Non-small Cell Lung Carcinoma Research Articles

Unravelling switch/sucrose non-fermentable (SWI-SNF) complex-deficient thoracic tumours: a clinicopathological comparative on undifferentiated tumours and non-small cell lung carcinomas with BRG1 and BRM deficiency.

This study was undertaken to compare and expand the clinicopathological characteristics of SMARCA4-deficient thoracic undifferentiated tumour (SMARCA4-dUT) and switch/sucrose non-fermentable-deficient non-small cell lung carcinomas (SWI/SNF-dNSCLC) and to address cases with intermediate features. The pathology department archive was searched for all primary mediastinal, pleural and lung-based malignancies that showed aberrant expression of two SWI/SNF proteins the Brahma (BRM) aka SMARCA2 and/or (Brahma-related gene 1 (BRG1) aka SMARCA4. Patient demographics, treatment and clinical outcomes were collected from records and telephonic interviews. Differences in histopathological features and immunohistochemical stains were analysed. Cases with characteristics intermediate between both tumour entities were sequenced to advance our understanding of their biology and to assign them a more accurate classification. We identified 50 tumours with SMARCA4 and/or SMARCA2 deficiencies, including 23 (46%) SMARCA4-dUT, 18 (36%) SMARCA4-dNSCLC and 2 (4%) SMARCA2-dNSCLC. Dyscohesive or undifferentiated cellular morphology versus frank gland formation along with keratin, claudin-4 and expression of >1 stem cell marker helped classify the SWI/SNF deficient tumours as SMARCA4-dUT or SWI/SNF-dNSCLC (p<0.05). Seven (14%) cases with BRG1 deficiency displayed 'intermediate' features of both SMARCA4-dNSCLC and SMARCA4-dUT and had the shortest overall survival. The smoking-related gene signature was observed on sequencing in all four cases examined. Tumours with intermediate features between SMARCA4-dUT and SWI/SNF-dNSCLC exist and portend an equally poor prognoses. Immunostains, including keratin, claudin-4, TTF1, HepPar1, stem cell markers, along with BRG1 and BRM testing, are essential adjuncts to morphology, while molecular studies can offer supplementary evidence in challenging cases.

SIRT3 Inhibits Cell Proliferation of Nonsmall Cell Lung Carcinoma by Inducing ROS Production.

Sirtuin 3 (SIRT3) is located in the mitochondrial matrix, regulating acetylation levels of metabolic enzymes. As an oncogene or a tumor suppressor gene, SIRT3 plays an important role in the commencement and progression of certain cancers. In this research, we investigated the role of SIRT3 in the progression of nonsmall cell lung carcinoma (NSCLC). In this study, bioinformatics was used to analyze the differential expression of SIRT3 in NSCLC tissue and normal tissues, prognosis, single-cell analysis, and related signaling pathways. The Lentiviral overexpressing SIRT3 was constructed, and CCK8 and colony formation assay were used to evaluate the NSCLC cells proliferation, ROS production was detected by flow cytometry, and the sea-horse test was used to measure cellular oxygen consumption (OCR). SIRT3 expression was significantly decreased in NSCLC, and low expression of SIRT3 was closely related to the poor prognosis. Besides, on the whole, upregulation of SIRT3 suppressed cell proliferation in A549 and SK-MES-1 cells via increasing oxidative phosphorylation (OXPHOS) and ROS production. Overall, our findings suggested that SIRT3 functions as a tumor suppressor that can suppress the progression of NSCLC via stimulating ROS production.

Mechanistic Overview on the Therapeutic Potential of Alkaloids in Combating Non-small Cell Lung Carcinoma

Mechanistic Overview on the Therapeutic Potential of Alkaloids in Combating Non-small Cell Lung Carcinoma

Prognostic Indicators for Precision Treatment of Non-Small Cell Lung Carcinoma

Non-small cell lung cancer (NSCLC) has established predictive biomarkers that enable decisions on treatment regimens for many patients. However, resistance to therapy is widespread. It is therefore essential to have a panel of molecular biomarkers that may help overcome therapy resistance and prevent adverse effects of treatment. We performed in silico analysis of NSCLC prognostic indicators, separately for adenocarcinomas and squamous carcinomas, by using The Cancer Genome Atlas (TCGA) and non-TCGA data sources in cBioPortal as well as UALCAN. This review describes lung cancer biology, elaborating on the key genetic alterations and specific genes responsible for resistance to conventional treatments. Importantly, we examined the mechanisms associated with resistance to immune checkpoint inhibitors. Our analysis indicated that a robust prognostic biomarker was lacking for NSCLC, especially for squamous cell carcinomas. In this work, our screening uncovered previously unidentified prognostic gene expression indicators, namely, MYO1E, FAM83 homologs, and DKK1 for adenocarcinoma, and FGA and TRIB1 for squamous cell carcinoma. It was further observed that overexpression of these genes was associated with poor prognosis. Additionally, FAM83 homolog and TRIB1 unexpectedly harbored copy number amplifications. In conclusion, this study elucidated novel prognostic indicators for NSCLC that may serve as targets to overcome therapy resistance toward improved patient outcomes.

Genetic profile of ferroptosis in non-small cell lung carcinoma and pharmaceutical options for ferroptosis induction.

Lung cancer (LC) is the leading cause of cancer-related deaths and the second most commonly diagnosed malignancy worldwide. Lung adenocarcinoma (LUAD) and lung squamous cell LC (LUSCC) are the most common subtypes of non-small cell LC (NSCLC). Early diagnosis of LC can be challenging due to a lack of biomarkers. The overall survival (OS) of patients with NSCLC is still poor despite the enormous efforts that have been made to develop novel treatments. Understanding fundamental molecular and genetic mechanisms is necessary to develop new therapeutic approaches for NSCLC. A recently identified type of programmed cell death known as ferroptosis is one potential approach. Ferroptosis causes oxidative damage and the death of cancerous cells by peroxidizing unsaturated phospholipids and accumulating reactive oxygen species (ROS) in an iron-dependent manner. Ferroptosis-related gene (FRG) signatures have recently been evaluated for their ability to predict patient OS and prognosis. These analyses show FRGs are involved in cancer progression, and may serve as promising biomarkers for tumor diagnosis and therapy. Moreover, we summarize the current pharmaceutical options of ferroptosis induction and their underlying molecular mechanism in LC. Therefore, this review aims to provide a comprehensive summary of FRG-based prognostic models, their associated metabolic and signaling pathways, and promising therapeutic options for ferroptosis induction in NSCLC.

Common epidermal growth factor receptor mutations in north Indian patients with non-small cell lung carcinoma: evidence from real-time polymerase chain reaction.

Lung carcinoma was the ace cause of cancer deaths globally in 2022, with non-small cell lung carcinoma (NSCLC) accounting for 81% of the burden. Due to promising tyrosine kinase inhibitor (TKI) trials, NSCLC patients harboring epidermal growth factor receptor (EGFR) gene mutations are of interest. Our aim was to determine EGFR mutation prevalence in north India and its histologic and demographic correlations. We investigated the frequency of EGFR mutations in 40 patients with histologically confirmed NSCLC using real-time polymerase chain reaction. A 15% mutation frequency was observed in the study sample, involving 32 males and 8 females with a median age of 59 years. Squamous cell carcinoma (SCC) patients had only EXON20 (T790M, exon20 insertion) mutations, while adenocarcinoma patients had mutations in both EXON20 (T790M) and 21 (L858R) with mutation frequencies of 22% and 10%, respectively. 28% of the SCC patients were non-smokers, and 60% of these non-smokers had an EGFR mutation. South Indian and Asian studies have identified EXON19 (19-Del) and EXON21 (L858R) mutations as "common mutations" that account for nearly 80-90% of all mutations and respond well to TKIs. Interestingly, "common mutations" were found seldom in our study population, while the uncommon variants constitute 83% of all mutations, which we assume is due to diverse Indian genetics and ethnicity and co-existing signature mutations that involve the tyrosine kinase domain of EXON20. We suggest future genome-wide association studies to identify plausible genetic polymorphisms responsible for interethnic differences in EGFR mutation, which will contribute to better treatment and prevention of NSCLCs.

Neoadjuvant Therapy and Lung Cancer: Role of Pathologists.

Recent neoadjuvant clinical trials in lung cancer have demonstrated the survival benefits in carefully selected patients. Standardization of the assessment of pathologic response to neoadjuvant therapy in surgically resected specimens is required. To review the current pathology practices in the gross processing and microscopic assessment of surgically resected non-small cell lung carcinoma specimens after neoadjuvant therapy. PubMed publications and experience of the author. Gross processing of the surgically resected lung carcinoma after neoadjuvant therapy needs further refinement and standardization in clinical trials and in a real-world clinical practice. Microscopic assessment of the response includes quantification of viable tumor, necrosis, and stroma. The best approach would be to use a single standardized and most reproducible scoring system. Published studies on gross processing of lung carcinoma specimens in the neoadjuvant setting and microscopic assessment of pathologic response provide a good foundation for the future standardization of pathology practice.

The Double-Edged Sword of Immunotherapy—Durvalumab-Induced Polyendocrinopathy—Case Report

Introduction: Immunotherapy is one of the greatest advancements in oncological patient care. The broader the treatment application, the more common the adverse events associated with the therapy. Immune checkpoint inhibitors (ICI) are currently used in numerous malignancies. These drugs influence the immune cells’ interactions, which translates to interruption of immune evasion and increased anti-tumor activity. However, the disruption of immunological signaling pathways often leads to adverse events, such as endocrinological insufficiencies, among which thyroid is the most common. Moreover, the co-appearance of several insufficiencies has been previously described. Case report: A 73-year-old female treated with durvalumab due to non-small cell lung carcinoma was admitted to the emergency unit due to symptoms of ketoacidosis. She had a history of well-controlled type 2 diabetes mellitus and autoimmune thyroiditis. Laboratory results showed increased anti-GAD antibodies, while the low C-peptide level indicated type 1 diabetes mellitus. Moreover, over the course of longer observation, the patient presented with abrupt aggravation of her autoimmune thyroiditis. Conclusions: The new onset of endocrinological insufficiencies is a rare adverse event of immunotherapy. Clinicians must pay particular attention to any signs indicating these life-threatening conditions. In case of the appearance of any endocrinological adverse event, the close cooperation of oncologists and endocrinologists is required to enhance patients’ quality of life.

Impact of PM2.5 exposure on mortality and tumor recurrence in resectable non-small cell lung carcinoma

This study aimed to explore the impact of PM 2.5 exposure on survival, post-operative outcomes, and tumor recurrence in resectable non-small cell lung cancer (NSCLC) patients. The study cohort comprised 587 patients at Chiang Mai University Hospital between January 1, 2010, and December 31, 2017. Patients were categorized based on their residents’ average PM 2.5 concentration into two groups: exposed (PM 2.5 ≥ 25 µg/m3 annual mean) and unexposed (PM 2.5 < 25 µg/m3 annual mean). The exposed group had 278 patients, while the unexposed group had 309 patients. Baseline differences in gender and surgical approach were observed between the groups. Multivariable regression analysis revealed that patients in the exposed group had a higher risk of death (HR 1.44, 95% CI, 1.08–1.89, p = 0.012). However, no significant associations were found between PM 2.5 and post-operative pulmonary complications (RR 1.12, 95% CI, 0.60–2.11, p = 0.718), in-hospital mortality (RR 1.98, 95% CI, 0.40–9.77, p = 0.401), and tumor recurrence (HR 1.12, 95% CI, 0.82–1.51, p = 0.483). In conclusion, a PM 2.5 concentration ≥ 25 µg/m3 annual mean was associated with decreased overall survival and a potential increase in in-hospital mortality among resectable NSCLC patients. Larger studies with extended follow-up periods are required to validate these findings.

Assessment of PD-L1 expression and tumour infiltrating lymphocytes in early-stage non-small cell lung carcinoma with artificial intelligence algorithms

AimsTo study programmed death ligand 1 (PD-L1) expression and tumour infiltrating lymphocytes (TILs) in patients with early-stage non-small cell lung carcinoma (NSCLC) with artificial intelligence (AI) algorithms.MethodsThe study included samples...

Expression of p63 and TTF1 in Non-small Cell Lung Carcinoma with Special Reference to Mutation of EGFR and ALK in Adenocarcinoma of the Lung: An Institutional Experience

Expression of p63 and TTF1 in Non-small Cell Lung Carcinoma with Special Reference to Mutation of EGFR and ALK in Adenocarcinoma of the Lung: An Institutional Experience

Pulmonary sarcomatoid carcinoma:report of three cases

Pulmonary sarcomatoid carcinoma (PSC) is a rare disease with strong aggressiveness, low response rates to treatment, short survival span and poor prognosis, belonging to a group of non-small cell lung carcinomas (NSCLC) that remains incompletely understood. Here, we presented three PSC cases with epidermal growth factor receptor (EGFR) L858R, BRAF V600E and ALK mutations respectively, described their clinical characteristics and conducted a review of literature, in order to improve its therapeutic level, which also provided evidence-based medical evidence for driver gene screening and molecular targeted drug application in PSC patients.

Characterization of Nonsmall Cell Lung Carcinoma in Limited Biopsy Samples and Identifying Optimal Immunohistochemical Marker Combinations in Resource-Constrained Setup: An Institutional Experience

Abstract Background The incorporation of immunohistochemical markers in the analysis of small biopsy samples, as outlined in the fourth edition of the World Health Organization Blue books, represents a noteworthy advancement in the diagnosis of advanced-stage lung carcinoma. This improved the histological classification for poorly differentiated nonsmall cell lung carcinomas (NSCLCs), especially in small biopsy specimens. Despite challenges in obtaining viable cells from diminutive tumor samples, a focused immunohistochemical panel effectively distinguishes histological types in most NSCLC. This preserves tissue for subsequent molecular testing. Material and Methods This study examined 130 consecutive lung biopsy cases initially diagnosed as NSCLC, including various biopsy types (transbronchial, endobronchial, ultrasound-guided, computed tomography-guided). Carcinomas were categorized based on specific characteristics, such as glands and/or mucin for adenocarcinomas, keratinization and/or intercellular bridges for squamous cell carcinomas, and recognition of poorly differentiated NSCLC. Cases lacking clear morphological attributes underwent reclassification using immunohistochemical markers (TTF1, Napsin A, p63, and p40). Results TTF1 exhibited superior sensitivity (97.56%) and specificity (96.77%) for adenocarcinoma compared with Napsin A, with sensitivity and specificity at 90.24 and 93.3%, respectively. p63 and p40 demonstrated 100% sensitivity for squamous cell carcinoma, with p40 being more specific than p63 (100% vs. 82.92%). Using TTF1 and p63 as a conventional panel, 87% of cases were subtyped. However, the combination of TTF1 and p40 achieved accurate classification in 94.66% (71/75) of cases, and all four markers allowed subtype identification in 97.2% (73/75) of cases. Conclusion In a resource-constrained setting, subtyping NSCLC in small biopsy can be effectively accomplished using a minimal panel consisting of TTF1 and p40 immunohistochemical markers.

Stephania tetrandra and Its Active Compound Coclaurine Sensitize NSCLC Cells to Cisplatin through EFHD2 Inhibition

Background: Adjuvant chemotherapy, particularly cisplatin, is recommended for non-small cell lung carcinoma (NSCLC) patients at high risk of recurrence. EF-hand domain-containing protein D2 (EFHD2) has been recently shown to increase cisplatin resistance and is significantly associated with recurrence in early-stage NSCLC patients. Natural products, commonly used as phytonutrients, are also recognized for their potential as pharmaceutical anticancer agents. Result: In this study, a range of Chinese herbs known for their antitumor or chemotherapy-enhancing properties were evaluated for their ability to inhibit EFHD2 expression in NSCLC cells. Among the herbs tested, Stephania tetrandra (S. tetrandra) exhibited the highest efficacy in inhibiting EFHD2 and sensitizing cells to cisplatin. Through LC-MS identification and functional assays, coclaurine was identified as a key molecule in S. tetrandra responsible for EFHD2 inhibition. Coclaurine not only downregulated EFHD2-related NOX4-ABCC1 signaling and enhanced cisplatin sensitivity, but also suppressed the stemness and metastatic properties of NSCLC cells. Mechanistically, coclaurine disrupted the interaction between the transcription factor FOXG1 and the EFHD2 promoter, leading to a reduction in EFHD2 transcription. Silencing FOXG1 further inhibited EFHD2 expression and sensitized NSCLC cells to cisplatin. Conclusions: S. tetrandra and its active compound coclaurine may serve as effective adjuvant therapies to improve cisplatin efficacy in the treatment of NSCLC.

Deferasirox's Anti-Chemoresistance and Anti-Metastatic Effect on Non-Small Cell Lung Carcinoma.

Clinically approved iron chelators, originally designed to address iron overload disorders, have emerged as potential anticancer agents. Deferasirox (Def), a tridentate iron chelator, has demonstrated antiproliferative effects in cancer. Background/Objectives: This study aims to elucidate the mechanism of action of Def and its impact on non-small cell lung carcinoma (NSCLC). Methods: NSCLC A549 cells were treated with Def to assess cytotoxicity, the effect on nuclear and mitochondrial pathways, and iron-containing proteins and genes to evaluate anti-metastasis and chemoresistance. A lung carcinoma mouse model was used for in vivo studies. Results: Our findings revealed that Def induced cytotoxicity, effectively chelated intracellular iron, and triggered apoptosis through the increase in phosphatidylserine externalization and caspase 3 activity. Additionally, Def caused G0/G1 cell cycle arrest by downregulating the ribonucleotide reductase catalytic subunit. Furthermore, Def perturbed mitochondrial function by promoting the production of reactive oxygen species and the inhibition of glutathione as a measurement of ferroptosis activation. Def demonstrated inhibitory effects on cell migration in scratch assays, which was supported by the upregulation of n-myc downstream-regulated gene 1 and downregulation of the epidermal growth factor receptor protein. Also, Def downregulated one of the main markers of chemoresistance, the ABCB1 gene. In vivo experiments using a lung carcinoma mouse model showed that Def treatment did not affect the animal's body weight and showed a significant decrease in tumor growth. Conclusions: This investigation lays the groundwork for unraveling Def action's molecular targets and mechanisms in lung carcinoma, particularly within iron-related pathways, pointing out its anti-metastasis and anti-chemoresistance effect.

The EXO1/Polη/Polι axis as a promising target for miR-3163-mediated attenuation of cancer stem-like cells in non-small cell lung carcinoma.

Cancer stem-like cells (CSLCs) drive tumour progression and chemoresistance. The concerted efforts of EXO1 and TLS polymerases safeguard DNA integrity against chemotherapeutic drugs. In absence of potential drug targets, non-small cell lung carcinoma (NSCLC) patients have few therapeutic options. In current scenario, microRNAs offer a potential avenue for eradicating CSLCs. EXO1 downregulation impact on CSLCs expansion was assessed via flow cytometry. Co-localisation of EXO1, Polη and Polι was validated through co-immunoprecipitation and confocal-imaging. The effects of co-downregulation of Polη and Polι on CSLC survival, repair synthesis, and mutagenesis were evaluated using flow cytometry and immunohistochemistry in cell lines and xenografts. MicroRNA targeting EXO1 was studied for its role in CSLCs regulation. EXO1 downregulation in NSCLC CSLCs induces DNA lesions, triggering apoptosis and enhances cisplatin sensitivity. It collaborates with Polη and Polι in DNA repair, contributing to cisplatin resistance in CSLCs. Absence of Polη and Polι impairs repair and reduces cisplatin-induced mutagenesis. Co-downregulation of Polη and Polι in xenografts reduces tumour proliferation significantly. MiR-3163 overexpression sensitises CSLCs to cisplatin via targeting EXO1/Polη/Polι axis, as shown in mechanistic studies. This study unveils a novel regulatory pathway involving EXO1/Polη/Polι axis and miR-3163, providing insights into CSLCs regulation in NSCLC. EXO1/Polη/Polι axistargeted by miR-3163, resulting in the inhibition of cell growth and induction of apoptosis inNSCLC CSLCs.

Stereologic consequences of iatrogenic collapse: The morphology of adenocarcinoma in situ overlaps with invasive patterns. Proposal for a necessary modified classification of pulmonary adenocarcinomas

Recognizing non-invasive growth patterns is necessary for correct diagnosis, invasive size determination and pT-stage in resected non-small cell lung carcinoma. Due to iatrogenic collapse after resection, the distinction between adenocarcinoma in-situ (AIS) and invasive adenocarcinoma may be difficult. The aim of this study is to investigate the complex morphology of non-mucinous non-invasive patterns of AIS in resection specimen with iatrogenic collapse, and to relate this to follow-up.The effects of iatrogenic collapse on the morphology of collapsed AIS were simulated in a mathematical model. Three dimensional related criteria applied in a modified classification, using also cytokeratin 7 and elastin as additional stains, in two independent retrospective cohorts of primary pulmonary adenocarcinomas ≤3 cm resection specimen with available follow-up information.The model demonstrated that infolding of alveolar walls occurs during iatrogenic collapse and lead to a significant increase in tumor cell heights in maximal collapse areas, compared to less collapsed areas. The morphology of infolded AIS overlaps with patterns described as papillary and acinar adenocarcinoma according to the WHO classification, necessitating an adaptation.The modified classification incorporates recognition of iatrogenic and biologic collapse, tangential cutting effect true invasion and surrogate markers of invasion i.e. grey zone, covering a multilayering falling short of micropapillary, cribriform and solid alveolar filling growth. The use of elastin and CK7 staining aids in the morphologic recognition of iatrogenic collapsed AIS and the distinction from invasive adenocarcinoma. Out of a total of 70 resection specimens 1 case was originally classified as AIS and 9 were reclassified as iatrogenic collapsed AIS. Patients with collapsed AIS showed a 100 % recurrence-free survival after a mean follow-up time of 69.5 months.With the current WHO classification, AIS is overdiagnosed as invasive adenocarcinoma due to infolding. The modified classification facilitates the diagnosis of AIS.

Deep learning to estimate response of concurrent chemoradiotherapy in non-small-cell lung carcinoma

BackgroundConcurrent chemoradiotherapy (CCRT) is a crucial treatment for non-small cell lung carcinoma (NSCLC). However, the use of deep learning (DL) models for predicting the response to CCRT in NSCLC remains unexplored. Therefore, we constructed a DL model for estimating the response to CCRT in NSCLC and explored the associated biological signaling pathways.MethodsOverall, 229 patients with NSCLC were recruited from six hospitals. Based on contrast-enhanced computed tomography (CT) images, a three-dimensional ResNet50 algorithm was used to develop a model and validate the performance in predicting response and prognosis. An associated analysis was conducted on CT image visualization, RNA sequencing, and single-cell sequencing.ResultsThe DL model exhibited favorable predictive performance, with an area under the curve of 0.86 (95% confidence interval [CI] 0.79–0·92) in the training cohort and 0.84 (95% CI 0.75–0.94) in the validation cohort. The DL model (low score vs. high score) was an independent predictive factor; it was significantly associated with progression-free survival and overall survival in both the training (hazard ratio [HR] = 0.54 [0.36−0.80], P = 0.002; 0.44 [0.28−0.68], P < 0.001) and validation cohorts (HR = 0.46 [0.24−0.88], P = 0.008; 0.30 [0.14−0.60], P < 0.001). The DL model was also positively related to the cell adhesion molecules, the P53 signaling pathway, and natural killer cell-mediated cytotoxicity. Single-cell analysis revealed that differentially expressed genes were enriched in different immune cells.ConclusionThe DL model demonstrated a strong predictive ability for determining the response in patients with NSCLC undergoing CCRT. Our findings contribute to understanding the potential biological mechanisms underlying treatment responses in these patients.

Endoscopic Ultrasound-guided Transesophageal Fine-Needle Biopsy of Lung Masses: Diagnostic Performance and Safety

Pulmonary masses are a diagnostic challenge in the field of endoscopic ultrasound(EUS) tissue acquisition, especially through transesophageal EUS-FNB(fine needle biopsy). Our study evaluated the feasibility, diagnostic performance, and safety of EUS-FNB of pulmonary lesions. Fifty-three patients were enrolled in a prospective registry. All of the EUS procedures were performed by experienced endosonographers. Outcomes were specimen adequacy, diagnostic accuracy, diagnostic sensibility, diagnostic specificity, and safety. The mean age was 70±10.4, and 71.7% were male. The mean lesion size was 52.4±23.3 mm, and patients had mostly a single lesion(86.8%). Most of the patients had advanced stage at diagnosis(stage IV, 41.82%), and the most common lung cancer was non-small cell lung carcinoma(69.4%). Diagnostic adequacy rate was 92.86%, and diagnostic accuracy was 87.5%. Adverse events were reported in 3 procedures. Transesophageal EUS-FNB is a feasible and safe diagnostic method of tissue sampling for lung masses reachable by EUS.

Adagrasib in KRYSTAL-12has Broken the KRAS G12C Enigma Code in Non-Small Cell Lung Carcinoma.

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 KRAS G12C-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 KRAS G12C enigma code in NSCLC.