KRAS-mutated Non-Small Cell Lung Cancer: Drugging the Undruggable

KRAS driver mutations have classically been considered undruggable by direct inhibitors in non-small cell lung cancer (NSCLC) as well as other solid tumors. However, recent advances have led to the first successful direct KRAS inhibitors, beginning with the development of KRASG12C inhibitors targeting the inactive GDP-bound state of KRAS. These initial KRASG12C (OFF) inhibitors demonstrated real but modest activity in KRASG12C-mutated mNSCLC. The development of more potent optimized KRASG12C (OFF) inhibitors has sought to improve upon the clinical activity of the initial raft of KRASG12C (OFF) inhibitors. Combination therapy with PD-1 inhibitors, as well as other classes of drugs, is also under intense investigation in NSCLC and other solid tumors. Nevertheless, primary and acquired resistance, as well as a variable and peculiar tendency to autoimmune hepatitis, have complicated efforts to develop this class of inhibitors in KRASG12C-mutated mNSCLC. In parallel, new direct inhibitor classes have emerged recently, including tri-complex ON-state inhibitors and dual-state ON/OFF inhibitors capable of targeting not only KRASG12C but also other KRAS mutations, as well as panKRAS and panRAS strategies. These agents have the potential to broaden the activity of initial KRASG12C (OFF) inhibitors and to avoid certain mechanisms of resistance and toxicity, but remain early in development with limited data. The KRAS therapeutic landscape is evolving rapidly, with many promising competing strategies each seeking to distinguish itself in an increasingly crowded therapeutic landscape.