ASCO Updates Guideline on Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer
New ASCO guideline emphasizes biomarker-driven treatment for advanced gastroesophageal cancer, recommending upfront testing for HER2, PD-L1, MSI/MMR, and CLDN18.2 to guide immunotherapy and targeted therapy selection.
A new guideline update on immunotherapy and targeted therapy for advanced gastroesophageal cancer has been published in the Journal of Clinical Oncology. The guideline emphasizes biomarker testing and biomarker-driven treatment strategies for patients with advanced disease.
The guideline recommends upfront testing for HER2, PD-L1, MSI/MMR, and CLDN18.2. For patients with PD-L1 ≥1, immunotherapy plus platinum/fluoropyrimidine chemotherapy is recommended, with greater benefit observed as PD-L1 increases, especially at ≥10. For CLDN18.2-positive disease, zolbetuximab plus chemotherapy is now a standard option. In HER2-positive, PD-L1 ≥1 disease, pembrolizumab plus trastuzumab plus chemotherapy is recommended. For dMMR/MSI-H disease, immunotherapy-based strategies remain foundational.
Immune checkpoint inhibitors have transformed the treatment landscape for gastroesophageal cancers and are now standard of care in the first-line setting for advanced disease when combined with chemotherapy. Three approved PD-1 inhibitors—nivolumab, pembrolizumab, and tislelizumab—are supported by pivotal trials CheckMate-649, KEYNOTE-590, and RATIONALE-305, respectively. The addition of immunotherapy to chemotherapy improved overall survival compared with chemotherapy alone, but greater benefit was observed at higher PD-L1 expression.
For HER2-positive disease, trastuzumab-based therapy provides survival benefits established in the ToGA trial. The addition of pembrolizumab in PD-L1–positive tumors is supported by findings from KEYNOTE-811.
For CLDN18.2–positive disease, zolbetuximab demonstrated survival benefits in the SPOTLIGHT and GLOW trials, in which approximately 20%-30% of patients were alive at 2 years.
In localized disease, the MATTERHORN study showed perioperative durvalumab plus FLOT provided improvements in event-free and overall survival versus chemotherapy. Localized dMMR disease may be treated with immunotherapy alone, while metastatic disease may be managed with either chemotherapy plus immunotherapy or immunotherapy combinations.
Most PD-L1-positive patients benefit from and tolerate immunotherapy, although autoimmune conditions such as Crohn's disease or ulcerative colitis may represent relative contraindications. Early recognition and management of treatment-related toxicities is important to optimize patient benefit.
The guideline authors noted that antibody–drug conjugates and bispecific antibodies are poised to further reshape the treatment landscape in the years ahead.