A randomized, double-blind, placebo-controlled phase 3 clinical trial known as ORIENT-16 has demonstrated improved survival outcomes for patients with advanced gastric or gastroesophageal junction cancer when the immunotherapy drug sintilimab is added to standard chemotherapy. The study, conducted at 62 hospitals across China, was funded by Innovent Biologics, Inc. and published in JAMA on December 5, 2023.
The primary objective of the ORIENT-16 trial was to evaluate whether combining sintilimab, a PD-1 inhibitor, with chemotherapy would improve overall survival compared to chemotherapy alone in patients with previously untreated, unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. The study enrolled 650 patients between January 3, 2019, and August 5, 2020, with final follow-up occurring on June 20, 2021.
To be eligible for inclusion, patients had to be at least 18 years old with histologically confirmed unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. Additional criteria included having at least one measurable or evaluable lesion according to RECIST v1.1, an ECOG performance status of 0 or 1, and adequate hematologic, hepatic, and renal function. Patients who had received prior adjuvant or neoadjuvant chemotherapy or radiotherapy were eligible if their disease recurred at least 6 months after their last treatment.
Key exclusion criteria encompassed prior systemic treatment for advanced or metastatic disease, known ERBB2-positive status, and active, known, or suspected autoimmune disease. The study population had a mean age of 59 years, with 74.3% being male. Approximately 18.5% of patients had gastroesophageal junction adenocarcinoma, while 92.0% had metastatic disease.
Patients were randomized 1:1 to receive either sintilimab (n=327) or placebo (n=323) in combination with capecitabine and oxaliplatin (XELOX regimen) every 3 weeks for up to 6 cycles. This was followed by maintenance therapy with sintilimab or placebo plus capecitabine for up to 2 years. The primary endpoint was overall survival time from randomization.
The results of the study were striking, particularly for patients with tumors expressing PD-L1 with a combined positive score (CPS) of 5 or more. In this subgroup, which comprised 61.1% of the study population, the median overall survival was 18.4 months in the sintilimab group compared to 12.9 months in the placebo group (HR 0.66, 95% CI 0.50-0.86, p=0.002). Among all randomized patients, regardless of PD-L1 expression, sintilimab improved median overall survival to 15.2 months versus 12.3 months with placebo (HR 0.77, 95% CI 0.63-0.94, p=0.009).
Secondary endpoints also favored the sintilimab group. Progression-free survival was significantly improved in both the CPS ≥5 subgroup (7.7 vs 5.8 months, HR 0.63, p<0.001) and the overall population (7.1 vs 5.7 months, HR 0.64, p<0.001). Objective response rates were higher with sintilimab, reaching 63.6% versus 49.4% in the CPS ≥5 subgroup (p=0.008) and 58.2% versus 48.4% in all patients (p=0.02).
The safety profile of sintilimab plus chemotherapy was generally consistent with expectations for immune checkpoint inhibitors combined with chemotherapy. The most common grade 3 or higher treatment-related adverse events in the sintilimab group were decreased platelet count (24.7%), decreased neutrophil count (20.1%), and anemia (12.5%). While these rates were slightly higher than in the placebo group, the overall incidence of treatment-related adverse events was similar between arms (97.3% vs 96.3%).
Immune-related adverse events, which are of particular interest with checkpoint inhibitors, occurred in 34.8% of patients receiving sintilimab, with 10.7% experiencing grade 3 or higher events. The most frequent immune-related adverse events were hypothyroidism (13.7%), hyperthyroidism (6.1%), and increased amylase (5.2%).
While the ORIENT-16 trial provides compelling evidence for the efficacy of sintilimab in this patient population, several limitations should be noted. First, the study was conducted entirely in China, which may limit its generalizability to other populations. Second, the primary PD-L1 positive population was revised from CPS ≥10 to CPS ≥5 after enrollment completion, based on results from another study (CheckMate 649) that used this threshold. Although this change was made before data analysis, it represents a deviation from the original protocol.
Additionally, microsatellite instability analysis was not performed, which could have provided valuable information on a subset of patients known to respond well to immunotherapy. The lack of independent central review for tumor response assessment may have introduced bias in the progression-free survival results. Lastly, some aspects of the study design, such as the timing of the primary outcome analysis, were not clearly defined in the original protocol and statistical analysis plan.
Despite these limitations, the authors conclude that sintilimab combined with first-line chemotherapy significantly improved survival for patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, particularly those with PD-L1 CPS ≥5. These findings are consistent with other recent studies of PD-1 inhibitors in this setting, such as the CheckMate 649 trial with nivolumab.
The potential clinical impact of this study is substantial. Gastric and gastroesophageal junction cancers remain significant global health burdens, with limited effective treatment options for advanced disease. The addition of sintilimab to standard chemotherapy could represent a new standard of care for many patients, especially those with PD-L1 positive tumors. The magnitude of benefit observed in this trial, with a 5.5-month improvement in median overall survival for PD-L1 positive patients, is clinically meaningful and could translate to real-world improvements in outcomes.
However, implementation of these findings into clinical practice will require careful consideration. PD-L1 testing would likely become routine for all patients diagnosed with advanced gastric or gastroesophageal junction cancer to guide treatment decisions. The cost-effectiveness of adding sintilimab to chemotherapy will need to be evaluated, particularly in healthcare systems with limited resources. Additionally, management of immune-related adverse events will require education and vigilance from oncology teams.
Further research will be needed to refine patient selection for this treatment approach. Subgroup analyses suggested that patients with liver metastases and those with gastroesophageal junction tumors may derive less benefit from sintilimab, although these findings were not statistically significant. Biomarker studies beyond PD-L1 expression, including assessment of tumor mutational burden and specific gene alterations, could help identify patients most likely to benefit from immunotherapy.
In conclusion, the ORIENT-16 trial represents an important advance in the treatment of advanced gastric and gastroesophageal junction cancers. By demonstrating a significant survival benefit with the addition of sintilimab to standard chemotherapy, particularly in PD-L1 positive tumors, this study adds to the growing body of evidence supporting the use of immune checkpoint inhibitors in this challenging disease. As with all advances in cancer therapy, the true impact of these findings will be realized as they are implemented in diverse clinical settings and as longer-term follow-up data become available.
References
Xu J, Jiang H, Pan Y, et al. Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial. JAMA. 2023;330(21):2064-2074. doi:10.1001/jama.2023.19918
