Lumakras (sotorasib)

Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-resistant and - sensitive organoid models and in vivo patient-derived xenograft (PDX) systems. These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, response duration, and to mitigate emergence of resistance.

These candidates displayed favorable predicted binding energetics, stable ligand-protein interactions over extended simulation timescales, and low structural similarity to clinically approved KRAS G12C inhibitors sotorasib and adagrasib. In cellular NanoBRET target-engagement assays, selected scaffolds, including K788-7251 and AN-989/14669131, exhibited sub-micromolar engagement of KRAS G12C with minimal endothelial cytotoxicity. Collectively, these findings identify structurally distinct, KRAS G12C inhibitor chemotypes and provide tractable starting points for the development of next-generation targeted therapies.

P1, N=104, Recruiting, Bayer | Trial completion date: Mar 2028 --> May 2027 | Trial primary completion date: Jul 2027 --> Jan 2027

Both KRAS "OFF"" G12C inhibitors, sotorasib and adagrasib, are considered standard second-line therapy, albeit with a modest progression-free survival benefit over standard chemotherapy. Critical clinical questions remain open regarding the optimal patient population for combinations, the influence of co-occurring genomic alterations, intracranial activity of KRAS inhibitors and dose optimization. This review synthesizes current evidence on the biology, clinical efficacy, safety, and practical considerations for treating KRAS G12C-mutant NSCLC, providing clinicians with an up-to-date, evidence-based framework for therapeutic decision-making and highlighting areas requiring further investigation.

P2, N=300, Not yet recruiting, Federation Francophone de Cancerologie Digestive

Methylation signature may be combined with genomic analysis to personalize therapeutic strategies for KRAS p. G12C mutated NSCLC patients. "Multiomic" analysis of tumor-informative molecular targets (genomic profile, methylation status) lay the basis for dynamic fingerprints of NSCLC patients preventing early relapses and augmenting clinical benefits of targeted therapies.

BBO-8520 exerted more potent and sustained inhibition of KRAS G12C and anti-tumor activity in vitro and in vivo compared with sotorasib, a KRAS G12C (OFF)-only inhibitor...Moreover, in some contexts, disruption of RAS-PI3Kα further increased the anti-tumor activity of BBO-8520 monotherapy. These results reveal mechanistic differences between KRAS (ON) and (OFF) inhibitors, highlight the importance of PI3Kα-AKT signaling in driving resistance to KRAS inhibition in lung cancer, and suggest combination strategies that suppress PI3Kα-AKT to improve the response to KRAS inhibitors.

Furthermore, combining sotorasib with either a DHX9 inhibitor or an SOS1 inhibitor significantly enhances its anti-tumor efficacy in both KRASG12C-mutant and sotorasib-resistant models. These findings provide previously uncharacterized mechanistic insights to guide therapeutic strategies aimed at overcoming sotorasib resistance.

P1/2, N=229, Recruiting, Orion Corporation, Orion Pharma

Long considered undruggable due to its molecular structure, the advent of sotorasib and adagrasib has ushered in multiple novel therapeutics targeting the RAS pathway, including mutation-selective, pan-KRAS, and pan-RAS inhibitors. Here, we detail the different areas of investigation targeting KRAS and other precision-based therapies in PDAC, as well as the potential emerging roles of local interventions (radiation, surgery) for select patients with oligometastatic disease. Composite predictive biomarkers using genomic, proteomic, and radiographic factors are needed to refine and individualize treatment selection and ultimately improve patient outcomes.

Treatment with 5-FU plus panitumumab and sotorasib could be a promising alternative to 5-FU ± targeted therapy in first-line setting in frail/elderly patients with unresectable KRAS G12C-mutated CRC.