Efficacy and safety of Nivolumab in patients with advanced esophageal, gastroesophageal, and gastric cancers: a meta-analysis of randomized controlled trials

Abstract Background Immune checkpoint inhibitors (ICI) have revolutionized care in oncology with improved overall survival in several cancer populations. Nivolumab has recently been approved for use in patients with upper gastrointestinal cancers. We quantitatively summarized the efficacy and safety of Nivolumab use in patients with advanced esophageal, gastroesophageal, and gastric carcinoma compared to standard chemotherapy. Methods Systemic search of electronic databases was performed to analyze phase III randomized controlled trials (RCTs) comparing Nivolumab versus standard chemotherapy in patients with advanced upper gastrointestinal cancers. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Data were pooled using random effects model via RevMan 5.4 software. Results Four RCTs with a total of 3369 patients and a median follow-up of 13 months were included. The patients’ mean age was 61 ± 20 years, 74.6% were males, and 26% had ≥1% PD-L1 expression. Compared to the chemotherapy group, Nivolumab group had a significantly favorable OS and PFS [HR 0.81;95% CI (0.74, 0.89), p < .001], [HR 0.82;95% CI (0.69, 0.98), p = .03], respectively. Nivolumab significant effect was only in patients with ≥1% PD L1 expression [HR 0.72; 95% CI (0.58, 0.89), p < .001]. No statistical difference was detected between groups regarding serious adverse effects (AE) [OR 1.47; 95%CI (0.94,2.31), p = 0.09]. Conclusions Compared to standard chemotherapy, the use of Nivolumab in patients with advanced esophageal, gastroesophageal, and gastric cancers is associated with improved overall and progression-free survival, with similar rates of AE and AE leading to death. The improvement in survival was significant in patients with ≥1% PD L1 expression.


Introduction
The incidence of esophageal, gastroesophageal, and gastric cancers continues to rise especially adenocarcinoma in all racial ethnicities [1,2]. They make up about 1% of the cancer cases in the United States (US) and are currently the seventh cause of cancer death in the US [3]. The current estimated five-year survival rate is currently 20% which has improved significantly from 5% in prior years [4]. Unfortunately, patients are usually at advanced stages, unresectable when they are diagnosed [5], making treating options limited to chemotherapy. Despite treatment options available, these patients have a median survival of about one year [6].
The use of immunotherapy has led to advancements in cancer therapy. Immune checkpoint inhibitors have been shown to improve overall survival in several cancers including upper gastrointestinal cancers (esophageal, gastroesophageal (GEJ), and gastric cancers) [7][8][9][10]. A recent metaanalysis that combined several immune checkpoint inhibitors reported statistically significant overall survival benefits in both adenocarcinomas and SCC [11]. Currently, nivolumab is one of the immune checkpoint inhibitors approved as a combination therapy for patients with advanced or metastatic esophageal, GEJ, gastric adenocarcinoma [12]. We therefore performed a meta-analysis of randomized controlled trials to evaluate the use of nivolumab specifically in patients with both adenocarcinoma and squamous cell carcinoma who have advanced stages of the disease.

Search strategy and data extraction
We systematically searched multiple data bases (PubMed, Cochrane library, google scholar, Scopus, Clinical trial.gov) from inception to 28 February 2022 using pre-specified search terms, 'Nivolumab' AND 'esophageal' OR 'esophagogastric' OR 'gastric' AND 'cancer' OR 'carcinoma' OR 'adenocarcinoma' OR 'squamous cell carcinoma. ' We updated the search in July 2022. Search was limited to English language. Two authors (RP, SS) independently screened studies titles and abstracts for eligibility using a standardized form, followed by full manuscript assessment and bibliography check. Consensus, if needed, was reached by a third investigator (MM or MO). One author (MM) extracted the data from eligible studies in a pre-designed spreadsheet, which was verified by another author independently (MO). All authors vouch to the correctness and completeness of data.

Inclusion/exclusion criteria
Inclusion was restricted to prospective randomized controlled trials (RCT) comparing Nivolumab with/without chemotherapy to any combination of chemotherapy in patients >18 years with esophageal, gastroesophageal, or gastric cancer, regardless of histological type or genetic expression. We included only patients with advanced, recurrent, unresectable disease or intolerant to previous chemotherapy according to respective studies definition. Studies must be reporting at least the primary outcome to be included in this analysis. We excluded observational, non-randomized trials, and trials with no active comparator arm.

Endpoint/outcomes
Co-primary outcomes of interest were overall survival (OS) and disease/progression-free survival (PFS) as defined per respective studies. Secondary efficacy outcomes were objective response rate and complete response rate. We reported safety outcomes/adverse events (AE) as follows; serious AE, AE leading to discontinuation/withdrawal, AE leading to death, and sample of AE reported in >10% in patients; rates of anorexia, fatigue, and diarrhea.

Statistical analysis
We calculated odd ratios (OR) for dichotomous data and generic inverse variance with hazard ratios (HR) for survival data, with 95% confidence intervals (CI). We reported heterogeneity via I 2 statistic and generated a funnel plot to assess for potential publication bias. We also conducted a sensitivity analysis based on PD-L1 expression status (<1% versus 1%) and Nivolumab use as 1 st line therapy. All analysis was conducted via RevMan 5.4 software, using random effects models, accounting for different trials weights.

Discussion
Our meta-analysis showed that patients with advanced esophageal, gastroesophageal or gastric cancer who were treated with nivolumab had a statistically higher disease-free survival and overall survival compared to those that were treated with standard of care. These patients were shown to have an objective and ongoing response to nivolumab. There was no difference in the adverse events in both groups.
Our findings are consistent with prior studies. Kamposioras et al in their meta-analysis found a statistically significant overall survival benefit when combined with chemotherapy in the first line setting and included all immune checkpoint inhibitors [11]. Also, use of nivolumab in combination with chemotherapy was found to have improved survival compared to chemotherapy alone. This has been shown in other cancers such as non-small lung cell cancer and breast cancer [17,18]. Currently, pembrolizumab and nivolumab are both FDA approved for treatment of advanced stages of esophageal and gastroesophageal, and gastric cancers. Both immune checkpoint inhibitors have showed improvement in overall survival though nivolumab and pembrolizumab have not been compared head-to-head for use in these cancers. In a recent network meta-analysis, nivolumab was superior to pembrolizumab and showed improved PFS and OS in patients with GC and GEJ cancers. These findings are similar to our study though they included both phase II and III trials [19]. In a study of patients with NSLC, there was no difference in PFS though pembrolizumab seemed to have a higher objective response in these patients [20].
Nivolumab targets programmed cell death 1(PD)-1 receptors and activates the anti-tumor response of the immune system which later results in a decrease in tumor growth [21]. Use of immunotherapy is usually related to PD-1 expression in patients though in a recent study, programmed cell death ligand 1 (PD L1) as a predictive biomarker was found to be predictive in about 29% of cases that were evaluated [22]. In our sensitivity analysis, the improvement in overall survival was in those with > ¼1 PD 1 expression.
Immunotherapies are usually tolerated by patients though there are immune-related adverse effects. Common adverse events that were reported included rash, diarrhea, fatigue, nausea. Though most symptoms are usually mild to moderate, tolerability was not a concern and discontinuation/withdrawal rate was significantly higher in the chemotherapy only group. Immune-related adverse effects unique to patients on immunotherapy still require close monitoring and a high index of suspicion.
The major strength of our meta-analysis is the use of only phase III trials in which there was head-to-head comparison with the current standard of care. A limitation of this metaanalysis might be low sample size in the number of trials that were included in the analysis since we focused on only phase III trials. Also, this study lacked patient level data. Our meta-analysis is the first to evaluate nivolumab specifically in the treatment of patients with advanced esophageal, gastroesophageal, and gastric cancer. In conclusion, in patients with advanced esophageal, gastroesophageal, gastric cancer, nivolumab improved progression free survival and overall survival. This finding was significant in patients with PD 1 expression.