SUMMARY: Gastroesophageal cancers consist of a group of heterogeneous tumors, including gastric cancer, gastroesophageal junction cancer, and esophageal cancer. The majority of gastric and gastroesophageal junction cancers are adenocarcinomas, while the two main histological subtypes of esophageal cancer are esophageal adenocarcinoma and esophageal squamous cell carcinoma. The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases and 21,560 new esophageal cancers will be diagnosed in 2023 and about 11,130 and 16,120 people respectively, will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with gastric and gastroesophageal junction adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure.
The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of advanced gastric and gastroesophageal (GE) junction cancers, overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody, Trastuzumab, as there is Overall Survival (OS) benefit with this combination regimen. Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor expressed on activated T cells, and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. In two Phase II studies, Pembrolizumab in combination with Trastuzumab and chemotherapy showed promising efficacy with manageable toxicities. The FDA in 2021 granted accelerated approval to Pembrolizumab in combination with Trastuzumab, Fluoropyrimidine and Platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma, based on Overall Response Rates (ORR).
KEYNOTE-811 is an ongoing, global, multicenter, randomized Phase III trial which evaluated the benefit of adding Pembrolizumab to Trastuzumab and chemotherapy in patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma. In this study, 698 treatment naïve eligible patients (N=698) were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV (N=350) or placebo (N=348) every 3 weeks plus Trastuzumab and investigator’s choice of Fluorouracil/Cisplatin or Capecitabine/Oxaliplatin. Trastuzumab was given at 6 mg/kg IV once every 3 weeks after a loading dose of 8 mg/kg IV. Chemotherapy consisted of 5-FU 800 mg/m2 IV on days 1 to 5 of each 3-week cycle and Cisplatin 80 mg/m2 IV once every 3 weeks, or Capecitabine 1,000 mg/m2 orally twice daily on days 1 to 14 of each 3-week cycle and Oxaliplatin 130 mg/m2 IV once every 3 weeks. Treatment was continued for up to 35 cycles or until disease progression or unacceptable toxicity. Approximately 81% were male and patients were stratified by PD-L1 status, and chemotherapy received. Over 80% of patients had a PD-L1 Combined Positive Score of 1 or more. The dual Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS). Secondary end points included Objective Response Rate (ORR), Duration of Response, and Safety. The researchers reported the results at the third interim analysis, after a median follow up of 38.5 months.
At the third interim analysis, the results continued to show superiority with the addition of Pembrolizumab to Trastuzumab and chemotherapy. The median PFS with Pembrolizumab versus placebo was 10 months versus 8.1 months, respectively (HR = 0.73; P=0.0002). This represented a 27% reduction in risk for progression with Pembrolizumab versus placebo. The median OS showed numerical improvement and was 20.0 months versus 16.8 months (HR=0.84), but did not meet prespecified criteria for significance. Follow up for Overall Survival is continuing, and results will be updated at the final analysis. Patients whose tumors had PD-L1 Combined Positive Score of 1 or more benefitted the most, and there was little to no benefit among patients whose tumors had PD-L1 Combined Positive Scores less than 1. The researchers had previously reported an ORR of 74% in the the Pembrolizumab group and 52% in the placebo group, yielding a 22% improvement for the Pembrolizumab group (P=0.00006). Disease Control Rates were 96.2% versus 89.3% respectively. Grade 3 or more treatment-related adverse events were higher among patients assigned to Pembrolizumab versus placebo group (58% versus 51%). The most common treatment-related adverse events of any grade were diarrhea, nausea and anemia.
The authors concluded that Pembrolizumab when combined with first line Trastuzumab and chemotherapy significantly improved Progression Free Survival when compared to placebo, in metastatic HER2-positive gastroesophageal cancer. This benefit was specifically noted among patients with tumors with a PD-L1 Combined Positive Score of 1 or more. Follow up for Overall Survival is ongoing and will be updated at the final analysis.
Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Janjigian YY, Kawazoe A, Bai Y, et al. Published:October 20, 2023. DOI:https://doi.org/10.1016/S0140-6736(23)02033-0
