What is the significance of Programmed Death-Ligand 1 (PD-L1)?

From the Guidelines

Pembrolizumab is the recommended treatment for patients with metastatic NSCLC and high tumor PD-L1 expression (≥ 50%), as it significantly improves median progression-free survival and overall survival compared to platinum-based chemotherapy. This is based on the results of the phase III KEYNOTE-024 study 1, which demonstrated a significant PFS benefit with pembrolizumab in the SqCLC subgroup. The study found that pembrolizumab monotherapy improved median PFS and OS versus platinum-based chemotherapy, with a hazard ratio of 0.50 for PFS and 0.63 for OS.

Key Findings

• Pembrolizumab significantly improved median PFS (10.3 vs 6.0 months) and OS (not reached vs 14.5 months) compared to platinum-based chemotherapy in patients with metastatic NSCLC and high PD-L1 expression 1.
• The significant PFS benefit with pembrolizumab was particularly pronounced in the SqCLC subgroup, with a hazard ratio of 0.35 1.
• Pembrolizumab was also associated with a clinically relevant improvement in health-related quality of life and fewer treatment-related adverse events than chemotherapy 1.

Clinical Implications

• PD-L1 testing is essential in determining which patients may benefit from pembrolizumab therapy.
• Patients with metastatic NSCLC and high PD-L1 expression (≥ 50%) should be considered for pembrolizumab as a first-line treatment option.
• The use of pembrolizumab in combination with other therapies may also be beneficial in certain patients, although this requires further study.

From the FDA Drug Label

Of the 419 patients, 48% had PD-L1 positive ESCC, defined as ≥1% of tumor cells expressing PD-L1. The remaining 52% had PD-L1 negative ESCC defined as <1% of tumor cells expressing PD-L1. In a pre-specified exploratory analysis by PD-L1 status, the hazard ratio (HR) for OS was 0.69 (95% CI: 0.51,0.94) with median survivals of 10.9 and 8. 1 months for the OPDIVO and investigator’s choice arms, respectively, in the PD-L1 positive subgroup. In the PD-L1 negative subgroup, the HR for OS was 0.84 (95% CI: 0.62,1.14) with median survivals of 10.9 and 9.3 months for the OPDIVO and investigator’s choice arms, respectively.

PD-L1 status is defined as ≥1% of tumor cells expressing PD-L1 for positive status and <1% for negative status.

• PD-L1 positive patients had a hazard ratio (HR) for OS of 0.69 (95% CI: 0.51,0.94) with median survivals of 10.9 and 8.1 months for the OPDIVO and investigator’s choice arms, respectively.
• PD-L1 negative patients had a HR for OS of 0.84 (95% CI: 0.62,1.14) with median survivals of 10.9 and 9.3 months for the OPDIVO and investigator’s choice arms, respectively 2.

From the Research

PD-L1 Expression and Immunotherapy

• PD-L1 expression has emerged as a potential biomarker for selection of patients more likely to respond to immunotherapy and as a prognostic factor in non-small cell lung cancer (NSCLC) 3.
• Studies have shown that PD-L1 inhibitor monotherapy improves efficacy outcomes in the first line setting of advanced NSCLC patients with high PD-L1 expression 3, 4.
• Pembrolizumab, a monoclonal antibody directed at PD-1, has been explored as a treatment for solid tumors, including NSCLC, and demonstrated survival benefits in several studies 5, 6.

Mechanisms of PD-L1 Regulation

• The factors associated with PD-L1 expression are still not well understood, but genomic alterations that activate KRAS, EGFR, and ALK, as well as the loss of PTEN, have been associated with increased PD-L1 expression 7.
• PD-L1 expression can be modulated by either tumor extrinsic or intrinsic factors, including interferon-γ release by immune cells and activation of the mechanistic target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Myc pathways 7.

Clinical Implications

• Pembrolizumab may be a better first-line treatment than chemotherapy for many patients with advanced non-small cell lung cancer, particularly those with PD-L1 expression of 1% or higher 4, 6.
• The use of PD-1 inhibitors such as nivolumab and pembrolizumab in advanced cancers is widespread, and pembrolizumab is available in more than 60 countries for at least one of the following: advanced melanoma, PD-L1-expressing NSCLC, head and neck squamous cell carcinoma, and adult and pediatric patients with refractory classical Hodgkin's lymphoma 5.