What is the significance of PD-L1 (Programmed Death-Ligand 1) expression using the 22C3 antibody in non-small cell lung cancer (NSCLC) for FDA-approved treatments like pembrolizumab (pembrolizumab)?

PD-L1 22C3 FDA for NSCLC: Understanding PD-L1 Expression

PD-L1 22C3 FDA for NSCLC refers to the FDA-approved companion diagnostic test that measures PD-L1 expression in non-small cell lung cancer using the 22C3 antibody, which determines eligibility for pembrolizumab therapy based on tumor proportion score (TPS). This test is critical for identifying patients who will benefit from immunotherapy treatment with pembrolizumab.

What is PD-L1 Expression?

PD-L1 (Programmed Death-Ligand 1) is a key immunoregulatory molecule that:

• When interacting with its receptor PD-1, inhibits CD8+ cytotoxic immune response
• Is overexpressed on tumor cells in many cancers, including NSCLC
• Plays an important role in modulating immune response to both tumor and host cells 1

The 22C3 Antibody Test for NSCLC

The PD-L1 IHC 22C3 pharmDx assay:

• Is an FDA-approved companion diagnostic test for pembrolizumab use in NSCLC
• Measures PD-L1 expression as a Tumor Proportion Score (TPS)
• TPS is calculated as the percentage of viable tumor cells showing partial or complete membrane staining 2

Clinical Significance of PD-L1 TPS Scores

PD-L1 expression levels are categorized into three groups:

• Negative: TPS <1%
• Low expression: TPS 1-49%
• High expression: TPS ≥50% 3

These categories directly determine treatment eligibility:

• TPS ≥50%: Eligible for pembrolizumab as first-line monotherapy
• TPS ≥1%: Eligible for pembrolizumab as first-line treatment for patients with no EGFR or ALK genomic tumor aberrations who are not candidates for surgical resection or definitive chemoradiation, or have metastatic disease 4
• TPS ≥1%: Eligible for pembrolizumab as second-line therapy after progression on platinum-containing chemotherapy 2

Clinical Outcomes Based on PD-L1 Expression

The level of PD-L1 expression correlates with treatment response:

• Patients with TPS ≥50% show significantly better outcomes:
  • Higher objective response rate (51.9% vs 26.7% in overall population)
  • Better 12-month progression-free survival (54% vs 35%)
  • Improved 12-month overall survival (85% vs 71%) 5

Important Considerations and Pitfalls

1. Heterogeneity of PD-L1 expression:

   • Discordance rates of 31.4% between biopsy and resected specimens
   • Discordance rates of 35.8% between different blocks from the same specimen
   • Discordance rates of 28.6% between primary tumors and lymph node metastases 3

2. Testing platform considerations:

   • The 22C3 antibody was validated on the Dako Autostainer Link 48 platform
   • Laboratory-developed tests using the 22C3 antibody concentrate on other platforms (like VENTANA BenchMark ULTRA) show high concordance with the FDA-approved test 6

3. Testing sequence:

   • PD-L1 testing should ideally be performed after testing for EGFR mutations, ALK rearrangements, and ROS1 rearrangements
   • Patients with these genetic alterations should receive targeted therapy rather than immunotherapy, regardless of PD-L1 expression 2

4. Dynamic nature of PD-L1 expression:

   • PD-L1 expression is continuously variable and dynamic
   • Cutoff values for positive results are somewhat artificial
   • Patients with TPS just below and just above 50% may have similar responses 2

Practical Implications

For oncologists managing NSCLC patients:

• Order PD-L1 testing using the 22C3 antibody for all newly diagnosed advanced NSCLC patients
• Consider repeat testing if initial results are negative but clinical suspicion for response to immunotherapy is high
• Interpret results in context with other molecular markers (EGFR, ALK, ROS1)
• Use TPS score to guide treatment decisions according to FDA-approved indications

The PD-L1 22C3 test is a critical biomarker that helps identify patients who will benefit from pembrolizumab therapy, potentially leading to significant improvements in survival and quality of life for appropriate NSCLC patients.