Abstract
Since 2011, the US FDA has approved 30 new drugs for use in advanced non-small cell lung cancer (NSCLC), mainly comprising tyrosine kinase inhibitors and immune checkpoint inhibitors. NSCLC with oncogene driver alterations is amenable to treatment with targeted drugs, usually small-molecule inhibitors. In these cases, the demonstration of high overall response rates, coupled with a lasting duration of response, has allowed for accelerated approval in the United States, based on single-cohort or multicohort trials. Confirmatory clinical evidence was subsequently provided through postmarketing trials. In NSCLC without such driver alterations, regulatory agencies in both the United States and the European Union set clinical evidence expectations that foster the conduct of studies primarily focused on determining survival or event-free survival, based on randomized controlled trial designs. This review analyzes the approval patterns of novel therapeutics for NSCLC with a focus on small-molecule inhibitors that target driver alterations, as well as biologics. The latter include mAbs inhibiting immune checkpoints like PD-(L)1 or cell surface receptors and antibody-drug conjugates, highly potent biologics linked to a cytotoxic compound. The differentiation of NSCLC into oncogene- and non-oncogene-addicted subtypes determines drug development strategies, the extent of the clinical development program, access to orphan drug development incentives, and regulatory approval strategies.