A pooled overall survival analysis at year showed
A pooled overall survival analysis at 1year showed no difference in survival between the two study arms, although these studies were not designed or powered to demonstrate a survival benefit. Among the 979 total patients in both ROMANA 1 and 2, about 55% continued on to the ROMANA 3 trial. That trial is looking at the effects of anamorelin and its tolerability in patients who take it for an additional 3months . In the extension study no new safety signals were identified. The ROMANA 3 data concurred with the safety profiles observed in ROMANA 1 and ROMANA 2. As in those studies, anamorelin treatment was well tolerated over 24weeks. Drug-related treatment-emergent AEs (TEAEs) were reported in 3.5% vs 1.2% of ANAM- vs placebo-treated patients, the most common being hyperglycemia (1.2% vs 0.0%); there were no drug-related grade ⩾3 TEAEs, or drug-related serious TEAEs. In the ANAM and placebo arms there were 35 (10.2%) and 22 (13.2%) deaths, respectively, none of which were drug-related.
Safety One supposed concern regarding use of ghrelin in cancer patients is that ghrelin may elicit tumor growth via its GH/IGF-1stimulatory effect or through other unidentified mechanism. In vitro studies have given opposing results on the effects of ghrelin on the growth of tumor cells, with some demonstrating a decrease and some demonstrating an increase in cell proliferation , . These conflicting data may be explained in part with different Sweroside of the GRLN receptor, variations between endocrine and non-endocrine tumor cell lines, and variances in testing methods and concentrations of test agents , .In a non small-cell lung cancer cachexia animal model, administration of ANAM or ghrelin for 28days increased mean bodyweight but did not promote tumor growth . Moreover, in this study, no treatment-related deaths occurred and no difference in incidence of tumor progression adverse events occurred between the ANAM and placebo groups. The results of this study are consistent with findings from other studies evaluating GH-based therapies in tumor-bearing animals as well as in formal carcinogenicity studies in tumor-free animals. Khan et al.  demonstrated that treatment with a GH releasing hormone (GHRH)-expressing plasmid in nude mice implanted with a human bronchoalveolar carcinoma cell line did not increase the growth of the tumor, but rather it reduced tumor volume by 40%, suggesting that the therapeutic role of GH-based therapies may not be limited to cachexia. In a study by Perboni et al., was highlighted that the addition of the ghrelin agonist growth hormone releasing peptide-2 (GHRP-2) to cytotoxic therapy with 5-fluorouracil (5-FU) avoid the anorexia associated with chemotherapy in tumor-bearing cachectic BALB/c mice, and there was also a trend of improved survival in the 5-FU+GHRP-2 treated mice compared with those with 5-FU alone . Farris et al. investigated the carcinogenetic potential of biologically active GH in rats and mice and they demonstrated that there were no increases in incidence or spectrum of neoplastic changes in either species, and there was a favorable effect on longevity . In a Phase II study with over 80 patients with different tumor types, there was no difference in the incidence of adverse events of “disease progression” between patients receiving placebo or anamorelin for up to 12weeks . However there is a need for future larger trials with extended follow-up to determine long-term safety of these interventions. As discussed above in the ROMANA 3 safety extension study, ANAM treatment over 24weeks was well tolerated and no new safety signals were identified.
Conclusions CACs is a multifactorial syndrome characterised by involuntary weight loss, muscle atrophy and physiological changes, which leads to progressive functional impairment. It is associated with a poor performance status, reduced survival  and an increased risk of treatment failure and toxicity . Treatment options for treating CACs are limited. The approach is multimodal and may include: treatment of secondary gastrointestinal symptoms, nutritional treatments, drug, and non-drug treatments. Nutritional counselling and physical training may be beneficial in delaying or preventing the development of anorexia–cachexia. ANAM is a first-in-class, orally active ghrelin receptor agonist that binds and stimulates the growth hormone secretagogue receptor centrally, thereby mimicking the appetite-enhancing and anabolic effects of ghrelin. It represents a new class of drug and an additional treatment option for this patient group, whose therapeutic options are currently limited. As with all new medications, the long-term efficacy and safety outcomes of novel drugs such as ANAM also need to be understood in order to answer questions such as whether any benefit is maintained and for how long.