In this retrospective study, we used real-world data regarding treatment of patients with AGC using FTD/TPI. We observed levels of efficacy and safety that were similar to those demonstrated in the TAGS trial, namely an RR of 4%, PFS of 2 months, OS of 5.7 months among patients undergoing third- or higher- line chemotherapy. However, there are some differences between the results of our study and those of the TAGS trial. In the TAGS trial, 63% of the patients received three or more number of prior regimens, and 34% received ramucirumab. In our study, 91% of the patients received three or more number of prior regimens, and 93% received ramucirumab. Our study included higher numbers of older patients, patients with poorer PS, and patients who underwent more pretreatments; all these factors reflected the situation in clinical practice. Our study suggests that FTD/TPI is an important regimen for treatment of patients with AGC who have received ramucirumab.
Immune check point inhibitors (ICIs), such as nivolumab, are one of the most important drugs used to treat AGC. The ATTRACTION-2 trial showed a significant clinical benefit in patients with AGC who had previously received two or more prior chemotherapy regimens [8]. In addition, nivolumab plus chemotherapy significantly improved OS compared with the use of chemotherapy alone in the CHECKMATE649 trial and has become the standard first-line treatment [2]. Although FTD/TPI in the third- or later- line chemotherapy is more effective when nivolumab is used in the first-line treatment, the efficacy and safety of FTD/TPI after administration of ICIs were unclear. In the TAGS trial, only 7% of the patients received ICIs before administration of FTD/TP, while in our study, 94% of the patients received ICIs before FTD/TPI administration, and the efficacy and safety exhibited in our study were similar to those in the TAGS trial, which suggests that FTD/TPI is one of the key drugs for treatment of AGC after administration of ICIs.
In our study, 48% of the patients experienced adverse events of grade 3 or 4. Furthermore, compared with the TAGS trial, our study had a similar safety profile and more cases requiring dose reduction or postponement.
Considering the results of the phase 3 trial of FTD/TPI in patients with colorectal cancer (CRC)[9, 10], it is possible that there are many cases of dose reduction and dosing delay when FTD/TPI is used to treat AGC. Although, the patient background is different, the frequency with which non-hematological toxicity of FTD/TPI occurs is higher in patients with AGC than in those with CRC [9, 10]. Thus, compared with patients having CRC, those with AGC treated using FTD/TPI require careful management. It has been suggested that biweekly administration of FTD/TPI may reduce toxicity in patients with CRC compared with normal dosages of FTD/TPI [11]; a similar investigation related to AGC is awaited.
Peritoneal dissemination is common in patients with AGC, approximately 40% of whom exhibit ascites as a clinical symptom [12, 13]. We found that there were significant differences in OS and DCR between patients with and without ascites. In addition, OS was significantly shorter in patients with HAB. There was no significant difference in the frequency of occurrence of adverse events of grade 3 or higher between patients with and without ascites. Therefore, FTD/TPI may be well tolerated, although the effect is inadequate in patients with AGC having ascites.
Kawazoe et al. [14] reported that in patients with AGC previously treated with second- to fourth- lines chemotherapy, FTD/TPI plus ramucirumab showed promising efficacy (RR, 16%; DCR, 77%; PFS, 5.3 months). Increased vascular endothelial growth factor receptor 2 ligand in patients with ascites may be associated with poor prognosis, and FTD/TPI plus ramucirumab may be effective in treating patients with AGC having ascites [15]. Nevertheless, data related to the efficacy and safety of this treatment is not available.
This study had certain limitations. It was a retrospective analysis, and the sample size was small. Therefore, a prospective multicenter study involving more patients with AGC having ascites must be conducted to clarify the efficacy and safety of FTD/TPI in this population.