Evaluation of Event-Free Survival Surrogating Overall Survival as the Endpoint in Neoadjuvant Clinical Trials of Gastroesophageal Adenocarcinoma

Abstract

BackgroundGastric cancer (GC) is one of the most common malignant cancers worldwide. The development of potential antitumor agents is being investigated and stimulates more clinical trials. Overall survival (OS) is consistently considered the primary endpoint for clinical trials on treatment effect assessment. However, finding an appropriate endpoint more sensitive and easy for trials is vital. For adjuvant chemotherapy, current evidence has shown that disease-free survival (DFS) could be a surrogate endpoint for randomized controlled trials (RCTs) with GC, but evidence for neoadjuvant chemotherapy (NCT) or chemoradiotherapy (NCRT) is inadequate. This study was designed to evaluate the possibility that event-free survival (EFS) surrogates OS in RCTs of NCT/NCRT of gastric orss gastroesophageal (GC or GEJ) adenocarcinoma patients (ADK).MethodsA literature search was conducted through databases including PubMed, the Cochrane Library, and Embase. References and articles from other sources were also included. A total of 8 RCTs with 2,837 patients were eventually analyzed. Hazard ratios (HRs) of OS and EFS were directly approached. The surrogacy of EFS was assessed through the correlation of determination R2. We used Review Manage pooling HRs of OS and EFS at the trial level. I2 was used to demonstrate the heterogeneity of inclusions. Publication bias was summarized and illustrated through funnel plots. All analyses were on two sides with a setting statistical significance as p < 0.05.ResultsEight RCTs of 2,837 patients were analyzed at the trial level. The I2 for OS was 21% and 51% for EFS, and a fixed-effect model was used. The pooled HR of OS was 0.83 (95% CI: 0.75–0.92, p < 0.001), and that of EFS was 0.78 (95% CI: 0.71–0.86, p < 0.001). The regression correlation coefficient between EFS and OS was 0.76 (95% CI: 0.41–1.11, p = 0.002), and the coefficient of determination R2 = 0.826.ConclusionsA strong correlation was observed between OS and EFS at the trial level. EFS could be a surrogate endpoint for neoadjuvant RCTs of GC and GEJ adenocarcinoma. Further studies and evidence from individual data are expected.

Identification on surrogating overall survival with progression-free survival of first-line immunochemotherapy in advanced esophageal squamous cell carcinoma—an exploration of surrogate endpoint

“…As far as we know, this was the first study to identify PFS-based endpoints systematically in advanced ESCC patients receiving immunotherapy in combination with chemotherapy as 1-L treatment. Previous studies have shown that three-year PFS is a reliable SE of 5-year OS in locally advanced ESCC treated with definitive RT; when treating resectable ESCC and esophageal adenocarcinoma (EAC) and gastroesophageal junction (GEJ) cancer, HR PFS can be used in neoadjuvant, perioperative, or adjuvant settings as a substitute for HR OS ; in addition, in neoadjuvant RCTs of gastric carcinoma(GC) and GEJ adenocarcinoma, event-free survival (EFS) could serve as a SE [ 35 – 37 ]. However, in the immune-oncology (IO) era, due to the special response patterns of Immuno-checkpoint inhibitors (ICIs) such as pseudoprogression and delayed response, whether the traditional SE for OS is applicable to IO trials is controversial [ 38 – 40 ].…”

What is the ideal endpoint in early-stage immunotherapy neoadjuvant trials in lung cancer?

“…Surrogacy of EFS for OS has been demonstrated in multiple other tumor types, including gastroesophageal cancer, breast cancer, and hematologic malignancies. [35][36][37][38] Despite the lack of proven surrogacy, EFS can provide useful information regarding treatment tolerability and toxicity which is not encapsulated by OS. Given its ease of measurement and earlier maturity compared to OS, we advocate for EFS' use in neoadjuvant clinical trials.…”