What immunotherapy is used for stomach cancer (gastric cancer)?

Immunotherapy for Gastric Cancer

For advanced gastric cancer, nivolumab combined with chemotherapy is the preferred first-line immunotherapy for patients with PD-L1 CPS ≥5, while pembrolizumab is recommended for second-line treatment in MSI-H/dMMR tumors. 1

First-Line Immunotherapy Options

HER2-Negative Gastric Adenocarcinoma

For patients with PD-L1 CPS ≥5:

• Nivolumab plus fluoropyrimidine- and platinum-based chemotherapy is the standard first-line treatment 1
• This combination demonstrated significant improvements in overall survival (HR 0.71; 98.4% CI 0.59-0.86; P < 0.0001) and progression-free survival (HR 0.68; 98% CI 0.56-0.81; P < 0.0001) compared to chemotherapy alone 1
• The ESMO guidelines assign this regimen a Level I, A recommendation with an ESMO-MCBS score of 4 1

For patients with PD-L1 CPS 1-5:

• Nivolumab plus chemotherapy may be considered on a case-by-case basis, though the evidence is weaker 1, 2
• This represents a conditional recommendation based on extrapolation from the CPS ≥5 population 1

For patients with PD-L1 CPS 0:

• Fluoropyrimidine- and platinum-based chemotherapy alone without immunotherapy is recommended 1, 2
• Adding PD-1 inhibitors provides no benefit in this population 1

HER2-Positive Gastric/GEJ Adenocarcinoma

Trastuzumab plus pembrolizumab combined with fluoropyrimidine- and oxaliplatin-based chemotherapy is recommended as first-line treatment 1, 2

• This triple combination is FDA-approved for HER2-positive, PD-L1-positive tumors 3
• The KEYNOTE-811 trial demonstrated superior response rates with this regimen 1

MSI-H/dMMR Tumors

Pembrolizumab monotherapy demonstrates exceptional activity in MSI-H gastric cancer 1

• Objective response rate of 45.8% with median PFS of 11 months in previously treated patients 1
• Nivolumab plus chemotherapy showed significant OS benefit (HR 0.38; 95% CI 0.17-0.84) in MSI-H tumors 1
• These tumors have high response rates and excellent long-term outcomes with anti-PD-1 therapy 1

Second-Line and Later Immunotherapy

MSI-H/dMMR Gastric Cancer

Pembrolizumab is the standard second-line treatment for MSI-H/dMMR gastric cancer 1

• ESMO assigns this a Level II, A recommendation with ESMO-MCBS score of 3 and ESCAT score I-B 1
• Dostarlimab-gxly is an alternative anti-PD-1 option for MSI-H/dMMR tumors 1

Unselected Populations

Pembrolizumab monotherapy failed to improve survival as second-line treatment in unselected gastric cancer patients 1

• The KEYNOTE-061 trial showed no OS benefit compared to chemotherapy 1
• Pembrolizumab is therefore not recommended as second-line therapy unless the tumor is MSI-H/dMMR 1

Nivolumab monotherapy is approved in Japan as third-line or later treatment regardless of PD-L1 status 1

• This approval is based on the ATTRACTION-02 study showing superior OS 4, 5
• However, this is not standard practice in Western countries 1

Essential Biomarker Testing

Before initiating immunotherapy, the following biomarkers must be tested: 2

• PD-L1 CPS score - Critical for selecting nivolumab or pembrolizumab therapy 1
• HER2 status (IHC and FISH) - Determines eligibility for trastuzumab-based combinations 1
• MSI-H/dMMR status - Identifies patients who benefit most from anti-PD-1 monotherapy 1

The combined positive score (CPS) is preferred over tumor proportion score (TPS) for gastric cancer, as it includes PD-L1-positive lymphocytes and macrophages 1

Chemotherapy Backbone Selection

The preferred chemotherapy regimen with immunotherapy is fluoropyrimidine plus platinum 1, 2

• Oxaliplatin is preferred over cisplatin, especially for tolerability 1
• Acceptable fluoropyrimidines include 5-FU, capecitabine, or S-1 (in Asian populations) 1
• Taxane-based triplet chemotherapy is not recommended due to higher toxicity without proven survival benefit 1

Common Pitfalls and Caveats

Do not use pembrolizumab monotherapy as first-line treatment in unselected gastric cancer patients 1

• The KEYNOTE-062 trial showed pembrolizumab was non-inferior but had lower response rates and inferior PFS compared to chemotherapy 1
• Pembrolizumab monotherapy is only appropriate for MSI-H tumors or as part of combination therapy 1

PD-L1 testing methodology matters 1

• Use CPS scoring, not TPS, for gastric cancer 1
• Different cutoffs (CPS ≥1, ≥5, ≥10) have different levels of evidence 1

Trastuzumab should not be continued beyond first-line in HER2-positive gastric cancer 1

• However, trastuzumab deruxtecan may be considered in second-line (FDA-approved, not EMA-approved) 1

Geographic variations exist in approvals 1

• FDA approved nivolumab plus chemotherapy without PD-L1 restriction 1
• EMA requires PD-L1 CPS ≥5 for nivolumab plus chemotherapy 1
• Asian countries have broader approvals for nivolumab monotherapy 4, 5