Lumakras (sotorasib)

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

Mechanistically, galangin suppressed M2 macrophage polarization, directly interacted with the efferocytosis-related targets CAMK2A and MERTK, and reduced their expression. Together, these findings establish efferocytosis as a novel and targetable vulnerability in drug-resistant NSCLC and highlight galangin as a promising sensitizer for overcoming resistance to two major targeted therapies.

Improvement from ECOG PS 2 to ECOG PS 0 to 1 was observed by the end of first cycle of treatment (57.9%). Safety and efficacy outcomes of sotorasib in this study were not affected with ECOG PS 2 and the history of CNS metastases and were consistent with those reported in key clinical trials.

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.

Sotorasib-protein conjugates were strongly localized to the villous epithelial cells of the small intestine but were scarcely detected in the colon, highlighting regional differences. This study elucidates the localization of sotorasib-protein conjugates in the gastrointestinal tract of rats and provides important insights into the mechanisms underlying sotorasib-induced gastrointestinal disorders.

P3, N=750, Recruiting, Amgen | Trial completion date: Jun 2031 --> Jun 2032 | Trial primary completion date: Jun 2026 --> Jun 2027

A 71-year-old woman with a medical history of metastatic non-small cell lung cancer treated with left-side pneumonectomy 10 years ago, stereotactic body radiation therapy of a single right lung metastasis 7 years ago, and targeted therapy with sotorasib for the last 6 years (+KRAS G12C tumor), obesity (BMI of 33), and OSA on nocturnal CPAP, presents to the pulmonary office with dyspnea.

P1, N=91, Terminated, Deciphera Pharmaceuticals, LLC | Phase classification: P1/2 --> P1 | N=144 --> 91 | Trial completion date: Aug 2028 --> Mar 2026 | Active, not recruiting --> Terminated | Trial primary completion date: Aug 2027 --> Mar 2026; Trial terminated due to business decision, not based on any safety or efficacy concerns.

P=N/A, N=102, Completed, Amgen | Recruiting --> Completed | Trial completion date: Jun 2026 --> Dec 2025

Toxicity included 13 grade 2 events (31%) and one grade 3 pneumonitis-with no significant differences between patients who held or continued inhibitors during radiotherapy. Estimated 6-month cumulative incidence of local failure was 5%.

P1, N=15, Recruiting, City of Hope Medical Center | Trial completion date: Mar 2026 --> Nov 2026 | Trial primary completion date: Mar 2026 --> Nov 2026

This review also highlights the drug's synthetic processes, structural features, and global patent coverage. SR approval marks a significant milestone in KRAS-targeted therapies, offering new hope for patients with difficult-to-treat lung cancer.