KRAS G12C Research Articles

Efficacy and Safety of KRASG12C Inhibitor IBI351 Monotherapy in Patients With Advanced NSCLC: Results From a Phase 2 Pivotal Study

IntroductionKRAS glycine-to-cysteine substitution at codon 12 (G12C) mutation is a well-recognized and increasingly promising therapeutic target with huge unmet clinical needs in NSCLC patients. IBI351 is a potent covalent and irreversible inhibitor of KRAS G12C. Here, we present the efficacy and safety of IBI351 from an open-label, single-arm, phase 2 pivotal study. MethodsEligible patients with NSCLC with KRAS G12C who failed standard therapy were enrolled. IBI351 was orally administered at a dose of 600 mg twice daily. The primary endpoint was confirmed objective response rate assessed by an independent radiological review committee (IRRC) as per Response Evaluation Criteria in Solid Tumors v1.1. Other endpoints were safety, IRRC-confirmed disease control rate, duration of response, progression-free survival (PFS), and overall survival. ResultsAs of December 13, 2023, 116 patients were enrolled (Eastern Cooperative Oncology Group Performance Status 1: 91.4%; brain metastasis: 30.2%; prior treatments with both anti-PD-1 or anti-PD-L1 inhibitors and platinum-based chemotherapy: 84.5%). As per the IRRC assessment, the confirmed objective response rate was 49.1% (95% confidence interval [CI]: 39.7–58.6), and the disease control rate was 90.5% (95% CI: 83.7–95.2). The median duration of response was not reached whereas disease progression or death events occurred in 22 patients (38.6%), and the median PFS was 9.7 months (95% CI: 5.6–11.0). overall survival data was immature. Treatment-related adverse events (TRAEs) occurred in 107 patients (92.2%) whereas 48 patients (41.4%) had equal to or higher than grade three TRAEs. Common TRAEs were anemia (44.8%), increased alanine aminotransferase (28.4%), increased aspartate aminotransferase (27.6%), asthenia (26.7%) and presence of protein in urine (25.0%). TRAEs leading to treatment discontinuation occurred in nine patients (7.8%). In biomarker evaluable patients (n = 95), all patients had positive KRAS G12C in tissue whereas 72 patients were blood-positive and 23 were blood-negative for KRAS G12C. Patients with KRAS G12C in both blood and tissue had higher tumor burden at baseline (p < 0.05) and worse PFS (p < 0.05). Tumor mutation profiling identified tumor protein p53 (45.3%), serine/threonine kinase 11 (STK11) (30.5%), and kelch-like ECH-associated protein 1 (21.1%) as the most common genes co-mutated with KRAS G12C. Among 13 genes with mutation frequency equal to or higher than 5%, mutations of six genes (STK11, kelch-like ECH-associated protein 1, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma, DNA polymerase epsilon, SMAD family member 4, and BMP/retinoic acid-inducible neural-specific protein 3) were significantly associated with worse PFS (p < 0.05). Mutation in STK11 was also found to have a significant association with higher tumor burden at baseline and lower response rate (p < 0.05). ConclusionsIBI351 monotherapy demonstrated promising and sustained efficacy with manageable safety, supporting its potential as a new treatment option for KRAS G12C-mutant NSCLC.

Patient-reported outcomes in CodeBreaK 200: Sotorasib versus docetaxel for previously treated advanced NSCLC with KRAS G12C mutation

BackgroundIn the CodeBreaK 200 phase III, open-label trial, sotorasib significantly improved efficacy versus docetaxel in previously treated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Patient-reported outcomes (PROs) for global health status, physical functioning, dyspnea, and cough favored sotorasib over docetaxel. Here, we report sotorasib’s additional impact on quality of life (QOL). MethodsIn CodeBreaK 200, 345 patients who had progressed after prior therapy received sotorasib (960 mg orally daily) or docetaxel (75 mg/m2 intravenously every 3 weeks). Validated questionnaires captured patients’ perception of their QOL and symptom burden for key secondary and exploratory PRO endpoints, including the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Quality-of-life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), question GP5 from the Functional Assessment of Cancer Therapy Tool General Form (FACT-G GP5), PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 5-level EuroQOL-5 dimensions (EQ-5D-5L) including visual analog scale (EQ-5D VAS). Change from baseline to week 12 was assessed with generalized estimating equations for ordinal outcomes. ResultsPatients receiving sotorasib were less bothered by treatment side effects than those receiving docetaxel (odds ratio [OR] 5.7) and experienced symptoms at lower severity (pain: OR 2.9; aching muscles: OR 4.4; aching joints: OR 4.2; mouth or throat sores: OR 4.3). Further, patients’ symptoms interfered less with usual/daily activities (pain: OR 3.2; aching muscles: OR 3.9; aching joints: OR 10.7). QOL remained stable with sotorasib but worsened with docetaxel (change from baseline in EQ-5D VAS score: 1.5 vs –8.4 at cycle 1 day 5 and 2.2 vs –5.8 at week 12). ConclusionsPatients receiving sotorasib reported less severe symptoms than those receiving docetaxel. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel, suggesting sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS G12C-mutated advanced NSCLC.

Genomic Profiling of Small Intestine Cancers From a Real-World Data Set Identifies Subgroups With Actionable Alterations.

Panel-based comprehensive genomic profiling (CGP) is used in clinical practice worldwide; however, large real-world data (RWD) of patients with advanced small intestine cancer have not been characterized. We investigated differences in the prevalence of clinically relevant alterations across molecularly defined or age-stratified subgroups. This was a collaborative biomarker study of RWD from CGP testing (Foundation Medicine, Inc). Hybrid capture was conducted on at least 324 cancer-related genes and select introns from up to 31 genes frequently rearranged in cancer. Overall, 1,364 patients with advanced small intestine cancer were available for analyses and were stratified by age (≥40 years/<40 years), microsatellite instability (MSI) status, tumor mutational burden (TMB) status (high ≥10/low <10 Muts/Mb), and select gene alterations. The frequency of alterations was analyzed using a chi-square test with Yate's correction. Genes with frequent alterations included TP53 (59.8%), KRAS (54.8%), APC (27.7%), and CDKN2A (22.4%). Frequent genes with amplifications were MYC (6.7%), MDM2 (5.9%), GATA6 (5.5%), and CCND1 (3.4%). Patients younger than 40 years had significantly lower frequency of APC mutations than those 40 years and older (10.4% v 28.7%; P = .0008). Druggable genomic alterations were detected in 22.3% of patients: BRAF V600E (1.2%), BRCA1 (1.8%), BRCA2 (3.2%), ERBB2 amplification (3.2%), KRAS G12C (3.3%), NTRK1/2/3 fusion (0.07%), MSI-high (7.0%), and TMB-high (12.2%), with no significant differences in the frequency according to age (<40 years v ≥40 years; 22.1% v 22.3%). TMB of 10-20 Mut/Mb was observed in 4.8% of patients, and TMB ≥20 Mut/Mb was seen in 7.3% of the cohort. RWD from clinical panel testing revealed the genomic landscape in small intestine cancer by subgroup. These findings provide insights for the future development of treatments in advanced small intestine cancer.

Intracranial efficacy of adagrasib in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC): are results KRYSTAL clear?

Intracranial efficacy of adagrasib in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC): are results KRYSTAL clear?

Prognostic value of KRAS G12C in advanced non-small cell lung cancer with high PD-L1 expression treated with upfront immunotherapy: a systematic review and meta-analysis.

This study aims to evaluate the prognostic role of the KRAS G12C mutation in patients with advanced non-small cell lung cancer and PD-L1 expression ≥50% who are treated with immune checkpoint inhibitor monotherapy. We conducted a systematic review of clinical studies fulfilling the following criteria: (1) enrolling patients with advanced/metastatic non-small cell lung cancer with high PD-L1 tumour expression receiving first-line therapy with anti-PD-(L)1 immune checkpoint inhibitors; (2) comparing the outcomes of patients with the KRAS G12C mutation to those without this mutation, and (3) reporting overall survival and progression-free survival (PFS). The electronic databases Medline, EMBASE, Cochrane and Google Scholar, along with reference lists, were systematically searched. We identified four publications that fulfilled the inclusion criteria, comprising a total of 469 patients. Of these, two studies reported hazard ratios (HR) for PFS, resulting in a final pooled patient sample of 163 for the meta-analysis. In patients with non-small cell lung cancer who received anti-PD-(L)1 monotherapy, the presence of a KRAS G12C mutation was associated with improved PFS compared to patients with KRAS wild-type tumours, with a pooled hazard ratio of 0.39 and a 95% Confidence Interval (CI) of 0.25-0.63. Among all patients with KRAS mutations, those harbouring a KRAS G12C mutation had improved PFS compared to patients with any other KRAS mutation (pooled HR 0.33, 95% CI 0.19-0.57). Patients with non-small cell lung cancer who have the KRAS G12C mutation and high PD-L1 expression demonstrate favourable PFS with first-line PD-(L)1 immune checkpoint inhibitor monotherapy compared to patients with KRASwt or other KRAS mutations and high PD-L1 expression.

High Resolution Ion Mobility Enables the Structural Characterization of Atropisomers of GDC-6036, a KRAS G12C Covalent Inhibitor.

GDC-6036 is a covalent KRAS G12C inhibitor that demonstrates high potency and selectivity. Structurally, GDC-6036 consists of several motifs that make the analytical characterization of this molecule challenging, including a highly basic pyrrolidine motif bonded to a quinazoline ring via an ether bond and an atropisomeric carbon-carbon bond between functionalized pyridine and quinazoline groups. Structurally, the desired atropisomer was synthesized via an atroposelective Negishi coupling with very high yield. However, having a direct way to analyze and confirm the presence of the atropisomeric species remained challenging in routine analytical workflows. In this study, both variable temperature nuclear magnetic resonance (VT-NMR) and two different approaches of in-line ion mobility coupled to liquid chromatography mass spectrometry (LC-MS) workflows were evaluated for the characterization of GDC-6036 and its undesired atropisomer (Compound B) to support synthetic route development. Briefly, both VT-NMR and traveling wave ion mobility spectrometry (TWIMS) enabled by structures for lossless ion manipulation (SLIM) technology coupled to high resolution MS (HRMS) are able to elucidate the structures of the atropisomers in a complex mixture. Drift tube IMS (DTIMS) was also evaluated, but lacked the resolving power to demonstrate separation between the two species in a mixture, but did show slight differences in their arrival times when multiplexed and injected separately. The determined resolving power (Rp) by multiplexing the ions via DTIMS was 67.3 and 60.5 for GDC-6036 and Compound B, respectively, while the two peak resolving power (Rpp) was determined to be 0.41, indicating inadequate resolution between the two species. Alternatively, the SLIM-IM studies showed Rp of 103.8 and 99.4, with a Rpp of 2.64, indicating good separation between the atropisomers. Furthermore, the CCS/z for GDC-6036 and Compound B was determined to be 231.2 Å2/z and 235.0 Å2/z, respectively. Quantitative experiments demonstrate linearity (R2 >0.99) for both GDC-6036 and Compound B while maintaining separation via SLIM-IM. Spike recoveries of one atropisomer relative to the other yielded strong recoveries (98.7% to 102.5%) while maintaining reproducibility (<7% RSD). The study herein describes the analytical process for evaluating new technologies and strategies for implementation in routine biopharmaceutical characterization workflows.

Sotorasib for Vascular Malformations Associated with KRAS G12C Mutation.

KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such KRAS-driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic Kras G12C mutation. We then administered sotorasib to two adult patients with severe KRAS G12C-related arteriovenous malformations. Both patients had rapid reductions in symptoms and arteriovenous malformation size. Targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations. (Funded by the European Research Council and others.).

Interstitial Lung Diseases and Non-Small Cell Lung Cancer: Particularities in Pathogenesis and Expression of Driver Mutations.

Interstitial lung diseases are a varied group of diseases associated with chronic inflammation and fibrosis. With the emerging and current treatment options, survival rates have vastly improved. Having in mind that the most common type is idiopathic pulmonary fibrosis and that a significant proportion of these patients will develop lung cancer as the disease progresses, prompt diagnosis and personalized treatment of these patients are fundamental. The scope of this review is to identify and characterize molecular and pathogenetic pathways that can interconnect Interstitial Lung Diseases and lung cancer, especially driver mutations in patients with NSCLC, and to highlight new and emerging treatment options in that view. Common pathogenetic pathways have been identified in sites of chronic inflammation in patients with interstitial lung diseases and lung cancer. Of note, the expression of driver mutations in EGFR, BRAF, and KRAS G12C in patients with NSCLC with concurrent interstitial lung disease is vastly different compared to those patients with NSCLC without Interstitial Lung Disease. NSCLC in patients with Interstitial Lung Disease is a challenging diagnostic and clinical entity, and a personalized medicine approach is fundamental to improving survival and quality of life. Newer anti-fibrotic medications have improved survival in IPF/ILD patients; thus, the incidence of lung cancer is going to vastly increase in the next 5-10 years.

Impact of a High-Fat Meal on the Pharmacokinetics of Sotorasib, a KRAS G12C Inhibitor.

Sotorasib is a small molecule drug that specifically and irreversibly inhibits the KRAS p.G12C mutant protein. This analysis investigated the impact of a high-calorie high-fat meal on the pharmacokinetics, safety, and tolerability of sotorasib in both healthy volunteers and patients with KRAS G12C advanced solid tumors. Each subject received a single oral dose of 360 or 960mg of sotorasib under fasted conditions or with a high-fat meal (fed conditions). The geometric least squares means (GLSM) ratios (fed/fasted) for 360mg of sotorasib Cmax and AUCinf were 1.03 and 1.38, respectively, in healthy volunteers (N=14). The GLSM ratios (fed/fasted) for Cmax and AUC0-24h were 1.38 and 1.75, respectively, with 360mg of sotorasib in cancer patients (N=2). The GLSM ratios (fed/fasted) for Cmax and AUC0-24h were 0.660 and 1.25, respectively, with 960mg of sotorasib in cancer patients (N=8). Sotorasib was well tolerated in fast and fed conditions. The impact of a high-fat meal on sotorasib exposure is less than a 2-fold increase or decrease in Cmax and AUCs.

Circulating Tumor DNA Dynamics Reveal KRAS G12C Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors.

To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study. Plasma samples were collected for serial ctDNA profiling at baseline (cycle 1 day 1 prior to treatment) and multiple on-treatment time points (cycle 1 day 15 and cycle 3 day 1). KRAS G12C ctDNA was detectable from plasma samples in 72.9% (43/59) and 92.6% (50/54) of patients with non-small cell lung cancer and colorectal cancer, respectively, the majority of whom were eligible for study participation based on a local test detecting the KRAS G12C mutation in tumor tissue. Baseline ctDNA tumor fraction was associated with tumor type, disease burden, and metastatic sites. A decline in ctDNA level was observed as early as cycle 1 day 15. Serial assessment showed a decline in ctDNA tumor fraction associated with response and progression-free survival. Except for a few cases of KRAS G12C sub-clonality, on-treatment changes in KRAS G12C variant allele frequency mirrored changes in the overall ctDNA tumor fraction. Across tumor types, the KRAS G12C mutation likely represents a truncal mutation in the majority of patients. Rapid and deep decline in ctDNA tumor fraction was observed in patients responding to divarasib treatment. Early on-treatment dynamics of ctDNA were associated with patient outcomes and tumor response to divarasib treatment.

Cyclopeptide RA-V from Rubia yunnanensis restores activity of Adagrasib against colorectal cancer by reducing the expression of Nrf2

Adagrasib (MRTX849), an approved and promising KRAS G12C inhibitor, has shown the promising results for treating patients with advanced non-small cell lung cancer (NSCLC) or colorectal cancer (CRC) harboring KRAS-activating mutations. However, emergence of the acquired resistance limits its long-term efficacy and clinical application. Further understanding of the mechanism of the acquired resistance is crucial for developing more new effective therapeutic strategies. Herein, we firstly found a new connection between the acquired resistance to MRTX849 and nuclear factor erythroid 2-related factor 2 (Nrf2). The expression levels of Nrf2 and GLS1 proteins were substantially elevated in different CRC cell lines with the acquired resistance to MRTX849 in comparison with their corresponding parental cell lines. Next, we discovered that RA-V, one of natural cyclopeptides isolated from the roots of Rubia yunnanensis, could restore the response of resistant CRC cells to MRTX849. The results of molecular mechanisms showed that RA-V suppressed Nrf2 protein through the ubiquitin-proteasome-dependent degradation, leading to the induction of oxidative and ER stress, and DNA damage in CRC cell lines. Consequently, RA-V reverses the resistance to MRTX849 by inhibiting the Nrf2/GLS1 axis, which shows the potential for further developing into one of novel adjuvant therapies of MRTX849.

Molecular Mechanisms and Potential Predictive Biomarkers in Advanced Non-small Cell Lung Cancer: A Summary of Current and Future Trends

Non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer cases and is associated with different risk factors (smoking habits, gender, and age). In this scenario, many studies have been conducted to pursue improvement of survival, faster and better therapy response, reduced adverse events, and expanded available therapies and treatments against tumor resistance to drugs. These studies have focused on defining the most prevalent NSCLC biomarkers (EGFR, HER2, ALK, MET, ROS1, BRAF, KRAS G12C, HER3, NTRK, and NRG1) and their actionability. It is noteworthy that expressed kinase receptors can have overlapping mechanisms of activation of different pathways (JAK-STAT, MAPK, PI3K-AKT-mTOR, and PLC-c), which can lead to the same outcome of cell proliferation, migration, and survival resulting in increased tumor resistance to treatment. This review provides an overview of the latest findings regarding NSCLC treatment, emphasizing particular biomarkers and potential molecularly altered pathways implicated as targeted therapies. Additionally, it explores the clinical significance of the proposed treatments, their implication on progression-free survival, ongoing clinical trials, and their perspective of evolution so far.

Sex- and Age-Associated Differences in Genomic Alterations among Patients with Advanced Non-Small Cell Lung Cancer (NSCLC).

Genomic mutations impact non-small cell lung cancer (NSCLC) biology. The influence of sex and age on the distribution of these alterations is unclear. We analyzed circulating-tumor DNA from individuals with advanced NSCLC from March 2018 to October 2020. EGFR, KRAS, ALK, ROS1, BRAF, NTRK, ERBB2, RET, MET, PIK3CA, STK11, and TP53 alterations were assessed. We evaluated the differences by sex and age (<70 and ≥70) using Fisher's exact test. Of the 34,277 samples, 30,790 (89.83%) had a detectable mutation and 19,923 (58.12%) had an alteration of interest. The median age of the ctDNA positive population was 69 (18-102), 16,756 (54.42%) were female, and 28,835 (93.65%) had adenocarcinoma. Females had more alterations in all the assessed EGFR mutations, KRAS G12C, and ERBB2 ex20 ins. Males had higher numbers of MET amp and alterations in STK11 and TP53. Patients <70 years were more likely to have alterations in EGFR exon 19 del/exon 20 ins/T790M, KRAS G12C/D, ALK, ROS1, BRAF V600E, ERBB2 Ex20ins, MET amp, STK11, and TP53. Individuals ≥70 years were more likely to have alterations in EGFR L861Q, MET exon 14 skipping, and PIK3CA. We provided evidence of sex- and age-associated differences in the distribution of genomic alterations in individuals with advanced NSCLC.

Current and Emerging Treatment Paradigms in Colorectal Cancer: Integrating Hallmarks of Cancer.

The treatment of unresectable metastatic colorectal cancer has evolved over the last two decades, as knowledge of cancer biology has broadened and new targets have emerged. 'The Hallmarks of Cancer' illustrate the crucial capabilities acquired by cells to become malignant and represent the evolution of knowledge of tumor biology. This review integrates these novel targets and therapies into selected hallmarks: sustaining proliferative signaling, inducing vasculature, avoiding immune destruction, genome instability and mutation, reprogramming cellular metabolism, and resisting cell death. The different strategies and combinations under study are based on treatments with anti-EGFR, anti-VEGF, and anti-HER2 agents, KRAS G12C inhibitors, BRAF and MEK inhibitors, and immune checkpoint inhibitors. However, new approaches are emerging, including vaccines, WEE1 inhibitors, and PARP inhibitors, among others. The further deciphering of cancer biology will unravel new targets, develop novel therapies, and improve patients' outcomes.

A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer.

This critical review investigates the impact of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations on survival outcomes in non-small cell lung cancer (NSCLC) through an analysis of 21 peer-reviewed articles. Survival analyses across this review demonstrated consistently worse outcomes for SMARCA4-mutated vs. SMARCA4 wild-type NSCLC patients, specifically emphasizing class 1 truncating mutations as an independent factor for poor overall survival. In addition, this review explores the clinicopathologic characteristics of SMARCA4 mutations and their impact on various treatment modalities, including immune checkpoint inhibitors (ICIs) both with and without Kirsten rat sarcoma viral oncogene homolog (KRAS) co-mutations. The potential ineffectiveness of ICI treatment in NSCLC is explored through the impact of SMARCA4/KRAS co-mutations on the tumor microenvironment. Moreover, this NSCLC review consistently reported statistically worse overall survival outcomes for SMARCA4/KRAS co-mutations than SMARCA4 wild-type/KRAS-mutated cohorts, extending across ICIs, chemo-immunotherapy (CIT), and KRAS G12C inhibitors. Designing prospective clinical SMARCA4-mutated or SMARCA4/KRAS co-mutated NSCLC trials to evaluate targeted therapies and immunotherapy may lead to a better understanding of how to improve cancer patients' outcomes and survival rates.

Early monitoring of plasma KRAS G12C with digital PCR predicts antitumor response to immunotherapy or sotorasib in advanced NSCLC: A brief report

BackgroundThe frontline management of non-oncogene addicted non-small cell lung cancer (NSCLC) involves immune-checkpoint inhibitors (ICI) alone or combined with chemotherapy (CT-ICI). The dynamic landscape of KRAS-positive NSCLC presents a spectrum of treatment options, including ICIs, targeted therapy and combination strategies currently under investigation. MethodsWe conducted a prospective project to detect circulating tumor DNA (ctDNA) in patients with KRAS G12C, advanced NSCLC. We included patients undergoing upfront ICIs or subsequent line sotorasib. We planned three-time points: baseline (T0), after 3 months of treatment (T1) and at disease progression (T2). Results24 consecutive patients have been included. The most frequent baseline characteristics were: nonsquamous histology (95.8%), male gender (62.5%), ECOG PS 0–1 (79.2%), <3 metastatic sites (13/24, 54.2%). 18 patients (75%) received ICI-based strategies and 6 patients (25%) sotorasib. Patients with liver metastases (p ​= ​0.01) and those with >3 metastatic sites (p ​= ​0.002) exhibited significantly elevated ctDNA. Median overall survival (OS) was 7.5 months, progression-free survival (PFS) was 4.0 months and the objective response rate (ORR) was 33.3%. Higher AF correlated with an increased risk of death (HR 1.04, p ​= ​0.03), though not progression. The mOS was 7.5 months (95% CI, 1.91-NR) in high-AF group and 11.3 months (95% CI, 6.6-NR) in low-AF group (p ​= ​0.38). Notably, a reduction in plasma DNA levels was significantly associated with objective response (p ​= ​0.01). Two patients received a T2 dosage showing increased ctDNA levels after a previous reduction associated with response. ConclusionEarly monitoring with ctDNA may offer potential benefits in the evolving scenario of KRAS G12C NSCLC treatment.

KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination

BackgroundKRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions.MethodsCell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model.ResultsOur research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression.ConclusionsWe posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.

KROCUS: A phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC.

LBA8511 Background: Fulzerasib (GFH925), a KRAS G12C inhibitor, showed substantial efficacy in previously treated NSCLC patients (pts) as monotherapy. Activation of epidermal growth factor receptor (EGFR) is identified to be one of the dominant mechanisms for KRAS inhibition resistance. Preclinical evidence showed synergistic activity in KRAS G12C mutant NSCLC modeling using fulzerasib in combination with cetuximab. Here we report the first results for a KRAS G12C inhibitor combined with an anti-EGFR antibody in NSCLC pts as front-line treatment. Methods: KROCUS (NCT05756153) was an open-label, single-arm, multi-center, Phase II study with the primary objective to evaluate the efficacy of fulzerasib in combination with cetuximab in pts with previously untreated advanced NSCLC harboring KRAS G12C mutation. Secondary objectives included safety/tolerability, pharmacokinetics and biomarkers. Pts were enrolled to receive fulzerasib (oral, 600 mg BID) and cetuximab (intravenous, 500 mg/m2, every two weeks [Q2W]) combination treatment in a 28-day cycle. Results: As of Jan. 30, 2024, a total of 27 pts (median age: 68 yrs old; 55.6% female) were treated, 11 (40.7%) with baseline brain metastases. Of 20 pts who had at least one post-treatment tumor assessment, ORR was 80.0% (95% CI: 56.3, 94.3, including one CR), of whom eight pts had ≥ 50% tumor shrinkages in the target lesions. Disease control rate (DCR) was 100% (95% CI: 83.2, 100.0). Five out of seven pts (71.4%) with brain metastases achieved PRs. Nine pts with baseline PD-L1 expression tested (six TPS≥1% and three TPS &lt;1%) all achieved PRs. The overall safety profile of the combination was favorable. Treatment-related adverse events (TRAEs) of any grade occurred in 21 (77.8%) pts. 5 pts (18.5%) experienced G3 TRAEs and no G4 or 5 TRAEs. Three pts (11.1%) had dose reduction/interruption with fulzerasib due to TRAEs but no pts discontinued treatment while one pt (3.7%) had dose reduction/interruption and three (11.1%) discontinued cetuximab due to TRAEs. Table 1 shows the most common TRAEs or G3 TRAEs. Conclusions: The preliminary data from ongoing KROCUS study has demonstrated very promising efficacy and favorable safety profile of fulzerasib + cetuximab in the first line setting of KRAS G12C mutated NSCLC. More data will be generated to provide clinical evidence supporting this combination as a potential frontline therapy. Clinical trial information: NCT05756153 . [Table: see text]

Triple Blockade of Oncogenic RAS Signaling Using KRAS and MEK Inhibitors in Combination with Irradiation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest of human malignancies and carries an exceptionally poor prognosis. It is mostly driven by multiple oncogenic alterations, with the highest mutation frequency being observed in the KRAS gene, which is a key oncogenic driver of tumorogenesis and malignant progression in PDAC. However, KRAS remained undruggable for decades until the emergence of G12C mutation specific KRAS inhibitors. Despite this development, this therapeutic approach to target KRAS directly is not routinely used for PDAC patients, with the reasons being the rare presence of G12C mutation in PDAC with only 1-2% of occurring cases, modest therapeutic efficacy, activation of compensatory pathways leading to cell resistance, and absence of effective KRASG12D or pan-KRAS inhibitors. Additionally, indirect approaches to targeting KRAS through upstream and downstream regulators or effectors were also found to be either ineffective or known to cause major toxicities. For this reason, new and more effective treatment strategies that combine different therapeutic modalities aiming at achieving synergism and minimizing intrinsic or adaptive resistance mechanisms are required. In the current work presented here, pancreatic cancer cell lines with oncogenic KRAS G12C, G12D, or wild-type KRAS were treated with specific KRAS or SOS1/2 inhibitors, and therapeutic synergisms with concomitant MEK inhibition and irradiation were systematically evaluated by means of cell viability, 2D-clonogenic, 3D-anchorage independent soft agar, and bioluminescent ATP assays. Underlying pathophysiological mechanisms were examined by using Western blot analyses, apoptosis assay, and RAS activation assay.

Lysophosphatidylcholine acyltransferase 1 suppresses nanoclustering and function of KRAS.

KRAS is frequently mutated in cancer, contributing to 20% of all human cancer especially pancreatic, colorectal and lung cancer. Signaling of the constitutively active KRAS oncogenic mutants is mostly compartmentalized to proteolipid nanoclusters on the plasma membrane (PM). Signaling nanoclusters of many KRAS mutants selectively enrich phosphatidylserine (PS) lipids with unsaturated sn-2 acyl chains, but not the fully saturated PS species. Thus, remodeling PS acyl chains may suppress KRAS oncogenesis. Lysophosphatidylcholine acyltransferases (LPCATs) remodel sn-2 acyl chains of phospholipids, with LPCAT1 preferentially generating the fully saturated lipids. Here, we show that stable expression of LPCAT1 depletes major PS species with unsaturated sn-2 chains while decreasing minor phosphatidylcholine (PC) species with the corresponding acyl chains. LPCAT1 expression more effectively disrupts the nanoclustering of oncogenic GFP-KRASG12V, which is restored by acute addback of exogenous unsaturated PS. LPCAT1 expression compromises signaling and oncogenic activities of the KRAS-dependent pancreatic tumor lines. LPCAT1 expression sensitizes human pancreatic tumor MiaPaCa-2 cells to KRASG12C specific inhibitor, Sotorasib. Statistical analyses of patient data further reveal that pancreatic cancer patients with KRAS mutations express less LPCAT1. Higher LPCAT1 expression also improves survival probability of pancreatic and lung adenocarcinoma patients with KRAS mutations. Thus, PS acyl chain remodeling selectively suppresses KRAS oncogenesis.