Elsevier

The Lancet Oncology

Volume 17, Issue 4, April 2016, Pages 519-531
The Lancet Oncology

Articles
Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials

https://doi.org/10.1016/S1470-2045(15)00558-6 Get rights and content

Summary

Background

Patients with advanced cancer frequently experience anorexia and cachexia, which are associated with reduced food intake, altered body composition, and decreased functionality. We assessed anamorelin, a novel ghrelin-receptor agonist, on cachexia in patients with advanced non-small-cell lung cancer and cachexia.

Methods

ROMANA 1 and ROMANA 2 were randomised, double-blind, placebo-controlled phase 3 trials done at 93 sites in 19 countries. Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia (defined as ≥5% weight loss within 6 months or body-mass index <20 kg/m2) were randomly assigned 2:1 to anamorelin 100 mg orally once daily or placebo, with a computer-generated randomisation algorithm stratified by geographical region, cancer treatment status, and weight loss over the previous 6 months. Co-primary efficacy endpoints were the median change in lean body mass and handgrip strength over 12 weeks and were measured in all study participants (intention-to-treat population). Both trials are now completed and are registered with ClinicalTrials.gov , numbers NCT01387269 and NCT01387282 .

Findings

From July 8, 2011, to Jan 28, 2014, 484 patients were enrolled in ROMANA 1 (323 to anamorelin, 161 to placebo), and from July 14, 2011, to Oct 31, 2013, 495 patients were enrolled in ROMANA 2 (330 to anamorelin, 165 to placebo). Over 12 weeks, lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 (median increase 0·99 kg [95% CI 0·61 to 1·36] vs −0·47 kg [–1·00 to 0·21], p<0·0001) and ROMANA 2 (0·65 kg [0·38 to 0·91] vs −0·98 kg [–1·49 to −0·41], p<0·0001). We noted no difference in handgrip strength in ROMANA 1 (−1·10 kg [–1·69 to −0·40] vs −1·58 kg [–2·99 to −1·14], p=0·15) or ROMANA 2 (−1·49 kg [–2·06 to −0·58] vs −0·95 kg [–1·56 to 0·04], p=0·65). There were no differences in grade 3–4 treatment-related adverse events between study groups; the most common grade 3–4 adverse event was hyperglycaemia, occurring in one (<1%) of 320 patients given anamorelin in ROMANA 1 and in four (1%) of 330 patients given anamorelin in ROMANA 2.

Interpretation

Anamorelin significantly increased lean body mass, but not handgrip, strength in patients with advanced non-small-cell lung cancer. Considering the unmet medical need for safe and effective treatments for cachexia, anamorelin might be a treatment option for patients with cancer anorexia and cachexia.

Funding

Helsinn Therapeutics.

Introduction

Anorexia and cachexia are devastating results of cancer and commonly coexist in patients with advanced disease.1 Although both are multifactorial in origin, anorexia often manifests as decreased appetite and food intake, whereas cachexia is characterised by loss of bodyweight and lean body mass.2 Weight loss in patients with cancer cachexia is due to a variable combination of decreased oral intake and metabolic change, leading to negative protein and energy balance.3 Patients with cancer cachexia frequently experience decreased quality of life, reduced chemotherapy tolerance, reduced physical functioning, and shortened survival.3, 4, 5, 6 Between 50% and 80% of patients with advanced cancer develop cachexia, with highest incidence reported in patients with lung and gastrointestinal cancer.7

Despite the high prevalence of cancer cachexia, few therapeutic options exist and there is no standard of care for its management. The cause of the condition is multifactorial, and a single-modality approach is unlikely to reverse all aspects of the syndrome and result in durable clinical benefits. Indeed, cachexia is thought to require a comprehensive intervention, including nutrition, exercise, and drugs. However, development of an evidence base for individual treatments is necessary to ultimately build an effective multimodality intervention.1 To address both nutrition and symptom burden, an ideal drug would improve anorexia and enhance food intake while also stimulating anabolism, thus overcoming the catabolic drive associated with cachexia and increasing lean body mass and bodyweight. Although several available drugs can improve patients' appetite or increase their bodyweight, none can substantially affect lean body mass and its key functional element, skeletal muscle.8, 31 Additionally, corticosteroids and progestational drugs, which are the most commonly used drugs in patients with anorexia, have substantial adverse events and potential toxic effects, which can include catabolism and muscle wasting.9, 10

Research in context

Evidence before this study

Although cachexia has long been recognised as a substantial source of morbidity and mortality in patients with cancer, treatment options are scarce. We did a literature review with PubMed from Jan 3, 2005, to Jan 3, 2015, with the terms “cancer” and “cachexia” and/or “anorexia” and “weight loss”, confirming the absence of evidence supporting the use of approved medications for the treatment of cancer cachexia. A systematic review of the treatment of cancer-associated anorexia concluded that progestins and corticosteroids are effective in increasing patients' appetite and weight, but had no effect on cachexia. Two Cochrane Database reviews of megestrol acetate, the most commonly used progestin for cancer-associated anorexia and cachexia, similarly concluded that use of megestrol acetate is associated with improvement in appetite and only slight weight gain. However, the more recent review noted that oedema, thromboembolic events, and death were frequent complications of megestrol acetate, and recommended that patients are informed of the risks associated with the drug. A comprehensive literature review of treatment options in cancer cachexia concluded that there are no available drugs for the treatment of cancer cachexia.

Added value of this study

We show in two international phase 3 clinical trials that patients with advanced non-small-cell lung cancer and cachexia who received anamorelin consistently increased lean body mass as well as bodyweight over the 12-week study period. Importantly, patients also had an improvement in their anorexia–cachexia symptoms.

Implications of all the available evidence

Anamorelin is an effective and well tolerated drug for the treatment of patients with advanced non-small-cell lung cancer and cachexia, and might be a novel treatment for such patients.

Anamorelin is an orally active, high-affinity, selective ghrelin-receptor agonist.11 Ghrelin is the natural ligand for the G-protein-coupled ghrelin receptor, which when activated has anabolic and appetite-stimulating effects.12 These effects are partly mediated through transient increases in growth hormone and insulin-like growth factor (IGF-1). Several double-blind, randomised phase 2 studies13, 14, 15 in patients with advanced cancer have shown that anamorelin is safe and efficacious in increasing patients' lean body mass, bodyweight, and appetite.

In theory, an effective treatment for cancer-associated muscle wasting, a key component of the cachexia, should improve muscle mass and, as a consequence, increase muscle strength. However, muscle wasting in patients with cancer is complex, arising from diverse factors such as age-related sarcopenia, cancer therapy, and comorbidity, in addition to the tumour. Moreover, muscle strength might not only be related to muscle mass, but also to other factors, such as persisting systemic inflammation and associated fatigue. A previous phase 2 study13 with anamorelin showed a significant effect on handgrip strength over a 12-week treatment period, whereas a subsequent phase 2 study did not.15 In the absence of an alternative internationally agreed standard for muscle strength and function, we assessed the efficacy with lean body mass and handgrip strength as co-primary endpoints and safety of anamorelin compared with placebo in two international, double-blind, phase 3 studies in patients with advanced non-small-cell lung cancer and cachexia.

Section snippets

Study design and participants

ROMANA 1 and ROMANA 2 were two international, double-blind, placebo-controlled, randomised phase 3 studies. Two identical trials were done as per regulatory advice in order to have evidence from two adequate and well-controlled trials. ROMANA 1 was done at 54 hospital and community sites in 15 countries between July 8, 2011, and Jan 28, 2014, and ROMANA 2 was done at 39 hospital and community sites in seven countries between July 14, 2011, and Oct 31, 2013 (see appendix p 1–2 for list of

Results

From July 8, 2011, to Jan 28, 2014, 484 patients were enrolled in ROMANA 1, and from July 14, 2011, to Oct 31, 2013, 495 patients were enrolled in ROMANA 2 (figure 1). In ROMANA 1, 161 patients were randomly assigned to placebo and 323 to anamorelin. Of the 481 treated patients in ROMANA 1, 354 (74%) completed treatment and 89 (19%) died during the 12-week study period (patients who died during the 12-week treatment period but had secondary endpoint assessments at week 3, 6, or 9 were included

Discussion

Findings from these two phase 3 studies show that anamorelin significantly improves lean body mass, but not handgrip strength, in patients with advanced non-small-cell lung cancer. Most participants in the trials had metastatic disease and were receiving chemotherapy, which is a population known to experience substantial cachexia-related weight loss. The increase in patients' weight with anamorelin was early and progressive, with significant differences emerging as early as 3 weeks. Patients

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