Introduction
Malignant pleural mesothelioma (MPM) is a rare and universally fatal cancer developing from the mesothelial monolayer of the thoracic and abdominal cavities1 and has a median survival of 9–12 months.2 Treatment is palliative, with combination chemotherapy providing only a modest improvement in overall survival.3 Australia has one of the highest rates of mesothelioma per capita worldwide due to asbestos mining and use. In 2017, the age-standardised rate of mesothelioma in Australia was 2.7/100 000 population, an increase of 123% since 1982, with 779 deaths nationally.4 Pleural mesothelioma accounts for ~95% of all mesothelioma cases.5 6
Weight loss, low muscle mass and malnutrition are common in patients with MPM and these are associated with poor quality of life (QoL), physical functioning and perhaps lower survival. A recent study examining patients with MPM found that high rates of malnutrition (38%) and low skeletal muscle mass (54%) were present shortly after diagnosis (median 2 months).7 Participants with malnutrition had lower QoL (p<0.001), while participants with low skeletal muscle mass were more inactive compared with those with normal muscle mass (p=0.001).7 Additionally, participants with malnutrition and had significantly higher levels of the proinflammatory cytokine, interleukin (IL) 6, compared with well-nourished participants (median 11.0 (IQR 4.7–18.8) pg/mL versus median 2.6 (2.0–7.9) pg/mL; p=0.002).7 These results suggest the presence of systemic inflammation in our malnourished participants with MPM and are indicative of cancer cachexia rather than simple malnutrition.
Numerous studies have shown that weight loss may be directly related to worse survival in MPM.2 8–10 A postmortem study of 318 patients with MPM found that body mass index (BMI) was significantly lower where there was no identifiable anatomic cause of death.8 The mean BMI of this cohort was 19.98 (SD 4.9) and BMI was significantly lower in patients with no identified anatomic cause of death, compared with those where causes were apparent (18.8 (SD 4.3) vs 21.0 (4.7); p=0.034).8 A recent prognostic model for MPM was consistent with this notion, demonstrating that the presence of weight loss at the time of diagnosis of MPM has the strongest association with survival.2 Additionally, post-hoc analyses of the Regular Early Specialist Palliative Care Mesothelioma (RESPECT-Meso) study also demonstrated that loss of appetite was associated with worse survival (HR 2.3 (95% CI 1.2 to 4.4, p=0.01)).9 10 Overall, these findings suggest any interventions that can potentially reduce weight loss or improve appetite associated with advanced cancer may positively impact on QoL, physical functioning and, perhaps, survival.
Current treatment options for cancer cachexia are very limited. Oral corticosteroids and progestins can improve appetite and total body weight (TBW) but have no beneficial effect on skeletal muscle mass.11 These drugs pose a significant risk of side effects that can impact multiple body symptoms.12 Ghrelin receptor agonists have been developed as a treatment for cancer cachexia. Ghrelin is predominantly produced in the stomach and rapidly stimulates appetite leading to increased food intake. Ghrelin also triggers other physiological changes such as stimulation of gastric emptying and increased skeletal muscle, probably from inducing growth hormone secretion and insulin-like growth factor (IGF)-1 release.13
Anamorelin is a ghrelin receptor agonist and in advanced cancers it improves TBW, lean body mass (LBM), appetite and QoL.14–17 A recent systematic review of the effects of anamorelin identified 6 randomised controlled trials of 1641 participants.18 These comprised two phase III trials in in non-small cell lung cancer (NSCLC) and four phase II studies with mixed cancer cohorts. In these studies, there is a consistent treatment effect favouring anamorelin, with statistically significant improvements in TBW, LBM and QoL.18 Since the systematic review, there has been a further phase III study trialling anamorelin in NSCLC and a phase II study in mixed gastrointestinal cancers (mainly colorectal).19 20 The phase III study in NSCLC demonstrated a mean increase in LBM by 1.38 kg ±0.18 (p<0.001) with associated increases in body weight (1.06 kg ±0.2, p<0.0001) and appetite (p=0.0005), compared with placebo over a 12-week period.19 The participants with gastrointestinal cancer in the phase II study demonstrated a similar increase in LBM of 1.89 kg ±0.36, and increase in appetite.20
The majority of these studies administered anamorelin to participants over a 12-week period. In responders, a pattern of rapid improvement in appetite and weight occurs within the first 3 weeks which progresses to sustained benefit for the duration of the studies.15 17 19 20 Improvement in cachexia-related biomarkers collected throughout these studies followed a similar pattern, with biomarkers such as IGF-1, IGF3, IGF-binding protein 3, prealbumin and transthyretin increasing to a peak at week 3 or 4, then plateauing or decreasing after this point.15 17 19 20
Despite the clear promise as a palliative therapeutic agent in both improvement in weight and QoL, anamorelin has not had regulatory approval, in part, because coprimary outcome measures were not significantly improved in the two large, phase III anamorelin in lung cancer cachexia (ROMANA) studies.17 The Federal Drugs Administration requirement for inclusion of hand grip strength as a coprimary outcome measure. These studies, with 979 participants, demonstrated a clear statistically significant benefit in LBM favouring anamorelin as well as a consistent improvement in appetite and QoL but failed the coprimary endpoint on hand grip strength.17 In our studies, we have found that hand grip strength is not sensitive to change in our MPM population in both observational and interventional cohorts.21
Anamorelin is well tolerated with no dose-limiting toxicities identified to date; the frequency of grade 3 and 4 toxicities is the same as for patients receiving placebo.18 Hyperglycaemia is the most common high-grade toxicity but occurs in <1% of participants.17 Mild nausea and abnormal liver function tests are the other most frequently reported adverse events (AE) in up to 1:10 patients. There have been concerns in early phase clinical studies about cardiovascular toxicity, but this was not borne out in later phase studies, with the rates of cardiovascular events being similar between anamorelin and placebo.17 Two dose levels of anamorelin have been examined (50 mg and 100 mg daily), with the 100 mg dose considered optimal to improve skeletal muscle mass without any increase in AE.
Anamorelin has yet to be examined in patients with MPM. The aim of this randomised controlled trial is to assess if anamorelin improves muscle mass and QoL in patients with MPM as compared with placebo.