Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials

Summary

Background

Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality. Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity. We assessed the effects of anamorelin on body composition, strength, quality of life, biochemical markers, and safety in patients with cancer anorexia-cachexia.

Methods

Data were pooled, a priori, from two completed phase 2, multicentre, placebo-controlled, double-blind trials in patients with advanced or incurable cancer and weight loss of 5% or more. Patients were stratified by weight loss severity (5–15%, >15%) and randomly allocated (1:1) with a computer-generated randomisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks. Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment. We assessed safety in all patients who received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT00219817 and NCT00267358.

Findings

Between June 29, 2005, and Oct 26, 2006, we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group. 74 patients were eligible for the efficacy analyses. Over 12 weeks, lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1·89 kg (95% CI 0·84 to 2·95) compared with a decrease of a least-squares mean of −0·20 kg (−1·23 to 0·83) for 36 patients in the placebo group (difference 2·09 kg [0·94–3·25]; p=0·0006). 42 (95%) of 44 patients treated with anamorelin and 33 (87%) of 38 patients treated with placebo had adverse events. The most common grade 3–4 adverse events (treatment-related or not) in the anamorelin group were fatigue, asthenia, atrial fibrillation, and dyspnoea (two [5%] each); in the placebo group, such events were pneumonia (three [8%]) and anaemia, thrombocytopenia, abdominal pain, anxiety, and dyspnoea (two [5%] each).

Interpretation

Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome. These findings support further investigation in this setting.

Funding

Helsinn Therapeutics (US), Helsinn Healthcare SA.

Introduction

Cancer anorexia-cachexia syndrome, a multifactorial syndrome, is characterised by involuntary weight loss. In a 2011 consensus statement, such weight loss was defined as greater than 5% within 6 months or greater than 2% in patients with a body-mass index [BMI] of less than 20 kg/m².¹ Identification and management of cancer anorexia-cachexia syndrome in advanced cancer is an unmet, under-recognised need;² the syndrome occurs in more than 50% of patients with various cancers.² Moreover, anorexia-cachexia is an adverse prognostic factor associated with poor performance status and quality of life,² reduced tolerance or responsiveness to therapy,1, 2, 3 and decreased survival, emphasising the importance of early detection and intervention.1, 2, 3, 4 Hallmarks are decreased muscle mass and strength, overall lean body mass, and lean body mass in the extremities (appendicular lean body mass). Appendicular lean body mass has been proposed as a surrogate for muscle mass.⁵ Both lean body mass and muscle strength, as measured by handgrip strength, are predictive of survival and quality of life.6, 7

Nutritional supplementation alone cannot reverse cancer anorexia-cachexia syndrome,1, 6 and data for present therapies generally show limited efficacy or concerns about tolerability, or are from small studies.7, 8 Available therapies, such as appetite stimulants and serotonin receptor antagonists, have failed to provide clinically meaningful benefits.⁸ Hypercaloric feeding has not been shown to increase lean muscle mass,⁶ whereas corticosteroids have only modest effects on appetite and food intake.⁴ Progestational agents are perhaps the most widely used but increase only fat mass⁷ and have potentially clinically important side-effects such as deep vein thrombosis and hypogonadism.9, 10 Other agents in development include anabolic agents, non-steroidal anti-inflammatory drugs, and anti-cytokine approaches.⁷ New effective therapies are needed.

Activation of the ghrelin receptor (GRLN receptor, formerly known as GHS-R1a) has anabolic effects and increases food intake and bodyweight.¹¹ In people without cancer, ghrelin-receptor agonists increase bodyweight and reverse the negative nitrogen balance induced by starvation, independently from their appetite-enhancing effects. These findings suggest that ghrelin's effects are not entirely mediated through increased appetite and that other mechanisms are involved, such as decreased energy expenditure.12, 13 This effect is relevant because patients with cancer have increased energy expenditure that contributes to cachexia.¹⁴

Inflammation is thought to play a part in cancer anorexia-cachexia syndrome. Interleukin 6 administration reduces bodyweight in rodents and human beings,15, 16 increases the resting metabolic rate, and suppresses appetite. In animal models of cancer anorexia-cachexia syndrome, ghrelin blunts the anorectic and weight-reducing effect of interleukin 1β, induces increased food intake and bodyweight, and downregulates production of interleukin 6, interleukin 1α, interleukin 1β, and tumour necrosis factor (TNF) α.¹⁷

Because ghrelin needs parenteral administration and is a peptide with a 30 min half-life, its efficacy in patients is restricted. Ghrelin-receptor agonists could be non-peptidic, orally available, small molecules with a longer half-life allowing for once-daily administration.¹⁸ Anamorelin is an orally available, selective ghrelin-receptor agonist.¹⁹ In phase 1 studies, anamorelin increased bodyweight versus placebo in volunteers who did not have cancer;¹¹ and in a 3 day crossover period of a phase 2 study, it acutely increased appetite, bodyweight, and quality of life in patients with cancer anorexia-cachexia,²⁰ but longer term effects of ghrelin-receptor agonists in this setting have not been reported.

We aimed to assess the effect of anamorelin hydrochloride treatment for 12 weeks on body composition, physical strength, quality of life, and biochemical markers in cancer anorexia-cachexia syndrome in patients with a diverse range of cancers potentially responsive to anamorelin's postulated mechanisms of action.¹⁷