Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer

Testing to determine the presence of predictive biomarkers PD-L1, deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H), claudin 18.2 (CLDN18.2), and HER2 in gastroesophageal adenocarcinoma is recommended, and PD-L1 and dMMR/MSI-H status should be tested for esophageal squamous cell carcinoma (ESCC). Clinicians should consider broad-based next-generation sequencing (NGS) testing, which includes pan-tumor biomarkers. The results of predictive biomarker testing should be available as soon as possible to inform treatment decision-making.

For patients with proficient mismatch repair (pMMR)/microsatellite stable (MSS) HER2-negative gastric/GEJ or esophageal adenocarcinoma with PD-L1 expression ≥1 and absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine- and platinum-based chemotherapy in combination with immunotherapy may be recommended.

For patients with pMMR/MSS HER2-negative gastric/GEJ adenocarcinoma with PD-L1 expression <1 and positive CLDN18.2 expression, fluoropyrimidine- and platinum-based chemotherapy combined with zolbetuximab should be offered.

For patients with pMMR/MSS HER2-negative gastric/GEJ adenocarcinoma with PD-L1 expression ≥1, and CLDN18.2 expression positivity, fluoropyrimidine- and platinum-based chemotherapy combined with immunotherapy or zolbetuximab may be offered on a case-by-case basis.

For patients with pMMR/MSS HER2-negative gastroesophageal adenocarcinoma, PD-L1 expression <1, and absence of CLDN18.2 expression, first-line therapy with fluoropyrimidine- and platinum-based chemotherapy should be offered.

For patients with pMMR/MSS HER2-positive gastroesophageal adenocarcinoma with PD-L1 expression ≥1, treatment with a HER2-targeting antibody plus immunotherapy should be offered in combination with fluoropyrimidine- and platinum-based chemotherapy.

For patients with pMMR/MSS HER2-positive gastroesophageal adenocarcinoma with PD-L1 expression <1, treatment with a HER2-targeting antibody should be offered in combination with fluoropyrimidine- and platinum-based chemotherapy.

For patients with pMMR/MSS ESCC and PD-L1 expression ≥1, first-line therapy with immunotherapy in combination with fluoropyrimidine- and platinum-based chemotherapy or nivolumab plus ipilimumab may be offered.

For patients with pMMR/MSS ESCC with PD-L1 expression <1, first-line therapy with fluoropyrimidine- and platinum-based chemotherapy may be offered.

Immunotherapy in combination with fluoropyrimidine- and oxaliplatin-based chemotherapy may be offered.

Immunotherapy alone is an additional treatment option that may be offered on a case-by-case basis.

For patients with pMMR/MSS advanced gastroesophageal adenocarcinoma whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel may be offered.

For HER2-positive patients with gastric/GEJ adenocarcinoma and progressive disease after first-line therapy, trastuzumab deruxtecan should be offered.

For patients with ESCC whose disease has progressed after first-line combination chemotherapy without immunotherapy and with PD-L1 ≥1, nivolumab or tislelizumab may be offered, and for patients with PD-L1 ≥10, pembrolizumab may be offered.