PD-1 and PD-L1 Inhibitors in Cancer Treatment

Safety Profile Differences

The National Comprehensive Cancer Network recommends monitoring patients more closely for pneumonitis when using PD-1 inhibitors, especially in patients with non-small cell lung cancer or pre-existing lung disease 1, 2
PD-1 inhibitors cause more immune-related adverse events, particularly pneumonitis and hypothyroidism, compared to PD-L1 inhibitors, with an overall incidence of 16% versus 11% for PD-L1 inhibitors (P=0.07) 1, 2
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, 2
High-grade pneumonitis is also more common with PD-1 inhibitors: 1.1% versus 0.4% (P=0.02) 1, 2
Hypothyroidism is more frequent with PD-1 inhibitors: 6.7% versus 4.2% (P=0.07) 1, 2

The Journal for ImmunoTherapy of Cancer notes that both PD-1 and PD-L1 blockade may reactivate latent tuberculosis and other opportunistic infections, requiring screening in high-risk patients 3
Combined PD-1 plus CTLA-4 blockade causes substantially more irAEs than PD-1 monotherapy: 55-60% high-grade events versus 10-20% 1, 4
Treatment discontinuation due to adverse events occurs in 39% with combination therapy versus 12% with PD-1 monotherapy 1, 4

In melanoma patients treated with PD-1 inhibitors, there is a higher incidence of GI and skin irAEs but lower pneumonitis compared to NSCLC patients 1, 4
Renal cell carcinoma patients experience a higher frequency of pneumonitis and dyspnea compared to melanoma patients 1, 4

PD-1 is a cell surface receptor that functions as a T cell checkpoint and negatively regulates T cell function, expressed on activated immune cells including T cells, and is a key component in the regulation of immune responses 5, 6
PD-L1 is a co-regulatory molecule and ligand that binds to the PD-1 receptor, expressed on tumor cells and antigen-presenting cells in the tumor microenvironment 5, 6

The interaction between PD-1 and PD-L1 inhibits T-cell–mediated cell death, allowing tumor cells to evade immune surveillance, and blockade of the PD-1/PD-L1 axis promotes T cell activation and immune killing of cancer cells 5, 6
The PD-1/PD-L1 axis plays a key role in modulating immune responses, and its blockade has been shown to be an effective strategy in cancer immunotherapy 7

Checkpoint inhibitor antibodies can target either PD-1 or PD-L1 to block their interaction, including anti-PD-1 antibodies such as nivolumab and pembrolizumab, and anti-PD-L1 antibodies such as avelumab and atezolizumab 5, 6, 7
PD-L1 expression testing is recommended for all patients with newly diagnosed advanced non-small cell lung cancer to guide treatment decisions, using immunohistochemistry assays evaluating membranous immunostaining of tumor cells 7
The relationship between PD-1/PD-L1 expression, microsatellite instability, and tumor mutational burden is complex and differs according to tumor types, highlighting the need for further research in this area 8, 9