Checkpoint inhibitors after chemoradiation: is it ready for prime time?

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death in the United States (1). About a third of the patients diagnosed with NSCLC are diagnosed at a locally advanced stage (stage III). Despite concurrent chemoradiation, the outcome for patients diagnosed with locally advanced NSCLC is very poor with a 5-year survival of <20% (2-4). Recently a new class of drugs blocking the immune checkpoint pathways have revolutionized the treatment paradigm for many solid tumors (5). Immune checkpoint pathways serve a critical role in maintaining immune-homeostasis and inducing immune tolerance to self. Immune checkpoint pathways, particularly the programmed death-1 (PD-1) axis is often co-opted by cancer cells to evade the anti-tumor immune response (6-8). Several such drugs targeting the PD-1 axis are approved by the United States Food and Drug Administration (US-FDA) for treating patients with metastatic NSCLC. However, the response rates are modest and are lower than 50% even in patients expressing high levels of programmed death ligand 1 (PD-L1) (>50% TPS) (9-11). Several pre-clinical and clinical studies demonstrate the possible synergistic effect of radiation and immunotherapy (12-14). Tumor antigen presentation, immune recognition, and activation are the key steps involved in generating an effective anti-tumor immune response (5). Radiation can induce damage-associated molecular patterns (DAMPs), the release of tumor-specific antigens and enhance antigen presentation thus augmenting an anti-tumor immune response (in-situ vaccination) (12). In a large phase 1 trial of pembrolizumab (PD-1 inhibitor) patients with metastatic NSCLC patients (KEYNOTE-1) who had prior radiation had nearly two-fold improvement in both progression-free survival (PFS) and overall survival (OS) [PFS: hazard ratio (HR), 0.56; 95% CI, 0.34–0.91, P=0.019; mPFS 4.4 vs. 2.1 months] and (OS: HR, 0.58, 95% CI, 0.36–0.94, P=0.026; mOS 10.7 vs. 5.3 months) (14)