The combination of pembrolizumab with chemotherapy previously demonstrated efficacy in gastric and gastro-oesophageal junction (GEJ) cancer. The interim analysis from the KEYNOTE-859 trial reveals that this combination results in a significant improvement in the overall survival of patients with locally advanced or metastatic HER2-negative gastric or GEJ adenocarcinoma, regardless of PD-L1 expression, compared to chemotherapy alone. Moreover, the combination therapy exhibits a manageable safety profile, making it a potential first-line treatment option for these patients.
Gastric cancer ranks as the fifth most commonly diagnosed cancer, with nearly 1.1 million new cases diagnosed and more than 768,000 deaths from the disease globally in 2020. It often progresses slowly, with minimal early symptoms, leading to late-stage diagnosis in over 70% of cases. Most cases are adenocarcinomas (around 90-95%), which develop from cells in the innermost lining of the stomach, known as the mucosa.1 Pembrolizumab, a high-affinity anti-programmed death 1 (PD-1) antibody, has previously demonstrated efficacy combined with chemotherapy in gastric or gastro-oesophageal junction (GEJ) cancer. The phase 3 KEYNOTE-859 trial compared this combination with chemotherapy alone in patients with locally advanced or metastatic HER2-negative gastric or GEJ adenocarcinoma. The interim analysis results are presented here.2
The phase 3 KEYNOTE-859 trial was conducted at 207 medical centres across 33 countries and enrolled adult patients (aged ≥18 years) with previously untreated locally advanced or metastatic HER2-negative gastric or GEJ adenocarcinoma. In total, 1,579 of 2,409 screened patients were randomly assigned (1:1) to receive pembrolizumab (n=790) or placebo 200 mg (n=789), administered intravenously every three weeks for up to 35 cycles. Additionally, all participants received fluorouracil plus cisplatin or capecitabine plus oxaliplatin. The primary endpoint was overall survival (OS), assessed in the intention-to-treat (ITT) population and the populations with a PD-L1 combined positive score (CPS) of ≥1 or ≥10. Safety was assessed in all randomly assigned participants who received at least one dose of the study intervention.2
After a median follow-up of 31.0 months, median OS was significantly longer in the pembrolizumab group in the ITT population (12.9 vs. 11.5 months in the placebo group; HR[95%CI]: 0.78 [0.70-0.87]; p<0.0001), in participants with a PD-L1 CPS ≥ 1 (13.0 vs. 11.4 months; HR[95%CI]: 0.74 [0.65-0.84]; p<0.0001), and in participants with a PD-L1 CPS ≥ 10 (15.7 vs. 11.8 months; HR[95%CI]: 0.65 [0.53-0.79]; p<0.0001). The most common grade 3-5 adverse events (AEs) of any cause were anaemia (12% vs. 10% of patients in the pembrolizumab and placebo groups, respectively) and decreased neutrophil count (10% vs. 8%). Serious treatment-related AEs occurred in 23% of participants in the pembrolizumab group and 19% in the placebo group. Treatment-related deaths occurred in eight (1%) vs. 16 (2%) participants in the pembrolizumab and placebo groups, respectively. No new safety signals were identified.2
In KEYNOTE-859, the combination of pembrolizumab plus chemotherapy resulted in a significant and clinically meaningful improvement in OS of patients with locally advanced or metastatic HER2-negative gastric or GEJ adenocarcinoma, regardless of PD-L1 expression. Additionally, the combination presented a manageable safety profile. Consequently, the combination of pembrolizumab with chemotherapy emerges as a potential first-line treatment option for these patients.2
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