Advancing Systemic Therapy in Gastric Cancer: Key Updates From the Korean Practice Guidelines for Gastric Cancer 2024

Laparoscopic distal gastrectomy for AGC

The recently published 5-year survival data from the JLSSG0901 trial [6] prompted a meta-analysis that included the KLASS-02, CLASS-01, and JLSSG0901 trials, which confirmed that both laparoscopic and open distal gastrectomy provide comparable survival outcomes, reaffirming that laparoscopic distal gastrectomy can be recommended for AGC.

Advances in systemic therapy for AGC

Surgical resection remains the standard treatment for resectable AGC, supplemented by systemic therapy to reduce recurrence and improve survival. Despite recent efforts to enhance systemic therapy with anti-programmed cell death-l (PD-1) antibodies in the perioperative setting, S-1 or capecitabine plus oxaliplatin remains the most strongly recommended post-surgery regimen. Meta-analyses incorporating long-term data from the Asian phase III PRODIGY and RESOLVE trials have confirmed overall survival benefits from neoadjuvant chemotherapy [7, 8]. However, with the need for multidisciplinary discussions on the use of neoadjuvant chemotherapy, there remains a need to optimize its application among various therapeutic approaches including up-front surgery followed by adjuvant chemotherapy. Therefore, this has led to the current guidelines maintaining the previous edition’s “conditional for” recommendation.

In locally advanced unresectable or metastatic AGC, conventional cytotoxic agents such as fluoropyrimidines; platinum-based agents (cisplatin, oxaliplatin); taxanes (docetaxel, paclitaxel); and irinotecan remain the cornerstone of treatment. However, the introduction of molecularly targeted therapies and immune checkpoint inhibitors (ICIs) have transformed the systemic treatment landscape, significantly improving survival outcomes. Nivolumab was the first successful ICI approved for combination with chemotherapy as palliative first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative gastric cancer. Until the 2022 guidelines, palliative first-line nivolumab combined with fluoropyrimidine/platinum-based chemotherapy was recommended for gastric cancer patients with a HER2-negative and programmed cell death ligand-1 (PD-L1) combined positive score (CPS) ≥5 [5]. Additionally, the KEYNOTE-859 trial demonstrated significant survival benefits with pembrolizumab combined with chemotherapy, regardless of PD-L1 status, with a more pronounced effect observed in PD-L1-positive patients [9]. A meta-analysis of 5 phase III trials comparing anti-PD-1 antibodies plus chemotherapy versus chemotherapy alone further reinforced the role of anti-PD-1 antibodies in first-line systemic therapy for PD-L1-positive AGC [1], strengthening the evidence supporting this combination in clinical practice. As the integration of anti-PD-1 antibodies into standard chemotherapy regimens for first-line treatment of HER2-negative gastric cancer has improved survival outcomes, these results have been extended to HER2-positive gastric cancer as well. The randomized, phase III KEYNOTE-811 trial demonstrated the efficacy of combining pembrolizumab and trastuzumab with standard fluoropyrimidine/platinum chemotherapy versus trastuzumab with standard chemotherapy as first-line treatment in patients with HER2-postive gastric cancer [10]. In patients with PD-L1 CPS ≥1, the pembrolizumab group exhibited a more pronounced survival improvement. Consequently, the addition of pembrolizumab to trastuzumab and chemotherapy is recommended for gastric cancer patients with HER2-positive and PD-L1 CPS ≥1.

In addition, zolbetuximab, a monoclonal antibody targeting claudin 18.2, demonstrated significant survival benefits when combined with chemotherapy as palliative first-line systemic therapy for HER2-negative gastric cancer in the phase III SPOTLIGHT and GLOW trials [11, 12]. A meta-analysis of these 2 phase III trials conducted for the current guidelines confirmed the significant survival benefits of zolbetuximab in combination therapy [1], providing stronger supporting evidence for its clinical application. Therefore, zolbetuximab combined with fluoropyrimidine/platinum chemotherapy is recommended as a first-line treatment in patients with HER2-negative and claudin 18.2-positive locally advanced, unresectable, or metastatic gastric cancer.

Although no major changes were made regarding second-line or later therapies, emerging agents and clinical trial results were highlighted, indicating potential future updates.