis defined as 10% improvement in analysis defined as 10% improvement in physical function and no loss in lean body physical function and no loss in lean body mass. mass. Secondary Durability of treatment effect on physical Durability of treatment effect on physical outcome/s function and lean body mass; overall function and lean body mass; overall survival; healthcare resource utilisation; survival; healthcare resource utilisation; adherence to chemotherapy and dose adherence to chemotherapy and dose intensity; total body weight; quality of life intensity; total body weight; quality of life assessed using FAACT-12a, FACIT using FAACT-12, FACIT fatigue scale, fatigue scaleb, patient reported outcomes Patient reported outcomes measurement measurement information system information system (PROMIS) physical (PROMIS) physical functioning, PROMIS functioning, PROMIS emotional distress- emotional distress-depression and EQ- depression and EQ-5D-5L. 5D-5L. Expected Study completion date reported as Study completion date reported as reporting second half of 2013. second half of 2013. date

Trial NCT00467844, G200502; enobosarm vs placebo; phase II. Sponsor GTx, Inc. Status Complete but unpublished. Source of Trial registry30, manufacturer. information Location USA and Canada. Design Randomised, placebo-controlled. Participants 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.

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weight loss; ECOG score ≤1; life expectancy >6 months. Schedule Randomised to enobosarm 1mg, 3mg or placebo, all once daily. Follow-up Active treatment for 16 weeks. Primary Lean body mass. outcome/s Secondary Body weight, muscle function and total body fat mass. outcome/s Key results 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), 16.81 watts (-77.7 to 93.1, p=0.001), 14.3 watts (-235.3 to 110.0, p=0.001), 2.2 watts (-156.4 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. Adverse For placebo, enobosarm 1mg and enobosarm 3mg groups respectively: effects (AEs) 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

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Other Issues

 Clinical uncertainty or other research question  None identified 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

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,2010. 2 Patient.co.uk. Cachexia. http://www.patient.co.uk/doctor/Cachexia.htm Accessed 14 September 2012. 3 Cancer research UK. Lung cancer mortality statistics. http://www.cancerresearchuk.org/cancer- info/cancerstats/types/lung/mortality/ Accessed 14 September 2012. 4 Cancer Research UK. Lung cancer - UK incidence statistics. http://info.cancerresearchuk.org/cancerstats/types/lung/incidence/ Accessed 14 September 2012. 5 Office for National Statistics. Mortality statistics: Deaths registered in 2010 (Series DR) Table 5. www.ons.gov.uk 6 Scottish Intercollegiate Guidelines Network. Management of patients with lung cancer. National clinical guideline 80. Edinburgh: SIGN; February 2005. 7 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. 8 Cancer Research UK. Types of Lung Cancer. http://www.cancerhelp.org.uk/type/lung- cancer/about/types-of-lung-cancer Accessed 14 September 2012. 9 GTx Inc. enobosarm (Ostarine®; GTx-024). http://www.gtxinc.com/Pipeline/OstarineMK2866.aspx?Sid=4 Accessed 14 September 2012. 10 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 2014. 12 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 2013. 13 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 2012. 14 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 2012. 15 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 2011. 16 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 2010. 17 National Institute for Health and Clinical Excellence. Pemetrexed for the maintenance treatment of non-small cell lung cancer. Technology appraisal TA190. London: NICE; June 2010. 18 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 2009. 19 National Institute for Health and Clinical Excellence. Erlotinib for the treatment of non-small cell lung cancer. Technology appraisal TA162. London: NICE; November 2008. 20 National Institute for Health and Clinical Excellence. Pemetrexed for the treatment of non-small cell lung cancer. Technology appraisal TA124. London: NICE; August 2007.

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21 National Institute for Health and Clinical Excellence. The diagnosis and treatment of lung cancer. Clinical guideline CG121. London: NICE; April 2011. 22 National Institute for Health and Clinical Excellence. Quality standard for lung cancer. Quality standard. QS17. London: NICE; March 2012 23 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- v119. 24 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. 25 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. 26 Cancer Services Collaborative Improvement partnership. Lung cancer service improvement guide. October 2004. http://www.ebc-indevelopment.co.uk/nhs/lung/index.html Accessed 14 September 2012. 27 ClinicalTrials.gov. Phase III study of the effect of GTx-024 on muscle wasting in patients with non- small cell lung cancer (NSCLC). http://clinicaltrials.gov/ct2/show/NCT01355484?term=NCT01355484&rank=1 Accessed 14 September 2012. 28 GTx Inc. News Releases: GTx provides corporate update and reports 2011 financial results. http://phx.corporate-ir.net/phoenix.zhtml?c=148196&p=irol-newsArticle&ID=1662984&highlight= Accessed 14 September 2012. 29 ClinicalTrials.gov. Effect of GTx-024 on muscle wasting in patients with non-small cell lung cancer (NSCLC) on first line platinum. http://clinicaltrials.gov/ct2/show/NCT01355497?term=NCT01355497&rank=1 Accessed 14 September 2012. 30 ClinicalTrials.gov. Study of GTx-024 on muscle wasting (cachexia) cancer. http://clinicaltrials.gov/ct2/show/NCT00467844?term=NCT00467844&rank=1 Accessed 14 September 2012.