Dealing with KRAS G12C inhibition in non-small cell lung cancer (NSCLC) - biology, clinical results and future directions

KRAS G12C mutation occurs in - 14 % of non-small cell lung cancer (NSCLC) patients and has been historically deemed undruggable, with immune-checkpoint inhibitors (ICIs) and platinum-based chemotherapy (PBC) representing the standard-of-care in the advanced setting. First-in-class, covalent KRAS G12C OFF-inhibitors sotorasib and adagrasib have revolutionized the therapeutic landscape and recently entered clinical practice. However, limited efficacy alongside toxicity profiles strengthen the need to design novel molecules and to optimize therapeutic strategies to address and overcome intrinsic and acquired resistance mechanisms. Moreover, KRAS G12C frequently co-occurs with STK11/KEAP1 mutations, that represent a negative prognostic factor, being associated with increased metastatic potential and reduced overall survival and poorer outcomes with ICIs. Furthermore, the high incidence of brain metastases is common in KRAS G12C-mutant NSCLC, and the efficacy of standard therapies and KRAS G12C inhibitors in treating or preventing central nervous system involvement is still suboptimal. In this context, novel inhibitors, such as broad-spectrum inhibitors targeting the active GTP-bound ON-state, pan-RAS ON inhibitors and allele-selective tricomplex inhibitors, have showed promising early clinical activity although their clinical utility needs to be further elucidated. In addition, targeting upstream, downstream and parallel signaling pathways through combination strategies might enhance the activity of KRAS G12C inhibitors and eventually improve clinical outcomes in this subset of NSCLC patients. Several combinations are currently under clinical investigation and promising approaches include combinations of KRAS G12C inhibitors with ICIs, SOS1, SHP2 inhibitors and PBC. Notwithstanding the potential improved efficacy of combination strategies, tolerability remains a critical challenge that must be carefully assessed and managed.