Introduction

Immune check inhibitors are widely used to treat a variety of cancer types, such as gastric, lung, breast, and head and neck cancers. Nivolumab is an immune check inhibitor and monoclonal antibody that targets the PD-1 receptor. Major clinical trials were conducted to analyze the clinical outcomes of nivolumab in patients with advanced gastric cancer. The first positive Phase III trial in advanced gastric cancer was the ATTRACTION-2 study, which was conducted in patients receiving third-line or later treatment. The results indicated that nivolumab monotherapy significantly prolonged overall survival (OS) compared with placebo [1]. Another Phase III study, the CHECKMATE 649 trial, was conducted in patients with previously untreated advanced gastric cancer, and the study demonstrated that nivolumab in combination with chemotherapy achieved superior OS versus chemotherapy alone [2]. Based on these promising results, nivolumab was recently proposed as an important component of treatment in patients with advanced gastric cancer.

Nivolumab is currently used in the first-line treatment of patients with advanced gastric cancer. However, progression is inevitable, and the treatment of advanced gastric patients after anti–PD-1 therapy is challenging. A previous study reported that rechallenge with immunotherapy beyond progression might be effective in other cancer types [3,4,5]. These studies described the efficacy of immune check inhibitor rechallenge in some patients who became refractory to the previous treatment. However, little research has been conducted in patients with advanced gastric cancer.

To evaluate the efficacy of nivolumab rechallenge in patients with advanced gastric cancer who had been treated on previous nivolumab treatment, we reviewed the clinical data of six patients.

Patients and Methods

This case series was approved by the Institutional Review Board of our institution and conducted in accordance with the Declaration of Helsinki and the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects. We retrospectively reviewed the medical records of patients at Ishikawa Prefectural Central Hospital between 2019 and 2021. The inclusion criteria were as follows: (1) histologically confirmed adenocarcinoma, (2) prior treatment with nivolumab alone or in combination with chemotherapy regardless of the duration of administration, and (3) treated the rechallenge of nivolumab monotherapy. Six patients meeting the inclusion criteria were enrolled.

Assessment

Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors. Patients without measurable lesions were excluded from the response rate analysis. Toxicity was assessed using the Common Toxicity Criteria for Adverse Events, version 5.0.

Progression-free survival (PFS) was measured from the first day of nivolumab rechallenge until the date of confirmed disease progression or the last day of follow-up without disease progression. OS was measured from the first day of nivolumab rechallenge until the date of death from any cause and was censored at the date of the last follow-up visit for surviving patients on treatment. Survival was calculated using the Kaplan–Meier method. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander designed to add statistical fusions frequently used in biostatistics [6].

Results

Patients

Six patients were included in this analysis. The detailed characteristics of the patients are summarized in Table 1. The median patient age was 67.5 years; five patients were male, and three patients had an Eastern Cooperative Oncology Group performance status of 0. Two patients received a combined nivolumab and platinum doublet regimen as first-line chemotherapy, and the other patients were treated with nivolumab monotherapy.

Table 1 Characteristics of patients
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Efficacy

Upon initial nivolumab treatment, three patients achieved partial responses, and one patient had stable disease (Table 2). Median PFS after the initial nivolumab regimen was 9.0 (range: 1.5–31.0) months. The reasons for discontinuing initial nivolumab therapy were progressive disease in five patients and immune-related adverse events in one patient.

Table 2 Clinical course of patients
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During the rechallenge with nivolumab, no patients achieved partial responses, and two patients exhibited stable disease (Table 2). Median PFS after nivolumab rechallenge was 2.5 (95% confidence interval [CI] = 1.6–not available [NA]) months (Fig. 1), and median OS was 7.4 (95% CI = 2.3–NA) months (Fig. 2).

Fig. 1
figure 1

Median progression-free survival for nivolumab rechallenge was 2.5 (95% confidence interval = 1.6–not available) months

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Fig. 2
figure 2

Median overall survival for nivolumab rechallenge was 7.4 (95% confidence interval = 2.3–not available) months

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Safety

Although one patient had discontinued prior nivolumab therapy and treated prednisolone because of immune-related arthritis. However, no immune-related adverse events were observed in any patients, and no treatment-related deaths were observed in nivolumab rechallenge.

Discussion

The present retrospective study evaluated the efficacy and safety of nivolumab rechallenge in patients with advanced gastric cancer who had received nivolumab in a prior treatment line. Rechallenge with immune check inhibitors has been reported [3,4,5]. However, these studies involved small numbers of patients and investigated other cancer types. Thus, a definitive conclusion could not be drawn regarding the immune check inhibitor rechallenge in patients with advanced gastric cancer. To the best of our knowledge, this is the first case series to examine nivolumab rechallenge in advanced gastric cancer. Although our study included a limited number of patients in clinical practice, several possibilities can be derived from our study.

First, the efficacy of nivolumab rechallenge in patients with advanced gastric cancer was limited in this study. The overall response rate (ORR) and disease control rate were 0% and 40%, respectively. Although most patients in this study responded to nivolumab in the prior line, and there was a sufficient interval between prior nivolumab therapy and nivolumab rechallenge, these data were not expected. Previous reports illustrated that the ORR was 20–30% for nivolumab and pembrolizumab in patients with ipilimumab-refractory melanoma [7, 8]. However, the response rate was lower for anti–PD-1 rechallenge after prior anti–PD-1 therapy [7, 8]. Another report recorded no responses after switching to another anti–PD1-1/anti–PD-L1 antibody [9]. It is well known that durable responses occur over a long period even after the discontinuation of immune check inhibitor therapy [10]. Nivolumab interferes with the suppressive signaling between cytotoxic T cells and tumors. Although a single dose of nivolumab has a half-life of only 13 ± 7 days [11], it was previously reported that the level of PD-1 occupancy on circulating T cells persists for much longer [11, 12]. The duration for which the effects of nivolumab on the immune system persist and affect subsequent therapy is unclear. Our study suggests that the effects of prior nivolumab therapy can persist through the period of nivolumab rechallenge, thereby limiting the efficacy of rechallenge with the same immune checkpoint inhibitor.

Second, there were no immune-related adverse events associated with nivolumab rechallenge. Nevertheless, our study included one patient who experienced an immune-related adverse event during previous nivolumab therapy. Although it is difficult to draw a firm conclusion because of the small number of patients in this study, previous research described the safety profile of immune check inhibitor rechallenge [13, 14]. One of these studies reported that retreatment with immune check inhibitors was feasible after severe immune-related hepatitis, even with the same immune check inhibitor [14]. Another systematic review mentioned that rechallenge with single-agent anti–PD-1 or anti–PD-L1 therapy had an acceptable safety profile that was similar to that observed in treatment-naïve patients [15]. Our study suggests that rechallenge with nivolumab might be well tolerated in the vast majority of patients as observed during the initial treatment.

Third, OS was relatively better with nivolumab rechallenge despite the low response rate and short PFS. The recommended drugs of third or later-line treatment for advanced gastric cancer include trifluridine/tipiracil (FTD/TPI), irinotecan, and so on. The median OS was reported to be 5.7 months in the FTD/TPI in the pivotal phase III study, the TAGS trial [16]. And the median OS was 6.61 months in the irinotecan in the retrospective study [17]. The OS in this study showed a longer trend compared to these studies. The treatment periods of nivolumab rechallenge are short, and thus, either the prior chemotherapy or the subsequent therapy might have positively influenced OS. From the perspective that our study included heavily pretreated patients and subsequent therapy options are limited, prior nivolumab treatment might provide a durable survival benefit.

This study had several limitations. First, this was a retrospective study in a single institution. Second, the sample size was insufficient for drawing definitive conclusions. Further studies considering these limitations should be conducted to verify the conclusions.

In conclusion, the efficacy of nivolumab rechallenge in patients with advanced gastric cancer was limited even in cases in which prior nivolumab therapy was effective. The effects of prior nivolumab therapy might persist through the period of nivolumab rechallenge, thereby limiting the efficacy of rechallenge with the same immune check inhibitor. Further prospective studies are needed to explore more promising methods of immune check inhibitor rechallenge for patients with advanced gastric cancer.