Lumakras (sotorasib)

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.

While KRAS was long considered undruggable, the development of mutant-specific inhibitors, including covalent inhibitors targeting KRASG12C (such as Sotorasib and Adagrasib) and non-covalent inhibitors targeting KRASG12D (such as Mirati's MRTX1133), has shown promise. In cellular models of KRAS-mutated NSCLC and PDAC, this nanoplatform achieved comparable or superior therapeutic outcomes with respect to the individual drugs. This study provides a compelling proof-of-concept for the in vitro delivery of KRASG12C mutant-specific inhibitors and degraders to human tumors through a tumor microenvironment-activated nanomedicine approach and lays the groundwork for future studies in physiologically relevant models to assess TME-specific activation and tumor selectivity.

P2, N=197, Recruiting, Gruppo Oncologico del Nord-Ovest | N=140 --> 197

Notably, one patient with acquired MET amplification achieved a renewed partial response to the combination of sotorasib and tepotinib after progression on sotorasib monotherapy. Our findings support rebiopsy at progression on sotorasib. Further prospective trials are warranted to validate MET amplification as a resistance mechanism and to define optimal therapeutic thresholds for combined KRAS and MET inhibition.

Case 1 harbored a truncal KRAS p.G12C mutation with high-level amplification of chromosome 11q13-q14, including CCND1, and demonstrated a clinical response to sotorasib...These findings highlight the molecular heterogeneity of Rb-retained SCLC and demonstrate that this subgroup can harbor clinically actionable oncogenic drivers. Accordingly, routine assessment of Rb expression in SCLC, followed by comprehensive molecular profiling of Rb-retained tumors, is warranted to uncover therapeutically relevant targets.