Lumakras (sotorasib) / Amgen, Roche - LARVOL DELTA

Discovery and preclinical characterization of KRAS G12C inhibitor fulzerasib (GFH925) for advanced solid tumors (ACS-Fall 2025) - "Notably, in the MIA PaCa-2 and NCI-H358 CDX models, the anti-tumor efficacy of GFH925 was superior to sotorasib at the same dose. In the NCI-H2122 NSCLC model, the concurrent administration of GFH925 and cetuximab significantly suppressed tumor growth and demonstrated preferable synergy in antitumor effects. The comprehensive preclinical evaluation of the rationally designed KRAS G12C inhibitor fulzerasib (GFH925) sets a solid foundation for its rapid clinical advancement in KRAS G12C-driven malignancies."

Metastases • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CYP3A4 • KRAS

Interaction Mechanisms of KRAS G12C Inhibitors (Sotorasib and Adagrasib) with Human Serum Albumin: Insights from Spectroscopic and Molecular Docking Studies. (PubMed, Molecules) - "This study uses multispectral technology and molecular docking to reveal the binding mechanism of Sotorasib and Adagrasib with HSA, providing a theoretical basis for designing highly targeted albumin nanocarriers. The strong binding properties of Adagrasib and HSA may reduce the toxicity of free drugs, providing direction for the development of long-acting formulations."

Journal • KRAS

Synergistic Antitumor Effect of an XPO1 Inhibitor And/Or Sotorasib With V-ATPase Inhibitors Pretreatment in KRAS G12C NSCLC (IASLC-WCLC 2025) - "It should be noted that pretreatment with omeprazole has demonstrated to potentially overcome resistance to both treatments. Future in vivo studies are necessary along with unveiling the role of XPO1 since XPO1 expression was present in cell lines and was not decreased by sotorasib, only by selinexor."

IO biomarker • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKA • KRAS • XPO1

KRAS mutations in Non-Small Cell Lung Cancer: translational aspects, current therapies and challenges for future research. (PubMed, Crit Rev Oncol Hematol) - "Although historically considered an "undruggable" target, recent research led to the development of specific KRAS-G12C inhibitors, like sotorasib and adagrasib which are currently approved for clinical use in patients affected by advanced NSCLC. This review provides a detailed overview of KRAS genetic alterations in NSCLC, focusing on the involved molecular pathways, current and potential targeted therapies, challenges related to tumor heterogeneity, as well as ongoing research and future perspectives. In addition, the role of TME in generating treatment resistance is discussed, along with emerging therapeutic options that target non-G12C KRAS mutations or combine different pharmacological approaches to disrupt both oncogenic signaling and immune evasion."

IO biomarker • Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Combined analysis of overall survival (OS) from the phase 3 CodeBreaK 300 and phase 1b CodeBreaK 101 studies of sotorasib 960 mg plus panitumumab (soto960+pani) therapy for chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC) (ESMO 2025) - No abstract available

Clinical • Metastases • P1 data • P3 data • Colorectal Cancer • Oncology • Solid Tumor • KRAS

Genomic Insights into Myelodysplastic Syndrome: Uncovering Understudied Mutations (SOHO 2025) - "In this study, we identified that MDS, as a clonal disorder, may harbor additional mutations for which FDA-approved targeted therapies are available. Our findings highlight actionable mutations such as EZH2, NF1, and KRAS, which can be potentially treated with agents like tazemetostat, selumetinib, and sotorasib. For patients with MDS, outcomes after relapse remain poor, often revealing undruggable oncogenic drivers, like NRAS."

Hematological Malignancies • Myelodysplastic Syndrome • Oncology • BRAF • EGFR • EZH2 • KRAS • NF1 • NRAS

Optimizing blood-brain barrier permeability in KRAS inhibitors: A structure-constrained molecular generation approach. (PubMed, J Pharm Anal) - "Retrospective validation with KRAS inhibitors, AMG510 and MRTX849, demonstrates the framework's effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications. This study provides a robust framework for accelerating the structural enhancement of lead compounds, advancing the drug development process across diverse targets."

Journal • Brain Cancer • Oncology • Solid Tumor • KRAS

Development of potent inhibitors against KRAS, its mutant G12R, allosteric and Switch-I/Switch-II site. (PubMed, In Silico Pharmacol) - "Virtual screening revealed four promising compounds NSC 374,037, NSC 655,101, V016-9984, and N060-0122 that outperformed known inhibitors such as Sotorasib in binding affinity...The results provide a strong basis for further experimental testing, bringing us closer to effective treatments for KRAS-driven cancers. The online version contains supplementary material available at 10.1007/s40203-025-00415-4."

Journal • Oncology • KRAS

CXCR2 Inhibitor Plus KRAS G12C Inhibitor Remodels Immunosuppressive Tumor Microenvironment in KRAS G12C-Mutant NSCLC? (IASLC-WCLC 2025) - "Hence, co-administration of SB225002, a C-X-C motif chemokine receptor 2 (CXCR2) antagonist targeting PMN-MDSCs, significantly enhanced the inhibitory effect of AMG510 on tumor burden in LLC-bearing mice. Conclusions : The combination therapy demonstrates dual efficacy by potently remodeling the immunosuppressive tumor microenvironment and directly inhibiting tumor cells proliferation. These findings establish a robust experimental foundation for advancing this therapeutic approach into clinical trials."

Biomarker • Tumor microenvironment • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CXCR2 • KRAS

Real World Evaluation of Sotorasib Among Chinese Non-Small Cell Lung Cancer Patients (clinicaltrials.gov) - P=N/A | N=115 | Recruiting | Sponsor: Amgen | Not yet recruiting ➔ Recruiting

Enrollment open • HEOR • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

New in CancerScope: New colorectal cancer therapies help patients live longer & manage disease. ✨ Sotorasib + panitumumab for rare mutations ✨ Nivolumab + ipilimumab now FDA approved CANCER Section Editor @cathyengMD comments: https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.70000 @OncoAlert

Real-world comparative effectiveness of sotorasib versus docetaxel monotherapy in second line and beyond for advanced or metastatic non-small cell lung cancer (NSCLC): A national database analysis from England (ESMO 2025) - No abstract available

Clinical • HEOR • Metastases • Monotherapy • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

V-Atpase Inhibitors Enhance the Effect of Tepotinib (c-Met Inhibitor) or RMC-6236 (Pan-Ras(ON) Inhibitor) in KRAS-Mutant NSCLC (IASLC-WCLC 2025) - "Introduction : KRAS G12C inhibitors (sotorasib or adagrasib) in monotherapy have short-lived response in metastatic KRAS G12C NSCLC patients. Western blot analysis shows several hints that the combination of omeprazole pretreatment + tepotinib or omeprazole + RMC-6236 both combinations can avoid upregulation of MRAS and YAP1 and several receptor tyrosine kinases. To further discern is the leverage of tepotinib in front of RMC-6236."

Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • EGFR • HES1 • KRAS • STAT3 • YAP1

Fulzerasib, a KRAS-G12C Inhibitor, Has Synergistic Antitumor Effect With Omeprazole Pretreatment in KRAS G12C NSCLC (IASLC-WCLC 2025) - "Fulzerasib (GFH925, IBI351), an irreversible KRAS G12C inhibitor, has demonstrated superior efficacy compared to sotorasib and adagrasib, achieving an objective response rate of 49.1% and a median progression-free survival of 9.7 months. Omeprazole, a proton pump inhibitor, has been shown to enhance cytoplasmic retention of cytotoxic drugs and sensitize cancer cells to chemotherapy and some target therapy, such as tepotinib...Conclusions : This study highlights that fulzerasib exhibits synergistic antitumor effects with omeprazole pretreatment, potentially through the suppression of multiple cancer-related proteins and pathways. Future studies will explore additional mechanisms, including autophagy and ferroptosis, to further elucidate the therapeutic potential of this combination."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CTNNB1 • HES1 • KRAS • SNAI2

Real-World Treatment and Survival in KRASG12C-Mutated Locally Advanced/Metastatic Non-Small Cell Lung Cancer in England (IASLC-WCLC 2025) - "The kaplan-Meier method was used to estimate overall survival (OS) from the start of sotorasib or a second-line treatment for the sotorasib and 2L+ cohorts, respectively...In the 2L+ cohort, the most common treatments were platinum-based chemotherapy in first line, anti-PD-1/PD-L1 ICI monotherapy in second line, and docetaxel ± nintedanib in third line ( Table )...Median OS in the 2L+ cohort by type of second-line treatment received ranged from 9.2 months with anti-PD-1/PD-L1 ICI monotherapy to 15.1 months with TKIs. Conclusions : These real-world results from England provide insights on the adoption of KRAS G12C inhibitors into routine clinical practice as second or later lines of therapy for patients with KRAS G12C -mutated LAM NSCLC and the associated survival outcomes."

Clinical • HEOR • IO biomarker • Metastases • Real-world • Real-world evidence • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Predictive Value of Gastrin for the Absorption of pH-Dependent Small-Molecule Inhibitors in Patients With NSCLC (IASLC-WCLC 2025) - P=N/A | "Since the solubility and absorption of the SMIs erlotinib and sotorasib are pH-dependent, we hypothesize that gastrin, as marker of AH, could predict drug absorption and exposure in patients with LC. Patients with AH are at heightened risk for reduced erlotinib exposure and subsequent treatment failure. Future studies should focus on the pre-therapeutic assessment of gastrin levels to identify patients with AH, and explore interventions to mitigate treatment failure, such as adjusting the initial erlotinib dose or implementing therapeutic drug monitoring during treatment."

Clinical • Gastrointestinal Disorder • Lung Cancer • Metabolic Disorders • Non Small Cell Lung Cancer • Solid Tumor • GAST

Integrative profiling of lung cancer biomarkers EGFR, ALK, KRAS, and PD-1 with emphasis on nanomaterials-assisted immunomodulation and targeted therapy. (PubMed, Front Immunol) - "Docking results showed strong EGFR-Gefitinib affinity (-5.94 kcal/mol, Kd 4.38 × 10-5 M), while KRAS inhibitors Adagrasib and Sotorasib demonstrated moderate binding (-3.94 and -3.72 kcal/mol, respectively). This integrative study combining structural modeling, molecular interaction analysis, and transcriptomic validation confirms EGFR, ALK, KRAS, and PD-1 supports their relevance as clinically actionable and structurally druggable biomarkers in NSCLC. These findings support their continued use in targeted therapy design and precision diagnostics, highlighting nanomaterials as ideal carriers due to their ability to enhance immune checkpoint blockade and drug bioavailability in NSCLC."

Biomarker • IO biomarker • Journal • Immunology • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • EML4 • KRAS • PD-1 • PD-L1 • PD-L2

A Rollover Study Evaluating Sotorasib With or Without Panitumumab in Participants With KRAS p.G12C Mutation (clinicaltrials.gov) - P2 | N=14 | Not yet recruiting | Sponsor: Amgen

New P2 trial • Oncology • Solid Tumor

Intermittent Caloric Restriction Synergies With KRAS(OFF) Inhibitors in Preclinical Models of KRASG12C Lung Adenocarcinoma (IASLC-WCLC 2025) - "Cells were treated with sotorasib with increasing concentrations to determine half-maximal inhibitory concentrations (IC 50 )...We established six distinct treatment arms with 2 mice each combining ICR with either vehicle control, selumetinib (MEK-inhibitor), or adagrasib...Conclusions : These preliminary findings suggest that ICR specifically enhance the activity of KRAS(OFF) inhibitors in KRAS G12C LUAD models. No safety concerns were observed during the in vivo experiments, supporting the potential feasibility of this combinatorial approach."

Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS

KRAS G12C Inhibition in Solid Tumors: Biological Breakthroughs, Clinical Evidence, and Open Challenges. (PubMed, Cancers (Basel)) - "The first targeted therapies for KRAS G12C-mutant cancers comprise sotorasib and adagrasib, both of which have been authorized for use in patients with previously treated NSCLC and CRC. In this review, we summarize recent advances in KRASG12C tumor biology and pharmacological targeting. We also provide additional insights to guide future efforts to overcome the limitations of the current approaches and implement the treatment of KRASG12C-mutant cancers."

Journal • Review • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Phase I Study of BAY3498264 Given Together With Sotorasib in Participants Who Have Advanced Solid Cancers With Specific Genetic Changes Called KRASG12C Mutation (clinicaltrials.gov) - P1 | N=104 | Recruiting | Sponsor: Bayer | Trial completion date: Nov 2027 ➔ Mar 2028 | Trial primary completion date: Jan 2027 ➔ Jul 2027

Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Fumarate and Ass1 in KRAS-Mutant NSCLC: The Influence of Cetuximab in Combination With KRAS G12C Inhibitors (Sotorasib and Fulzerasib) (IASLC-WCLC 2025) - "Low ASS1 expression is shown to harbour a poor prognosis. Further research could clarify the relevance of ASS1 and fumarate as a biomarker and therapeutic target."

Combination therapy • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • ASS1 • CDC37 • EGFR • ERBB3 • ERRFI1 • FASN • HSP90AA1 • KRAS • YAP1

Overall survival (OS) with sotorasib plus carboplatin and pemetrexed in KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) from the global phase 1b CodeBreaK 101 study (ESMO 2025) - No abstract available

Clinical • Metastases • P1 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Long-Term Real-World Outcomes of Sotorasib in Second-Line and Beyond Treatment of KRAS G12C-Mutated Advanced NSCLC (IASLC-WCLC 2025) - "Conclusions : Sotorasib in 2L and 2L+ settings demonstrated long-term survival in a real-world population of patients with KRAS G12C-mutated advanced NSCLC, including those with poor ECOG PS. $$graphic_4080BE6C-F792-448A-AE61-75D950997A01$$"

Clinical • Metastases • Real-world • Real-world evidence • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Solid Tumor • Squamous Cell Carcinoma • KRAS

Actionable but Overlooked: Targetable Mutations in AML (SOHO 2025) - "Our findings highlight the presence of actionable mutations in AML, including KRAS, which is targetable with the FDA-approved inhibitor sotorasib, and NRAS, for which mutation-specific therapies are in development. Despite their clinical relevance, these mutations remain underexplored in AML. While MEK inhibitors have been studied in select subtypes, relapse outcomes remain poor, often driven by undruggable oncogenic pathways, as observed in our cohort."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • KRAS • NF1 • NRAS