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For the past two decades, platinum-based combination chemotherapy has been the standard-of-care, first-line treatment for patients with advanced non–small-cell lung cancer (NSCLC) without mutations that were sensitive to targeted therapy.1,2 However, chemotherapy has provided only a moderate benefit, with a limited safety profile. In phase 3 clinical trials, the median progression-free survival with platinum-based chemotherapy was 4 to 6 months, and the median overall survival was 10 to 13 months.3–8
In two phase 3 trials, nivolumab, a programmed death 1 (PD-1) immune-checkpoint–inhibitor antibody, resulted in significantly longer overall survival than docetaxel among patients with metastatic NSCLC who had disease progression during or after platinum-based chemotherapy.9–11 Benefit was seen regardless of the PD-1 ligand 1 (PD-L1) expression level but was enhanced in patients with nonsquamous NSCLC with increasing PD-L1 expression.9,10
In a multicohort phase 1 study involving previously untreated patients with NSCLC (CheckMate 012),12 preliminary data from a cohort of 20 patients who received nivolumab monotherapy showed durable responses and a favorable safety profile. Among the 10 patients with a PD-L1 expression level of 5% or more, the objective response rate was 50%, the rate of progression-free survival at 24 weeks was 70%, and the median progression-free survival was 10.6 months.13 Although an increasing PD-L1 expression level was associated with greater benefit in the expanded cohort, clinical activity was also seen in patients with a low PD-L1 expression level or with no PD-L1 expression.12 On the basis of this preliminary data set and the finding that approximately 12 to 15% of the patients had a PD-L1 result showing expression between 1% and 4% across studies of nivolumab involving patients with NSCLC (Bristol-Myers Squibb, data on file), progression-free survival among patients with a PD-L1 expression level of 5% or more was chosen as the primary end point because this population was thought to be more likely to show a progression-free survival benefit with nivolumab than patients with a lower (<5%) PD-L1 expression level.
Owing to the complexity of the immune system, biomarkers for response to immuno-oncologic agents beyond PD-L1 expression levels are being explored. Early data support the hypothesis that a high tumor-mutation burden may increase the likelihood of benefit from immunotherapy,...