Non-small cell lung cancer (NSCLC) arises when epithelial cells lining the bronchial tubes undergo aberrant cell growth due to upregulation of programmed death (PD-1) ligands, thereby affording evasion of immune surveillance. Pembrolizumab, a monoclonal antibody, is an immune checkpoint inhibitor. By blocking PD-1 from binding its ligands, i.e. programmed death ligand (PD-L1) and programmed death ligand 2 (PD-L2), pembrolizumab restores T-cell activation, thus enabling effective detection and destruction of tumour cells.

In the phase III, KEYNOTE-189 study, 616 patients with untreated metastatic non-squamous NSCLC without targetable epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) aberrations -regardless of PD-L1 expression- were randomised 2:1 to pemetrexed and platinum-based chemotherapy plus either pembrolizumab or saline placebo every three weeks for four cycles, followed by pembrolizumab or placebo for 35 cycles plus pemetrexed maintenance therapy. Adding pembrolizumab to chemotherapy conferred longer overall survival (OS) than chemotherapy alone (not reached versus 11.3 months). Compared with chemotherapy alone, pembrolizumab increased progression-free survival (PFS) by 3.9 months. Increased PFS was consistent across subgroups except for patients with PD-L1 tumour proportion scores (TPS) <1% and those over 65 years of age. Pembrolizumab increased the overall response rate (ORR) by 28.7% and the median duration of response (DOR) by 3.4 months compared with chemotherapy alone. Anaemia and neutropenia were the most frequently reported adverse events (AEs) of grade ≥3 in severity. Common immune-mediated AEs occurring in pembrolizumab combination patients included hypothyroidism (6.7%), hyperthyroidism (4.0%), colitis (2.2%), nephritis (1.7%), and hepatitis (1.2%).

Overall, adding pembrolizumab to platinum-based chemotherapy increases OS, PFS, and ORR, and reduces the risk of death and progression for patients with metastatic NSCLC. While the survival benefit of pembrolizumab combination over chemotherapy alone was observed regardless of PD-L1 tumour expression, the greatest relative benefit was achieved in patients whose tumours exhibited higher PD-L1 levels. Due to possible cross-overs (to the intervention grup), only relative 12 month OS data are available; absolute OS data are not (and will not) be available. Data regarding quality of life and central nervous system activity are needed to ensure patients derive a clinically relevant benefit over time despite manageable toxicity. Without direct comparison trials, physicians may need to discuss whether adding pembrolizumab to platinum-based chemotherapy would provide patients with greater individualised efficacy than pembrolizumab monotherapy.