Lumakras (sotorasib)

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.

Postmortem examination revealed pleomorphic carcinoma. ERBB3 amplification may contribute to off-target resistance to sotorasib, and transformation to pleomorphic carcinoma may represent an additional resistance mechanism.

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.

P3, N=450, Recruiting, Amgen | Trial completion date: Aug 2031 --> Apr 2032 | Trial primary completion date: Jan 2028 --> Sep 2028

Sotorasib was associated with significantly improved OS, TTNTD, and TTDD compared with docetaxel in 2 L+ for locally advanced or metastatic NSCLC under real-world conditions in England.

The labeled 960 mg dose did not demonstrate meaningful improvement in efficacy, while toxicity remained substantial. These findings support efforts under Project Optimus to identify the lowest effective dose. Lower doses, including 240 mg, may provide comparable outcomes while reducing toxicity, pill burden, and treatment costs.

P1, N=49, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=500 --> 49 | Trial completion date: Oct 2031 --> Nov 2026 | Trial primary completion date: Oct 2028 --> Oct 2026

Mouse experiments confirmed the biosafety and efficacy of AMG510 combined with 3-MA in vivo. The results of this study revealed that AMG510 exhibited favorable antitumor activity against KRAS G12C-mutant pancreatic cancer in vitro and in vivo, and the combination of AMG510 and 3-MA may represent a candidate therapeutic regimen for the clinical treatment of KRAS G12C-mutant pancreatic cancer.

P1/2, N=13, Not yet recruiting, Orion Corporation