The first report about the activity

The first report about the activity of ANAM in CACs it is due to Garcia et al. [19] which treated 16 cancer patients with oral ANAM 50mg once daily vs placebo for 3days followed by a washout A-71623 of 5–7days and then cross-over to the other group for 3 more days. It was described a weight gain of about 1kg with ANAM compared to placebo and also the patient-reported QOL scores were in favor of ANAM. This study produced the initial evidence that ANAM can provide significant benefits in the management of CACs even if the sample size was small (only 16 patients) and the exposure time was short. Furthermore, patient-reported symptom assessments should be interpreted with caution because these exploratory analyses are inherently subjective and may be subject to variability over time. More encouraging results came by a randomized, double-blind Phase II study conducted in 226 patients with Stage 3 or 4 non small cell lung cancer who received ANAM for 12weeks [24]. The primary objectives were to evaluate the effects of anamorelin on body weight and handgrip strength (HGS) and related CACS. Patients were randomized to placebo [n=76] or oral ANAM 50mg [n=76] or 100mg [n=73] per day. A beneficial effect on body weight was observed as early as 1week after ANAM treatment initiation. Over 12weeks, the group that received 100mg ANAM gained on average 0.14kg compared with baseline, whereas mean losses of 0.3kg and 1.32kg occurred in the 50-mg and placebo group [p=.0005]. No effect was noted on hand-grip strength or survival. QoL total and domain scores assessed using the MD Anderson Symptom Inventory improved in the anamorelin 100mg group compared with placebo, but the differences were not statistically significant. These data were confirmed by a recent integrated analysis of two Phase 2, multicentre, placebo-controlled, double-blind trials conducted in 82 patients with advanced or incurable cancer and weight loss of 5% or more [25]. In the two studies the patients were randomly assigned, between June 2005 and October 2006 at 20 U.S. sites, to receive anamorelin at 50mg [n=44] or placebo [n=38] once daily for 12weeks. The primary outcome measure was lean body mass [LBM] measured by dual-energy X-ray absorptiometry over the 12-week treatment period. Among the 38 anamorelin recipients and 36 placebo recipients eligible for efficacy analysis, LBM increased by a least-squares mean of 1.89kg [95% confidence interval [CI]=0.84–2.95kg] vs a decrease of −0.20kg [−1.23 to 0.83, difference=2.09kg, p=.0006] at 12weeks. Total body mass was increased by a least-squares mean of 0.48kg vs a loss of 1.80kg [p=.0057]. There was no difference in change in fat mass [decreases of least-square means of 0.89 vs 1.70, p=.15]. Three pivotal Phase III studies of anamorelin are currently ongoing. Combined results from – ROMANA 1 and 2 were reported recently [26]. ROMANA 1 and ROMANA 2 are two international, double-blind, Phase III trials evaluating the efficacy and safety of ANAM in patients with unresectable Stage III/IV NSCLC with an ECOG performance score of 0–2 and cachexia [⩾5% weight loss within six months or BMI<20kg/m]. Patients were randomized [2:1] to 100mg ANAM or placebo, given daily orally for 12weeks and were permitted to receive chemotherapy while on study. Co-primary endpoints were change from baseline over 12weeks in LBM and in handgrip strength. Secondary endpoints included change in body weight and in the anorexia–cachexia subdomain of the Functional Assessment of Anorexia/Cachexia Therapy [FAACT] questionnaire, assessment of QoL with the Anderson Symptom Assessment Scale (ASAS) and safety. Safety assessments included laboratory values and adverse events. Over 12weeks, ANAM significantly increased LBM compared with placebo [p<0.0001] in both studies. In ROMANA 1, the median change in LBM was 1.10kg [95% CI 0.76; 1.42] for ANAM compared with −0.44kg [95% CI −0.88; 0.20] for placebo. In ROMANA 2, the median change in LBM was 0.75kg [95% CI 0.51; 1.00] for ANAM compared with −0.96kg [95% CI −1.27; −0.46] for placebo. Change in handgrip strength was not statistically different between study arms and this lack of effect could be related to the fact that muscle function was assessed by handgrip strength which measures only upper but not lower extremity strength, and tumor suppressor genes does not inform enough about physical function and daily living. ANAM [vs placebo] increased body weight [2.20±0.3 vs 0.14±0.4kg; p<0.0001; and 0.95±0.4 vs −0.57±0.4kg; p<0.0001] and improved Functional Assessment of Anorexia–Cachexia Treatment [FAACT] subdomain scores [4.12±0.8 vs 1.92±0.8; p=0.0004; and 3.48±0.9 vs 1.34±1.0; p=0.0016]. ANAM was well tolerated when administered daily over 12weeks.