Advanced Gastric Cancer: Prognosis With Nivolumab Monotherapy
Later-line treatments for advanced gastric cancer have always been debated. Although chemotherapy is the recommended option. For the last decade, immune checkpoint inhibitors have been used for the treatment of various malignancies. Trials have also been performed for gastric cancer. In this study, a phase 3 trial indicated the survival benefit of nivolumab monotherapy for gastric cancer patients treated with prior chemotherapy regimens.
Nivolumab as Treatment Remains Controversial
Nivolumab is an immune checkpoint inhibitor that is used in the treatment of unresectable or recurrent chemotherapy-resistant gastric cancer. Based on a recent study of a phase 3 trial of Asian patients with gastric and gastroesophageal junction cancer that was treated with prior chemotherapy regimens—the overall survival was 5.26 months with nivolumab and 4.14 months with placebo.
Nivolumab treatment was then recommended for gastric cancer patients as ≥ third-line chemotherapy in the gastric cancer treatment guidelines of Asian countries. However, nivolumab treatment has only been approved as later-phase chemotherapy for gastric cancer in very limited countries. As the European Society of Medical Oncology, clinical practice guidelines for the diagnosis, treatment, and follow-up of gastric cancer do not recommend any third-line treatment, the effectiveness of later-line chemotherapy for advanced gastric cancer is still controversial.
Gastric Cancer in Numbers Worldwide
In 2018, there were a total of 782,685 gastric cancer-related deaths. Gastric cancer incidence is rising. It reached 1,033,701 and was frequently found in Eastern Asia, Eastern Europe, South America, Western Asia, and other countries. In Japan, gastric cancer deaths are at 30,000 patients per year while the gastric cancer mortality in Asahikawa city, Hokkaido which has a population of 350 million— is approximately 140 patients per year.
Patients and Methods
A regional cohort study was done to understand data of nivolumab treatment for patients with advanced or recurrent gastric cancer. Patients were enrolled in the study starting from October 2017 to October 2019. They were then prospectively followed for a year to examine their overall survival.
During the enrollment period, 70 gastric cancer patients received nivolumab treatment. The median age was 69 years, 65.7% were male, and 62.3% were elderly (≥65). All patients were histologically diagnosed with gastric adenocarcinoma, with an unresectable tumor and/or recurrent metastatic cancer.
The study group includes a special function hospital and four cancer medical cooperation base hospitals in Asahikawa city, Hokkaido, Japan. All clinical data were collected and analysis was performed at the Cancer Genomic Medicine in Asahikawa Medical University.
The patients received 3 mg/kg or 240 mg/body nivolumab intravenously every 2 weeks. The patients received treatment until disease progression or until the development of unacceptable toxicity. Tumor responses were analyzed using computed tomography (CT) or magnetic resonance imaging (MRI). Their characteristics were analyzed, then a nomogram was generated to predict the probability of survival.
The median OS and 95% confidence interval (CI) were calculated using the Kaplan– Meier method. The log-rank test was used to compare the difference in OS between the groups. Hazard ratios (HRs) with 95% CIs were calculated using a stratified Cox proportional hazards model.
The prognostic variables were assessed in a multivariable analysis. The histological type, liver metastasis, peritoneal metastasis, and CRP were selected as explanatory variables, as their values in the univariable analysis were significant (p≤ 0.001).
The NLR was selected as a variable based on a retrospective observational study. All analyses were performed using the SPSS software program, version 25 (IBM, New York, NY, USA), and values of <0.05 were considered to indicate statistical significance.
Construction and validation of a nomogram
Independent risk factors associated with longer survival were chosen to construct a nomogram using R version 4.0.3 software (The R Foundation for Statistical Computing, Vienna, Austria).
The nomogram was generated by the Bell Curve for Excel (Social Survey Research Information Co. Ltd., Tokyo, Japan). The probability of survival at the time of the mean OS was predicted from the nomogram.
Validation of the nomogram was performed through repeated independent samplings based on our cohort. The concordance index (C- index) provided a probability value between the observed and predicted probability. A receiver operator characteristics (ROC) curve was created using the nomogram and independent risk factors.
The final analysis was performed 12 months after the end of the enrollment period. At this time point, 57 patients (81.4%) had died. Among 13 surviving patients (18.6%), 5 patients (7.1%) continued to receive nivolumab treatment. The response rate was 18.6% (PR, n = 13; CR, n = 0) and the disease control rate was 41.4%. The median duration of treatment was 3.0 months with six cycles of nivolumab. Subsequent chemo-therapy after the discontinuation of nivolumab was administered to 26 patients (37.1%). As the primary endpoint, the median OS reached 7.5 (95% CI, 4.8– 10.2) months.
In this clinical cohort, the median total survival period from the beginning of the first-line chemotherapy was 27.5 (95% CI, 23.2– 31.8) months. A subgroup analysis of OS according to the response was performed using the Kaplan– Meier curves. Responders (patients with PR) showed longer median OS (32.0 months, 8.0, and 5.0 for PR, SD, and PD, respectively, p < 0.001).
In total, there are 70 patients who received nivolumab as ≥ third-line chemotherapy were included in the Asahikawa Gastric Cancer Cohort. The study reveals that there are specific prognostic factors and a nomogram that could predict the probability of survival.
The median OS was 7.5 (95% CI, 4.8– 10.2) months and the response rate was 18.6%. Diffuse type classification, bone metastasis, high neutrophil/lymphocyte ratio, and high CRP were associated with poor OS/prognosis in the multivariate analysis. A nomogram was developed based on these clinical parameters and the concordance index was 0.80 (95% CI, 0.68– 0.91).
The researchers found extremely long total survival from the initiation of the primary chemotherapy to the death. Patients who received nivolumab as the third-line regime or later for gastric cancer survived >27 months.
The elongation of survival was associated with the development of second-line chemotherapy or later. For example, a review reported that the second-line chemotherapy rate influenced the OS in phase III trial series for advanced gastric cancer. Third-line chemotherapy or later may prolong the total OS. Combination treatment with cytotoxic chemotherapy and immunotherapy may contribute to improving survival.
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