sotorasib and Carcinoma--Non-Small-Cell-Lung

Following the CodeBreak 100 study, since 2021 sotorasib has been available in France, with authorization for early access in treatment of non-small cell lung cancer with a KRAS G12C mutation. Our retrospective observational study was designed to determine the efficacy and safety of sotorasib under real-life conditions in patients treated at the Tours CHRU. Our study of 15 patients showed sotorasib to be effective in 47% of cases, with overall survival of 4 months and median progression-free survival of 5.5 months for responders. Tumor control was achieved in 7/8 (87%) of patients with PS of 0 or 1 and in 1/7 (14%) of patients with a PS of 2 or greater. Grade 3 acute hepatitis occurred in 3/15 patients (20%). While sotorasib is an interesting therapeutic option, with efficacy that seems better in patients in good general condition, it entails a possible risk of drug-induced hepatitis, which remains to be specified in dedicated studies.

Topics: Carcinoma, Non-Small-Cell Lung; Hospitals, University; Humans; Lung Neoplasms; Mutation; Observational Studies as Topic; Proto-Oncogene Proteins p21(ras)

Sotorasib, a direct inhibitor of the enzyme Kirsten rat sarcoma viral oncogene (KRAS) with the G12C mutation, was approved by the U.S. Food and Drug Administration (FDA), as a second-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) containing the KRAS G12C mutation, on the basis of results of a phase II clinical trial (Code- BreaK100). In this article, we review the mechanism of action of KRAS G12C inhibitors and the latest clinical trials with sotorasib to provide a comprehensive understanding of its efficacy and toxicity. We also review the mechanisms that produce resistance to the KRAS G12C inhibitors and the preclinical research related to combination treatments for KRAS G12C-mutated tumors. Currently, clinical data suggests that sotorasib monotherapy has significant efficacy in NSCLC patients with the KRAS G12C mutation and tolerable toxicity, and it could represent a novel targeted therapy. Additional research will be required to delineate the mechanisms of resistance to sotorasib and determine the efficacy and safety of combination therapy for the treatment of NSCLC containing the KRAS G12C mutation.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Improving the clinical outcomes of patients with. In this review, we survey the epidemiology of. While sotorasib's development has been unique and exciting, questions persist regarding its intracranial penetrance, optimal dose, and efficacy relative to standard-of-care therapy. Improvements in the clinical activity of KRAS inhibition will hinge on better understanding of resistance mechanisms, the development of broad-spectrum inhibitors with activity beyond G12C mutations, and combination therapy targeting multiple mediators of KRAS signaling and alternative pathways. From a regulatory perspective, sotorasib's development may, in time, prove to be an instructive example for early-phase clinical trialists and regulators focused on dose optimization.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Proto-Oncogene Proteins p21(ras)

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Sotorasib (LUMAKRAS

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Approval; Humans; Lung Neoplasms; Piperazines; Pyridines; Pyrimidines; ras Proteins; United States; United States Food and Drug Administration

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; United States

Sotorasib showed anticancer activity in patients with. In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with. Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in. In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; B7-H1 Antigen; Biomarkers; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Piperazines; Progression-Free Survival; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

No therapies for targeting. We conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the. A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.. Sotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the

Topics: Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasms; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras)

The objectives of this study were to evaluate the effect of sotorasib on metformin pharmacokinetics and pharmacodynamics and the effect of metformin on sotorasib pharmacokinetics in healthy subjects. Sotorasib is an oral, small molecule inhibitor of the Kirsten rat sarcoma oncogene homolog (KRAS) G12C mutant protein (KRASG12C) protein approved by the U.S. Food and Drug Administration in 2021 for the treatment of KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) in adults who have received at least one prior systemic therapy METHODS: This was a phase I, single-center, open-label, three-period, fixed-sequence study. Subjects received single oral doses of metformin 850 mg, sotorasib 960 mg, and metformin 850 mg with sotorasib 960 mg. Urine and plasma were collected and assayed for metformin and sotorasib pharmacokinetics. Blood glucose was also measured for metformin pharmacodynamics. In addition, an in vitro study was conducted to determine whether sotorasib was an inhibitor of MATE1/2K or OCT2 transport.. Geometric least-squares mean ratio of sotorasib area under the concentration-time curve from time 0 to infinity and peak plasma concentration were 0.910 and 0.812, respectively, when sotorasib was coadministered with metformin compared with administration of sotorasib alone. Geometric least-squares mean ratio of metformin area under the concentration-time curve from time 0 to infinity and peak plasma concentration were 0.99 and 1.00, respectively, when comparing metformin coadministered with sotorasib to metformin alone. Geometric mean estimates of serum glucose area under the concentration-time curve from time 0 to 2 h following metformin alone, sotorasib alone, and metformin with sotorasib were 179, 222, and 194, respectively.. These results demonstrated that coadministration of metformin with sotorasib does not impact sotorasib exposure to a clinically significant extent. Coadministration of sotorasib with metformin does not affect metformin exposure or its antihyperglycemic effect, in contrast to the inhibitory effect observed in vitro. Doses of sotorasib 960 mg and metformin 850 mg were safe and well tolerated when coadministered to healthy subjects.

Topics: Area Under Curve; Carcinoma, Non-Small-Cell Lung; Drug Interactions; Healthy Volunteers; Humans; Lung Neoplasms; Metformin

Topics: Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Humans; Incidence; Lung Neoplasms; Proto-Oncogene Proteins p21(ras)

Novel inhibitors of KRAS with G12C mutation (sotorasib) have demonstrated short-lasting responses due to resistance mediated by the AKT-mTOR-P70S6K pathway. In this context, metformin is a promising candidate to break this resistance by inhibiting mTOR and P70S6K. Therefore, this project aimed to explore the effects of the combination of sotorasib and metformin on cytotoxicity, apoptosis, and the activity of the MAPK and mTOR pathways. We created dose-effect curves to determine the IC50 concentration of sotorasib, and IC10 of metformin in three lung cancer cell lines; A549 (KRAS G12S), H522 (wild-type KRAS), and H23 (KRAS G12C). Cellular cytotoxicity was evaluated by an MTT assay, apoptosis induction through flow cytometry, and MAPK and mTOR pathways were assessed by Western blot. Our results showed a sensitizing effect of metformin on sotorasib effect in cells with KRAS mutations and a slight sensitizing effect in cells without K-RAS mutations. Furthermore, we observed a synergic effect on cytotoxicity and apoptosis induction, as well as a notable inhibition of the MAPK and AKT-mTOR pathways after treatment with the combination, predominantly in KRAS-mutated cells (H23 and A549). The combination of metformin with sotorasib synergistically enhanced cytotoxicity and apoptosis induction in lung cancer cells, regardless of KRAS mutational status.

Topics: Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line; Humans; Lung Neoplasms; Metformin; Mutation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); Ribosomal Protein S6 Kinases, 70-kDa; TOR Serine-Threonine Kinases

The CodeBreaK 200 trial showed that sotorasib led to a 34% decrease in relative risk of disease progression or death compared with docetaxel but yielded no improvement in overall survival. Despite the KRAS inhibitor's high cost, less toxicity likely tips the balance in its favor. Subgroup analyses and combination trials are underway to optimize treatment with sotorasib and other KRAS inhibitors.

Topics: Carcinoma, Non-Small-Cell Lung; Disease Progression; Docetaxel; Drug Costs; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Survival Analysis

Sequential anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti-PD-(L)1. This study was designed to address whether sequential anti-PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs.. This is a multicenter, retrospective study of consecutive advanced KRAS. We identified 102 patients who received sotorasib, including 48 (47%) in the sequence group and 54 (53%) in the control group. Patients in the control group received an anti-PD-(L)1 followed by at least one treatment regimen before sotorasib in 87% of the cases or did not receive an anti-PD-(L)1 at any time before sotorasib in 13% of the cases. Severe sotorasib-related AEs were significantly more frequent in the sequence group compared with those in the control group (50% versus 13%, p < 0.001). Severe sotorasib-related AEs occurred in 24 patients (24 of 48, 50%) in the sequence group, and among them 16 (67%) experienced a severe sotorasib-related hepatotoxicity. Severe sotorasib-related hepatotoxicity was threefold more frequent in the sequence group compared with that in the control group (33% versus 11%, p = 0.006). No fatal sotorasib-related hepatotoxicity was reported. Non-liver severe sotorasib-related AEs were significantly more frequent in the sequence group (27% versus 4%, p < 0.001). Severe sotorasib-related AEs typically occurred in patients who received last anti-PD-(L)1 infusion within 30 days before sotorasib initiation.. Sequential anti-PD-(L)1 and sotorasib therapy are associated with a significantly increased risk of severe sotorasib-related hepatotoxicity and severe non-liver AEs. We suggest avoiding starting sotorasib within 30 days from the last anti-PD-(L)1 infusion.

Topics: Antineoplastic Agents, Immunological; Carcinoma, Non-Small-Cell Lung; Cell Death; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Humans; Ligands; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Retrospective Studies

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Pyridines; Pyrimidines

With the recent approval of the KRAS G12C inhibitor sotorasib for patients with advanced. We conducted a multicenter retrospective study of patients treated with sotorasib outside of clinical trials to identify factors associated with real-world progression free survival (rwPFS), overall survival (OS), and toxicity.. Among 105 patients with advanced. Among patients treated with sotorasib in routine practice,

Topics: Carcinoma, Non-Small-Cell Lung; Genomics; Humans; Kelch-Like ECH-Associated Protein 1; Lung Neoplasms; NF-E2-Related Factor 2; Proto-Oncogene Proteins p21(ras); Retrospective Studies

We evaluated the risk factors and outcomes for patients who experienced hepatotoxicity after use of sotorasib in KRAS G12C mutated NSCLC.. Retrospective review of medical records of patients with KRAS G12C mutated NSCLC who received sotorasib between May 28th, 2021, and December 31st, 2021 across all Mayo Clinic sites, with follow up until December 31st, 2022.. Thirty-one patients received sotorasib as standard of care treatment. Grade 3 or higher hepatoxicity was seen in 32% (10/31) patients presenting at a median of 51 days (range, 27-123) of sotorasib initiation. Baseline demographics were comparable between patients with and without ≥grade 3 hepatotoxicity, except for presence of CNS metastases and time from prior immune checkpoint inhibitor (ICI) treatment. Improvement in liver tests was observed in all patients after stopping sotorasib, and it was restarted at a lower dose in 8 patients. Despite dose reduction, hepatotoxicity requiring sotorasib discontinuation occurred in 2 patients. Twenty-eight of 31 patients had received prior ICI. Median time from prior ICI therapy was 69 days (range, 4-542). Rates of ≥grade 3 hepatoxicity were 75% (3/4), 64% (7/11) and 0% (0/13) for patients who received ICI within 30 days, 31-90 days and >90 days. None of the 3 patients without prior ICI exposure developed hepatoxicity. The median PFS and OS were 3.9 months and 9.9 months respectively.. One-third of patients developed grade 3 or higher sotorasib induced hepatotoxicity. Risk of hepatotoxicity was higher in patients who received sotorasib within 90 days of ICI treatment.

Topics: Carcinoma, Non-Small-Cell Lung; Chemical and Drug Induced Liver Injury; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Proto-Oncogene Proteins p21(ras)

Sotorasib, an oral small-molecule inhibitor, reportedly exerts promising activity against Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant tumors. However, the currently administered dose may fail to represent the optimal dose based on the therapeutic efficacy. Herein, we developed a simple and sensitive method using high-performance liquid chromatography with ultraviolet (HPLC-UV) to measure the sotorasib concentration in human plasma. The sotorasib calibration curve exhibited linearity across the concentration range of 0.10-20.0 μg/mL (r

Topics: Carcinoma, Non-Small-Cell Lung; Chromatography, High Pressure Liquid; Drug Monitoring; Humans; Lung Neoplasms; Proto-Oncogene Proteins p21(ras)

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Guanosine Triphosphate; Humans; Lung Neoplasms; Mice; Mutation; Proto-Oncogene Proteins p21(ras)

Effective therapy for non-small-cell lung cancer (NSCLC) depends on morphological and genomic classification, with comprehensive screening for guideline-recommended biomarkers critical to guide treatment. Companion diagnostics, which provide robust genotyping results, represent an important component of personalized oncology. We evaluated the clinical validity of Guardant360 CDx as a companion diagnostic for sotorasib for detection of KRAS p.G12C, an important oncogenic NSCLC driver mutation.. KRAS p.G12C was tested in NSCLC patients from CodeBreaK100 (NCT03600833) in pretreatment plasma samples using Guardant360 CDx liquid biopsy and archival tissue samples using therascreen® KRAS RGQ polymerase chain reaction (PCR) kit tissue testing. Matched tissue and plasma samples were procured from other clinical trials or commercial vendors, and results were compared. Demographics and clinical characteristics and objective response rate (ORR) were evaluated.. Of 126 CodeBreaK patients, 112 (88.9%) were tested for KRASp.G12C mutations with Guardant360 CDx. Among 189 patients in the extended analysis cohort, the positive and negative percent agreement (95% CI) for Guardant360 CDx plasma testing relative to therascreen® KRAS RGQ PCR kit tissue testing were 0.71 (0.62, 0.79) and 1.00 (0.95, 1.00), respectively; overall percent agreement (95% CI) was 0.82 (0.76, 0.87). TP53 co-mutations were the most common regardless of KRAS p.G12C status (KRAS p.G12C-positive, 53.4%; KRAS p.G12C-negative, 45.5%). STK11 was co-mutated in 26.1% of KRAS p.G12C-positive samples. The ORR was similar among patients selected by plasma and tissue testing.. Comprehensive genotyping for all therapeutic targets including KRAS p.G12C is critical for management of NSCLC. Liquid biopsy using Guardant360 CDx has clinical validity for identification of patients with KRASp.G12C-mutant NSCLC and, augmented by tissue testing methodologies as outlined on the approved product label, will identify patients for treatment with sotorasib.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

On May 28, 2021, the FDA granted accelerated approval to sotorasib (Lumakras, Amgen) for the treatment of adults with advanced non-small cell lung cancer (NSCLC) with a Kirsten rat sarcoma proto-oncogene (KRAS) G12C mutation who have received at least one prior systemic therapy. The approval was based on CodeBreaK 100 (Study 20170543), a dose-escalation and dose-expansion trial in patients with an advanced, KRAS G12C-mutated, solid tumor. The overall response rate (ORR) observed in patients with KRAS G12C-mutated NSCLC treated with sotorasib (n = 124) was 36% [95% confidence interval (CI), 28-45]. The median duration of response was 10.0 months (95% CI, 6.9-not estimable). The most common adverse reactions (≥20%) were diarrhea, musculoskeletal pain, nausea, fatigue, hepatotoxicity, and cough. This is the first approval of a targeted therapy for KRAS G12C-mutated NSCLC. Because of pharmacokinetic data and ORRs of patient cohorts who took sotorasib at lower doses in the dose-escalation portion of CodeBreaK 100, a dose comparison study is being conducted as a post-marketing requirement.

Topics: Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase I as Topic; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

In the past two decades, there have been rapid advances in the number and range of regulatory approvals of targeted therapy for patients with advanced non-small cell lung cancer (NSCLC) and other cancers. The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene has a high mutation rate in human cancers and is associated with some of the most aggressive types of cancer, including NSCLC, pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC). Until recently, several common and highly aggressive cancers with KRAS mutations expressing the 'death star' KRAS proteins were considered 'undruggable' and not amenable to targeted therapy. The main KRAS mutations are single-base missense mutations, with 98% occurring at codon 12 (G12C). KRAS G12C is the most common KRAS mutation in NSCLC. Sotorasib is a first-in-class specific small molecule that irreversibly inhibits KRAS G12C. Based on the results from the phase 1/2 CodeBreaK 100 safety and tolerability study, on May 28, 2021, the US Food and Drug Administration (FDA) granted accelerated approval for sotorasib for adults with advanced NSCLC and KRAS G12C mutation. This Editorial aims to present the current status of regulatory approval and the supporting clinical trial data for sotorasib, the first targeted therapy for patients with advanced NSCLC with the KRAS G12C mutation.

Topics: Adult; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Lung Neoplasms; Mutation; Proto-Oncogene Proteins p21(ras)

Topics: Carcinoma, Non-Small-Cell Lung; Drug-Related Side Effects and Adverse Reactions; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Maximum Tolerated Dose; Piperazines; Pyridines; Pyrimidines; United States; United States Food and Drug Administration

Mutant RAS guanosine triphosphate hydrolases (GTPases) are key oncogenic drivers in many cancers. The KRAS. A biopsy from progressing lung cancer of a patient treated with the KRAS. We demonstrated acquisition of HER2 copy number gain and KRAS. These findings establish HER2 copy number gain as a clinically relevant mechanism of resistance to pharmacological KRAS

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Mice; Mice, Nude; Middle Aged; Piperazines; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Receptor, ErbB-2; Xenograft Model Antitumor Assays

Topics: Acetonitriles; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line; Cohort Studies; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Female; GTP Phosphohydrolases; Humans; MAP Kinase Signaling System; Membrane Proteins; Mice; Mutation; Neoplasms; Piperazines; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines; Xenograft Model Antitumor Assays

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Mutant-selective KRAS

Topics: Acetonitriles; Aged; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Neoplasm Metastasis; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance.. We chronically exposed Ba/F3 cells transduced with KRAS. We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib.. We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mutation; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperazines; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Piperazines; Pyridines; Pyrimidines

The latest results from the CodeBreak 100 trial evaluating AMG 510 indicate that this first-in-class KRAS inhibitor, having shown promise in non-small cell lung cancer, is modestly active in several other types of solid tumors, including colorectal cancer.

Topics: Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; ErbB Receptors; Humans; Lung Neoplasms; Piperazines; Pyridines; Pyrimidines

To identify potential resistance mechanisms, we defined the sensitivity of a panel of KRAS G12C-mutant lung cancer cell lines to a KRAS G12C inhibitor, AMG510. Gene set enrichment analyses were performed to identify pathways related to the sensitivity, which was further confirmed biochemically. In addition, we created two cell lines that acquired resistance to AMG510 and the underlying resistance mechanisms were analyzed.. KRAS expression and activation were associated with sensitivity to KRAS G12C inhibitor. Induction of epithelial-to-mesenchymal transition (EMT) led to both intrinsic and acquired resistance to KRAS G12C inhibition. In these EMT-induced cells, PI3K remained activated in the presence of KRAS G12C inhibitor and was dominantly regulated by the IGFR-IRS1 pathway. We found SHP2 plays a minimal role in the activation of the PI3K pathway in contrast to its critical role in the activation of the MAPK pathway. The combination of KRAS G12C inhibitor, PI3K inhibitor, and SHP2 inhibitor resulted in tumor regressions in mouse models of acquired resistance to AMG510.. Our findings suggest that EMT is a cause of both intrinsic and acquired resistance by activating the PI3K pathway in the presence of KRAS G12C inhibitor.

Topics: Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Insulin Receptor Substrate Proteins; Mitogen-Activated Protein Kinase Kinases; Mutation; Phosphatidylinositol 3-Kinases; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridines; Pyrimidines

Evidence continues to grow that KRAS, once considered an "undruggable" target, can be targeted successfully in non-small cell lung cancer. In a phase I trial, the KRAS

Topics: Brain; Carcinoma, Non-Small-Cell Lung; Humans; Immunotherapy; Lung Neoplasms; Mutation; Piperazines; Pyridines; Pyrimidines; Receptors, Chimeric Antigen; Single-Cell Analysis; T-Lymphocytes