Krazati (adagrasib)

P2, N=170, Recruiting, Mirati Therapeutics Inc. | Not yet recruiting --> Recruiting

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.

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.

In vivo xenograft models confirmed that the combination of RO and ADA significantly reduced tumor growth. These findings suggest that RO and ADA act synergistically against KRAS-mutant tumors by suppressing NRF2, supporting their potential as a targeted combination strategy for KRAS-driven cancers.

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.

In this single-center, real-world, retrospective analysis, among the 38 patients with advanced NSCLC receiving KRAS G12C inhibitors, a never or light smoking history, poor performance status, and the presence of tumor pathogenic KEAP1 mutations were associated with worse clinical outcomes. Within the limitations of the study, clinicians should consider these variables when formulating treatment for KRAS G12C-mutant NSCLC.

P3, N=461, Active, not recruiting, Mirati Therapeutics Inc. | Trial completion date: Jan 2026 --> Jul 2026

P2, N=68, Active, not recruiting, ETOP IBCSG Partners Foundation | Trial completion date: Mar 2026 --> Jul 2026

Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), had received accelerated approvals for clinical use. This seems to be due to a lack of effect on downstream KRAS effectors such as the ribosomal protein S6, highlighting the need for strategies that take into account potential context-dependent processes. Together with other recent reports on high-affinity binding of MRTX1133 to other non-G12D KRAS mutants, our findings further reveal the usefulness of MRTX1133 as a chemical probe that continues to provide novel insights on KRAS biology and inhibition mechanisms.

KRAS mutations represent the most prevalent oncogenic drivers in non-small cell lung cancer (NSCLC), defining a clinically heterogeneous subset that was historically considered "undruggable." The identification of a mutant-specific allosteric pocket in KRAS G12C led to the development of sotorasib and adagrasib, fundamentally altering the treatment paradigm for pretreated patients...This review provides a comprehensive synthesis of the expanding therapeutic landscape, moving beyond G12C-selective inhibition toward next-generation allele-specific agents, such as G12D inhibitors, and groundbreaking pan-RAS/RAS(ON) tri-complex inhibitors like RMC-6236...As the field transitions from single-allele blockade to multi-selective RAS(ON) inhibition and rational vertical pathway targeting, personalized, biomarker-guided treatment algorithms will be essential. By outlining the trajectory from G12C to pan-RAS strategies, this review captures the evolving precision oncology framework necessary to achieve durable clinical benefit in KRAS-mutant NSCLC.

P2, N=29, Not yet recruiting, Roswell Park Cancer Institute

However, pioneering work by Shokat and colleagues has led to the discovery of KRAS G12C-GDP mutant specific inhibitors, with two such inhibitors adagrasib and sotorasib now FDA approved for treatment of non-small cell lung cancer (NSCLC). Recent studies support the view that integration of AI algorithms with experimental methods is a key aspect in stream-lining the drug discovery process and identifying molecules with greater structural diversity, less off target effects than traditional screening methods. Furthermore, the authors believe that AI will eventually become standardized in drug discovery and existing pipelines specific to KRAS mutant inhibitor design will be expanded for additional KRAS mutations as well as other aggressive driver oncogenes across multiple cancers.