Abstract
Background/Aim: Based on the CheckMate 649 study, nivolumab plus chemotherapy is the first-line treatment for human epidermal growth factor receptor 2-negative advanced gastric cancer (AGC). 5-fluorouracil/leucovorin+oxaliplatin (FOLFOX) is often used for patients with AGC with severe peritoneal metastasis (PM) who cannot tolerate oral intake. Nivolumab monotherapy has shown efficacy against PM. However, the efficacy and safety of nivolumab plus FOLFOX (NIVO+FOLFOX) remain unclear.
Patients and Methods: We retrospectively examined 15 patients with AGC with severe peritoneal metastasis who received NIVO+FOLFOX between January 2022 and December 2023 at our institution. Severe PM was defined as massive ascites and/or inadequate oral intake.
Results: Patients had a median age of 68 years, with 73.3% being male. Eastern Cooperative Oncology Group Performance Status 2 was observed in 20% of patients. Massive ascites was present in 86.7%, and 26.7% had inadequate oral intake. Combined positive score ≥5 was observed in 60%, and no patient had microsatellite instability-high. Median progression-free survival was 4.2 months [95% confidence interval (CI)=0.62–10.6], and median overall survival was 4.5 months (95%CI=1.48–22.5). Despite poor overall prognosis, 20.0% achieved disease control beyond 1 year. Of 13 patients with massive ascites, 38.5% responded, and 30.7% achieved complete ascites resolution. Grade ≥3 immune-related adverse events included sialadenitis, myocarditis, and hepatitis (n=1 each). No treatment-related deaths occurred.
Conclusion: NIVO+FOLFOX was feasible for patients with AGC with severe PM, providing potential for long-term survival and ascites reduction.
Introduction
Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer-related death worldwide (1). Palliative chemotherapy has been developed for advanced gastric cancer (AGC), but the prognosis remains relatively poor. Human epidermal growth factor receptor 2 (HER2), a transmembrane tyrosine kinase receptor protein, is overexpressed in approximately 20% of AGC and is a therapeutic target (2). For HER2-positive gastric cancer, trastuzumab plus chemotherapy is recommended as the first-line treatment (2). In contrast, patients with HER2-negative AGC are recommended to receive chemotherapy or chemo-therapy plus immune checkpoint inhibitors (ICI) as standard treatment. Median overall survival (OS) was reported as 14-17 months in patients with HER2-positive AGC (2, 3), and 10-14 months in those with HER2-negative AGC (4-7).
Peritoneal metastasis (PM) is a poor prognostic factor in AGC, especially in severe cases such as massive ascites or inability to take oral nutrition owing to PM (8-11). For these patients, intravenous administration is preferred to ensure adequate anticancer drug delivery. The Japanese Gastric Cancer Treatment Guidelines 2021 recommends 5-fluorouracil/leucovorin (5-FU/LV), 5-fluorouracil/leucovorin+paclitaxel (FLTAX), and 5-fluorouracil/leucovo-rin+oxaliplatin (FOLFOX) as a treatment option, but the therapeutic effect remain insufficient (9-19). Previous studies have reported progression-free survival (PFS) of 1.7-7.5 months and OS of 3.3-13.2 months, with an ascites response rate of 15-77.8% and an improved oral intake rate of 27-84.6%.
Recently, the CheckMate 649 study established nivolumab plus chemotherapy as the first-line treatment for HER2-negative AGC (20), with FOLFOX as the backbone chemotherapy. A previous retrospective study reported a reduction in ascites with nivolumab monotherapy, suggesting that nivolumab monotherapy may be effective against PM (21). Therefore, nivolumab plus FOLFOX (NIVO+FOLFOX) is expected to be effective for severe PM. However, patients with severe PM were excluded from the CheckMate 649 study, and efficacy in these subgroup remains limited. Only one small retrospective study (n=14) has reported the efficacy and safety of NIVO+FOLFOX for patients with severe PM (22), emphasizing the need for further study. This study aimed to evaluate the efficacy and safety of NIVO+FOLFOX for patients with AGC and severe PM.
Patients and Methods
Patients. We retrospectively examined patients with AGC with severe PM initiated with NIVO+FOLFOX between January 2022 and December 2023 at Kanagawa Cancer Center Hospital. The other inclusion criteria involved patients with histologically proven adenocarcinoma, previously untreated disease, HER2-negative, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 (23), adequate bone marrow (neutrophil ≥1,000/mm3 and platelets ≥7.5×104/mm3), and hepatic and renal function [aspartate transaminase/alanine aminotransferase ≤100 IU/l in patients without liver metastasis (≤200 IU/l in patients with liver metastasis), total bilirubin ≤1.5 mg/dl, and serum creatinine ≤1.5 mg/dl]. Patients with a combination of ECOG PS2, massive ascites, and inadequate oral intake were excluded based on their poor prognosis, as previously reported (10, 19).
Severe PM was defined as fulfilling at least one of the following conditions: massive ascites (continuous from the upper to lower abdominal cavity) and/or inadequate oral intake (intravenous nutrition or hydration is necessary).
Written informed consent for treatment was obtained from all of the study patients. Our institutional review committee approved the study (approval number: 2023 epidemiologic study-144), which met the standards outlined in the Declaration of Helsinki.
Chemotherapy. Nivolumab (240 mg on day 1) and mFOLFOX6 (leucovorin 200 mg/m2 on day 1, fluorouracil 400 mg/m2 on day 1 and 2,400 mg/m2 46 h on days 1-2, and oxaliplatin 85 mg/m2 on day 1) were intravenously administered every two weeks. Treatment was continued until disease progression, intolerable toxicity, or a patient’s request to discontinue. Investigators determined dose reductions based on adverse events or suspended administration due to toxicity.
Assessment. Computed tomography was performed every 8-12 weeks or when clinical signs suggested progressive disease. Tumor response was assessed following the guidelines of the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (24). We defined ascite levels as follows: no ascites, small ascites (located only in the upper or lower abdominal cavity), moderate ascites (neither mild nor massive), and massive ascites (extending throughout the abdominal cavity) (10). We defined ascites response as follows: complete remission (CR) is the disappearance of ascites, partial remission (PR) is a decrease in ascites level, stable disease is the same level of ascites, progressive disease is an increase in ascites level, and not evaluated is drainage after treatment or not evaluated. The ascites response rate was defined as the percentage of CR or PR, and the ascites control rate was defined as the percentage of CR, PR, or stable disease (14). Inadequate oral intake was defined as a condition in which oral intake is difficult owing to severe PM and requires transvenous nutrition or intravenous infusion. Improvement in oral intake was defined as discontinuation of the need for intravenous nutrition or infusion. Adverse events were assessed following the Common Terminology Criteria for Adverse Events version 5.0 (25).
The Glasgow prognostic score (GPS) is a prognostic factor reported by Forrest et al. (26). This classification divides patients into three groups using a 1.0 mg/dl cut-off for the baseline C-reactive protein level (CRP) and 3.5 mg/dl for serum albumin level (albumin). GPS0 was defined as CRP ≤1.0 mg/dl and albumin ≥3.5 g/dl, GPS1 was defined as either CRP >1.0 mg/dl or albumin <3.5 g/dl, and GPS2 was defined as albumin <3.5 g/dl (26).
Statistical analysis. Continuous variables are presented as median and range, and categorical variables as number and percentage. OS was defined as the duration from the initiation of treatment to death from any cause. PFS was calculated as the period from the initiation of treatment to tumor progression. Time-to-treatment failure (TTF) was defined as the time from the start of treatment to the decision to stop treatment or death. The data cut-off date was August 20, 2024. Kaplan–Meier curves of estimated OS, PFS, and TTF were generated. All statistical analyses were conducted using EZR software, version 1.32 (Saitama Medical Center, Jichii Medical University, Saitama, Japan) (27).
Results
Patient characteristics. Between January 2022 and December 2023, 81 patients received nivolumab plus chemotherapy for HER2-negative AGC in our institution. Among these patients, chemotherapy included S1 and oxaliplatin (n=39), capecitabine and oxaliplatin (n=5), and FOLFOX (n=37). Severe PM was observed in 15 patients who received NIVO+FOLFOX (Figure 1).
Patient flow diagram. HER2: Human epidermal growth factor receptor 2; FOLFOX: fluorouracil, leucovorin, and oxaliplatin; SOX: S1 and oxaliplatin; CAPOX: capecitabine and oxaliplatin.
Table I summarizes the patient characteristics. Median age was 68 years (range=54-77 years). Eleven patients (73.3%) were male. ECOG PS 0, 1, and 2 were observed in two (13.3%), 10 (66.7%), and three (20%) patients. Massive ascites were found in 13 (86.7%) patients, and inadequate oral intake owing to PM was found in four (26.7%) patients. Two patients (13.3%) had massive ascites and inadequate oral intake owing to PM. Combined positive score (CPS) status ≥5 was found in nine (60%) patients; microsatellite instability-high patients were not included. GPS 1 and 2 were observed in four (26.7%) and 10 (66.7%) patients, respectively. None of the patients had the combination of massive ascites, inadequate oral intake, and ECOG PS2.
Patient characteristics.
Treatment efficacy. At the time of data cutoff, disease progression was observed in 13 of the 15 patients. The median PFS was 4.2 months [95% confidence interval (CI)=0.62-10.6] (Figure 2A). For TTF, events were observed in 14 of 15 patients at the data cutoff. Median TTF was 2.5 months (95%CI=0.62-5.95) (Figure 2B). Fatal events were observed in 12 of 15 patients. Median OS was 4.5 months (95%CI=1.48-22.5) (Figure 2C). The 1-year survival rate was 37.3% (95%CI=0.14-0.62), and the 6-month PFS rate was 30.4% (95%CI=0.62-10.6).
Survival curves of nivolumab (NIVO)+ fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for patients with advanced gastric cancer harboring massive ascites. (A) Progression-free survival (PFS). (B) Time-to-treatment failure (TTF). (C) Overall survival (OS). CI: Confidence interval.
Of the 13 patients with massive ascites, ascites response was observed in five patients (38.5%), including four CR patients and one PR patient. Of the four patients who had inadequate oral intake, two (50%) patients showed improvement in oral intake. One patient had measurable lesions according to RECIST ver1.1, and the tumor response was PR.
Figure 3 shows the swimmer plots for all 15 patients. Three patients lasted more than 1 year of treatment; all three patients had massive ascites, and all of them had CR for ascites response. One of the three patients was unable to eat orally, and oral intake improved. All three long-term responders had CPS ≥5, but no other similarities were found in their characteristics (Table II).
Swimmer plot of all 15 patients treated with nivolumab (NIVO)+ fluorouracil, leucovorin, and oxaliplatin (FOLFOX) for advanced gastric cancer with severe peritoneal metastasis. Listed in order of progression-free survival (PFS) duration. One patient remains on treatment, whereas the others discontinued therapy owing to tumor growth or adverse events. Three patients achieved disease control and continued NIVO+FOLFOX for over a year. Ascites response was observed only in patients with massive ascites. BSC: Best supportive care; CR: complete remission; PR: partial remission; SD: stable disease; PD: progressive disease; NE: not evaluated.
Patient characteristics and efficacy in individual patients.
Adverse events. Table III presents adverse events. Immune-related adverse events (irAE) included pneumonitis grade 2 (n=2), rash grade 1 (n=1), rash grade 2 (n=1), hypothyroidism grade 2 (n=1), hyperthyroidism grade 2 (n=1), sialadenitis grade 3 (n=1), myocarditis grade 3 (n=1), and hepatitis grade 3 (n=1).
Adverse events (AEs).
Three patients discontinued treatment owing to adverse events: one on day 371 owing to irAE pneumonitis, one on day 51 owing to irAE myocarditis, and one on day 82 owing to irAE hepatitis. No treatment-related deaths were observed.
Discussion
The efficacy and safety of NIVO+FOLFOX as a first-line treatment in patients with AGC with severe PM remain unclear. Only one small retrospective study has investigated this topic, highlighting the need for more research (22). Therefore, our study is valuable as it provides more information. Our study revealed the efficacy and safety of NIVO+FOLFOX in clinical practice, suggesting that it may be a treatment option for such patients.
Survival outcomes remain poor in patients with AGC with severe PM, despite the introduction of NIVO+ FOLFOX. A prospective study of FOLFOX in a similar population showed a 6-month PFS rate of 31.4% and a 1-year survival rate of 29.4% (19). The FLTAX study reported a 6-month PFS rate of 19.6% for FU/LV and 44.0% for FLTAX, and a 1-year survival rate of 22.5% for FU/LV and 22.0% for FLTAX (10). Compared with these previous studies, the additional therapeutic effect of nivolumab in the overall population appears to be small. However, three (20.0%) patients achieved disease control beyond one year, a relatively rare outcome before the introduction of ICIs. Considering that the efficacy of ICIs is characterized by low response rates but a long-tail effect in successful cases, adding nivolumab may be effective in such limited cases (28). In contrast, a retrospective study investigating the efficacy of NIVO+FOLFOX for patients with AGC with severe PM reported no cases of disease control beyond one year (22). Selection bias might occur because of the small sample size. CPS is a predictor of ICI efficacy; nine of 15 (60%) patients had CPS ≥5 in our study, whereas only one of 14 (7.1%) patients had CPS ≥5 in the other retrospective study (20, 22). Our study is worth reporting because it identified patients in whom ICIs were particularly effective. All three patients who achieved disease control for over a year had CPS ≥5, suggesting that ICIs may be worth considering for patients with severe PM, especially those with CPS ≥5.
In patients with gastric cancer, massive ascites have a negative impact on quality of life (29). Therefore, reducing ascites as well as improving PFS and OS is beneficial for patients. In our study, the ascites response rate among patients with massive ascites was 38.5%, with four patients achieving CR (30.7%). Another retrospective study evaluating NIVO+FOLFOX reported an ascites response rate of 50.0% in patients with massive ascites, whereas a prospective phase II study of FOLFOX reported a response rate of 36% in similar patients. However, these two studies did not show a complete ascites response (19, 22), making it challenging to assess the additional effect of nivolumab. In contrast, only our study achieved complete ascites response. Considering the small proportion of patients with AGC who are super-responders to nivolumab, only our study may have included such patients, suggesting that the addition of nivolumab might contribute to complete ascites response in these cases (28). Regarding oral intake, improvement was observed in two of four patients (50%) in our study and 10 out of 11 patients (90.9%) in a retrospective study (22). A prospective phase II study on FOLFOX reported an oral intake improvement rate of 46% (19). These findings indicate that the addition of nivolumab to FOLFOX might contribute to improving oral intake. However, the number of patients was limited, hindering the ability to conclude the efficacy of improving oral intake and massive ascites. Therefore, further studies are warranted to confirm this effect.
Patients with severe PM often have poor general condition, increasing their risk of intolerance to chemotherapy. Special attention should be paid to irAEs as they can be severe. In the CheckMate 649 study, organ-specific irAEs were observed in 3-34% of patients, and organ-specific grade 3-4 irAEs occurred in ≤5% of patients (20). In our study, organ-specific irAEs were observed in 6.7-13.3% of patients and organ-specific grade 3-4 irAEs occurred in 0-6.7% of patients, with no treatment-related deaths. In the other retrospective study evaluating NIVO+FOLFOX, only 14% of patients experienced irAEs, and no grade ≥3 irAEs were observed (22). These findings indicate that irAEs rates in patients with severe PM were similar to those previously reported in the CheckMate 649 study, with no new safety signals observed (20, 28). Regarding non-immunological adverse events, our study and the other retrospective study obtained similar results, which were comparable to those reported in the CheckMate 649 study (22). These results suggest that NIVO+FOLFOX may be a feasible treatment option for patients with AGC with severe PM.
Study limitations. First, this is a single-center, retrospective study with a small sample size, necessitating further evaluation in larger cohorts. Second, selection bias may be present. Our study excluded patients with inadequate organ function and those with ECOG PS2, massive ascites, and inadequate oral intake because they were ineligible for palliative chemotherapy (10). However, depending on the treating physician, some study patients might have been considered ineligible for palliative chemotherapy owing to their poor general condition. Moreover, our study included a higher proportion of patients with massive ascites than previous reports. These factors could affect the results on the efficacy of NIVO+FOLFOX. Third, we were unable to identify predictive factors for the efficacy of NIVO+FOLFOX other than CPS. CPS is a predictive marker of ICI efficacy, but complete prediction remains challenging (20). Nivolumab is effective in some patients but ineffective in others, and unnecessary irAEs could be avoided by refraining from its use in patients who are not expected to benefit from it. Inflammation and nutrion markers have been reported as prognostic factors for nivolumab monotherapy, but GPS was not a predictive marker for long-term survival in our study (30, 31). Identifying additional predictive factors for the efficacy of nivolumab remains an important topic for future research.
Conclusion
NIVO+FOLFOX was feasible for patients with AGC with severe PM and, especially in those with CPS ≥5, contributed to long-term survival and significant reduction of massive ascites. NIVO+FOLFOX may be a treatment option for these patients. However, the additive effect of nivolumab may be limited to a small proportion of patients. Further investigations are necessary to confirm these findings.
Acknowledgements
The Authors would like to thank Charles McKay and Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
Conceptualization and Writing - original draft: KF, MF, and NM. Methodology: KF, MF, MO, TH, SI, KH, HN, KS, KT, and NM. Formal analysis: KF and MF. Writing - review & editing: FJ and SM. All authors read and approved the final manuscript.
Conflicts of Interest
The Authors declare the following conflicts of interest: Kyoko Furusawa reports personal fees from Viatris, outside the submitted work; Mitsuhiro Furuta reports personal fees from Bristol-Myers Squibb, MSD, and Taiho, outside the submitted work; Nozomu Machida reports grants and personal fees from Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Merck Serono, MSD, Ono Pharmaceutical Co., Ltd., and Taiho, grants from ALX oncology, Amgen, Astra Zeneca, and JAZZ Pharmaceuticals, personal fees from BeiGene, Chugai Pharma, Eli Lilly Japan, Takeda, and Yakult Honsha, outside the submitted work; Junji Furuse reports grants and personal fees from Astra Zeneca, Astellas, Chugai Pharma, Daiichi Sankyo, Delta-Fly Pharma, Eisai, Incyte Biosciences Japan, J-Pharma, MSD, Ono Pharmaceutical Co., Ltd., Taiho, and Takeda, grants from Sanofy, and Sumitomo Dainippon, personal fees from Bayer, EA Pharma, Eli Lilly Japan, Fuji film, Merck Bio Incyte Biosciences, Novartis Pharma, Ohhara Pharma, Onco Therapy Science, Pfizer, Servier, Teijin pharma, Terumo, TME Therapeutics, and Yakult Honsha, outside the submitted work; Shin Maeda reports grants and personal fees from Chugai Pharma, Mochida Pharma, Otsuka Pharma, Taiho, ZERIA Pharmaceutical Co., Ltd., grants from Eli Lilly Japan, and Kyowa Kirin, personal fees from AbbVie GK, AI Medical Service Inc., Ajinomoto Co., Inc., Aska Pharma, Astra Zeneca, EA Pharma, Gilead Sciences, Kissei Pharma, Mitsubishi Tanabe Pharma, Miyarisan Pharma, Olympus Marketing Inc., Takeda Pharma, and Yakult Honsha, outside the submitted work; others have declared no potential conflicts of interest in relation to this study.
- Received February 12, 2025.
- Revision received February 26, 2025.
- Accepted February 28, 2025.
- Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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