Cancer cachexia: treatment and what anamorelin evidence shows

What is cancer cachexia and how many patients does it affect?

An international expert panel defined cancer cachexia as a multifactorial syndrome characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment. Its pathophysiology combines reduced food intake with abnormal metabolism, producing a negative protein and energy balance¹. ICD-10 codes it as R64.

How common it is depends on the criteria used. A systematic review of 125 articles with 137,960 patients found an overall prevalence of 33.0% (95% CI 32.8 to 33.3), ranging from 13.9% to 56.5% depending on the diagnostic criteria. With the 2011 criteria, cachexia was associated with a hazard ratio for death of 1.58 (95% CI 1.45 to 1.73) compared with patients without cachexia².

Symptoms and diagnosis: how cachexia is recognized

The diagnostic criterion agreed in the international consensus is weight loss greater than 5%, or greater than 2% in someone already showing depletion by a body-mass index under 20 kg/m² or by low muscle mass (sarcopenia)¹. The same consensus describes a staged course, from pre-cachexia to cachexia to refractory cachexia, and proposes assessing anorexia or reduced intake, catabolic drive, muscle mass and strength, and functional and psychosocial impairment¹.

In practice this means weight loss, poor appetite, weakness and declining function are measured systematically rather than only observed. Anorexia is very common: a recent trial notes that it occurs in 30% to 80% of patients with advanced malignancies and may worsen with chemotherapy⁵.

Standard treatment today: what guidelines recommend

The American Society of Clinical Oncology (ASCO) guideline of 2020 reviewed 20 systematic reviews and 13 additional randomized trials. It concluded that dietary counseling, with or without oral nutritional supplements, increased body weight in some trials although the evidence is limited; that enteral tube feeding and parenteral nutrition should not be used routinely; and that, in the absence of more robust evidence, no specific pharmacological intervention can be recommended as the standard of care, so clinicians may choose not to prescribe medications specifically for cachexia. When a drug is tried to improve appetite or weight, the options it names are progesterone analogs and short-term (weeks) corticosteroids³.

The European Society for Clinical Nutrition and Metabolism (ESPEN) practical guideline of 2021 presents 43 recommendations on the nutritional and metabolic management of patients with neoplastic disease, preceded by general recommendations on assessing nutritional status⁴.

Among drugs that are not peptides, a double-blind trial of 124 patients with gastric, hepatopancreaticobiliary or lung cancer starting chemotherapy (112 analyzable) found that 60% of the olanzapine group gained more than 5% of body weight versus 9% with placebo (P < .001), and appetite improvement on a visual scale was 43% versus 13%⁵. The results are promising but come from a single moderately sized trial.

What research on peptides and ghrelin-receptor agonists has shown

Ghrelin is an acylated peptide described in 1999 as a growth-hormone-releasing peptide isolated from the stomach⁶. Anamorelin is an oral ghrelin-receptor agonist: it is not the natural peptide but a drug that acts on the same receptor. It is included here as the agent closest to peptide biology with human evidence in cachexia. The history of this family is in GHRP and ghrelin: the history, an overview of secretagogues in Growth hormone secretagogue guide and the oncology landscape in Peptides in oncology.

ROMANA 1 and ROMANA 2. These were two phase 3, double-blind, placebo-controlled trials at 93 sites in 19 countries, enrolling 484 and 495 patients with stage III or IV non-small-cell lung cancer and cachexia, randomized 2:1 to anamorelin or placebo. At 12 weeks, lean body mass increased with anamorelin (median 0.99 kg in ROMANA 1 and 0.65 kg in ROMANA 2) and decreased with placebo (−0.47 kg and −0.98 kg; P < 0.0001 in both). There was no difference in handgrip strength (P = 0.15 and P = 0.65). The authors concluded that anamorelin increased lean body mass but not handgrip strength; funding was from Helsinn⁷.

Japanese studies. A phase 2 trial of 181 patients with non-small-cell lung cancer found weight changes of 1.77 kg with the higher dose versus −0.93 kg with placebo and improved quality of life, with no handgrip effect detected⁸. Trial ONO-7643-04, with 174 patients, showed a lean-mass change of 1.38 kg versus −0.17 kg with placebo (P < .0001), but no changes in handgrip strength or the 6-minute walk test⁹.

Longer follow-up. ROMANA 3 extended treatment another 12 weeks in 513 patients (345 on anamorelin, 168 on placebo). Treatment-emergent adverse events were similar (52.2% versus 55.7%), as were grade 3 or higher events (22.4% versus 21.6%); 10.5% and 13.8% died, with no deaths attributed to the drug. There was also no significant improvement in handgrip strength¹⁰.

Other tumors. In the first randomized trial in gastric cancer, open-label and multicenter, with 217 patients recruited and 203 randomized, lean body mass at 8 weeks increased 0.99 kg with anamorelin versus 0.14 kg without, but the difference did not reach statistical significance (P = 0.063)¹³. In 38 patients with metastatic urothelial carcinoma receiving chemotherapy, changes in prealbumin, albumin, body weight and muscle mass were similar between groups¹⁴.

Meta-analyses. A 2023 analysis of seven trials and 1,944 patients found that anamorelin increased total body weight (mean difference 1.73 kg), lean body mass (1.06 kg) and quality of life (standardized difference 0.16), with no significant differences in adverse events, overall survival, handgrip strength or appetite¹⁵. An earlier meta-analysis of four studies also found increased lean mass without a difference in handgrip strength¹⁶. A 2024 network meta-analysis of seven trials (1,421 patients) estimated weight gains of 4.6 kg with olanzapine and 2.36 kg with anamorelin, although it could not confirm the superiority of one over the other¹⁷.

Regulatory status. Ono Pharmaceutical received marketing approval in Japan on January 22, 2021, for cachexia associated with non-small-cell lung, gastric, pancreatic or colorectal cancer; the basis included the phase 2 trial ONO-7643-04 in lung cancer and an open-label, uncontrolled phase 3 trial in gastric, pancreatic and colorectal tumors¹¹. In Europe, the committee of the European Medicines Agency (EMA) adopted a negative opinion on May 18, 2017 and confirmed the refusal on September 14, 2017 after re-examination; it considered that the studies showed a marginal effect on lean body mass and no proven effect on handgrip strength or quality of life, and that safety data at some sites had not been recorded adequately¹². The sources consulted did not show a United States FDA approval.

Anti-GDF-15 antibody (not a peptide). For context, ponsegromab is a humanized monoclonal antibody against GDF-15, not a peptide. In a phase 2 trial of 187 patients with cachexia and elevated GDF-15, the median weight difference versus placebo at 12 weeks was 1.22, 1.92 and 2.81 kg across dose levels, and adverse events of any cause were 70% in the ponsegromab groups and 80% with placebo¹⁸.

Safety: adverse effects and precautions

In ROMANA 1 and 2, there were no differences in grade 3-4 treatment-related adverse events; the most common was hyperglycemia, in one of 320 patients (under 1%) in ROMANA 1 and four of 330 (1%) in ROMANA 2⁷. In the gastric trial, grade 1-2 hyperglycemia occurred in 4 patients (4%) and grade 3 in one (1%), with none in the control group and no treatment-related deaths¹³.

In the 2023 meta-analysis there was no significant difference in serious adverse events or overall survival¹⁵, and in ROMANA 3 mortality was similar between groups with no deaths attributed to the drug¹⁰. Even so, the EMA noted in 2017 that a thorough risk evaluation was not possible because of inadequate data recording at some sites¹², so long-term safety outside trials depends on the post-marketing surveillance Japan required¹¹.

Summary by agent

Frequently asked questions

What is cancer cachexia? It is a multifactorial syndrome of ongoing muscle loss, with or without fat loss, that cannot be fully reversed by conventional nutritional support¹.

How many patients with cancer does it affect? In a review of 125 articles, overall prevalence was 33.0%, ranging from 13.9% to 56.5% depending on the diagnostic criterion².

Is there an approved drug for cancer cachexia? Japan approved anamorelin in January 2021¹¹. The EMA refused authorization in Europe in 2017¹², and the 2020 ASCO guideline recommends no specific drug as standard of care³.

Does anamorelin improve strength? Not in the trials reviewed: in ROMANA 1 and 2, ROMANA 3 and the Japanese studies there was no significant improvement in handgrip strength⁷⁹¹⁰.

Is anamorelin a peptide? It is not the natural peptide: it is an oral agonist of the ghrelin receptor, which is activated by ghrelin, a peptide described in 1999⁶⁷.

What does the ASCO guideline recommend? Offer dietary counseling, do not use enteral tube feeding or parenteral nutrition routinely and, if a drug is tried, consider progesterone analogs or short-term corticosteroids³.