Tyrosine Kinase Inhibitors, Antibody-Drug Conjugates, and Proteolysis-Targeting Chimeras: The Pharmacology of Cutting-Edge Lung Cancer Therapies

The number of therapeutic options available for patients with advanced non–small-cell lung cancer has been led by deeper understanding of molecular drivers, immune function, and fundamental biology. In this article, we describe the relevant clinical pharmacologic characteristics of three broad classes of existing and investigational treatments, with a focus on mechanisms of action, adverse event profiles, pharmacokinetic and pharmacodynamic properties, and known and predicted resistance pathways. Specifically, within the kinase inhibitor class, agents directed against the RET, MET, and KRAS pathways are reviewed. Additionally, the first antibody-drug conjugates that target HER2 and HER3 are in trials and will ideally be available for patients soon. Finally, proteolysis-targeting chimeras approach pathway inhibition through enzyme degradation rather than target inhibition and are a promising platform for new agents in non–small-cell lung cancer and across cancer types. Each of these classes requires knowledge of clinical pharmacologic principles in development and use to ensure patient care in clinics and trials is optimized and personalized, including dosing and scheduling strategies, potential drug interactions, use in special populations, and monitoring parameters. Ideally, oncologists will continue to have new agents available across the non–small-cell lung cancer treatment spectrum to offer to a patient group that, until relatively recently, had few options.