What are the recommendations for immunotherapy in a patient with advanced or metastatic gastric carcinoma?

Immunotherapy for Gastric Carcinoma

For HER2-negative gastric adenocarcinoma with PD-L1 CPS ≥5, first-line treatment with nivolumab plus fluoropyrimidine- and platinum-based chemotherapy is the standard of care, demonstrating significant survival benefits with moderate toxicity. 1

First-Line Treatment Algorithm

Step 1: Biomarker Testing (Mandatory Before Treatment)

• Test PD-L1 expression using Combined Positive Score (CPS) - this includes PD-L1-positive tumor cells, lymphocytes, and macrophages, making it more prognostic than tumor proportion score (TPS) alone 1, 2
• Test HER2 status via immunohistochemistry (IHC) and in situ hybridization (ISH) if IHC is 2+ 1
• Test for microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) 1

Step 2: Treatment Selection Based on Biomarkers

For HER2-Negative Gastric Adenocarcinoma:

• PD-L1 CPS ≥5: Nivolumab 200 mg IV every 3 weeks plus fluoropyrimidine (5-FU, capecitabine, or S-1) and platinum (oxaliplatin preferred over cisplatin for tolerability) 1
• PD-L1 CPS 1-5: Consider nivolumab plus chemotherapy on a case-by-case basis, though evidence is weaker 1
• PD-L1 CPS 0: Fluoropyrimidine- and platinum-based chemotherapy alone, without nivolumab 1

For HER2-Positive Gastric or GEJ Adenocarcinoma:

• Trastuzumab 8 mg/kg loading dose (then 6 mg/kg) plus pembrolizumab 200 mg IV every 3 weeks plus fluoropyrimidine and oxaliplatin-based chemotherapy - this combination achieved 74% objective response rate versus 52% with trastuzumab-chemotherapy alone (p<0.0001) 1, 3
• HER2 positivity defined as IHC 3+ or IHC 2+ with positive ISH (ratio ≥2.0 or HER2 copy number >6) 1
• This regimen applies regardless of PD-L1 status, though 87% of trial patients had CPS ≥1 1, 3

For MSI-H/dMMR Tumors (Any Line):

• Pembrolizumab monotherapy is highly effective regardless of PD-L1 status, with Level II, A recommendation 1, 2
• Dostarlimab-gxly is an alternative anti-PD-1 option 2

Second-Line Treatment After Progression

For All Gastric/GEJ Adenocarcinoma:

• Ramucirumab 8 mg/kg IV plus paclitaxel is the standard second-line regimen, improving overall survival (HR 0.81,95% CI 0.68-0.96) and progression-free survival (HR 0.64,95% CI 0.54-0.75) 1
• Ramucirumab monotherapy is an option if paclitaxel is not tolerated 1
• Alternative single agents: docetaxel, paclitaxel, or irinotecan monotherapy 1

For HER2-Positive Disease After First-Line:

• Trastuzumab deruxtecan is recommended after progression on trastuzumab-based first-line therapy 1
• Do NOT continue trastuzumab beyond progression - the Japanese WJOG 7112G trial showed no benefit 1, 2

For MSI-H/dMMR Tumors:

• Pembrolizumab as second-line achieves Level II, A recommendation with ESMO-MCBS score of 3 1, 2

Third-Line and Beyond

• Trifluridine-tipiracil is recommended for patients who have progressed after two lines of therapy 1
• Nivolumab monotherapy is approved in Japan as third-line or later treatment regardless of PD-L1 status, based on the ATTRACTION-02 study 2, 4

Critical Pitfalls to Avoid

PD-L1 Testing Methodology

• Use CPS scoring, not TPS, for gastric cancer - CPS includes immune cells and is more predictive of immunotherapy benefit 1, 2
• Various cutoffs (≥1, ≥5, ≥10) have been used across trials; the panel acknowledges not all possible cutoffs have been assessed 1

Pembrolizumab Monotherapy Caution

• Do NOT use pembrolizumab monotherapy as first-line in unselected gastric cancer patients - it showed inferior progression-free survival compared to chemotherapy in KEYNOTE-061 and KEYNOTE-063 1, 2
• Pembrolizumab monotherapy is only appropriate for MSI-H/dMMR tumors or as second-line for PD-L1 CPS ≥1 1, 2

Chemotherapy Backbone Selection

• Oxaliplatin is preferred over cisplatin, especially for older patients, due to superior safety profile 1
• Acceptable fluoropyrimidines include IV 5-FU, oral capecitabine, or S-1 (primarily in Asian populations) 1
• Avoid triplet chemotherapy regimens (fluoropyrimidine + platinum + taxane) as first-line due to higher toxicity without clear survival benefit over doublets 1

Duration of Immunotherapy

• Continue immunotherapy until RECIST v1.1-defined progression, unacceptable toxicity, or maximum 24 months 1, 3
• Patients without progression at 24 months should discontinue immunotherapy 1

Toxicity Monitoring

• Ramucirumab: Monitor for bleeding, hypertension, proteinuria, and thromboembolic events 1
• Trastuzumab: Assess left ventricular ejection fraction (LVEF) before initiating therapy due to cardiac failure risk 1
• Immune checkpoint inhibitors: Monitor for immune-related adverse events affecting any organ system 1

Clinical Trial Participation

In all cases, participation in a clinical trial is strongly recommended, as the panel expects targeted treatment options for gastroesophageal cancer will continue to evolve rapidly 1