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ESMOPharma 2013 (ECC 2013): Dr Florian Scotté
The POWER Trial, Enobosarm, and the Prevention and Treatment of Cachexia
Cachexia is a symptom often linked to non-small cell lung cancer; 70% of patients will be affected by muscle wasting during the course of their disease (Baracos VE et al., Am J Clin Nutr 2010). It is associated with an increase in catabolic activity and a regression of anabolism. A selective androgen receptor modulator (SARM) is involved in increasing muscle and bone mass, with positive effects on mood, energy level, sensation of wellbeing, and even libido. Three clinical trials have demonstrated the positive effect of enobosarm (active on SARM) on low muscle mass and functional physical improvement (one phase I and two phase II trials). Other studies using other products, including anamorelin, are also underway; in particular, for the latter molecule, there are two phase III studies.
Jeffrey Crawford, principal investigator in enobosarm trials, reported results from phase III studies testing 3 mg of the product versus a placebo in stage 3 and 4 non-small cell lung cancer, treated by platinum plus taxane doublet chemotherapy (POWER 1 trial ) or platinum plus non taxane doublet chemotherapy (POWER 2 trial). Product efficacy was evaluated according to FDA criteria and European criteria.
FDA Criteria: Lean body mass: the responders must maintain or increase their lean body mass.
Stair climb power: the responders must increase this power by more than 10% (measured in watts).
Stair climb power: evaluated based on mixed models of repeat measurements.
Lean body mass: considered a significant secondary objective. Note that the stair climb power uses the following formula: 9.8 (m/s2) X Height of stairs (m) X Weight (kg) / duration of climbing (s).
Following the FDA criteria, enobosarm had significant efficacy (p=0.036) on the increase in lean body mass in the POWER 1 trial (cohort with taxane) through the 84 days of treatment. Following European criteria, enobosarm had a significant impact versus placebo in the POWER 1 trial (with taxane) both for the main objective of stair climbing (p=0.0336) and for the secondary objective of increasing lean body mass (p=0.0003).
The results were positive in the POWER 2 trial (without taxane) only for the secondary objective (muscle mass) with the European criteria (p=0.0227). A significant improvement in survival, correlated with the response in lean body mass, was also reported in these two studies. The tolerance to enobosarm was good, compared to the placebo, making this treatment a likely option in the future for treating lung cancer-related cachexia.
The results associated with the use of anamorelin (ghrelin receptor agonist in oral tablet form) in non-small cell lung cancer were presented in two abstracts. In the first abstract, a multi-centre, randomised, double-blind phase II study evaluated anamorelin versus a placebo in the prevention of mineral bone loss in patients with anorexia and cachexia [2013 ECC, Abs 1316]. The product was tested with the intent to treat with a daily oral dose of 50 mg vs. the placebo in 74 patients. No difference was found in terms of tolerance between the anamorelin arm and the placebo arm.
While patients in the placebo arm presented with a continuation in the decrease in their bone mass, patients in the anamorelin arm demonstrated stabilisation of bone mass starting from the 4th week of treatment. Likewise, as secondary criteria, body mass and lean body mass were significantly greater versus placebo throughout the analysis time (4th, 8th and 12th weeks). An increase in lean body mass was found in the anamorelin arm at the 12th week. Finally, the values of various inflammation markers regressed under anamorelin (CRP, IL6, TNF alpha).
Long-term results (1 year and greater) will allow conclusions to be drawn on the effect of this molecule on bone mass. In a second study presented by J. Temel [ECC 2013, Abs 1308], anamorelin was evaluated on body mass and wrist strength in the non-dominant hand. This evaluation was also performed as part of a multi-centre, double-blind, phase II study versus a placebo. Two different doses (100 and 50 mg) were tested against the placebo. A significant impact on body mass was recorded versus the placebo from the first week in favour of anamorelin (p<0.05). The difference in favour of the product tested was not significant with respect to wrist strength.
As a secondary objective, the impact on the values of Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) was also positive and significant. In contrast, no difference was found in quality of life or overall survival.
If work progresses in the areas of cachexia and weight loss, new studies (and treatment strategies) will be completed in the future in order to truly change habits and support patients in these situations.