In a patient with advanced gastric or gastro‑oesophageal junction cancer, how do I differentiate between Vyloy (zolbetuximab) and pembrolizumab regarding biomarker eligibility, line of therapy, and safety profile?

Differentiating Vyloy (Zolbetuximab) and Pembrolizumab in Advanced Gastric Cancer

Vyloy (zolbetuximab) and pembrolizumab target completely different biomarkers and patient populations: zolbetuximab requires CLDN18.2-positive (≥75% tumor cells) and HER2-negative status for first-line therapy, while pembrolizumab requires PD-L1 CPS ≥10 (or MSI-H/dMMR status) and is used across multiple lines of therapy. 1

Biomarker Eligibility: The Critical Differentiator

Zolbetuximab (Vyloy) Requirements

• CLDN18.2 positivity: ≥75% of tumor cells must show moderate-to-strong membranous staining on immunohistochemistry 1
• HER2-negative status: Mandatory requirement (IHC 0-1+ or IHC 2+ with negative FISH) 1
• No PD-L1 testing required for zolbetuximab eligibility 1

Pembrolizumab Requirements

• PD-L1 CPS ≥10: For gastric/GEJ adenocarcinoma in first-line setting 1
• PD-L1 CPS ≥1: May be considered on case-by-case basis for esophageal/GEJ adenocarcinoma 1
• MSI-H/dMMR status: Pembrolizumab is highly effective regardless of PD-L1 status (HR 0.38 for OS) 1
• HER2 status: Can be used in HER2-positive disease when combined with trastuzumab and chemotherapy 1

Line of Therapy: Sequential vs. Restricted Use

Zolbetuximab

• First-line only: Approved exclusively for treatment-naïve patients with unresectable locally advanced or metastatic disease 1
• Combination requirement: Must be given with fluoropyrimidine- and platinum-based chemotherapy (mFOLFOX6 or CAPOX) 1
• Category 1 recommendation by NCCN as preferred first-line option when biomarkers match 1

Pembrolizumab

• First-line: Combined with chemotherapy for PD-L1 CPS ≥10 in gastric cancer 1
• Second-line: Monotherapy for MSI-H/dMMR tumors after progression on first-line therapy 1, 2
• Third-line and beyond: For patients with PD-L1 positive tumors who have exhausted other options 1

Efficacy Profile: Location-Specific Differences

Zolbetuximab Performance by Tumor Location

Critical caveat: Zolbetuximab shows markedly different efficacy based on primary tumor site 1

• Gastric adenocarcinoma: Strong benefit with HR 0.67-0.72 for overall survival 1
• GEJ adenocarcinoma: Minimal to no benefit with HR 1.01-1.07 for overall survival 1
• Overall survival benefit: SPOTLIGHT trial showed median OS 18.23 vs 15.54 months (HR 0.75); GLOW trial showed 14.39 vs 12.16 months (HR 0.77) 1

This is a critical pitfall: Do not use zolbetuximab for GEJ tumors despite CLDN18.2 positivity, as subgroup analyses demonstrate lack of benefit 1

Pembrolizumab Performance by Tumor Location

• Gastric adenocarcinoma: HR 0.64 for OS with nivolumab (similar PD-1 inhibitor) in CPS ≥5 population 1
• GEJ adenocarcinoma: HR 0.82 for OS with nivolumab in CPS ≥5 population 1
• MSI-H tumors: Exceptional response regardless of location (HR 0.38 for OS) 1

Safety Profile: Distinct Toxicity Patterns

Zolbetuximab-Specific Adverse Events

• Gastrointestinal toxicity predominates: Nausea (63-90%, grade ≥3 in 4.8-6.7%) and vomiting (33-67%, grade ≥3 in 6.7-9.5%) 3
• Hematologic toxicity: Anemia and neutropenia (grade ≥3) when combined with chemotherapy 1
• Decreased appetite: Common grade ≥3 adverse event in SPOTLIGHT trial 1
• No immune-related adverse events as zolbetuximab is not an immune checkpoint inhibitor 3

Pembrolizumab-Specific Adverse Events

• Immune-related adverse events: Can affect any organ system; requires vigilant monitoring 2
• Lower overall toxicity as monotherapy: Grade 3-5 treatment-related AEs only 17% vs 69% with chemotherapy 4
• When combined with chemotherapy: Grade 3-5 AEs approximately 73%, similar to chemotherapy alone 4
• Specific immune toxicities: Nephritis, colitis, pneumonitis, hepatitis, endocrinopathies 5

Clinical Decision Algorithm

Step 1: Confirm HER2 Status

• HER2-positive: Consider trastuzumab + pembrolizumab + chemotherapy (if PD-L1 CPS ≥1) 1, 6
• HER2-negative: Proceed to Step 2 1

Step 2: Test CLDN18.2 and PD-L1

• CLDN18.2 ≥75% AND gastric primary (not GEJ): Zolbetuximab + chemotherapy is preferred first-line 1
• CLDN18.2 ≥75% BUT GEJ primary: Do NOT use zolbetuximab; proceed to PD-L1-based decision 1
• CLDN18.2 <75%: Proceed to PD-L1-based decision 1

Step 3: PD-L1/MSI Status Determines Immunotherapy

• MSI-H/dMMR: Pembrolizumab + chemotherapy first-line OR nivolumab + ipilimumab (any line) 1, 2
• PD-L1 CPS ≥10: Pembrolizumab + chemotherapy first-line 1
• PD-L1 CPS 5-9: Nivolumab + chemotherapy preferred over pembrolizumab 1
• PD-L1 CPS 1-4: Consider immunotherapy on case-by-case basis for GEJ/esophageal tumors 1
• PD-L1 CPS 0: Chemotherapy alone first-line; reserve pembrolizumab for later lines if MSI-H 1

Common Pitfalls to Avoid

Do not use zolbetuximab for GEJ tumors despite CLDN18.2 positivity—subgroup analyses from SPOTLIGHT/GLOW trials show HR >1.0 for GEJ location 1

Do not assume CLDN18.2 testing is widely available—it is not currently commercially available in many centers, limiting zolbetuximab use 1

Do not use pembrolizumab monotherapy in first-line for non-MSI-H gastric cancer—KEYNOTE-062 showed it was noninferior but not superior to chemotherapy, with worse PFS 1, 4

Do not overlook MSI-H status—this predicts exceptional response to pembrolizumab (HR 0.38) regardless of PD-L1 expression 1

Do not continue trastuzumab beyond first-line in HER2-positive disease—switch to trastuzumab deruxtecan after progression 1, 2, 6