Krazati (adagrasib)

P3, N=338, Active, not recruiting, Hoffmann-La Roche | Trial primary completion date: Sep 2027 --> May 2026

Although recent advances have led to covalent inhibitors such as Sotorasib and Adagrasib for the KRAS G12C mutation, effective therapies for other common variants, particularly KRAS G12D, which is highly prevalent in aggressive pancreatic cancers, remain limited...To further validate the predictive capability of the models, two compounds identified as high-confidence candidates, Cobimetinib and Etrasimod, were selected for experimental evaluation...While additional biochemical and pathway-level studies are required to confirm direct target engagement, these results support the model's utility in prioritizing candidate compounds with allele-specific activity profiles. Overall, this study provides a data-driven framework for identifying potential KRAS-targeted therapies and highlights the value of integrating machine learning predictions with experimental validation.

JMKX1899 selectively inhibited cell viability across multiple KRAS G12C-mutant cell lines, exhibiting slightly greater potency than AMG510 and MRTX849. Early clinical data from KRAS G12C-mutant NSCLC patients with BM treated by JMXK1899 further confirm its blood-brain barrier penetration and antitumor activity. These findings strongly support the continued clinical development of JMKX1899 as a promising therapeutic candidate for NSCLC patients with KRAS G12C mutations and BM.

Mutant-specific KRAS G12C inhibitors have shown promising therapeutic efficacy, leading to FDA approval of sotorasib and adagrasib, although their use is limited to patients with the relatively rare G12C KRAS mutation...While just a few years ago, pan-RAS inhibitors were predicted to be severely toxic or even fatal, the apparent safety profile of RMC-6236 (daraxonrasib), a pan-RAS inhibitor currently in clinical trials, suggests otherwise. Indeed, pan-RAS inhibitors are now considered by many in the RAS field to be the most promising class in development. In this review, we summarize the evolution and current status of pan-RAS and pan-KRAS inhibitors in preclinical and clinical development and highlight emerging human-relevant tumor models that are advancing preclinical evaluation.

KRAS G12C-mutant non-small cell lung cancer (NSCLC) has transitioned from a therapeutically problematic disease to a precision-targetable cancer, anchored by the landmark approvals of sotorasib and adagrasib. We further highlight patient-derived 3D models, multi-omics technologies, and ctDNA-guided monitoring as essential translational platforms. Finally, we propose an integrated translational roadmap that combines mechanistic insights with clinical innovation, offering new directions for precision therapy and improved patient outcomes in KRAS-driven NSCLC.

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