Profiling opnurasib (JDQ-443) for the treatment of non-small cell lung cancer (NSCLC)

Oncogenic activation of KRAS is a common driver of solid tumor malignancies and has been considered ‘undruggable’ for several decades. Oral small molecule inhibitors, including sotorasib and adagrasib, have demonstrated moderate efficacy in targeting KRAS G12C in NSCLC. More potent inhibitors are needed, and the landscape is rapidly evolving. Opnurasib (JDQ-443) is an irreversible covalent inhibitor of GDP-bound KRAS G12C that has been under investigation in patients with KRAS G12C-mutated solid tumors, including NSCLC. Here, we review its mechanism of action, pharmacologic properties, clinical efficacy, role within the NSCLC landscape prior to its withdrawal from the market, as well as the regulatory and market-driven dynamics that may result in the abandonment of aspiring drugs. JDQ-443’s unique binding within the switch II pocket of KRAS G12C allows for novel interactions and helps define its characteristic profile of anti-tumor activity, tolerability, and resistance. JDQ-443 has demonstrated promising early clinical activity in KRAS G12C-mutated NSCLC. More data is necessary to allow comparison of available agents and combination strategies. In the face of an expanding market, development of JDQ-443 has been halted despite promising safety and efficacy outcomes and ongoing innovative trials, highlighting critical challenges in the drug development process. The existing body of work characterizing JDQ-443 remains extremely informative.