Lumakras (sotorasib)

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.

This case highlights the potential of sotorasib in combination regimens as a first-line treatment strategy for KRAS G12C-mutated NSCLC and underscores the importance of individualized treatment planning. However, the use of sotorasib in the first-line setting remains an exploratory off-label approach and requires further clinical evidence to validate this treatment strategy.

When combined with EGFR inhibitors (osimertinib and gefitinib) in PC9 cells, the mimics showed a higher rate of growth inhibition compared with the controls and reduced IC50 values. Similarly, conmiR-15/107 enhanced growth inhibition by the KRAS inhibitors sotorasib and adagrasib in H358 cells...Long-term assays showed that the mimics reduced the survival and delayed the proliferation of DTPs in osimertinib-treated PC9 cells as well as sotorasib-treated H358 cells. These findings support conmiR-15/107 as a potential adjunct to targeted therapy, capable of enhancing treatment efficacy and delaying resistance in lung adenocarcinoma.

P2, N=14, Recruiting, Amgen

P3, N=345, Active, not recruiting, Amgen | Trial completion date: Feb 2026 --> May 2026

Although covalent inhibitors like sotorasib against KRASG12C have been developed, their efficacy is often limited by acquired resistance...Here, we report DJX-A-KM, a small-molecule degrader of KRASG12C, designed by incorporating an acrylamide warhead into the MRTX849 scaffold...This strategy also enables the development of pan-KRAS degraders against a broader spectrum of KRAS mutations. Our work presents a small-molecule degrader recruiting FBXO28 and provides a blueprint for exploring E3 ligases in protein degradation.

P1, N=12, Completed, Amgen | Active, not recruiting --> Completed | Trial completion date: Jun 2026 --> Feb 2026

According to the results, 17Beta-Hydroxywithanolide K and Ginkgolide A demonstrated strong binding affinity to IGF-1R (-9.4 Kcal/mol) and KRAS (-6.9 Kcal/mol), respectively, compared to the synthetic inhibitors Picropodophyllin (-7.7 Kcal/mol) and Sotorasib (-5.9 Kcal/mol). Overall, 17Beta-Hydroxywithanolide K and Ginkgolide A have potential as natural therapeutic agents for the treatment of lung cancer. However, additional in vitro and in vivo experiments are needed to validate these computational results.

P1/2, N=713, Active, not recruiting, Amgen | Trial primary completion date: Feb 2026 --> May 2026

Two covalent inhibitors, sotorasib and adagrasib, which target a specific codon 12 mutation (G12C), had received accelerated approvals for clinical use. This appears 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.