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IO Therapy in Gastric GEJ Cancers
Biomarker Analysis and Immunotherapy-Based Treatment of Advanced Gastric/GEJ Cancers

Released: July 21, 2026

Jaffer A. Ajani
Jaffer A. Ajani, MD
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Key Takeaways
  • Four biomarkers—claudin 18.2, HER2, MSI, and PD-L1—should be assessed in patients with newly diagnosed advanced gastric/GEJ carcinoma.
  • Nivolumab, pembrolizumab, and tislelizumab are approved in combination with chemotherapy for patients with newly diagnosed advanced gastric/GEJ carcinoma with a PD-L1 CPS ≥1.
  • SC formulations of nivolumab and pembrolizumab are approved for administration in patients with gastric/GEJ cancers.

Biomarkers Determine Therapy Selection for Treatment of Advanced Gastric/GEJ

Jaffer Ajani, MD:
The standard of care in advanced/metastatic unresectable gastric cancer or gastroesophageal junction (GEJ) carcinoma includes doublet chemotherapy unless the tumor is positive for a biomarker, which necessitates the addition of another appropriate agent to this regimen or potentially the use of immunotherapy alone. All major guidelines recommend immunohistochemistry (IHC) testing for 4 tumor biomarkers in untreated patients with newly diagnosed metastatic gastric/GEJ adenocarcinoma, including claudin 18.2, HER2, mismatch repair deficient (dMMR)/microsatellite instability (MSI)–high, and PD-L1. In patients with previously treated advanced gastric/GEJ adenocarcinoma, the detection of additional biomarkers including NTRK and RET gene fusions, BRAF mutations, and tumor mutational burden (TMB) can further guide therapy decisions.

For newly diagnosed patients with claudin 18.2–positive tumors (≥75% tumor cells expressing CLDN 18.2 at 2+ or 3+ intensity), adding zolbetuximab, an anti–claudin 18.2 antibody, to chemotherapy in gastric/GEJ adenocarcinoma led to longer progression-free survival (PFS) and improved overall survival (OS) compared with chemotherapy alone. More specifically, in the combined analysis of 2 clinical trials, SPOTLIGHT and GLOW, the median PFS was 9.2 months among the patient group (n = 537) treated with zolbetuximab plus chemotherapy compared with 8.2 months in the placebo plus chemotherapy group (n = 535; HR: 0.71; CI: 0.61-0.83). In addition, the median overall survival (mOS) was 16.4 months with zolbetuximab added, compared with 13.7 months in the placebo group (HR: 0.77; CI: 0.67-0.89)

In gastric and GEJ carcinomas, HER2 alterations are seen in approximately 15% of cases, with HER2 amplification being the most common alteration. With equivocal HER2 IHC 2+ test results, it is important to reflex to in situ hybridization testing to accurately determine HER2 status and eligibility for HER2-targeted therapy. Patients with newly diagnosed advanced HER2-positive gastric/GEJ tumors (HER2 IHC 3+) should receive trastuzumab plus chemotherapy. In a subgroup analysis, the combination improved OS in HER2-positive patients (IHC 2+ and FISH positive or IHC 3+) to 16 months compared with 11.8 months in HER2-negative tumors.

Another biomarker in gastric and GEJ carcinomas is MSI. It is considered a treatment biomarker because in the newly diagnosed patient population with MSI-high tumors (≥30% markers exhibiting instability or loss of 1 of 4 DNA damage repair proteins: MLH1, PMS2, MSH2, MSH6), there was tremendous benefit from immunotherapy. Therefore, for first-line therapy of advanced gastric/GEJ disease, the population with MSI-high tumors may receive immunotherapy—pembrolizumab, dostarlimab, nivolumab, or ipilimumab/nivolumab. Chemotherapy is not recommended for patients with MSI-high/dMMR tumors because they are more responsive to immunotherapy. Therefore, healthcare professionals (HCPs) can start a patient on immunotherapy and then add chemotherapy later depending on testing results. They may also screen these patients for Lynch Syndrome. Finally, in rare patients (<1%) with advanced gastric/GEJ biomarker-negative disease—HER2-negative, PD-L1 negative (combined positive score [CPS] <1), claudin 18.2 negative (<75% of tumor cells), MSI-high negative (ie, MSI-low or 1%-29% of markers exhibiting instability)—chemotherapy alone is used.

Immunotherapy in Advanced Gastric/GEJ Cancer

Jaffer Ajani, MD:
Patients with a PD-L1–positive tumor (CPS ≥1; 37% of patients) are candidates to receive 1 of the 3 PD-1 inhibitors that are approved in combination with chemotherapy: pembrolizumab, nivolumab, or tislelizumab. If the tumor is PD-L1 negative (CPS <1), the patient should not receive anti–PD-1 because they will not benefit from the immunotherapy but will experience toxicity. We do not want to recommend a drug to a patient knowing that the likelihood of benefit is near zero and the likelihood of toxicity is certainly there.

Patients with gastroesophageal adenocarcinoma tumors who have higher CPS scores (CPS ≥5) in their PD-L1–positive tumors have a better OS compared with those with CPS 1 to <5 if they receive treatment with immunotherapy. This was evidenced by the 5-year follow-up of the phase III CheckMate 649 trial, where the OS of cohorts with PD-L1–positive CPS ≥1 (HR: 0.76), CPS ≥5 (HR: 0.71), and CPS ≥10 (HR: 0.68) demonstrated that a higher CPS correlates with a better outcome achieved from nivolumab. The survival curve for the cohort of patients with a CPS ≥5 has a tail of approximately 15% to 18% of patients with durable benefit extending to 85 months, which is remarkable. For this cohort of patients with CPS ≥5, the mOS was 14.4 months (CI: 13.1-16.2) for nivolumab plus chemotherapy compared with 11.1 months (CI: 10.1-12.1) for chemotherapy alone. But looking at the smaller patient population with CPS ≥10, there is an even higher percentage of patients with durable benefit (17%-20%), extending to 84 months. For this cohort of patients with CPS ≥10, the mOS was 15.0 months (CI: 13.6-16.7) with nivolumab plus chemotherapy compared with 10.9 months (CI: 9.9-12.0) for chemotherapy alone. Similar results were observed in the phase III KEYNOTE 859 trial evaluating pembrolizumab plus chemotherapy compared with placebo plus chemotherapy. For patients with CPS ≥1, the mOS was 13.0 months (range: 11.6-14.2) vs 11.4 months (range: 10.5-12.0) (HR: 0.74), and for patients with CPS ≥10, the mOS was 15.8 months (range: 14.0-19.3) vs 11.8 months (range: 10.3-12.7) (HR: 0.64). Trends for overall response rate and PFS mimicked the OS results, and patients with CPS ≥10 had a remarkable OS tail lasting beyond 3 years. Finally, the phase III RATIONALE-305 trial evaluating tislelizumab plus chemotherapy demonstrated superior OS (HR: 0.79; P = .0003) in the intention-to-treat population of tislelizumab plus chemotherapy vs placebo plus chemotherapy (15.0 vs 12.9 months, respectively), showing a clear advantage of the addition of tislelizumab. For this clinical trial, instead of evaluating CPS, Tumor Area Positivity (TAP) score was used to evaluate PD-L1 positivity. The stratified data include the intention-to-treat population compared with PD-L1 TAP score ≥ 5%. The OS was 16.4 (CI: 13.6-19.1) months in the cohort treated with tislelizumab and chemotherapy vs 12.8 (CI: 12.0-14.5) months in the placebo group (HR: 0.71). All 3 immune checkpoint inhibitors (ICIs), nivolumab, pembrolizumab, and tislelizumab, seem to produce very similar clinical results, and there is a group of patients who are living beyond 3 years, which is highly desirable. Therefore, with immunotherapy and a tumor with high CPS, an HCP can discuss the possibility of very long-term benefit with their patient.

ICIs in SC Formulation Approved in Gastric/GEJ

Jaffer Ajani, MD:
The ICIs nivolumab and pembrolizumab are approved for SC administration (tislelizumab is approved as IV), which may be advantageous for patients. There is an ongoing clinical trial, a single-arm phase II study called Cancer CARE, that is currently assessing patient comfort level and their preferred location for immunotherapy administration, either at home or in the clinic. Patients in this trial receive 2 cycles of SC nivolumab in clinic and then switch to at-home care for 4 cycles. At that point, some participants will resume their treatment back in the clinic. This will inform HCPs on future prescribing preferences with IV and SC formulations.

An advantage of SC administration is the reduced time spent at the clinic and particularly in the maintenance phase. Patients can have their blood drawn and then come home and get their drug injection. In addition, it may be that the lower systemic exposure in circulation with SC administration will produce some advantages. Another advantage of the SC administration is that it removes the need for a port.

By contrast, the challenges that emerge with transitioning from IV to SC administration include a requirement for more individuals to assist the patient at home. Patients may need a nurse to come to their homes, which can be challenging in some circumstances. Home administration also reduces opportunities for patients to bond with one another in person and increases the need for online patient support communities. Finally, the SC injection can produce a local skin reaction because the immune milieu of skin is different than when immunotherapy is given via IV. There are some safety concerns with SC formulations, including the immune response of the host, whereby the host could form antidrug antibodies (ADAs) that neutralize the drug. Theoretically, there is a possibility of that happening with SC injection because of the skin’s highly active immune environment within the subcutaneous layer; however, available clinical data suggest that the development of ADAs is not common. One study showed a comparable increase of 1.6% in ADAs occurring in the SC compared with the IV formulation.

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