Krazati (adagrasib)

Adagrasib with ICI improved long-term survival and blocked CNS progression in dual extra- and intracranial BM models.  These findings support investigation of adagrasib with ICI in patients with KRASG12C-mutant BM.

To investigate this, we developed a preclinical model that mimics the development of resistance to KRAS-G12C inhibitors (G12Ci), such as adagrasib and RMC-4998...Mechanistically, these combination therapies led to profound remodeling of the tumor immune microenvironment, making it less immunosuppressive, and promoted cancer cell death that primed an immune response, with an influx of cytotoxic T lymphocytes recognizing tumor associated antigens shared between G12Ci resistant and sensitive cancer cells. Promotion of immune-mediated bystander elimination of drug-resistant cells may provide a paradigm for tackling the problem of drug resistance in cancer more broadly.

[18F]KRAS490 showed specific, blockable tumor uptake and favorable pharmacokinetics, making it a promising tracer for noninvasive imaging of KRAS-G12C mutant tumors. Its ability to penetrate the CNS supports potential application in imaging both peripheral and brain lesions.

A lead mAb (mAb7) sensitized tumors to the US Food and Drug Administration-approved MAPK kinase inhibitor trametinib and the KRASG12C inhibitor adagrasib. Moreover, a murinized antibody (Ms-mAb7) improved antitumor immunity in a KrasG12D syngeneic tumor model by enhancing infiltration and activation of cytotoxic immune cells. These findings provide an important advance in the clinical development of PCDH7-targeting antibodies for lung cancer treatment.

P1, N=437, Recruiting, Bristol-Myers Squibb | Active, not recruiting --> Recruiting

KRASG12C inhibitors such as adagrasib and sotorasib have shown promise in treating KRASG12C- mutant non-small cell lung cancer (NSCLC), but treatment resistance remains a major challenge. Given the observed HER2 expression in a subset of patient tumors, this combination is promising and it is currently under investigation (NCT07012031). Our findings also highlight the limitations of applying current HER2 IHC interpretation guidelines to NSCLC, underscoring the need for optimized assays to guide patient treatment selection.

P2/3, N=626, Recruiting, Mirati Therapeutics Inc. | Trial completion date: Oct 2029 --> Jun 2032 | Trial primary completion date: Oct 2028 --> Jun 2032

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.