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The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease. Article highlights Advances in targeted therapy Covalent inhibitors like sotorasib, adagrasib and divarasib represent significant advancements in targeted therapy aimed specifically at tumors harboring the KRASG12C mutation. Clinical efficacy Clinical trials have shown that KRAS G12C inhibitors improved objective response rates and progression-free survival compared with standard treatments. These trials have obtained promising results in personalized cancer therapy for non-small cell lung cancer (NSCLC) patients harboring the KRASG12C mutation. Importance of co-mutations Co-mutations in genes like KEAP1, SMARCA4 and CDKN2A can significantly impact patient outcomes and response to KRAS G12C inhibitors, with certain co-mutations associated with poor prognosis. Pharmacokinetics & safety Each KRAS G12C inhibitor comes with its own pharmacokinetics profile. Sotorasib and adagrasib are both well tolerated, though gastrointestinal adverse events are common and can be managed with supportive care. Predictive biomarkers Liquid biopsies show promise in detecting KRAS mutations, monitoring treatment response and predicting overall survival, making them a valuable tool in managing NSCLC. Resistance mechanisms Development of resistance to KRAS inhibitors can occur through various genetic alterations and activation of alternative pathways. Combination therapies may help overcome these resistance mechanisms. Future directions Ongoing and future clinical trials aim to further explore the efficacy of KRAS G12C inhibitors, their combinations with immunotherapies, and other novel compounds to improve treatment outcomes in NSCLC. [ABSTRACT FROM AUTHOR]

Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a poor 5‑year survival rate. The majority of PDAC cases harbor KRAS mutations, predominantly at codon 12, with G12D being the most common. While selective inhibitors like sotorasib have shown promise in KRASG12C-mutated PDAC, these mutations are rare, and resistance develops rapidly. Efforts to target more prevalent mutations like KRASG12D are ongoing, with compounds such as MRTX1133 showing preclinical efficacy. Resistance mechanisms include secondary mutations and pathway reactivation, prompting the development of pan-(K)RAS inhibitors (e.g., RMC-6236) and combination strategies targeting upstream effectors. Novel approaches, such as KRAS-targeted vaccines and T‑cell receptor (TCR) therapies, offer additional potential. Continued clinical trials are crucial to optimizing KRAS-targeted therapies in PDAC. [ABSTRACT FROM AUTHOR]

Introduction: Sotorasib was the first drug approved for adults with Kirsten rat sarcoma G12C-mutated locally advanced/metastatic non-small cell lung cancer (NSCLC) who received prior systemic therapy in the US. This study aimed to provide initial real-world evidence on patient characteristics, treatment patterns, healthcare resource utilization (HCRU), and healthcare costs (HCC) associated with sotorasib in US clinical practice. Methods: A retrospective observational study was conducted using the Optum Clinformatics® Data Mart US claims database spanning January 2016 to March 2023. The study population included adults with a diagnosis of lung cancer (diagnosis (Dx) date), claims for sotorasib on/post-Dx date (index date), Continuous enrollment for medical/pharmacy benefits from 180 days pre-Dx date to ≥ 30 days post-index date was required. Patients receiving treatments for small-cell lung cancer (SCLC) pre-index were excluded. Outcomes were analyzed for patients receiving sotorasib as second or subsequent line (2L+) treatment and included adherence [proportion of days covered (PDC)], treatment duration, time to next treatment (TTNT), HCRU, and HCC during sotorasib treatment. Results: Among 169 patients with lung cancer that met all inclusion criteria, 140 patients received sotorasib as 2L+ treatment (mean age: 71 years; 67.1% females). Mean PDC for sotorasib was 94.9%. Kaplan–Meier median treatment duration was 4.3 months. Median TTNT in patients with subsequent treatment (n = 31) was 6.8 months. During sotorasib treatment, patients had a mean 3.87 outpatient, 0.09 inpatient, and 0.11 emergency visits per month. Mean monthly HCC during sotorasib treatment were US$23,063 versus $25,541 during the 180-day pre-index period. Conclusions: Patients in the US receiving sotorasib as 2L+ therapy for NSCLC in real-world clinical practice showed high adherence, TTNT comparable to progression-free survival observed in clinical trials, and HCC similar to those immediately prior to treatment demonstrating real-world benefits with no additional impact on healthcare resources with sotorasib. [ABSTRACT FROM AUTHOR]

Sotorasib exhibits pH‐dependent solubility, making it susceptible to altered exposures when coadministered with acid‐reducing agents (ARAs). Several clinical studies were conducted to investigate the impact of ARAs on sotorasib pharmacokinetics under different clinically relevant scenarios and to identify potential mitigation strategies. Upon coadministration of 960 mg of sotorasib and 40 mg of omeprazole under fasted conditions, sotorasib area under the concentration‐time curve (AUC) and maximum observed plasma concentration (Cmax) decreased approximately 42% and 57%, respectively. Following coadministration with 40 mg of famotidine under fed conditions, sotorasib AUC and Cmax decreased approximately 38% and 35%, respectively. The coadministration of sotorasib and 40 mg of omeprazole under fed conditions led to a 57% and 65% decrease in sotorasib AUC and Cmax, respectively. When sotorasib was coadministered with omeprazole and an acidic beverage compared to sotorasib alone, AUC and Cmax decreased approximately 23% and 32%, respectively, leading to a 19.0 percentage‐point increase in AUC and a 24.6 percentage‐point increase in Cmax for sotorasib when compared to coadministration of sotorasib with omeprazole under fasted conditions. Sotorasib exposure decreased when coadministered with proton pump inhibitors and H2 receptor antagonists. Coadministration with an acidic beverage increased sotorasib exposure upon concomitant administration with omeprazole, which may represent a clinically attractive method to allow ARA use with sotorasib. [ABSTRACT FROM AUTHOR]

Background: Basket clinical trials targeting the KRASG12C-mutation in solid tumors have shown initial promise, including in orphan KRASG12C head and neck cancer (HNC). However, development of resistance to KRASG12C-mutant-specific inhibitors (KRASG12Ci) remains a major obstacle. Here, we investigated the intrinsic (tumor-cell autonomus) and tumor-microenvironment (TME) mechanisms of resistance to the KRASG12Ci—MRTX849 and AMG510 in a unique syngenic murine KRASG12C-mutated HNC cell line. Methods: Western-blotting was used for protein abundance and activation, overexpression, and ligand activation studies to verify the intrinsic mechanism of resistance to KRASG12Ci in KRASG12C-mutated HNC cell line, 4NQO-L. In vitro KRASG12C-acquired-resistant cells were developed from 4NQO-L (4NQO-L-AcR). MRTX849/lapatinib combination efficacy, and CD8+ T-cells depletion, were assessed in C57BL/6 J mice and supplementation of anti-PD-1 (αPD-1) to MRTX849/lapatinib was also performed in 4NQO-L– KRASG12Ci-senisitve and 4NQO-L-AcR tumors. Immunohistochemistry (IHC) and Immunoflourescence (IF) analyses were performed to profile the TME and programmed death-ligand 1 (PD-L1) expression in tumors. Results: Activation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRASG12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and AKT/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8+ T-cells after treatment combination, and these CD8+ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8+ T-cells and enabled immune escape and tumor progression. Supplementation of αPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8+ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with αPD-1 did not improve the outcome. Conclusions: Our study highlights the critical need for blocking both intrinsic and extrinsic mechanisms of resistance for the prolonged response and shows that such treatment is ineffective in KRASG12Ci-AcR tumors. [ABSTRACT FROM AUTHOR]

Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, particularly among patients with a specific mutation in the KRAS gene known as KRAS G12C. Two targeted therapies, adagrasib and sotorasib, have been developed for this mutation. This manuscript reviews three key clinical trials that evaluated the efficacy of these drugs in patients with KRAS G12C-mutated NSCLC. We compare their effectiveness in slowing disease progression and examine their differing side effect profiles, both of which are crucial for treatment decisions. While both drugs demonstrate efficacy, their side effects can influence patient tolerance and overall experience. Understanding these differences enables physicians to make more informed choices about the most appropriate treatment for each patient. Our analysis indicates that, although the overall survival rates for both drugs are comparable, certain patients may derive greater benefits from one therapy over the other, depending on individual characteristics and the management of side effects. Background: The KRAS G12C mutation, prevalent in various malignancies, including non-small cell lung cancer (NSCLC), represents a unique therapeutic target. Adagrasib and sotorasib, two FDA-approved agents specifically targeting this mutation, have shown promise in clinical trials. This study aims to compare their efficacy in treating KRAS G12C-mutated NSCLC, drawing insights from pivotal clinical trials. Methods: We analyzed data from three key clinical trials: KRYSTAL-1, CodeBreak100, and CodeBreak200. Our methodology involved reconstructing individual patient data from published Kaplan–Meier curves using the IPDfromKM tool (Version 0.1.10). The primary endpoints were progression-free survival (PFS) and overall survival (OS), evaluated through hazard ratios (HRs) and the restricted mean survival time (RMST) method. Results: The HR for PFS favored adagrasib (HR: 0.90 [95% CI: 0.69, 1.19], p = 0.473), suggesting a non-significant trend toward better disease control compared to sotorasib. For OS, the HR was 0.99 [95% CI: 0.75, 1.33] (p = 0.969), indicating no significant difference between the two drugs. RMST analysis supported these findings, with adagrasib showing a consistently higher RMST in PFS at 6, 12, and 18 months. However, OS benefits converged over time, with adagrasib marginally surpassing sotorasib by the 18-month mark. Conclusions: This comprehensive analysis reveals that while adagrasib may offer a slight advantage in PFS, both drugs demonstrate comparable efficacy in OS for KRAS G12C-mutated NSCLC. The subtle differences observed, particularly in PFS, could inform clinical decision-making, emphasizing the need for personalized treatment strategies. Future research should focus on long-term effects and identifying patient subgroups that may benefit more from one drug over the other. [ABSTRACT FROM AUTHOR]

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 960 mg of sotorasib under fasted conditions or with a high‐fat meal (fed conditions). The geometric least squares means (GLSM) ratios (fed/fasted) for 360 mg 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 360 mg 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 960 mg 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. [ABSTRACT FROM AUTHOR]

The Kirsten rat sarcoma (KRAS) oncogene was considered “undruggable” until the development of sotorasib, a KRASG12C selective inhibitor that shows favorable effects against lung cancers. MRTX1133, a novel KRASG12D inhibitor, has shown promising results in basic research, although its effects against pancreatic cancer are limited when used alone. Therefore, there is an urgent need to identify effective drugs that can be used in combination with KRAS inhibitors. In this study, we found that administration of the KRAS inhibitors sotorasib or MRTX1133 upregulated STAT3 phosphorylation and reactivated ERK through a feedback reaction. The addition of the MEK inhibitor trametinib and the JAK2 inhibitor fedratinib successfully reversed this effect and resulted in significant growth inhibition in vitro and in vivo. Analyses of sotorasib‐ and MRTX1133‐resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2‐mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS‐mutant pancreatic cancer. [ABSTRACT FROM AUTHOR]

Evidence indicates that combinations of anti‐EGFR antibodies and KRAS p.G12C (c.34G>T) inhibitors can be an effective treatment strategy for advanced colorectal cancer. We hypothesized that KRAS c.34G>T (p.G12C)‐mutated colorectal carcinoma might be a distinct tumor subtype. We utilized a prospective cohort incident tumor biobank (including 1347 colorectal carcinomas) and detected KRAS c.34G>T (p.G12C) mutation in 43 cases (3.2%) and other KRAS mutations (in codon 12, 13, 61, or 146) in 467 cases (35%). The CpG island methylator phenotype (CIMP)‐low prevalence was similarly higher in KRAS c.34G>T mutants (52%) and other KRAS mutants (49%) than in KRAS‐wild‐type tumors (31%). KRAS c.34G>T mutants showed higher CIMP‐high prevalence (14%) and lower CIMP‐negative prevalence (33%) compared with other KRAS mutants (6% and 45%, respectively; p = 0.0036). Similar to other KRAS mutants, KRAS c.34G>T‐mutated tumors were associated with cecal location, non‐microsatellite instability (MSI)‐high status, BRAF wild type, and PIK3CA mutation when compared with KRAS‐wild‐type tumors. Compared with BRAF‐mutated tumors, KRAS c.34G>T mutants showed more frequent LINE‐1 hypomethylation, a biomarker for early‐onset colorectal carcinoma. KRAS c.34G>T mutants were not associated with other features, including the tumor tissue abundance of Fusobacterium nucleatum (F. animalis), pks+Escherichia coli, Bifidobacterium, or (enterotoxigenic) Bacteroides fragilis. Among 1122 BRAF‐wild‐type colorectal carcinomas, compared with KRAS‐wild‐type tumors, multivariable‐adjusted colorectal cancer‐specific mortality hazard ratios (95% confidence interval) were 1.82 (1.05–3.17) in KRAS c.34G>T (p.G12C)‐mutated tumors (p = 0.035) and 1.57 (1.22–2.02) in other KRAS‐mutated tumors (p = 0.0004). Our study provides novel evidence for clinical and tumor characteristics of KRAS c.34G>T (p.G12C)‐mutated colorectal carcinoma. [ABSTRACT FROM AUTHOR]

Brian Warnecke,1 Misako Nagasaka1,2 1Department of Medicine, University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA; 2Department of Medicine, St. Marianna University School of Medicine, Kawasaki, JapanCorrespondence: Misako Nagasaka, Department of Medicine, University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, 92868, USA, Email nagasakm@hs.uci.eduAbstract: One of the most common mutations seen in lung cancers are mutations in Kristen Rat Sarcoma Viral Oncogene Homolog (KRAS), observed in 25– 30% of patients with NSCLC. Mutations in KRAS result in oncogenesis via persistent activation of the MAPK/ERK pathways. Although once thought to be “undruggable”, KRAS p.G12C inhibitors such as sotorasib and adagrasib have been developed. This paper focuses on adagrasib, the second KRAS p.G12C inhibitor to obtain regulatory approval by the FDA and describes the details on its study design, development and current place in therapy.Keywords: Kristen Rat Sarcoma Viral Oncogene Homolog, sotorasib, AMG510, MRTX849, KRYSTAL, CodeBreaK, brain penetration

Abstract Background Basket clinical trials targeting the KRASG12C-mutation in solid tumors have shown initial promise, including in orphan KRASG12C head and neck cancer (HNC). However, development of resistance to KRASG12C-mutant-specific inhibitors (KRASG12Ci) remains a major obstacle. Here, we investigated the intrinsic (tumor-cell autonomus) and tumor-microenvironment (TME) mechanisms of resistance to the KRASG12Ci—MRTX849 and AMG510 in a unique syngenic murine KRASG12C-mutated HNC cell line. Methods Western-blotting was used for protein abundance and activation, overexpression, and ligand activation studies to verify the intrinsic mechanism of resistance to KRASG12Ci in KRASG12C-mutated HNC cell line, 4NQO-L. In vitro KRASG12C-acquired-resistant cells were developed from 4NQO-L (4NQO-L-AcR). MRTX849/lapatinib combination efficacy, and CD8+ T-cells depletion, were assessed in C57BL/6 J mice and supplementation of anti-PD-1 (αPD-1) to MRTX849/lapatinib was also performed in 4NQO-L– KRASG12Ci-senisitve and 4NQO-L-AcR tumors. Immunohistochemistry (IHC) and Immunoflourescence (IF) analyses were performed to profile the TME and programmed death-ligand 1 (PD-L1) expression in tumors. Results Activation and upregulation of EGFR and HER2/3 (pan-HERs) are the intrinsic mechanism of resistance to KRASG12Ci in 4NQO-L cells, and blocking pan-HERs signaling with lapatinib enhanced MRTX849 efficacy in vitro by inhibiting the MAPK and AKT/mTOR pathways. 4NQO-L-AcR upregulated the expression of pan-HERs, and lapatinib treatment re-sensitized 4NQO-L-AcR to MRTX849. In mice, MRTX849 showed a slight anti-tumor effect, but in combination with lapatinib a significant tumor growth delay was observed, but all tumors progressed over time. Histopathology analysis of the TME revealed infiltration of CD8+ T-cells after treatment combination, and these CD8+ T-cells play a key role in MRTX849/lapatinib efficacy. MRTX849/lapatinib treatment upregulated PD-L1 overexpression in both stromal and tumor cells, which presumably suppressed CD8+ T-cells and enabled immune escape and tumor progression. Supplementation of αPD-1 prolonged the progression-free survival of 4NQO-L-bearing mice treated with MRTX849/lapatinib. MRTX849/lapatinib treatment delayed tumor growth of 4NQO-L-AcR in mice; however, the percentages of CD8+ T-cells in 4NQO-L-AcR were low, and supplementation of MRTX849/lapatinib with αPD-1 did not improve the outcome. Conclusions Our study highlights the critical need for blocking both intrinsic and extrinsic mechanisms of resistance for the prolonged response and shows that such treatment is ineffective in KRASG12Ci-AcR tumors.

Abstract Lung cancer remains a significant health challenge, characterized by aberrant tissue growth within the pulmonary system. Early carcinogenic events often involve genomic instability and the emergence of a mutator phenotype. In this study, we aimed to explore the mutator phenotype in 89 patients diagnosed with non-small-cell lung cancer (NSCLC). RNA isolation from formalin-fixed paraffin-embedded (FFPE) tissue samples was performed using the Promega ReliaPrep RNA Miniprep System, facilitating gene amplification relevant to cancer through the Archer® FusionPlexComprehensiveThyroid and Lung (CTL) kit. Next-generation sequencing (NGS) on the Illumina NextSeq platform enabled comprehensive analysis of target areas. Utilizing Archer Analysis software, secondary analyses involving data cleansing, alignment, and variant/fusion identification were executed against the human reference genome hg19 (GRCh37). Expression patterns were visualized using HeatMap graphics. Our findings revealed a notable presence of KRAS gene mutations in approximately 20% of NSCLC patients. Among these mutations, the G12C variant was predominant at 50%, followed by G12V and G12D variants at 11.2% each. Notably, patients harboring the G12C variant responded favorably to sotorasib medication. These results underscore the importance of mutational profiling and targeted therapeutic approaches in managing NSCLC, particularly highlighting the promising efficacy of sotorasib in G12C-mutated cases.

Faustine X Luo,1,2 Zhaohui Liao Arter1,2 1University of California Irvine School of Medicine, Orange, CA, 92868, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, 92868, USACorrespondence: Zhaohui Liao Arter, Department of Medicine, Division of Hematology/Oncology, UC Irvine, Orange, CA, 92602, USA, Email zarter@hs.uci.eduAbstract: Kirsten rat sarcoma viral oncogene homolog (KRAS)G12C-mutant non-small cell lung carcinoma (NSCLC) accounts for approximately 10– 13% of advanced nonsquamous NSCLC cases in Western populations, presenting a significant therapeutic challenge owing to the difficulty of directly targeting KRAS. Adagrasib, an oral small-molecule covalent inhibitor, irreversibly and selectively targets KRASG12C in its inactive state. It received accelerated Food and Drug Administration (FDA) approval on December 12, 2022, following the KRYSTAL-1 Phase II trial. The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with docetaxel (HR, 0.58; 95% CI: 0.45– 0.76; P< 0.0001) and increased the intracranial objective response rate (ORR) to 40% in the central nervous system (CNS) evaluable population. This paper evaluates the clinical efficacy of adagrasib in KRASG12C-mutated advanced NSCLC discussing its potential advantages over other inhibitors such as sotorasib. Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRASG12C enigma code in NSCLC.Keywords: non-small-cell lung cancer, KRASG12C mutations, adagrasib, sotorasib, KRYSTAL, targeted therapy, intracranial efficacy

Introduction: Pulmonary sarcomatoid carcinomas (PSCs) are a rare subgroup of non-small cell lung cancer (NSCLC). In contrast to other NSCLCs, PSCs have a poor prognosis due to limited efficacy of radiation and chemotherapy. Therefore, other therapeutic approaches are needed. KRAS mutations occur in PSC with a significant proportion of 30%, and most of them are G12C with the therapeutic option of sotorasib. Case Report: Here, we describe the case of a patient with PSC and pleural metastases. After first-line chemotherapy, the patient presented with new neurological symptoms such as a hemiparesis of the right arm and focal seizures. Following the detection of new brain metastases, we switched the therapy to sotorasib due to the presence of a KRAS G12C mutation. During treatment with sotorasib, the patient’s condition worsened progressively and his neurological symptoms got more severe. A CCT performed during the course of treatment showed progression of the brain metastases. After 48 days being on drug, decision to discontinuate therapy with sotorasib due to patient’s inability to take oral medication and change to a best supportive care concept was made. The patient died few weeks after termination of therapy with rapidly progressive disease. Discussion/Conclusion: This case emphasizes the poor prognosis of patients with PSC due to a lack of therapeutic response to chemotherapy, radiation, and, as seen in this case, current targeted therapy as well. Our case emphasizes the need to further evaluate therapeutic responses of targeted therapy in this rare subtype of NSCLC.

Introduction: Pulmonary sarcomatoid carcinomas (PSCs) are a rare subgroup of non-small cell lung cancer (NSCLC). In contrast to other NSCLCs, PSCs have a poor prognosis due to limited efficacy of radiation and chemotherapy. Therefore, other therapeutic approaches are needed. KRAS mutations occur in PSC with a significant proportion of 30%, and most of them are G12C with the therapeutic option of sotorasib. Case Report: Here, we describe the case of a patient with PSC and pleural metastases. After first-line chemotherapy, the patient presented with new neurological symptoms such as a hemiparesis of the right arm and focal seizures. Following the detection of new brain metastases, we switched the therapy to sotorasib due to the presence of a KRAS G12C mutation. During treatment with sotorasib, the patient’s condition worsened progressively and his neurological symptoms got more severe. A CCT performed during the course of treatment showed progression of the brain metastases. After 48 days being on drug, decision to discontinuate therapy with sotorasib due to patient’s inability to take oral medication and change to a best supportive care concept was made. The patient died few weeks after termination of therapy with rapidly progressive disease. Discussion/Conclusion: This case emphasizes the poor prognosis of patients with PSC due to a lack of therapeutic response to chemotherapy, radiation, and, as seen in this case, current targeted therapy as well. Our case emphasizes the need to further evaluate therapeutic responses of targeted therapy in this rare subtype of NSCLC. [ABSTRACT FROM AUTHOR]

The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS (OFF)). The KRASG12C mutation results in the accumulation of KRASG12C(OFF), promoting cell cycle survival and proliferation primarily through the canonical MAPK and PI3K pathways. The KRASG12C mutation is found in 13% of lung adenocarcinomas. Previously considered undruggable, sotorasib and adagrasib are the first available OFF-state KRASG12C inhibitors, but treatment resistance is frequent. In this review, after briefly summarizing the KRAS pathway and the mechanism of action of OFF-state KRASG12C inhibitors, we discuss primary and acquired resistance mechanisms. Acquired resistance is the most frequent, with "on-target" mechanisms such as a new KRAS mutation preventing inhibitor binding; and "off-target" mechanisms leading to bypass of KRAS through gain-of-function mutations in other oncogenes such as NRAS, BRAF, and RET; or loss-of-function mutations in tumor suppressor genes such as PTEN. Other "offtarget" mechanisms described include epithelial-to-mesenchymal transition and histological transformation. Multiple co-existing mechanisms can be found in patients, but few cases have been published. We highlight the lack of data on non-genomic resistance and the need for comprehensive clinical studies exploring histological, genomic, and non-genomic changes at resistance. This knowledge could help foster new treatment initiatives in this challenging context. [ABSTRACT FROM AUTHOR]

Introduction: Sotorasib and adagrasib have been widely used for the non-small cell lung cancer (NSCLC) patients harboring Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation. It's necessary to assess their safety profiles in the real-world population. Methods: A retrospective pharmacovigilance was conducted to examine adverse events (AEs) associated with sotorasib and adagrasib therapies using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Disproportionality analysis was performed employing Venn analysis and four data-mining algorithms, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS). Results: The most commonly reported system organ classes (SOCs) for both adagrasib and sororasib were general, gastrointestinal, and investigations disorders. Notably, sotorasib exhibited significant signals for neoplasms and hepatobiliary disorders in four algorithms. Specifically, AEs related to neoplasms were predominantly associated with lung malignancies, all of which were consistent with the therapeutic indications of KRAS G12C mutation inhibitor. A total of 19 common AEs were identified in sotorasib and adagrasib, spanning gastrointestinal, general, hepatobiliary, investigations, metabolism, musculoskeletal, neoplasms, and respiratory disorders. 4 severe AEs (SAEs) were identified in sotorasib, with 3 SAEs displaying significant signals in four algorithms, including drug-induced liver injury, pancreatitis, and hepatic failure. In adagrasib, only 2 SAEs were detected, with renal failure showing significant signals in four algorithms. Conclusion: This study offers a comprehensive evaluation of the major safety signals associated with sotorasib and adagrasib, providing valuable information for clinicians regarding drug selection and safety considerations, thereby facilitating the design of future prospective safety studies. [ABSTRACT FROM AUTHOR]