Real-world effectiveness of anamorelin in patients with unresectable and relapse pancreatic cancer: a prospective observational study

Introduction

Cancer cachexia is a multifaceted syndrome characterized by nonvolitional weight loss, sarcopenia, fatigue, weakness, and anorexia. Cancer-secreted cytokines are the primary cause (1,2). It is typically empirically treated with anti-inflammatory medications, nutritional support, rehabilitation, and pharmacological agents. Few effective treatments for cancer cachexia exist, including pharmacological agents (2). According to some studies, cancer cachexia or body weight (BW) loss at the time of diagnosis has no bearing on the prognosis of pancreatic cancer (PC) (3,4). However, Furuse discovered that cancer cachexia was associated with a shorter time-to-treatment failure and fewer doses in patients with PC who received first-line folfilinox (FFX) or gemcitabine plus ablaxan treatment (3). Furthermore, studies have shown that nutritional status is associated with prognosis in a variety of cancers, including PC (5-7).

Additionally, increasing appetite may improve the patient’s quality of life (QOL). Therefore, a good nutritional status is preferable for a patient with PC.

Recently, anamorelin, a ghrelin receptor agonist, has been used to treat cancer cachexia (8-11). Anamorelin is thought to enhance growth hormone secretion, increase appetite and lipogenesis (9,12), and regulate BW (12,13). Anamorelin was authorized for the first time in the world in Japan on December 11, 2020, for the treatment of cancer cachexia caused by inoperable and relapsed non-small cell lung cancer (NSCLC), gastric cancer, PC, and colorectal cancer. Anamorelin was shown to improve lean body mass, BW, and appetite (10,11). However, in the previously published studies, given the small sample size and the selection of patients with higher performance statuses, the main impact of anamorelin on patients with PC, who have significant cachexia (1), has not been fully studied. In this study, we prospectively assessed the efficacy of anamorelin in real-world patients with inoperable and relapsed PC, including those with worse performance status. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-162/rc).

Methods

Study design and ethics-related information

This was a prospective observational cohort study that ran from October 2021 to December 2024 at the National Hospital Organization Kure Medical Center and Chugoku Cancer Center. Ethical approval was granted by the review board of the National Hospital Organization Kure Medical Center and Chugoku Cancer Center (No. 2021-46) and the study followed the principles outlined in the Declaration of Helsinki and its subsequent amendments. This study was registered with the Japan University Hospital Medical Information Network (No. UMIN000047457) on 27^th, September 2021. Before enrolling in this study, all participants gave their written informed consent.

Patients

The study included patients with unresectable or relapsed PC. Inclusion criteria included a pathological diagnosis, anamorelin therapy for anorexia, weight loss >5% within 6 months, and two or more of the following: (I) fatigue or malaise; (II) muscle weakness; and (III) C-reactive protein (CRP) >0.5 mg/dL, hemoglobin <12 g/dL, and/or albumin (Alb) <3.2 g/dL. Patients with advanced heart failure, pathological arrhythmia, or ischemic heart disease were excluded.

Patients received 100 mg of anamorelin once daily for 16 weeks during the treatment period, followed by a 4-week follow-up to assess therapeutic efficacy and adverse drug reaction (ADR).

Patients with diabetes were given anamorelin while taking oral drugs and insulin with strict guidance from specialists of diabetes. We continued anamorelin when the patient requested it because the effect was not objectively sufficient.

Evaluation

We assessed the efficacy of anamorelin at 0, 1, 2, 3, and 4 months after starting treatment. The general condition was assessed using the Eastern Cooperative Oncology Group Performance Status (PS). Appetite was examined using question 8 (Did you have a good appetite?) in the QOL questionnaire for patients with cancer treated with anticancer drugs (QOL-ACD) (14). Simultaneously, questions 9 (Did you enjoy your meals?) and 22 (Please circle the number of the face that best represents your feelings in the last few days?) were evaluated. Nutritionists assessed meal intake amounts and determined the meal intake sufficiency rate. Nutritionists were also consulted regarding the patient’s nutritional concerns. BW, muscle weight, fat weight, and smooth muscle index (SMI) were identified using bioelectrical impedance analysis (® INBODY770, InBody Japan Inc., Tokyo, Japan). Blood tests were performed to assess serum glucose, Alb, retinol binding protein (Ret), total cholesterol (T-cho), cholinesterase, hemoglobin A1c, CRP, and D-dimer levels. Additionally, the psoas index was calculated at 0- and 4-month using the amount of area at the level of the 3rd lumber vertebrate in computed tomography. The definition of a patient with worsening glucose tolerance is the following: blood glucose >200 mg/dL without medication; under oral medication; additional insulin usage; and increased insulin dosage.

Factors associated with effectiveness of anamorelin

We considered patients who had improved appetite, meal intake sufficiency rate, increased BW (excluding patients with ascites, pleural effusion, and massive edema), and had been taking anamorelin for at least 4 months to be effective. Patients who discontinued anamorelin due to poor compliance were excluded from this analysis, and the remaining patients were classified as ineffective for anamorelin.

Statistical analysis

Data were presented as the median value [range or interquartile range (IQR)]. The Fisher’s exact test was used to compare categorical variables, while the median test was used to compare quantitative data. The Wilcoxon signed-rank test was used to compare results before and after anamorelin administration. Logistic regression analysis was used to identify independent predictors of anamorelin efficacy. The cut-off values for serum biomarkers were determined using receiver operating characteristics curve analysis. The log-rank test and the Kaplan-Meier method was used to assess the survival of patients with or without anamorelin response. All statistical analyses of recorded data were carried out using the Excel statistical software package (Ekuseru-Toukei 2015 version; Social Survey Research Information Co., Ltd., Tokyo, Japan). To predict response to anamorelin, variables identified as potentially significant (P<0.09) in univariate analysis were entered into multiple logistic regression analyses. Alb, CRP, and CRP/Alb ratio had P values <0.05 in univariate analysis. However, we did not include these items in the multivariate regression analysis due to multiplicity issues. P<0.05 was deemed statistically significant.

Results

Patient characteristics

Table 1 shows the patients’ characteristics. Anamorelin was first prescribed to 45 patients. The median age of the patients was 75 years (49–90 years), with 18 females (40%). There were 40 inoperable patients (88.9%), with 30 having distant metastasis (66.7%). Antitumor chemotherapy was prescribed for 39 patients (86.7%), while modified folfiriinox (mFFX) was prescribed for 5 patients. The median body mass index was 19.6 (13.5–29.3) kg/m², and the performance status at 0, 1, 2, 3, and 4 months were 15, 9, 12, 2, and 19, respectively. Nineteen patients (42.2%) were treated for cancer pain, and 14 patients had diabetes mellitus (31.1%, with 7 using oral medication and 7 using insulin).

Patient flowchart

Figure 1 illustrates patient flow. Patients who took anamorelin for one month and four months were 31 and 20, respectively. The most common reasons for discontinuation were a worsening of the overall condition due to tumor progression and poor anamorelin compliance.

Figure 1 Patient flowchart. A total of 45 patients with PC began taking anamorelin. Thirty-one and 20 patients continued to take it for 1 and 4 months, respectively. The most prevalent reason for discontinuation was a worsening of the general condition as cancer progressed. PC, pancreatic cancer.

Evaluation after one month

Appetite improved in 18 patients (Table S1), and the appetite score (question 8 in QOL-ACD) increased significantly (median: +1, range 0–4, P<0.001) (Table 2). Subsequently, 14 and 13 patients improved their food and protein intake sufficiency rates, with medians of 3.2% (range: 0–20.4%) and 3.3% (range: 0–22.9%), respectively. BW, muscle weight, and SMI all improved in 21, 19, and 16 patients, respectively. The improvement was significant [BW: +1.8 (IQR 0.13–3.08) kg, P<0.05, muscle weight: +0.9 (IQR −0.05 to 2.6) kg, P<0.05]. PS, current mood score (question 22 in QOL-ACD), and rip strength did not show significant improvement. In laboratory examination, T-cho and Ret were greatly improved (T-cho: median +18 mg/dL, IQR: 2.3–27.8 mg/dL, and Ret: +0.2 g/dL, IQR: 0–0.6 g/dL) (Table S1, Table 2).

Evaluation after 4 months

Thirteen patients reported improved appetite (Table S1), with a significant increase in appetite score (median +1, range −1 to +2, P<0.01) (Table 3). Subsequently, food and protein intake sufficiency rates were also increased in 14 and 13 patients, respectively, and the improvements were significant, with medians of 19.9% (range: 10.4–33.3%) and 20% (0–26.7%), respectively.

BW, muscle weight, and SMI had also improved in 15 patients each. Significant improvements were observed (BW: +3, IQR 0.7–4.1 kg, P<0.05, muscle weight: +2.0, IQR 0–3.3 kg, P<0.05, and SMI: +0.3, IQR 0.1–0.7 kg/mm², P<0.05) (Table S1, Table 3). There were seven patients whose BW returned to their original weight. However, PS, current mood score, and rip strength did not show significant improvement. Laboratory tests showed significant increases in T-cho (median +18, IQR: −11 to 29 mg/dL) and decreases in Alb after 4 months (median −0.2, IQR: −0.5–0 g/dL, P<0.05).

Safety

There were no serious ADR recorded. A few patients reported elevated hepatobiliary enzymes, and some had abnormal glucose tolerance. One patient had mildly elevated levels of aspartate transaminase and alkaline phosphatase, γ-glutamyl transferase and leucine aminopeptidase (LAP), and lactate dehydrogenase and LAP. Table 4 presents the results of glucose tolerance. Regarding patients who continued anamorelin treatment, 15 patients out of 35 (33.3%) developed worsening glucose tolerance. There were eight patients with casual blood sugar levels >200 mg/dL, two with additional oral medication, and five starting or increasing insulin dosage. These patients were managed safely in conjunction with diabetologists. No patients discontinued the anamorelin therapy due to hyperglycemia.

Factors associated with good efficacy of anamorelin

Table 5 compares those with and without anamorelin efficacy. In univariate analysis, more effective patients had a good PS, no cancer pain, higher serum Alb and Ret concentrations, and lower D-dimer, CRP, and CRP/Alb ratios. In multivariate analysis (Table 6), fine PS (PS0,1) was an independent predictor of good anamorelin efficacy.

Kaplan-Meier analysis (survival analysis)

Survival was significantly higher in patients who demonstrated good efficacy with anamorelin than in those who did not (median survival time: 366 vs. 106 days, respectively) (Figure 2).

Figure 2 Kaplan-Meier analysis for survival in patients with and without anamorelin effectiveness. The median survival days in anamorelin-effectiveness patients were significantly longer than in those with anamorelin ineffectiveness (366 vs. 106 days, P<0.001).

Other findings

Four patients with modified folfirinox (mFFX) were not sensitive to anamorelin. Two of them continued anamorelin at the patients’ request and responded well when their chemotherapeutic regimens were changed from mFFX to gemcitabine plus ablaxan (data not shown).

Discussion

This is the first report to prospectively assess the efficacy of anamorelin targeting inoperable and relapse PC after its market release in 2021. We assessed patients’ PS, appetite, recent mood, and food intake amount using a questionnaire and hearing from nutritionists, as well as body composition, including BW and muscle weight, using the impedance method. Most patients who continued taking anamorelin for 4 months showed good results. Some patients discontinued the medication due to a worsening of their overall condition as a result of cancer progression; however, they demonstrated few preferable effects. Anamorelin’s ineffectiveness was predicted by poor PS, concurrent cancer pain treatment, poor nutritional status, high inflammation, and short survival after anamorelin, in univariate analysis, and poor PS (2, 3, 4 vs. 0, 1) in multivariate analysis. These findings suggest that anamorelin may be only effective in patients with relatively good general health, not in those with significant cachexia or poor survival. Anamorelin did not significantly improve these patients’ conditions. Thus, it may be preferable to use anamorelin early on in patients with relatively good general health and no significant cachexia.

Cachexia is a chronic malnutrition condition caused by a serious underlying disease, such as heart failure, chronic renal failure, or cancer. Anorexia, BW loss, and decreased skeletal muscle mass are common symptoms of these diseases and related conditions (2). Cancer cachexia can be caused by a variety of factors, including proteolysis-inducing factors, lipid-mobilizing factors, proinflammatory cytokines, inflammatory cytokines (e.g., TNFα), and parathyroid hormone-related protein. These factors can lead to fat loss, muscle degeneration, insulin resistance, and anorexia, resulting from metabolic, immunological, and neurological abnormalities (2). Thus, cancer cachexia is considered distinct from mere malnutrition (2,15,16). Cancer cachexia is linked to poor QOL, ineffective anticancer treatments, and a poor prognosis (1,17). However, it could not be improved through usual nutritional supplementation. It accounts for nearly 20% of cancer-related deaths (18). Cachexia is more common in gastrointestinal and PC cases (18), with up to 33% of patients with PC dying from it (19). All of these findings suggest that prompt control of cachexia may improve patients’ QOL and survival even if tumor progression has continued.

To treat cachexia, ESPEN, and ESMO guidelines suggest combining nutritional counseling, anti-inflammation therapy, rehabilitation, and pharmaceutical agents (2,20-24). However, there are few effective cancer cachexia treatment regimens available today. Progesterone and corticosteroids were used in the United States (25). They are used as an orexigenic agent and are thought to inhibit cytokines and restore normal state (18). Unfortunately, progesterone does not always result in improved QOL in humans. Furthermore, corticosteroids are prescribed to cancer patients as a palliative treatment for a limited time. As a result, a more effective drug is required to improve the control of cancer cachexia.

Our current study found that anamorelin effectiveness in patients with PC who took the medication for 4 months was associated with better appetite, food intake, and BW. The increased BW amount was comparable to those previously reported in the literature (26,27). As a result, we believed that anamorelin could be an effective palliative therapy in such patients.

In our study, although anamorelin use significantly increased muscle mass, it did not improve muscle function (hand grip strength). This is consistent with previous reports (8,27,28) indicating no positive impact on muscle function, and anamorelin has not been approved for use in Europe. An early published multidisciplinary intervention recommended nutritional counseling, exercise, and pharmacotherapy for cancer cachexia (2,20,22,23,29). Additionally, combining anamorelin therapy with rehabilitation has been shown to be beneficial (24). So, rehabilitation therapy may be required in addition to nutritional support and pharmacotherapy in those cases.

More than half of the patients in our study did not experience a positive effect from anamorelin. Anamorelin ineffectiveness was associated with poorer PS, shorter survival after anamorelin, poorer nutritional status, and high levels of inflammatory markers, indicating that anamorelin may not have a preferable effect for patients with refractory cachexia, which is associated with cancer progression and higher inflammation. Takaeda (21) found that patients with poorer PS did not respond well to anamorelin. Consistent with this, previous research reported that systemic inflammation was a factor linked to the ineffectiveness of anamorelin (high modified Glasgow prognostic score (30) and high CRP/Alb ratio (31). Our findings revealed that high CRP, Alb/CRP ratio and D-dimer levels were associated with anamorelin ineffectiveness in univariate analysis. Cancer cachexia is caused by cytokine-mediated systematic inflammation. As a result, using only anamorelin, which increases appetite through growth hormone release, was ineffective in treating severe cachexia. Although ghrelin has been shown to have anti-inflammatory properties (32,33), however, we believe it may not be as effective as other agents. Research suggests that incorporating NSAIDS into a multidisciplinary intervention is more effective (1,34). Furthermore, the initial nutritional status when starting anamorelin had a significant impact on its effectiveness, with patients with poorer nutritional status having worse outcomes. In patients with PC, poor nutritional status at first diagnosis is linked to a poor prognosis (6,14). Many reports showed that nutritional status was associated with efficacy for anamorelin (7,35). Approximately 50% of patients with PC had cancer cachexia at the start of first-line chemotherapy (36), which was higher than in patients with NSCLC (37). As a result, we must closely monitor patients’ overall health and detect anorexia and appetite loss to begin anamorelin treatment early on. We believe that anamorelin could be prescribed even for patients with operable PC who have anorexia and BW loss prior to surgery. Sleep, pain, bowel movement abnormality, anxiety, and antitumor agent side effects can all contribute to appetite loss. In this study, all patients receiving mFFX were not sensitive to anamorelin, and the presence of cancer pain predicted the ineffectiveness of anamoreline in univariate analysis. In the case of gastric and colorectal cancer, early administration of anamorelin improves prognosis (35).

There were no serious adverse events reported. The most common ADR was impaired glucose tolerance. A previous study (38) found that some patients stopped taking anamorelin due to hyperglycemia and that diabetes mellitus was linked to anamorelin ineffectiveness. Although none of our patients discontinued anamorelin due to hyperglycemia, we believe this can be attributed to involving a diabetologist from the start of cancer treatment. We believe that patients who had diabetes mellitus before taking anamorelin and now require diabetes therapy should be managed by diabetologists.

Regarding survival, no studies have found that anamorelin use is associated with longer survival. We hypothesized that anamorelin would improve patient’s survival by improving nutritional status. Nutritional status has been linked to prognosis in various cancers, including PC (5-7).

Our study has a few limitations. First, this is a single-center analysis. Second, it does not include a control group. Third, BW and composition were determined using bioelectrical impedance analysis. Thus, water composition may influence muscle and fat weight, although we excluded patients with ascites and massive edema from the analysis. Fourth, there is a small sample size of included patients. Larger multicenter clinical trials are required to highlight the safety and efficacy of anamorelin in patients with PC.

Conclusions

Anamorelin improved appetite, food intake sufficiency rate, and BW in patients with relatively good PS and long survival. It may be better to have an effective anti-inflammatory drug and multidisciplinary intervention in addition to anamorelin for patients with severe cachexia. We should also closely monitor the patient’s overall health, including appetite and BW, and give anamorelin as soon as possible.

Acknowledgments

We are thankful to Tomoyuki Akita for direction and review of statistical analysis, Kana Uchida for data input and collection of literature.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-162/rc

Data Sharing Statement: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-162/dss

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-162/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2025-162/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was performed in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of National Hospital Organization Kure Medical Center and Chugoku Cancer Center (No. 2021-46), and informed consent was obtained from all patients before starting this study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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