Sintilimab Plus Chemotherapy for Unresectable Gastric or Gastroesophageal Junction Cancer: The ORIENT-16 Randomized Clinical Trial

Abstract

Importance: Gastric and gastroesophageal junction cancers are diagnosed in more than 1 million people worldwide annually, and few effective treatments are available. Sintilimab, a recombinant human IgG4 monoclonal antibody that binds to programmed cell death 1 (PD-1), in combination with chemotherapy, has demonstrated promising efficacy.

Objective: To compare overall survival of patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancers who were treated with sintilimab with chemotherapy vs placebo with chemotherapy. Also compared were a subset of patients with a PD ligand 1 (PD-L1) combined positive score (CPS) of 5 or more (range, 1-100).

Design, setting, and participants: Randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 62 hospitals in China that enrolled 650 patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma between January 3, 2019, and August 5, 2020. Final follow-up occurred on June 20, 2021.

Interventions: Patients were randomized 1:1 to either sintilimab (n = 327) or placebo (n = 323) combined with capecitabine and oxaliplatin (the XELOX regimen) every 3 weeks for a maximum of 6 cycles. Maintenance therapy with sintilimab or placebo plus capecitabine continued for up to 2 years.

Main outcomes and measures: The primary end point was overall survival time from randomization.

Results: Of the 650 patients (mean age, 59 years; 483 [74.3%] men), 327 were randomized to sintilimab plus chemotherapy and 323 to placebo plus chemotherapy. Among the randomized patients, 397 (61.1%) had tumors with a PD-L1 CPS of 5 or more; 563 (86.6%) discontinued study treatment and 388 (59.7%) died; 1 patient (<0.1%) was lost to follow-up. Among all randomized patients, sintilimab improved overall survival compared with placebo (median, 15.2 vs 12.3 months; stratified hazard ratio [HR], 0.77 [95% CI, 0.63-0.94]; P = .009). Among patients with a CPS of 5 or more, sintilimab improved overall survival compared with placebo (median, 18.4 vs 12.9 months; HR, 0.66 [95% CI, 0.50-0.86]; P = .002). The most common grade 3 or higher treatment-related adverse events were decreased platelet count (sintilimab, 24.7% vs placebo, 21.3%), decreased neutrophil count (sintilimab, 20.1% vs placebo, 18.8%), and anemia (sintilimab, 12.5% vs placebo, 8.8%).

Conclusions and relevance: Among patients with unresectable locally advanced or metastatic gastric and gastroesophageal junction adenocarcinoma treated with first-line chemotherapy, sintilimab significantly improved overall survival for all patients and for patients with a CPS of 5 or more compared with placebo.

Trial registration: ClinicalTrials.gov Identifier: NCT03745170.

Figure 1.. Patient Flow in the ORIENT-16 Trial

^aThe total number of patients approached for participation in the trial was not recorded. ^bOther reasons included a screening period exceeding 28 days or having an ineligible condition. ^cPatients were randomized in a 1:1 ratio and stratified according to Eastern Cooperative Oncology Group performance status score (0 or 1), liver metastasis (yes or no), and programmed cell death ligand 1 (PD-L1) expression (combined positive score [CPS], <10 or ≥10). See Table 1 footnotes for more information. One patient who was assigned with 2 randomization numbers was counted as 1. ^dFor the safety analysis, 1 patient who received 1 dose of sintilimab was analyzed in the sintilimab group, and 2 patients who did not receive planned treatment were excluded. ^ePD-L1 expression was measured by CPS, which was defined as the number of PD-L1 staining cells (tumor cells, lymphocytes and macrophages) divided by the total number of viable tumor cells present in the sample multiplied by 100. The maximum score is defined as 100 when the calculation exceeds 100. A CPS of 5 or more was defined as PD-L1 positive. ^fOther reasons included clinical progression, maximum benefit reached for patients who became eligible to undergo radical surgery after study treatment, and dose interruption up to the maximum duration of 12 weeks.

Figure 2.. Overall Survival

For patients with a combined positive score (CPS) of 5 or more, the median follow-up for overall survival was 19.4 (IQR, 14.1-23.2) months for sintilimab plus chemotherapy and 18.9 (IQR, 13.8-24.5) months for placebo plus chemotherapy; the median overall survival was 18.4 months vs 12.9 months. For all randomized patients, median follow-up for overall survival was 19.3 (IQR, 14.1-22.4) months for sintilimab plus chemotherapy and 18.1 (IQR, 13.5-22.7) months for placebo plus chemotherapy; median overall survival was 15.2 months vs 12.3 months. See Figure 1 legend footnote e for programmed cell death ligand 1 CPS calculations. A CPS of 5 or more was defined as PD-L1 positive.

Figure 3.. Subgroup Plot for Prespecified Subgroup Analyses of Overall Survival in All Randomized Patients at the Interim Efficacy Analysis

^aInteraction P values. ^bSee Figure 1 legend footnote e for programmed cell death ligand 1 (PD-L1) combined positive score (CPS) calculations. A CPS of 5 or more was defined as PD-L1 positive. ECOG indicates Eastern Cooperative Oncology Group; HR, hazard ratio; TPS, tumor proportion score.

Figure 4.. Post Hoc Overall Survival at the Interim Efficacy Analysis in Patients With a Combined Positive Score Less Than 5

The median follow-up for overall survival was 18.8 (IQR, 13.7-20.7) months for sintilimab plus chemotherapy and 17.4 (IQR, 13.1-20.3) months for placebo plus chemotherapy; the median overall survival was 11.7 months vs 12.0 months. See Figure 1 legend footnote e for programmed cell death ligand 1 (PD-L1) combined positive score (CPS) calculations. A CPS of 5 or more was defined as PD-L1 positive.