Outcome In Non-small Cell Lung Cancer Research Articles

CD57+CD8+ T cells and response to PD-1/PD-L1 blockade in patients with NSCLC.

e21189 Background: Immune checkpoint inhibitors (ICIs) are currently widely used and have made significant advances in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Despite available biomarker stratification, clinical responses vary. Thus, potential biomarkers for identifying patients who will benefit from the immunotherapy are urgently needed. Methods: We applied mass cytometry (CyTOF) to deeply analyze the association of cell subpopulations in PBMC before and after single-agent immunotherapy with clinical outcomes in advanced NSCLC. We then performed flow cytometry of peripheral blood and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) of tumor samples to validate our conclusion. In addition, RNA sequencing (RNA-seq) was performed to explore the mechanism of the ICIs treatment efficacy of NSCLC. Results: In a prospective cohort (n = 20), high CD57+ CD8+ T cell proportion in PBMC detected by CyTOF was associated with good response ( p= 0.014) in advanced NSCLC patients. The result was confirmed in an independent, prospective cohort (n = 30) using flow cytometry, and the specificity and sensitivity of flow cytometry was then assessed in this cohort. CD57+CD8+ T cell proportion, as determined by flow cytometry, successfully stratified responders and non-responders to ICIs ( P< 0.001). We also confirmed this result in FFPE samples (n = 31) ( p= 0.004). In addition, transcriptomic differences between CD57+CD8+ T cells and CD57-CD8+ T cells were found performed by RNA sequencing (RNA-seq). Conclusions: Our results suggest that CD57+CD8+ T cell proportion may serve as a predictive value of response to PD-1/PD-L1 checkpoint blockade. Further validation in additional NSCLC cohorts is warranted.

Impact of minocycline on outcomes of EGFR-mutant non-small cell lung cancer patients treated with EGFR-TKIs

Minocycline is often administered prophylactically or therapeutically to non-small cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for skin rash as an adverse event. We examined the effects of minocycline on the outcomes of EGFR-mutant NSCLC treated with first-line EGFR-TKIs based on a single-center retrospective analysis. In this retrospective cohort study, data were collected on NSCLC patients treated with first-line EGFR-TKIs between January 2010 and June 2021. The treatment efficacy of first-line EGFR-TKIs was compared between patients who received minocycline and those who did not. Median progression-free survival (PFS) with first-line EGFR-TKIs was significantly longer in the minocycline group (N = 32) than in the control group (N = 106); 714 (95% confidence interval CI 411–1247) days vs. 420 (95% CI 343–626) days, p = 0.019. A multivariate analysis including skin rash as a variable confirmed that the administration of minocycline for 30 days or longer correlated with good PFS and overall survival (OS) with first-line EGFR-TKIs (HR 0.44 [95% CI 0.27–0.73], p = 0.0014 and HR 0.50 [95% CI 0.27–0.92], p = 0.027, respectively). The administration of minocycline influenced good treatment efficacy with first-line EGFR-TKIs independently of skin rash.

Abstract 5119: Nano-immunotherapy targeting PD-L1, PLK1, and TLR9 for treatment of non-small cell lung cancer

Abstract Given the complexity of cancer, it is becoming apparent that combination therapy - in which complementary biological pathways are simultaneously targeted - is required to achieve clinically meaningful responses. To that end, PDX Pharma, in collaboration with Oregon Health & Science University, has developed a proprietary nanoparticle platform (Pdx-NP™) that can effectively co-deliver a plethora of therapeutic modalities while maintaining a small size in saline (100 nm), suitable for infusion and tumor accumulation. This enables the targeting of complementary cancer and immune pathways, leading to synergistic clinical benefits. Herein, we report on the second generation ARAC-02 (Antigen Release Agent and Checkpoint Inhibitor) which is designed to improve the efficacy of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). While ICIs have improved survival in a subset of patients with advanced NSCLC, only a minority of patients respond to ICIs, highlighting the need for combination immunotherapy. ARAC-02 co-delivers a polo-like kinase 1 (PLK1)-targeted therapy (volasertib), a PD-L1 antibody, and the immune-stimulant CpG. These three agents were carefully selected based on their roles in cancer and immune pathways. Volasertib 1) selectively kills cancer cells, 2) modulates the immune-suppressive tumor microenvironment, and 3) upregulates PD-L1 expression in cancer cells, providing opportunity for targeted delivery with PD-L1 antibody on the nanoparticles. CpG is a TLR9 agonist that enhances antigen presentation to generate tumor-specific T cells. PD-L1 antibodies serve as tumor targeting agent for nanoparticle delivery as well as an ICI (i.e., PD-L1 degradation upon internalization with the nanoparticles), releasing the brakes and allowing T cells to attack the cancer. We found that the optimized ARAC-02 is preferentially internalized in PD-L1 expressing NSCLC cells, demonstrating a 10-fold greater uptake to PD-L1(high) NSCLC cells than PD-L1(low) normal cells. ARAC-02 effectively kills NSCLC cells regardless of their mutational status, while sparing normal cells. In a metastatic lung tumor model, ARAC-02 treatments reduced the tumor burden by 30-fold vs. saline control and 8-fold vs. the first generation ARAC (not containing CpG), whose effect was mainly mediated by CD8+ T cells. ARAC-02 was found to be safe to mice as assessed by body weight, serum biomarkers, and histology. Importantly, intravenous infusions of the platform was also found to be safe in a preliminary toxicology study in non-human primates. Due to its unique ability to catalyze various steps of the adaptive immune response, ARAC-02 is anticipated to provide superior outcomes in NSCLC and a broad range of tumor types regardless of baseline PD-L1 expression. Citation Format: Moataz Reda, Worapol Ngamcherdtrakul, Ruijie Wang, Noah Crumrine, Cole Baker, Alyssa Wallstrum, Jeremy Saito, Natalie White, Wassana Yantasee. Nano-immunotherapy targeting PD-L1, PLK1, and TLR9 for treatment of non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5119.

Integrative bioinformatics approaches to establish potential prognostic immune-related genes signature and drugs in the non-small cell lung cancer microenvironment.

Introduction: Research has revealed that the tumor microenvironment (TME) is associated with the progression of malignancy. The combination of meaningful prognostic biomarkers related to the TME is expected to be a reliable direction for improving the diagnosis and treatment of non-small cell lung cancer (NSCLC). Method and Result: Therefore, to better understand the connection between the TME and survival outcomes of NSCLC, we used the "DESeq2" R package to mine the differentially expressed genes (DEGs) of two groups of NSCLC samples according to the optimal cutoff value of the immune score through the ESTIMATE algorithm. A total of 978 up-DEGs and 828 down-DEGs were eventually identified. A fifteen-gene prognostic signature was established via LASSO and Cox regression analysis and further divided the patients into two risk sets. The survival outcome of high-risk patients was significantly worse than that of low-risk patients in both the TCGA and two external validation sets (p-value < 0.05). The gene signature showed high predictive accuracy in TCGA (1-year area under the time-dependent ROC curve (AUC) = 0.722, 2-year AUC = 0.708, 3-year AUC = 0.686). The nomogram comprised of the risk score and related clinicopathological information was constructed, and calibration plots and ROC curves were applied, KEGG and GSEA analyses showed that the epithelial-mesenchymal transition (EMT) pathway, E2F target pathway and immune-associated pathway were mainly involved in the high-risk group. Further somatic mutation and immune analyses were conducted to compare the differences between the two groups. Drug sensitivity provides a potential treatment basis for clinical treatment. Finally, EREG and ADH1C were selected as the key prognostic genes of the two overlapping results from PPI and multiple Cox analyses. They were verified by comparing the mRNA expression in cell lines and protein expression in the HPA database, and clinical validation further confirmed the effectiveness of key genes. Conclusion: In conclusion, we obtained an immune-related fifteen-gene prognostic signature and potential mechanism and sensitive drugs underling the prognosis model, which may provide accurate prognosis prediction and available strategies for NSCLC.

The Impact of Social Determinants of Health, Namely Financial Assistance, on Overall Survival in Advanced-Stage Non-Small Cell Lung Cancer Patients.

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer. Studies have evaluated the association of social determinants of health (SDH) with outcomes in early-stage NSCLC. These studies have shown statistically and clinically significant associations between overall survival (OS) and other SDH (e.g marital status, educational attainment).The aim of our study was to better understand the role of various SDH on OS in advanced-stage NSCLC patients in a community oncology practice in Florida. Methods: In this retrospective study, 125 patients with stage III and IV NSCLC were identified between January 1, 2014, and December 31, 2018. We performed Pearson's chi-square and Kruskal-Wallis test to evaluate the association between median OS and several independent variables, including; gender, race, marital status, insurance status, living status, receiving financial assistance (FA), alcohol use, and smoking histories. OS is defined as the date of diagnosis up to the date of death. Other confounders that were analyzed included histology, treatment modality, comorbidities, and performance status of the patients. Results: Our results demonstrated that patients receiving FA had nearly a two-fold increase in median OS compared to patients without FA (median OS = 1.01 years vs. 0.545 years, respectively; p = 0.012). Overall, this study highlighted the importance of reducing the financial burden of advanced-stage NSCLC on patients and how FA impacts patient outcomes. However, future prospective cohort studies with a larger sample size are warranted to identify other SDH, as well as the underlying mechanisms affecting median OS, in patients with advanced-stage NSCLC.

Prospects and feasibility of synergistic therapy with radiotherapy, immunotherapy, and DNA methyltransferase inhibitors in non-small cell lung cancer.

The morbidity and mortality of lung cancer are increasing, seriously threatening human health and life. Non-small cell lung cancer (NSCLC) has an insidious onset and is not easy to be diagnosed in its early stage. Distant metastasis often occurs and the prognosis is poor. Radiotherapy (RT) combined with immunotherapy, especially with immune checkpoint inhibitors (ICIs), has become the focus of research in NSCLC. The efficacy of immunoradiotherapy (iRT) is promising, but further optimization is necessary. DNA methylation has been involved in immune escape and radioresistance, and becomes a game changer in iRT. In this review, we focused on the regulation of DNA methylation on ICIs treatment resistance and radioresistance in NSCLC and elucidated the potential synergistic effects of DNA methyltransferases inhibitors (DNMTis) with iRT. Taken together, we outlined evidence suggesting that a combination of DNMTis, RT, and immunotherapy could be a promising treatment strategy to improve NSCLC outcomes.

Real-World Treatment and Outcomes of ALK-Positive Metastatic Non-Small Cell Lung Cancer in a Southeast Asian Country.

Anaplastic lymphoma kinase (ALK) inhibitors are associated with good overall survival (OS) for ALK-positive metastatic non-small cell lung cancer (NSCLC). However, these treatments can be unavailable or limited by financial constraints in developing countries. Using data from a nationwide lung cancer registry, the present study aimed to identify treatment patterns and clinical outcomes of ALK-positive NSCLC in Malaysia. This retrospective study examined data of patients with ALK-positive NSCLC from 18 major hospitals (public, private, or university teaching hospitals) throughout Malaysia between January 1, 2015 and December 31, 2020 from the National Cardiovascular and Thoracic Surgical Database (NCTSD). Data on baseline characteristics, treatments, radiological findings, and pathological findings were collected. Overall survival (OS) and time on treatment (TOT) were calculated using the Kaplan-Meier method. There were 1581 NSCLC patients in the NCTSD. Based on ALK gene-rearrangement test results, only 65 patients (4.1%) had ALK-positive advanced NSCLC. Of these 65 patients, 59 received standard-of-care treatment and were included in the analysis. Crizotinib was the most commonly prescribed ALK inhibitor, followed by alectinib and ceritinib. Patients on ALK inhibitors had better median OS (62 months for first-generation inhibitors, not reached at time of analysis for second-generation inhibitors) compared to chemotherapy (27 months), but this was not statistically significant (P=0.835) due to sample-size limitations. Patients who received ALK inhibitors as first-line therapy had significantly longer TOT (median of 11 months for first-generation inhibitors, not reached for second-generation inhibitors at the time of analysis) compared to chemotherapy (median of 2 months; P<0.01). Patients on ALK inhibitors had longer median OS and significantly longer TOT compared to chemotherapy, suggesting long-term benefit.

Uncovering Novel Stage I Molecular Biomarkers for the Early Detection of Non-Small Cell Lung Cancer

Although a number of driver biomarkers that are clinically relevant in the management of patients with non-small cell lung cancer (NSCLC) have been well documented, there is still about 25% unidentified genes and somatic mutations involved in the early onset of the disease. Most importantly, a clear distinction must be made between stage I vs. II and III of NSCLC (i.e., the early stages) in terms of biomarker discovery to refine inclusion criteria for screening programs and to benefit therapeutic decision in the neoadjuvant and adjuvant setting. There is much room for improvement in early-stage NSCLC outcome, identification of stage I-specific biomarkers herein could be the key to refine riskstratification, prognosis and treatment of these patients. In this study, we aim to identify both tissue and circulating stage I biomarkers in NSCLC as the stepstone to improve clinical decision-making, especially regarding early detection, diagnostics and adjuvant therapy

Regulatory T cells infiltrate the tumor-induced tertiary lymphoïd structures and are associated with poor clinical outcome in NSCLC

On one hand, regulatory T cells (Tregs) play an immunosuppressive activity in most solid tumors but not all. On the other hand, the organization of tumor-infiltrating immune cells into tertiary lymphoid structures (TLS) is associated with long-term survival in most cancers. Here, we investigated the role of Tregs in the context of Non-Small Cell Lung Cancer (NSCLC)-associated TLS. We observed that Tregs show a similar immune profile in TLS and non-TLS areas. Autologous tumor-infiltrating Tregs inhibit the proliferation and cytokine secretion of CD4+ conventional T cells, a capacity which is recovered by antibodies against Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4) and Glucocorticoid-Induced TNFR-Related protein (GITR) but not against other immune checkpoint (ICP) molecules. Tregs in the whole tumor, including in TLS, are associated with a poor outcome of NSCLC patients, and combination with TLS-dendritic cells (DCs) and CD8+ T cells allows higher overall survival discrimination. Thus, Targeting Tregs especially in TLS may represent a major challenge in order to boost anti-tumor immune responses initiated in TLS.

A subset of VEGFR-TKIs activates AMPK in LKB1-mutant lung cancer.

The mutation of tumor suppressor gene liver kinase B1 (LKB1) has a prevalence of about 20% in non-small cell lung cancer (NSCLC). LKB1-mutant lung cancer is characterized by enhanced aggressiveness and immune escape and is associated with poor prognosis. Therefore, it is urgent to develop effective therapeutic methods for LKB1-mutant NSCLC. Recently, apatinib, a VEGFR-TKI, was found to significantly improve the outcome of LKB1-mutant NSCLC, but the mechanism is not completely clear. In this study, AMP-activated protein kinase (AMPK), the crucial downstream kinase of LKB1 was excavated as the potential target of apatinib. Biochemical experiments verified that apatinib is a direct AMPK activator. Moreover, clinically available VEGFR-TKIs were found to regulate AMPK differently: Apatinib and anlotinib can directly activate AMPK, while axitinib and sunitinib can directly inhibit AMPK. Activation of AMPK by apatinib leads to the phosphorylation of acetyl-CoA carboxylase (ACC) and inhibition of de novo fatty acid synthesis (FAsyn), which is upregulated in LKB1-null cancers. Moreover, the killing effect of apatinib was obviously enhanced under delipidated condition, and the combination of exogenous FA restriction with apatinib treatment can be a promising method for treating LKB1-mutant NSCLC. This study discovered AMPK as an important off-target of apatinib and elucidated different effects of this cluster of VEGFR-TKIs on AMPK. This finding can be the basis for the accurate and combined application of these drugs in clinic and highlights that the subset of VEGFR-TKIs including apatinib and anlotinib are potentially valuable in the treatment of LKB1-mutant NSCLC.

Yes-associated protein 1 mediates initial cell survival during lorlatinib treatment through AKT signaling in ROS1-rearranged lung cancer.

Tyrosine kinase inhibitors (TKIs) that target the ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) gene have shown dramatic therapeutic effects in patients with ROS1-rearranged non-small-cell lung cancer (NSCLC). Nevertheless, advanced ROS1-rearranged NSCLC is rarely cured as a portion of the tumor cells can survive the initial stages of ROS1-TKI treatment, even after maximum tumor shrinkage. Therefore, understanding the mechanisms underlying initial cell survival during ROS1-TKI treatment is necessary to prevent cell survival and achieve a cure for ROS1-rearranged NSCLC. In this study, we clarified the initial survival mechanisms during treatment with lorlatinib, a ROS1 TKI. First, we established a patient-derived ezrin gene-ROS1-rearranged NSCLC cell line (KTOR71). Then, following proteomic analysis, we focused on yes-associated protein 1 (YAP1), which is a major mediator of the Hippo pathway, as a candidate factor involved in cell survival during early lorlatinib treatment. Yes-associated protein 1 was activated by short-term lorlatinib treatment both in vitro and in vivo. Genetic inhibition of YAP1 using siRNA, or pharmacological inhibition of YAP1 function by the YAP1-inhibitor verteporfin, enhanced the sensitivity of KTOR71 cells to lorlatinib. In addition, the prosurvival effect of YAP1 was exerted through the reactivation of AKT. Finally, combined therapy with verteporfin and lorlatinib was found to achieve significantly sustained tumor remission compared with lorlatinib monotherapy in vivo. These results suggest that YAP1 could mediate initial cell resistance to lorlatinib in KTOR71 cells. Thus, combined therapy targeting both YAP1 and ROS1 could potentially improve the outcome of ROS1-rearranged NSCLC.

Proteomic and Phosphoproteomic Analyses Reveal the Oncogenic Role of PTK7-NDRG1 Axis in Non-small-cell Lung Cancer Cell Resistance to AZD9291.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the most important chemotherapeutics for non-small-cell lung cancer (NSCLC) therapy. The resistance to EGFR-TKIs is one of the biggest obstacles to NSCLC outcome. In this study, taking advantage of phospho- and proximal proteomic techniques, we analyzed the network rearrangement in cell lines responding to AZD9291 treatment and found that cell-cell adhesion was dramatically enhanced in AZD9291-resistant cells. Further analysis revealed that protein tyrosine kinase 7 (PTK7) expression was significantly elevated. Knockdown or overexpression assays showed that PTK7 played a critical role in improving cell adhesion, which enhanced drug resistance. Because PTK7 is a membrane-localized pseudokinase, the proximal labeling probe BirA* was fused to reveal PTK7-interacting proteins. We found that PTK7 interacted with and stabilized NDRG1, which is located predominantly adjacent to adherens junctions. Downregulation of PTK7 or NDRG1 eliminated the resistance of H1975-resistant (H1975-R) and PC9-resistant (PC9-R) cells to AZD9291, suggesting that the PTK7-NDRG1 axis might be a potential target to eliminate the EGFR-TKI resistance during NSCLC therapy.

Association of race, ethnicity, and socioeconomic characteristics as predictors of cachexia risk and survival in stage IV non–small cell lung cancer (NSCLC).

151 Background: Cachexia, seen in more than a third of patients with non-small cell lung cancer (NSCLC), directly leads to functional and survival detriments. As screening and interventions for cachexia and NSCLC improve, deficits of healthcare access and quality among patients disadvantaged by race and socioeconomic factors must be addressed. Methods: Through retrospective and prospective data collection, we established a cohort of 957 patients diagnosed with stage IV NSCLC between 2014-2020 in Dallas, Texas. Presence of cachexia at diagnosis was determined using consensus criteria for substantial (5% for BMI≥20 and 2% for BMI &lt; 20) unintentional weight loss in the 6 months leading to diagnosis. Analyses including multivariate logistic regression and log-rank testing evaluated for significant associations of variables with cachexia incidence and survival. Results: Black race and Hispanic ethnicity independently associated with more than a 70% increased risk of cachexia at NSCLC diagnosis (Table; P &lt; 0.05). Inclusion of private insurance status as a covariate diminished this finding for Hispanic patients only. Black patients presented at younger ages than White patients (Kruskal-Wallis P =0.0012; T-test P = 0.0002), with an average difference of 3 years. Cachexia at diagnosis was a major predictor of survival, highlighting the importance of addressing differential cachexia risk across race/ethnicity. Conclusions: The elevated cachexia risk observed for Black patients independent of insurance status reveals broader causative factors of disparity. A lack of private insurance may be a primary contributor in Hispanic cachexia prevalence. Targeting these differences could mitigate survival detriments linked to cachexia in minority groups. Supported contributors in broader NSCLC outcome inequities include poor representation in trials substantiating USPSTF guidelines as well as preventable barriers to primary and preventative care. Our interpretation of NSCLC outcome disparity in the context of cachexia demonstrates further consequences of these deficits. Moreover, our findings suggest novel targets for health policy by highlighting the prevalence of undiagnosed unintentional weight loss in minority populations with late-stage NSCLC.[Table: see text]

177 (PB057) - BLU-945 or BLU-701 as single agents versus their combination with osimertinib in EGFR L858R driven tumor models

Background: The most common activating EGFR mutations (EGFRm) in non-small cell lung cancer (NSCLC) are exon 19 deletions (ex19del) and L858R substitutions. EGFR tyrosine kinase inhibitors (TKIs) as first-line (1L) therapy have improved outcomes in EGFR-driven advanced NSCLC; however, treatment resistance eventually occurs. Patients with EFGR L858R-driven advanced NSCLC (39% of all EGFR mutations in NSCLC) have shorter progression-free survival than those with EGFR ex19del, suggesting a significant unmet need. BLU-945 and BLU-701 are investigational, reversible, selective, orally available TKIs optimized for use as singleagent or combination therapy to suppress activating and on-target resistance EGFR mutants while sparing wild-type EGFR. in vivo studies have shown antitumor activity of BLU-945 against EGFR L858R, L858R/C797S, L858R/ T790M and EGFRm/T790M/C797S mutants, and BLU-701 against EGFRm and EGFRm/C797S mutants. Combination of BLU-945 and BLU-701 has also shown in vivo activity in EGFRm/C797S-driven mutant NSCLC. Combining BLU-945 or BLU-701 with osimertinib could potentially enable superior coverage of frequent on-target resistance mechanisms as well additional potency on the primary EGFR activating mutations. Central nervous system (CNS) metastases are an ongoing challenge in NSCLC. BLU-701 has already shown preclinical CNS activity; and both BLU-945 and BLU-701 are currently being investigated for potential treatment or prevention of CNS metastases. Due to poorer outcomes in patients with EGFR L858R-driven advanced NSCLC treated with osimertinib, and the inevitability of treatment resistance, studies were conducted to evaluate the activity of BLU-945 or BLU-701 in combination with osimertinib in prolonging duration of response (DOR) in preclinical NSCLC tumor models driven by the L858R mutation. Material and Methods: The antitumor activity of BLU-945 or BLU-701, as single agents or in combination with osimertinib was evaluated in EGFR L858R-driven tumor models. Results: Administration of single-agent BLU-945 or BLU-701 resulted in tumor growth inhibition in EGFR L858R-driven PDX models. BLU-945 in combination with osimertinib resulted in prolonged DOR and survival when compared with BLU-945 or osimertinib as single agents. BLU-701 in combination with osimertinib resulted in superior tumor growth inhibition compared with BLU-701 or osimertinib as single agents. Conclusions: The in vivo antitumor activities of BLU-945 and BLU-701 as single agents suggest both BLU-945 and BLU-701 have the potential to be used as 1L therapy in patients with EGFR L858R-driven NSCLC. The superior in vivo antitumor activity of BLU-945 or BLU-701 in combination with osimertinib in prolonging the DOR or increasing tumor growth inhibition in these models may have clinical application in improving outcomes of patients with EGFR L858R-driven NSCLC in 1L settings. Conflict of interest: Other Substantive Relationships: Tavera L, Dhande A, Dineen T, Iliou M, Rouskin-Faust T, Rozsahegyi E, Conti C: Employee and/or equity holder of Blueprint Medicines Corporation.

An evaluation of sotorasib for the treatment of patients with non–small cell lung cancer with KRASG12C mutations

ABSTRACT Introduction Improving the clinical outcomes of patients with KRASG12C -mutated non-small cell lung cancer (NSCLC), the majority of whom are current or former smokers, has been a barrier to improving population-level outcomes in NSCLC. Novel and effective KRASG12C inhibitors are emerging, and sotorasib is the first member of that class to achieve commercial availability. Areas covered In this review, we survey the epidemiology of KRASG12C -mutated NSCLC, as well as sotorasib’s chemistry, pharmacology, and clinical trial data. Expert opinion 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.

Biomimetic Red Blood Cell Membrane-Mediated Nanodrugs Loading Ursolic Acid for Targeting NSCLC Therapy.

Simple SummaryLung cancer is the second most common cancer after breast cancer. Non-small-cell lung cancer, which represents more than 85% of all lung cancer subtypes, is known for its tumor progression and metastasis, resulting in poor clinical outcomes. Conventional therapies for NSCLC, such as surgery, chemotherapy, and radiotherapy, always fail due to therapeutic resistance. In recent years, ursolic acid (UA), a natural pentacyclic triterpenoid compound, has been shown to be a promising antitumor drug by regulating multiple signaling pathways in cancers. Unfortunately, the poor water solubility, low bioavailability, and systemic toxicity of UA limit its clinical application. In this study, a biomimetic red blood cell membrane nanocarrier was developed to deliver UA to targeted tumor sites efficiently, and it inhibited tumor growth by inducing the apoptosis and autophagy of cancer cells both in vitro and in vivo.As one of the most common cancers worldwide, non-small-cell lung cancer (NSCLC) treatment always fails owing to the tumor microenvironment and resistance. UA, a traditional Chinese medicine, was reported to have antitumor potential in tumor models in vitro and in vivo, but showed impressive results in its potential application for poor water solubility. In this study, a novel biomimetic drug-delivery system based on UA-loaded nanoparticles (UaNPs) with a red blood cell membrane (RBCM) coating was developed. The RBCM-coated UANPs (UMNPs) exhibited improved water solubility, high stability, good biosafety, and efficient tumor accumulation. Importantly, the excellent antitumor efficiency of the UMNPs was confirmed both in vitro and in vivo in cancer models. In addition, we further investigated the antitumor mechanism of UMNPs. The results of Western blotting showed that UMNPs exerted an anticancer effect by inducing the apoptosis and autophagy of NSCLC cells, which makes it superior to free UA. In addition, body weight monitoring, hematoxylin and eosin (HE) analysis, and immunohistochemical (IHC) analysis showed no significant difference between UMNPs and the control group, indicating the safety of UMNPs. Altogether, the preparation of biomimetic UMNPs provides a promising strategy to improve outcomes in NSCLC.

Implications of m6A methylation and microbiota interaction in non-small cell lung cancer: From basics to therapeutics.

N6-methyladenine (m6A) is one of the most common RNA epigenetic modifications in all higher eukaryotes. Increasing evidence demonstrated that m6A-related proteins, acted as oncogenes or tumor suppressors, are abnormally expressed in the cell lines and tissues of non-small cell lung cancer (NSCLC). In addition, lung as the special immune organ contacts with the outer environments and thereby inevitably suffers from different types of microbial pathogen attack. Those microbial pathogens affect the development, progression, and clinical outcomes of NSCLC via altering host m6A modification to disrupt pulmonary immune homeostasis and increase the susceptibility; conversely, host cells modulate m6A modification to repress bacterial colonization. Therefore, m6A harbors the potential to be the novel biomarkers and targets for predicting poor prognosis and chemotherapy sensitivity of patients with lung cancer. In this paper, we provided an overview of the biological properties of m6A-modifying enzymes, and the mechanistic links among lung microbiota, m6A modification and NSCLC. Although the flood of novel m6A-related inhibitors represents many dramatic improvements in NSCLC therapy, their efficacy and toxicity in NSCLC are explored to address these pivotal gaps in the field.

Integrative Network Modeling Highlights the Crucial Roles of Rho-GDI Signaling Pathway in the Progression of non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most prevalent form of lung cancer and a leading cause of cancer-related deaths worldwide. Using an integrative approach, we analyzed a publicly available merged NSCLC transcriptome dataset using machine learning, protein-protein interaction (PPI) networks and bayesian modeling to pinpoint key cellular factors and pathways likely to be involved with the onset and progression of NSCLC. First, we generated multiple prediction models using various machine learning classifiers to classify NSCLC and healthy cohorts. Our models achieved prediction accuracies ranging from 0.83 to 1.0, with XGBoost emerging as the best performer. Next, using functional enrichment analysis (and gene co-expression network analysis with WGCNA) of the machine learning feature-selected genes, we determined that genes involved in Rho GTPase signaling that modulate actin stability and cytoskeleton were likely to be crucial in NSCLC. We further assembled a PPI network for the feature-selected genes that was partitioned using Markov clustering to detect protein complexes functionally relevant to NSCLC. Finally, we modeled the perturbations in RhoGDI signaling using a bayesian network; our simulations suggest that aberrations in ARHGEF19 and/or RAC2 gene activities contributed to impaired MAPK signaling and disrupted actin and cytoskeleton organization and were arguably key contributors to the onset of tumorigenesis in NSCLC. We hypothesize that targeted measures to restore aberrant ARHGEF19 and/or RAC2 functions could conceivably rescue the cancerous phenotype in NSCLC. Our findings offer promising avenues for early predictive biomarker discovery, targeted therapeutic intervention and improved clinical outcomes in NSCLC.

P1.11-01 Cobolimab with Dostarlimab and Docetaxel in Patients with Advanced Non-small Cell Lung Cancer (NSCLC): COSTAR Lung

TIM-3 and PD-1 are markers of T-cell exhaustion co-expressed on tumor-infiltrating T cells (CD4+, CD8+) and antigen presenting cells in lung cancer. TIM-3 expression has also been associated with poor overall survival (OS) outcomes in NSCLC.

Squamous cell carcinoma predicts worse prognosis than adenocarcinoma in stage IA lung cancer patients: A population-based propensity score matching analysis.

BackgroundAlthough numerous studies have reported the association between histological types and the prognosis of IA non-small-cell lung cancer (NSCLC) patients, few studies have deeply investigated the impact of pathology on the outcome of NSCLC patients. In this study, we comprehensively explored whether the type of histology influenced the outcome of IA-stage NSCLC patients.MethodsThe study population was obtained from the Surveillance, Epidemiology, and End Results (SEER) program, which is supported by the National Cancer Institute of the United States. To avoid potential bias, the method of propensity score matching (PSM) was used to obtain a balanced cohort for further analysis.ResultsThe results from univariate and multivariate regression models showed that lung squamous cell carcinoma (LSQCC) patients were at a significantly greater risk of undergoing shorter overall survival (OS) and lung cancer–specific survival (LCSS). After PSM analysis, LSQCC was still closely associated with a reduction in OS and LCSS. All of these suggested that the histological type was an independent prognostic factor for OS and LCSS.ConclusionOur study demonstrated that squamous cell carcinoma predicted worse OS and LCSS in IA-stage NSCLC patients compared with lung adenocarcinoma (LUAD). We suggest that the outcomes of LSQCC and LUAD are very different and that the two histological types should be differently analyzed.