The Influence of the Evolution of First-Line Chemotherapy on Steadily Improving Survival in Advanced Non-Small-Cell Lung Cancer Clinical Trials

Over the past three decades, survival in advanced non–small-cell lung cancer (NSCLC) clinical trials has doubled with an increase in 1-year survival from 25% to 50 to 55%. This has been mainly attributed to improvements in systemic therapy. Although modern first-line chemotherapy regimens have more favorable toxicity profiles, a statistically significant improvement in overall survival has not been demonstrated in existing meta-analyses of second-generation versus third-generation combinations. Moreover, pivotal trials demonstrating statistically significant survival superiority of third-generation regimens are consistently not reproducible even for nonsquamous populations using pemetrexed–platinum combinations. As enhancement in the efficacy of first-line systemic therapy in patients without identifiable driver mutations is questionable, other factors are discussed that explain the doubling of 1-year survival reported in clinical trials. These factors include second-line or third-line therapy, maintenance chemotherapy, performance status selection, stage migration, sex migration, improved treatment of brain metastases, and better palliative care.