Trifluridine/tipiracil with and without ramucirumab for advanced gastric cancer: a comparative observational study

The combination of trifluridine/tipiracil hydrochloride (FTD/TPI) plus ramucirumab has demonstrated clinical activity in patients with advanced gastric cancer (AGC). We evaluated the efficacy and safety of this combination compared with those of FTD/TPI monotherapy in patients with AGC. We retrospectively reviewed data of patients with AGC who received FTD/TPI plus ramucirumab or FTD/TPI monotherapy as third- or later-line treatment. This study included 36 patients treated with FTD/TPI plus ramucirumab and 70 patients receiving FTD/TPI monotherapy. The objective response rate (ORR) and disease control rate (DCR) were 25.8% and 58.1%, respectively, in the FTD/TPI plus ramucirumab group and 5.0% and 38.3%, respectively, in the FTD/TPI group (ORR, P = 0.007; DCR, P = 0.081). The median progression-free survival (PFS) was significantly longer in the FTD/TPI plus ramucirumab group (median PFS, 2.9 vs. 1.8 months; hazard ratio [HR]: 0.52; P = 0.001). A numerical survival benefit was also observed (median overall survival, 7.9 months vs. 5.0 months; HR: 0.68, P = 0.089). In the multivariate analysis, PFS was significantly longer in the FTD/TPI plus ramucirumab group than in the FTD/TPI monotherapy group (HR: 0.61, P = 0.030). The incidence of febrile neutropenia was higher in the FTD/TPI plus ramucirumab group than in the FTD/TPI group (13.8% vs. 2.9%); however, no new safety signals were identified. Compared with FTD/TPI monotherapy, FTD/TPI plus ramucirumab offers clinical benefits with acceptable toxicity in heavily pretreated patients with AGC. Further investigation via randomized trials is warranted to confirm these findings.


Procedures
FTD/TPI plus ramucirumab therapy involved administering oral FTD/TPI at a dose of 35 mg/m 2 twice daily on days 1-5 and 8-12 of each 28-day treatment cycle combined with ramucirumab administered intravenously at a dose of 8 mg/kg, repeated every 2 weeks.FTD/TPI monotherapy included oral FTD/TPI at a dose of 35 mg/ m 2 twice daily on days 1-5 and 8-12 of each 28-day cycle.Dose modifications and treatment interruptions were performed at the discretion of each clinician, guided by established clinical trials 5,10 .

Evaluation of treatment
Clinical data were retrospectively collected from patient medical records.Patients were categorized into FTD/ TPI plus ramucirumab and FTD/TPI monotherapy groups for outcome evaluation.Tumor response in patients with measurable lesions was assessed by each clinician according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 17 .ORR was defined as the proportion of patients with measurable lesions who exhibited either a complete or partial response, as determined by investigators.Disease control rate (DCR) refers to the proportion of patients who achieved complete response, partial response, or stable disease.Progressionfree survival (PFS) was calculated from the date of the first administration of the study treatment to the date of disease progression, as indicated by imaging findings, clinical progression, or death owing to any cause.OS was defined from the date of study treatment initiation to the date of death because of any cause or the last followup.Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 18 .

Statistical analysis
The data cut-off date was November 15, 2023.PFS and OS were estimated using the Kaplan-Meier method, and the stratified log-rank test was utilized to compare variables among patients with respect to survival.Cox proportional hazards regression analysis was employed for survival analysis across different patient groups.The variables included in the multivariate Cox proportional model were selected based on factors with P-values < 0.2 in the univariate analysis.Age (≥ 65 vs. < 65 years), sex (male vs. female), ECOG PS (≥ 1 vs. 0), histology (diffuse vs. intestinal), history of gastrectomy (yes vs. no), lymph node metastasis (yes vs. no), liver metastasis (yes vs. no), peritoneal metastasis (yes vs. no), number of metastatic sites (≥ 2 vs. 1), number of prior chemotherapy regimens (≥ 3 vs.1-2), duration of prior ramucirumab (≥ 3 months vs. < 3 months), ramucirumab-free interval (≥ 3 months vs. < 3 months), and anti-PD-1 inhibitor-free interval (IFI) (< 60 days vs. ≥ 60 days) were incorporated as confounders in the multivariate analysis of PFS and OS.To determine the potential benefits of continuation or re-challenge of ramucirumab and the synergistic effect of anti-PD-1 inhibitor and ramucirumab, cut-off values of three for ramucirumab-free interval and 60 days for IFI were adopted as previously described 19,20 .Exploratory efficacy analyses based on subgroups of liver metastasis (LM) and IFI were conducted, and all outcomes were compared.Statistical analyses were performed using R software version 4.1.0(R Project for Statistical Computing, Vienna, Austria).All tests were two sided, and P-values < 0.05 indicated statistically significant differences.

Ethics approval
The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of Aichi Cancer Center Hospital (No. IR051103).

Informed consent
The requirement for written informed consent for this study was waived by the Institutional Review Board of Aichi Cancer Center Hospital due to the retrospective study design without intervention, with an opt-out opportunity provided on the institution's website.

Safety
Disease progression was the most common reason for discontinuing study treatment in both the groups (91.7% in the FTD/TPI plus ramucirumab group vs. 94.2% in the FTD/TPI monotherapy group), and 2.8% and 2.9% of patients, respectively, discontinued study treatment because of adverse events.After such discontinuation, the proportions of patients receiving subsequent chemotherapy (38.2% vs. 42.6%)and best supportive care (61.8% vs. 57.4%)were similar between the two groups.
Table 5 lists the adverse events occurring during study treatment.The proportion of patients with any grade of decreased appetite was higher in the FTD/TPI plus ramucirumab group than in the FTD/TPI monotherapy Table 1.Patient characteristics.a The patients who did not recieve ramucirumab before study treatment were excluded from this patient characteristics classification.b The patients who did not recieve anti-PD-1 inhibitor before study treatment were excluded from this patient characteristics classification.c MSI was tested for 41 patients in FTD/TPI group and for 29 patients in FTD/TPI plus ramucirumab group, respectively.FTD/TPI, trifluridine tipiracil; PD-1, programmed death receptor-1; MSI, microsatellite instability; MSI-H, microsatellite instability high; MSS, microsatellite stable; GEJ, esophagogastric junction; HER2, human epidermal growth factor 2.   www.nature.com/scientificreports/

Discussion
To the best of our knowledge, this is the largest retrospective study to demonstrate the clinical benefit of FTD/TPI plus ramucirumab over FTD/TPI monotherapy in heavily pretreated patients with AGC.The significant improvements in ORR and PFS in the combination therapy group, though not paralleled by an increase in OS, suggest a notable therapeutic advantage, especially in patients with LM and a short IFI of < 60 days.This observation suggests that certain subgroups of patients with AGC might derive more benefit from this combination therapy.
In the present study, patients in the FTD/TPI plus ramucirumab group showed clinical improvement compared with those in the FTD/TPI monotherapy group.The outcomes of the FTD/TPI monotherapy group (DCR, 38.3%; median OS, 5.0 months) are consistent with those reported in the phase III TAGS trial, suggesting that our cohort is representative of the broader patient population with AGC receiving this treatment (DCR, 44%; median OS, 5.7 months) 5 .Moreover, the addition of ramucirumab in our study (ORR, 25.8%; median PFS, 2.9 months) www.nature.com/scientificreports/showed a pattern of clinical benefit comparable with that observed in earlier phase II trials and retrospective studies (ORR, 0-16%; median PFS, 2.9-5.3 months) 10,11,21 .Despite these improvements in ORR and PFS, we did not observe a corresponding increase in OS.This phenomenon, in which improvements in intermediate endpoints do not translate into survival benefits, mirrors findings from other studies, including the RINDBeRG trial, which evaluated the addition of ramucirumab to irinotecan 22 .One possible explanation for the lack of OS benefit in our study could be the higher proportion of patients with favorable baseline characteristics, including ECOG PS of 0 and longer interval without previous ramucirumab exposure, in the combination therapy group.
In addition, a substantial proportion of patients (40%) received subsequent chemotherapy.Thus, despite shortterm efficacy based on ORR and DCR, these do not translate into a survival benefit.An ongoing randomized phase II trial comparing FTD/TPI plus ramucirumab with FTD/TPI monotherapy will provide further insight into this strategy 23 .When optimizing ramucirumab treatment for patients with AGC with poor prognosis, identifying clinicopathologic predictors of efficacy is crucial.Our study results showed that adding ramucirumab to FTD/TPI numerically improved PFS and OS in patients with LM, consistent with previous findings that VEGF inhibitors benefit patients with LM across various cancers [24][25][26] .This result is supported by our previous analysis of 1355 patients with AGC, in which we observed a significant OS improvement in cases with LM post-ramucirumab www.nature.com/scientificreports/approval 25 .These results are consistent with those from major trials such as the RAINBOW 25,26 .Preclinical data showed an association between anti-VEGF discontinuation and enhanced liver metastasis, indicating a strong correlation between VEGF and liver metastasis 27 .The mechanism by which VEGF inhibitors are effective against LM remains unclear; however, the unique tumor microenvironment in LM may enhance the effectiveness of VEGF inhibitors 28 .
Our study also explored the impact of prior anti-PD-1 inhibitor use and found only modest improvements in outcomes 12,29 .However, a more pronounced difference was noted in patients with a shorter IFI of < 60 days.One plausible explanation for this difference could be that therapeutic levels of anti-PD-1 inhibitor present at chemotherapy initiation do not persist 30 .No significant differences were observed in outcomes based on the ramucirumab-free interval or previous treatment patterns, consistent with previous efficacy evaluations of VEGF inhibitors 19,22 .This suggests that the timing of anti-PD-1 inhibitor therapy relative to chemotherapy initiation might be crucial.
In our study, a higher proportion of patients in the combination group experienced a decreased appetite (80.6% vs. 55.7%),consistent with data from a phase III trial of FTD/TPI plus a VEGF inhibitor for colorectal cancer 7 .The addition of a VEGF inhibitor to FTD/TPI increased the risk of severe neutropenia without significantly affecting the frequency of febrile neutropenia 7,8,31 .However, we observed that febrile neutropenia was more common in the combination therapy group (13.8%), with a rate higher than those previously reported for AGC treatment but without any treatment-related deaths 10,21 .This increased toxicity trend in the combination therapy group might have influenced treatment choices, especially for patients with high bleeding risks, potentially introducing selection bias.For instance, patients with massive ascites were more likely to receive monotherapy.The occurrence of neutropenia is associated with improved survival outcomes in patients treated with FTD/ TPI 32,33 .These findings underscore the critical need to develop effective management strategies, including dose modifications and granulocyte colony-stimulating factor use, tailored to individual patient needs among those receiving FTD/TPI plus ramucirumab therapy.
The retrospective, small sample size, non-randomized, study design is a limitation, potentially introducing selection bias.This is particularly relevant given that treatment decisions were made at the discretion of the treating physicians.Additionally, the fact that a significant proportion of patients in both the groups received subsequent lines of chemotherapy suggests that other factors may have influenced OS.
In conclusion, the study results provide evidence of the clinical benefits of FTD/TPI plus ramucirumab with respect to ORR and PFS, as well as acceptable toxicity, in heavily pretreated patients with AGC.These findings highlight the potential of this combination therapy as a treatment option and underscore the need for further research, ideally through randomized controlled trials, to confirm these results and refine treatment strategies for this patient population.

Figure 1 .
Figure 1.Waterfall plot displaying the percentage changes from baseline in the sum of measurable lesions in the (A) FTD/TPI monotherapy and (B) FTD/TPI plus ramucirumab groups.FTD/TPI, trifluridine/tipiracil hydrochloride; PR, partial response; SD, stable disease; PD progressive disease.

Table 2 .
Tumor response a .a Tumor response was analyzed for the population with measurable lesions according to RECIST ver.1.1 b ORR was defined as the proportion of patients with CR or PR.

Table 5 .
Adverse events.FTD/TPI, trifluridine tipiracil a The data on proteinuria in the FTD/TPI group was not evaluated.