Difference Between PD-1 and PD-L1 Inhibitors
PD-1 inhibitors block the receptor on immune cells while PD-L1 inhibitors block the ligand on tumor cells, and PD-1 inhibitors cause more immune-related adverse events—particularly pneumonitis and hypothyroidism—compared to PD-L1 inhibitors, though both achieve similar efficacy in cancer treatment. 1
Molecular Mechanism and Target Location
PD-1 Inhibitors
- Target the receptor on activated immune cells, specifically T cells, preventing the inhibitory signal that would normally suppress T cell function 2, 3
- Block PD-1 expressed on the surface of T cells and other activated immune cells 2
- FDA-approved agents include nivolumab (Opdivo) and pembrolizumab (Keytruda) 2, 4
PD-L1 Inhibitors
- Target the ligand expressed on tumor cells and antigen-presenting cells in the tumor microenvironment 2, 5
- Block PD-L1 on tumor cells, preventing it from binding to PD-1 receptors 5, 6
- FDA-approved agents include atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio) 2, 4
Functional Outcome
- Both approaches achieve the same end result: disrupting the PD-1/PD-L1 interaction to restore T cell-mediated tumor killing 2, 5
- The blockade prevents tumor cells from evading immune surveillance and promotes T cell activation 2, 3
Safety Profile Differences
PD-1 Inhibitors Have Higher Toxicity
- Overall immune-related adverse events (irAEs) trend higher with PD-1 inhibitors: 16% versus 11% for PD-L1 inhibitors (P=0.07) 1
- Pneumonitis occurs twice as frequently with PD-1 inhibitors: 4% versus 2% (P=0.01) for any-grade, and 3.6% versus 1.3% (P=0.001) in another meta-analysis 1
- High-grade pneumonitis is also more common: 1.1% versus 0.4% (P=0.02) 1
- Hypothyroidism is more frequent with PD-1 inhibitors: 6.7% versus 4.2% (P=0.07) 1
Severe Toxicity Rates Are Similar
- The incidence of severe (high-grade) irAEs is not significantly different: 5% for PD-1 versus 3% for PD-L1 inhibitors (P=0.4) 1
- Both classes can cause vitiligo, thyroid dysfunction, hepatotoxicity, and pneumonitis, though frequencies differ 1
Clinical Implication
- Monitor more closely for pneumonitis when using PD-1 inhibitors, especially in patients with non-small cell lung cancer or pre-existing lung disease 1
- The safety data for PD-L1 inhibitors are still maturing, with ongoing data collection 1
Clinical Efficacy Considerations
Biomarker Testing
- PD-L1 expression testing is recommended for all patients with newly diagnosed advanced NSCLC to guide treatment decisions 2, 5
- Testing uses immunohistochemistry assays evaluating membranous immunostaining of tumor cells 2, 5
- PD-L1 is not a perfect biomarker: less than half of biomarker-selected patients benefit, and some responses occur in biomarker-negative cohorts 5
Treatment Selection
- Either PD-1 or PD-L1 inhibitors can be selected based on FDA approvals for specific cancer types, as both block the same pathway 2, 4
- The choice between PD-1 and PD-L1 inhibitors should factor in the lower pneumonitis risk with PD-L1 agents when treating patients with baseline lung compromise 1
Important Clinical Pitfalls
Infectious Complications
- Both PD-1 and PD-L1 blockade may reactivate latent tuberculosis and other opportunistic infections, requiring screening in high-risk patients 1
- The immune modulation can unmask chronic underlying infections with detrimental effects on outcomes 1
Combination Therapy Toxicity
- Combined PD-1 plus CTLA-4 blockade causes substantially more irAEs than PD-1 monotherapy: 55-60% high-grade events versus 10-20% 1
- Treatment discontinuation due to adverse events occurs in 39% with combination therapy versus 12% with PD-1 monotherapy 1