This study evaluated the real-world treatment course, efficacy, and safety of ANAM for a range of gastrointestinal cancers, including gastric, pancreatic, and colorectal cancers.

Patients with gastric and pancreatic cancer together accounted for 64% of the total sample, and patients with poor condition of ECOG PS2 or higher accounted for 27%, which was higher than the proportion reported in the ONO-7643-05 trial [16]. Overall, the most common chemotherapy regimen for ANAM administration was an early line of two or fewer regimens. However, the early line was commonly administered to patients with pancreatic and gastric cancers, reflecting the differences in the timing of cachexia onset according to the cancer type. Namikawa et al. reported that half of gastric cancer patients had cancer cachexia within 6 months of starting chemotherapy and that patients with cachexia had a significantly worse prognosis than those without cachexia [20]. This may be because absorption disorders are more likely to occur in advanced gastric cancer [21]. One study reported that 32% of patients with pancreatic cancer developed cancer cachexia within the first 12 weeks of anticancer therapy [22]. The high frequency of cachexia in pancreatic cancer can be attributed to the fact that cell signaling through KRAS mutations, which are highly prevalent in pancreatic cancer, promotes skeletal muscle protein degradation and lipolysis, and that cancer impairs exocrine and endocrine functions of the pancreas, resulting in nutrient malabsorption [23]. Therefore, since cancer cachexia is recognized relatively early in patients with gastric and pancreatic cancer, it is important to weigh patients from the start of chemotherapy and monitor cancer cachexia.

In the ONO-7643-05 trial, 89.9% of the patients were able to receive ANAM for more than 3 weeks; however, 37.8% of the patients discontinued within 3 weeks, primarily due to low-grade AEs. However, retrospectively, many of these AEs were manageable with supportive care. For example, although elevated blood glucose level is a common AE associated with ANAM, the study included patients who continued ANAM with an oral hypoglycemic agent. Therefore, even if low-grade adverse events occur, it may be possible to obtain benefits if ANAM is continued with appropriate management.

In this study, the ANAM response rate was 63.6% in the group that could receive ANAM for at least 3 weeks, similar to the 63.3% ANAM response rate in the ONO-7643-05 study. In the ONO-7643-05 trial, ANAM efficacy was defined as the maintenance of or increase in lean body weight. In contrast, in this study, efficacy was defined as maintenance or increase in body weight and improvement in anorexia. Efficacy analysis showed no significant differences in body weight at the 3-week intervals. This could be attributed to the fact that some non-responders who did not increase their appetite included patients who maintained or gained weight. However, after accounting for improvement in anorexia, the ANAM response rate in this study was 63.6%, consistent with the ANAM response rate observed in the ONO-7643-05 trial. Given the comparable results of these and the ONO-7643-05 studies, body weight rather than lean body mass along with appetite maintenance can be used to determine ANAM’s efficacy in clinical practice.

Further, among patients with gastric and pancreatic cancers, the maximum weight gain was observed at 6 weeks, whereas among those with colorectal cancer, it was frequently observed after 9 weeks. This result reflects the differences in the propensity for disease progression based on the cancer type.

Currently, the predictive factors for the effectiveness of ANAM remain unclear. When evaluating ANAM efficacy and background factors in this study, Fisher’s exact test revealed that only age > 75 years was associated with poor ANAM efficacy. Cancer cachexia is a condition that progresses in proportion to the worsening of the underlying disease with systemic inflammation [1], and when there is a significant response to chemotherapy, cachexia can improve, and body weight gain may be achieved with chemotherapy alone. Therefore, we hypothesized that the effectiveness of ANAM could be anticipated in cases where disease control was achieved through chemotherapy. Therefore, we investigated the relationship between control of the underlying disease and the effectiveness of ANAM. The results showed that significantly more patients with disease control experienced ANAM efficacy in terms of the timing of ANAM implementation. While these results are intriguing, it is uncertain whether this weight maintenance and enhancement in appetite were solely achieved through disease control, with or without ANAM. It may be difficult to improve cachexia with chemotherapy alone, and the combination of ANAM with chemotherapy may help improve cachexia.

Hyperglycemia was the most frequent treatment-related AE. In addition to hyperglycemia, most events were of low-grade severity that can be safely managed in clinical practice and have little effect on anticancer therapies. Only in two cases of hyperglycemia and one case of fatigue, the severity was grade 3 or higher. The incidence of hyperglycemia was higher in our study than in the ONO-7643-05 study. Takeda et al. reported that a history of diabetes is a risk factor for hyperglycemia during ANAM treatment for pancreatic cancer [24]. The proportion of patients with pancreatic cancer was higher in our study than in the ONO-7643-05 study (36.5% vs. 10.0%). This may have led to a higher frequency of hyperglycemia in our study which included a large number of patients with pancreatic cancer. Ando et al. [25]. reported that impaired glucose tolerance is a risk factor for ANAM-induced hyperglycemia, which is consistent with our findings. Further research is necessary to ascertain how pancreatic cancer and impaired glucose tolerance interact with ANAM-induced hyperglycemia.

However, whether ANAM should be continued with the addition of insulin or diabetes medications or discontinued when hyperglycemia occurs is unclear. In our study, two of the ten patients with hyperglycemia discontinued ANAM within 3 weeks. However, the ANAM response rate of the patients who were able to continue was 37.5%. Thus, even if hyperglycemia is observed, it may be advantageous to continue ANAM with induction of insulin therapy or an oral hypoglycemic agent.

This study has some limitations. First, this retrospective study was conducted at a single institution and included a small number of patients. Second, because this is a retrospective study, it lacks information on body composition and functional outcome and an assessment of anorexia using a questionnaire. Third, in clinical practice, it is impossible to perform an image assessment at every 3-week evaluation point, and the association between anamorelin efficacy and disease status may not be accurately assessed. The issues raised in our study warrant further investigation by means of large-scale, multicenter studies to determine the patient characteristics that are particularly suitable for ANAM.