Abstract
Background/Aim: To evaluate the impact of development of nivolumab monotherapy-induced immune-related adverse events (irAEs) and continuing nivolumab with irAEs on the survival of patients with gastric cancer (GC). Patients and Methods: Patients with unresectable advanced GC and recurrence after curative resection who received nivolumab monotherapy were included in the study. Survival was compared between patients who did and did not develop irAEs, and between those who continued and discontinued treatment due to irAEs. Results: Of 110 GC patients, 22 developed irAEs. Grade ≥3 IrAEs included rash and diarrhoea associated with enteritis. Progression-free and overall survival (OS) were significantly better in patients with irAEs than in those without. The overall survival of patients who continued treatment despite irAEs was better than that of those who discontinued treatment. Conclusion: irAE development was associated with better survival in patients with GC who received nivolumab monotherapy. Continuing nivolumab with appropriate treatment in GC patients with irAEs may improve survival.
Gastric cancer (GC) is the fifth most prevalent carcinoma worldwide, and the fourth leading cause of cancer-related deaths globally (1). Despite the development of systemic chemotherapies, the prognosis of patients with unresectable or recurrent advanced GC remains poor, with a median survival of 10-13 months (2, 3).
Nivolumab is a monoclonal antibody that targets programmed cell death protein-1 (PD-1) on T lymphocytes, and an immune checkpoint inhibitor (ICI) that has been proven to be effective in various malignant tumours (4-7). Nivolumab has become one of the standard treatments for various cancers, such as malignant melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (4-6). Moreover, the ATTRACTION-2 trial confirmed that nivolumab monotherapy improves survival when used as a third or later-line treatment for advanced GC (7). Based on the results of this study, nivolumab was recommended as a third-line treatment for advanced GC in the Japanese Gastric Cancer Treatment Guidelines (8). However, the objective response rate and disease control rate of nivolumab monotherapy were only 11.2% and 40.3%, respectively. Therefore, it is important to identify patients who will benefit from nivolumab and factors that can determine continuation or discontinuation of such. A previous study reported biomarkers, such as PD-L1 overexpression, high microsatellite instability, high tumour mutational burden, and Epstein-Barr virus infection, among others (9-13).
While, ICIs, such as nivolumab, have characteristic immune-related adverse events (irAEs) due to excessive autoimmune reactions (14-16). It has been reported that irAEs induced by the administration of ICI were associated with survival benefits in malignant melanoma and NSCLC (17, 18). However, there are only few reports showing the effect of nivolumab on the development of irAEs in GC, and the association between them remains unclear (19-22). Therefore, in this study, we retrospectively investigated the association between irAEs and treatment response in patients with advanced GC who underwent nivolumab monotherapy.
Patients and Methods
Patients. Patients with unresectable advanced or metastatic GC who received nivolumab monotherapy at Kanagawa Cancer Center between December 2014 and December 2019 were included. The inclusion criteria of patients in this study were 1) histologically proven primary adenocarcinoma of the stomach or gastroesophageal junction, 2) advanced unresectable or metastatic GC, and 3) administration of nivolumab monotherapy. Those with a history of ICI administration and other cancers in the past 5 years were excluded.
Treatment and assessment. The patients were administered nivolumab (3 mg/kg or 240 mg/body) intravenously every 2 weeks. The anti-tumour effect of nivolumab monotherapy was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 (23) using computed tomography scans.
Definition of irAEs. The irAEs were defined as adverse events with a potential immunological basis that may require intervention with immunosuppressive or endocrine therapy. The adverse events associated with the use of nivolumab were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (24). Patients who received nivolumab monotherapy were divided into two groups: those who developed irAEs (irAE group) and those who did not (non-irAE group). We compared the clinicopathological characteristics and efficacy of nivolumab monotherapy between the two groups.
Statistical analyses. Student’s t-test was used to compare continuous variables, whereas a chi-square analysis or Fisher’s exact test was used to compare categorical variables. Progression-free survival (PFS) was defined as the time from the beginning of nivolumab treatment to disease progression or death from any cause. Overall survival (OS) was defined as the time from the beginning of nivolumab treatment to death from any cause. In addition, we conducted a landmark analysis to evaluate PFS and OS, excluding patients who had an event (death) within 6 weeks. The survival rate was analysed using Kaplan-Meier survival curves and compared using the log-rank test. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). All p-values were two-sided, and p<0.05 indicated statistical significance.
Ethics. This study was approved by the Institutional Review Board of the Kanagawa Cancer Center (2021.epidemiologic study-42).
Results
Patient characteristics. A total of 110 patients with GC treated with nivolumab monotherapy were included. A total of 22 patients (20%) experienced irAEs (any grade). The clinical characteristics of the irAE and non-irAE groups are summarized in Table I. The best overall response rate was significantly better in the irAE group than in the non-irAE group (p=0.005). There were no differences in other patient characteristics between the groups.
Characteristics of patients in irAE and non-irAE groups.
Adverse events. Details of the irAEs are shown in Table II. The most frequent irAE was pruritus, which was observed in eight patients (36%). Grade 3 or higher IrAEs included rash and diarrhoea associated with enteritis.
Summary of irAEs.
Survival analyses. The median observation period was 198 (range=19-1068) days. PFS was significantly better in the irAE group than in the non-irAE group (p=0.008). The median PFS in the irAE and non-irAE groups were 129 and 65 days, respectively (Figure 1a). OS was significantly better in the irAE group than in the non-irAE group (p=0.030). The median OS in the irAE and non-irAE groups were 373 and 172 days, respectively (Figure 1b). PFS and OS at the 6-week landmark analysis were also significantly better in the irAE group than in the non-irAE group (p=0.012, p=0.044, respectively) (Figure 1c and d). The median PFS at the 6-week landmark analysis in the irAE and non-irAE groups were 133 and 73 days, respectively. The median OS at the 6-week landmark analysis in the irAE and non-irAE groups were 439 and 209 days, respectively.
Kaplan–Meier survival curve for progression-free survival (a) and overall survival (b) between the irAE and non-irAE groups in all patients. Kaplan-Meier survival curves for progression-free survival (c) and overall survival (d) between irAE and non-irAE groups in a 6-week landmark analysis. In the 6-week landmark analysis, PFS and OS were significantly better in the irAE group than in the non-irAE group for all patients.
Sub-analysis between the discontinue and continue groups due to irAEs. Nivolumab was discontinued in six patients due to irAEs, of which three were due to interstitial pneumonia (IP) and three were due to grade 3 diarrhoea (colitis), liver dysfunction, and skin rash. Conversely, nivolumab was continued or restarted after irAEs were controlled in 16 patients. The best overall response among the six patients who could not continue treatment due to irAEs was partial response (PR) in one patient, stable disease (SD) in two patients, and progressive disease (PD) in three patients. When comparing patients who discontinued irAEs with those who continued treatment or restarted nivolumab after improvement in irAEs, OS was worse in the group that discontinued irAEs (p=0.021) (Figure 2). The median OS was 507 days in the continuous group and 209 days in the discontinue group.
Kaplan-Meier survival curves for overall survival between nivolumab discontinuation and continuation groups in all patients. When comparing patients who discontinued due to irAEs with those who continued treatment or restarted nivolumab after improvement in irAEs, OS was worse in the group that discontinued irAEs.
Discussion
The major finding of this study was that irAEs induced by nivolumab monotherapy were associated with survival benefits in patients with advanced unresectable or metastatic GC. Previous studies have reported that the development of irAEs by ICIs, including nivolumab, is associated with survival in patients with several malignant tumours, such as malignant melanoma, lung cancer, and renal cancer (16-18, 25-29). Our results in patients with GC were consistent with those of previous reports.
Kono et al. (19) and Masuda et al. (20) previously reported that the survival rate of patients with GC who developed irAE was significantly longer than that of patients who did not develop irAEs. In their studies, landmark analyses were performed at 8 and 12 weeks for the former and at 1, 2, and 3 months for the latter. In this study, we examined the relationship between irAEs and treatment response using data from 110 patients who received nivolumab monotherapy. As in previous studies, our findings demonstrated that patients who developed irAEs showed better OS and PFS than those who did not develop irAEs. Since there is a lead-time bias in this type of analysis that short-term survivors may have a lower risk of developing irAEs, we performed a landmark analysis set at 6 weeks and obtained equivalent results. Regarding the criteria for landmark analysis, it was reported that most irAEs with nivolumab were observed within 3 months in the ATTRACTION-2 trial (30). The median PFS in the ATTRACTION-2 trial was 1.6 months (95% CI=1.5-2.3), and the PFS in the non-irAE group in our study was 2.1 months (95% CI=1.6-2.6).
Next, we compared survival between patients with GC who continued and discontinued nivolumab monotherapy after developing irAEs. Mouri et al. reported that in patients with NSCLC who ceased nivolumab due to irAEs, there was no difference in survival between the re-treated and discontinued groups (31). Santin et al. compared patients with NSCLC who continued and discontinued ICI treatment due to irAEs, and reported that there was no difference in survival and in patients who achieved PR or CR before the onset of irAE between the discontinuation and re-treated groups. However, the discontinuation group, which included patients who discontinued the treatment before achieving outcomes, had a worse survival rate than the re-treated group (32). Our findings are similar to the latter data presented.
The mechanism underlying the association between survival and irAEs due to nivolumab remains unclear. Previous studies have shown that there is no significant difference between irAEs of immune-related liver dysfunction and survival (33). The types of irAEs associated with survival are not well-known; however, discontinuing nivolumab may lead to a decrease in OS. Moreover, in patients who develop irAEs such as IP or colitis, it is difficult to continue nivolumab, thus resulting in poorer survival than in patients who develop irAEs such as skin rash.
We also compared the OS of patients who discontinued treatment due to irAEs with those who continued treatment despite irAEs, and noted improvements among those who resumed treatment after irAEs improved. We found that the OS of patients who could not continue treatment was the poorest. Six patients were unable to continue treatment due to irAEs: three patients due to IP and three patients due to grade 3 diarrhoea (colitis), liver dysfunction, and skin rash. No subsequent treatment was administered in any of the patients. Patients with grade 3 irAEs had worsening of their general condition, making subsequent treatment difficult, whereas those with IP had difficulty with subsequent treatment due to the IP itself.
This study demonstrated that the survival of patients who received nivolumab and developed irAEs was excellent in GC that had been reported in a few reports, as well as well as reports in other cancers. However, this study is limited by its retrospective design and the fact that it was conducted in a single institution. Thus, further multicentre prospective studies with larger cohorts are needed to validate the association between the incidence of irAEs and the efficacy of nivolumab.
In conclusion, the incidence of irAEs was associated with survival after nivolumab monotherapy in patients with advanced unresectable or metastatic GC.
Footnotes
↵* These Authors contributed equally to this study.
Authors’ Contributions
All authors contributed to the conception and design of the study. HS, KK, and TO performed material preparation, data collection, and analysis. HS wrote the first draft of the manuscript, and all authors commented on the previous versions of the manuscript. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest in association with the present study.
- Received December 10, 2021.
- Revision received January 11, 2022.
- Accepted January 26, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
