Lumakras (sotorasib)

P1/2, N=37, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Dec 2025 --> Aug 2026

Recent phase I/II trials of KRAS G12C inhibitors have shown promising results, and the phase III CodeBreaK 300 study confirmed that sotorasib combined with panitumumab significantly improved efficacy compared with standard treatment, establishing a new therapeutic option for KRAS G12C-mutant metastatic CRC. Strategies under investigation include targeting alternative signaling pathways, developing next-generation inhibitors and specific degraders, and exploring multi-mechanism or multi-target combination strategies. This review systematically outlines the development of KRAS G12C inhibitors in mCRC, summarizes resistance mechanisms, and discusses emerging combination regimens, aiming to provide a theoretical basis and future directions for treatment optimization.

In lung cancer xenograft studies, representatives from both substance classes demonstrated monotherapeutic antitumor activity. For one selected example, the combination effect with the KRASG12C inhibitor sotorasib was demonstrated in vivo.

Although covalent KRAS^G12C inhibitorsi such as sotorasib and adagrasib have demonstrated clinical activity, pooled analyses indicate only modest response rates and short progression-free survival, with no effective options for non-G12C subtypes...Cell viability, colony formation, and cell cycle distribution were assessed, and the involvement of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling axis was examined by western blot...SP09 exerts potent and selective antiproliferative effects in KRAS-mutant NSCLC through dual regulation of cell cycle and metabolic signaling pathways. Given the restricted efficacy and rapid resistance associated with current KRAS-targeted therapies, our data highlight SP09 as a promising candidate for further preclinical development with potential translational value in KRAS-driven NSCLC.

Patients with acquired resistance to sotorasib may benefit from follow-up monotherapy with CDK12/13 inhibitors, the first of which recently entered clinical trials. Targeting CDK12/13 thus offers a promising strategy to overcome or prevent resistance to KRAS inhibitors.

In targeted therapies, KRASG12C targeted drugs, including Sotorasib, Adagrasib, Fulzerasib, Garsorasib, and Glecirasib, have demonstrated certain therapeutic efficacies in clinical trials and have obtained marketing approval. To tackle drug resistance and enhance patient's prognoses, combination therapeutic strategies that integrate targeted agents with chemotherapy, immune checkpoint inhibitors, Src homology region 2 domain-containing phosphatase 2 (SHP2) inhibitors, and epidermal growth factor receptor (EGFR) monoclonal antibodies have emerged. This paper systematically reviews the advancements in the diagnosis and targeted therapy of NSCLC with KRASG12C mutation, aiming to offer a reference for the selection of clinical treatment regimens and subsequent research..

Real-world data showed lower reporting of diarrhea, fatigue, nausea, and liver enzyme elevations (p < 0.0001). Real-world pharmacovigilance supports the RCT findings and highlights sex-specific risks, thus emphasizing the importance of sex-aware monitoring and personalized toxicity management.

P1, N=610, Active, not recruiting, Amgen | Recruiting --> Active, not recruiting | N=1200 --> 610 | Trial primary completion date: Jun 2026 --> Dec 2026

P2, N=10, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=160 --> 10

P2, N=27, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Oct 2025 --> Oct 2027 | Trial primary completion date: Oct 2025 --> Oct 2027

RAS genes are among the most mutated genes in human cancers, with KRAS G12C now being targetable by the specific inhibitor Sotorasib...Additionally, a novel fusion, RHOH::PDCD1LG2 (PD-L2), was identified in the lymphoma, alongside the KRAS mutation. This fusion likely contributes to tumorigenesis through immune evasion.

P1/2, N=144, Active, not recruiting, Deciphera Pharmaceuticals, LLC | Recruiting --> Active, not recruiting