Treatment Of NSCLC Research Articles

Pedunculoside inhibits epithelial-mesenchymal transition and overcomes Gefitinib-resistant non-small cell lung cancer through regulating MAPK and Nrf2 pathways

BackgroundLung cancer is the primary cause of cancer-related mortality worldwide owing to its strong metastatic ability. EGFR-TKI (Gefitinib) has demonstrated efficacy in metastatic lung cancer therapy, but most patients ultimately develop resistance to Gefitinib, leading to a poor prognosis. Pedunculoside (PE), a triterpene saponin extracted from Ilex rotunda Thunb., has shown anti-inflammatory, lipid-lowering and anti-tumor effects. Nevertheless, the therapeutic effect and potential mechanisms of PE on NSCLC treatment are unclear. PurposeTo investigate the inhibitory effect and prospective mechanisms of PE on NSCLC metastases and Gefitinib-resistant NSCLC. MethodsIn vitro, A549/GR cells were established by Gefitinib persistent induction of A549 cells with a low dose and shock with a high dose. The cell migratory ability was measured using wound healing and Transwell assays. Additionally, EMT-related Markers or ROS production were assessed by RT-qPCR, immunofluorescence, Western blotting, and flow cytometry assays in A549/GR and TGF-β1-induced A549 cells. In vivo, B16-F10 cells were intravenously injected into mice, and the effect of PE on tumor metastases were determined using hematoxylin-eosin staining, Caliper IVIS Lumina, DCFH2-DA staining, and western blotting assays. ResultsPE reversed TGF-β1-induced EMT by downregulating EMT-related protein expression through MAPK and Nrf2 pathways, decreasing ROS production, and inhibiting cell migration and invasion ability. Moreover, PE treatment enabled A549/GR cells to retrieve the sensitivity to Gefitinib and mitigate the biological characteristics of EMT. PE also significantly inhibited lung metastasis in mice by reversing EMT proteins expression, decreasing ROS production, and inhibiting MAPK and Nrf2 pathways. ConclusionsCollectively, this research presents a novel finding that PE can reverse NSCLC metastasis and improve Gefitinib sensitivity in Gefitinib-resistant NSCLC through the MAPK and Nrf2 pathways, subsequently suppressing lung metastasis in B16-F10 lung metastatic mice model. Our findings indicate that PE is a potential agent for inhibiting metastasis and improving Gefitinib resistance in NSCLC.

Analysis of the relation between adverse events and overall survival in patients treated with pembrolizumab as a first-line treatment for metastatic NSCLC

BackgroundMany trials supported pembrolizumab as a first-line monotherapy to significantly improve overall survival (OS) in selected patients with previously untreated metastatic Non–Small Cell Lung Cancer (mNSCLC) and a PD-L1 TPS of ≥50% without EGFR/ALK mutations. The aim of this study was to reveal the correlation between OS and adverse events in real-world settings after 42 months.MethodsThis retrospective observational study involved 98 patients with mNSCLC, TPS ≥ 50%, and no EGFR/ALK aberrations. Patients were treated with pembrolizumab (200 mg q3w) as a first-line treatment. Clinical data, including PD-L1 expression, Performance Status (ECOG-PS), treatment duration, toxicity, and outcomes were retrieved from local electronic medical records and from the Italian Regulatory Agency Registry.ResultsThe cohort’s main characteristics were as follows: median age 73 [44-89] years, 64.3% were male and 35.7% were female, an ECOG-PS score of 0 (n = 73) and 1 or 2 (n = 25), and a PD-L1 > 90% in 29.6% of patients. The entire cohort had stage IV NSCLC at diagnosis. The median number of cycles was 8.5 at a median follow-up of 13 months. The median OS of 13.6 months (95% CI: 11.7-NA) was not influenced by sex and PD-L1, but was significantly associated with ECOG-PS (p = 0.02). Immune-Related Adverse Events (irAEs) occurred in 77.5% of patients (30.1% cutaneous, 27.5% gastrointestinal, and 20.4% endocrinological), but no grade 4 or 5 irAEs were identified. Patients experiencing any type of toxicity had a significantly longer median OS (20.39 months, 95% CI: 13.08-NA) than those with no toxicities (6.46 months, 95% CI: 1.41-NA, p = 0.006).ConclusionThe percentage of irAEs detected was comparable to that reported in KEYNOTE-024 and KEYNOTE-042. These real-world findings demonstrated the significant correlation between OS and cutaneous toxicities.

Chitosan functionalized PCL nanoparticles bearing tyrosine kinase inhibitor osimertinib mesylate for effective lung cancer therapy

Lung cancer ranks second position among the cancer-related deaths. Osimertinib mesylate (OSM) is a tyrosine-kinase-inhibitor which can effectively treat non-small cell lung cancer (NSCLC), but still there are certain limitations and side effects which could be circumvented by polymeric nanoparticles approach. Hence, this research was aimed to develop drug-loaded biodegradable polycaprolactone nanoparticles (PCL-NPs) such as OSM-loaded PCL-NPs (PCL-OSM-NPs) and chitosan fabricated OSM-loaded PCL-NPs (CS-PCL-OSM-NPs) to achieve active-targeting of OSM in the cancerous lung tissue. Thus, CS-PCL-OSM-NPs enhance the anticancer efficacy due to active targeting nature and thereby reduces off-target side effects of OSM in the NSCLC treatment. Blank PCL-NPs, PCL-OSM-NPs, and CS-PCL-OSM-NPs were prepared by nanoprecipitation method. Optimized blank PCL-NPs, PCL-OSM-NPs, and CS-PCL-OSM-NPs exhibited the mean particle size of 90.2 ± 4.7 nm, 167.7 ± 2.9 nm, and 233.7 ± 4.8 nm respectively. The encapsulation efficiency % (%EE) of PCL-OSM-NPs was found to be 68.4 ± 3.2%. In vitro drug release study demonstrated sustained release profile of 69.5 ± 5% and 65.7 ± 1.5% for OSM from both the PCL-OSM-NPs and CS-PCL-OSM-NPs, respectively. The PCL-OSM-NPs and CS-PCL-OSM-NPs demonstrated the inhibition of 82.2 ± 0.5% and 81.9 ± 0.2% in A549 cancer cells respectively which clearly signified the improved efficacy. Moreover, the PCL-OSM-NPs and CS-PCL-OSM-NPs exhibited significantly less hemolysis than OSM indicating safety of the formulation. These findings indicate that biohemocompatible CS-PCL-OSM-NPs is an attractive option to treat NSCLC with enhanced anticancer activity and reduced side effects.

Socioeconomic Inequalities in Novel NSCLC Treatments During the Era of Tumor Biomarker-Guided Therapy: A Population-Based Cohort Study in a Publicly Funded Health Care System

IntroductionSocioeconomic inequalities in the utilization of conventional NSCLC treatments are well documented. Nevertheless, it is not known whether these inequalities are also observed with novel anticancer therapies. This study evaluated associations between deprivation and utilization of novel anticancer therapies targeting tumor biology, the immune system, or both, within the English national publicly funded health care system. MethodsA retrospective analysis of 90,785 patients diagnosed with having a histologically confirmed stage IV NSCLC from January 1, 2012, to December 31, 2017, sourced from the English national population-based cancer registry and linked Systemic Anti-Cancer Therapy database, was undertaken. Multivariable logistic regression evaluated the likelihood of novel anticancer therapy utilization by deprivation category of area of residence at diagnosis (measured by quintiles of the income domain of the index of multiple deprivation). ResultsMultivariable analyses revealed marked treatment inequalities by deprivation. Patients residing in the most deprived areas were more than half as likely to use any novel therapy (multivariable OR [mvOR] = 0.45, 95% confidence interval [CI]: 0.41–0.49) compared with patients residing in the most affluent areas. Deprivation associations with treatment utilization were slightly stronger with targeted treatments ([most versus least deprived] mvOR = 0.39, 95% CI: 0.35–0.43) than immune checkpoint inhibitors (mvOR = 0.58, 95% CI: 0.51–0.66). ConclusionsThere are marked socioeconomic inequalities in NSCLC novel treatment utilization, even in the English National Health Service where treatment is free at the point of delivery. These findings have important implications for equitable delivery of drugs, which have transformed outcomes in metastatic lung cancer. Further work exploring the underlying causes is now needed.

Mitochondrial creatine kinase 1 regulates the cell cycle in non-small cell lung cancer via activation of cyclin-dependent kinase 4

BackgroundNon-small cell lung cancer (NSCLC) is the main type of the most common malignant tumor in the world. Previous studies have shown that the expression level of mitochondrial creatine kinase 1 (CKMT1) is abnormal in NSCLC, but the mechanism of its effect remains unclear. Therefore, in this study, we intend to clarify the potential mechanism of CKMT1 in NSCLC and provide the theoretical basis for the clinical application of CKMT1.MethodsThe function of CKMT1 in NSCLC was identified by analyzing the GEO dataset and evaluating using in vitro and in vivo models. Protein mass spectrometry was used to find proteins interacting with CKMT1, and Co-immunoprecipitation (Co-IP) and GST-pull down experiments were used to verify the interaction between proteins. The immunofluorescence (IF) assay was used to explore the functional position of CKMT1 in cells. The effect of CKMT1 expression level on the efficacy of paclitaxel (TAX) in the treatment of NSCLC was analyzed by a combined TAX experiment in vivo and in vitro.ResultsCKMT1 expression was increased in NSCLC and CKMT1 promoted the proliferation of NSCLC cells in vitro and in vivo. CKMT1 knockdown resulted in a significantly increased G0/G1 fraction and decreased S phase cell fraction, indicating G1 phase arrest. Mechanically, the cyclin-dependent kinase 4 (CDK4) was identified to interact with CKMT1, and the crucial binding areas were focused on the DH domain of CKMT1 and the N- and C-terminal of CDK4. A fraction of the CDK4 proteins colocalize and interact with the CKMT1 at mitochondria, the level of phosphorylated CDK4 was regulated by CKMT1. Hence, the decrease in CKMT1 expression level could increase the antitumor effect of G2/M cell cycle antagonist-TAX in NSCLC in vitro and in vivo.ConclusionsCKMT1 could interact with CDK4 in mitochondria and regulate the phosphorylated level of CDK4, thus contributing to the proliferation and cell cycle transition of NSCLC cells. And CKMT1 could be a potential target to improve the sensitivity of chemotherapy based on TAX.

The Role of Immunotherapy in the First-Line Treatment of Elderly Advanced Non-Small Cell Lung Cancer

Immune checkpoint inhibitors have changed the history of NSCLC treatment by becoming, alone or in combination with platinum-based chemotherapy, a mainstay of first-line therapy for advanced NSCLC. This increasingly dictates the identification of predictive biomarkers of response that can guide patient selection, in order to rationalize and personalize therapies, particularly in elderly patients. Immunotherapy in these patients raises questions of efficacy and tolerability related to aging, which is accompanied by a progressive decline in various body functions. Physical, biological and psychological changes contribute to individual validity status and, preferably, ‘fit’ patients are generally enrolled in clinical trials. In elderly patients, especially frail and complex patients with more than one chronic disease, data are poor and specific prospective studies are needed. This review reports the main available results on the use of immune checkpoint inhibitors in older patients with advanced NSCLC, in terms of efficacy and toxicity, and aims to highlight the need to better predict which patients might benefit from immunotherapy agents by probing knowledge and integrating information on immune system changes and age-related physiopathological modifications.

Cost-effectiveness of adjuvant atezolizumab for patients with stage II-IIIA PD-L1+ non-small-cell lung cancer.

Aim: Atezolizumab improved disease-free survival (DFS) versus best supportive care (BSC) as adjuvant treatment following resection and platinum-based chemotherapy for stage II-IIIA PD-L1+ NSCLC in IMpower010. Materials & methods: This cost-effectiveness study evaluated atezolizumab versus BSC (US commercial payer perspective) using a Markov model with DFS, locoregional recurrence, first- and second-line metastatic recurrence and death health states, and a lifetime time horizon with 3% annual discounting. Results: Atezolizumab provided 1.045 additional quality-adjusted life-years (QALY) at an incremental cost of $48,956, yielding an incremental cost-effectiveness ratio of $46,859/QALY. Scenario analysis showed similar findings in a Medicare population ($48,512/QALY). Conclusion: At a willingness-to-pay threshold of $150,000/QALY and an incremental cost-effectiveness ratio of $46,859/QALY, atezolizumab is cost-effective versus BSC for adjuvant NSCLC treatment.

Abstract 4627: Immune profiling of immunotherapy and adjuvant chemotherapy pretreatment NSCLC tissues by CODEX

Abstract Non-small cell lung cancer (NSCLC), including adenocarcinoma and squamous cell carcinoma subtypes, is a leading cause of cancer deaths worldwide. Treatment of NSCLC has advanced from chemotherapy modalities to the use of immunotherapy, namely immune checkpoint inhibitors (ICIs) which enhance the adaptive immune response against tumour cells. Thus, while the immune cell composition of tumours and its influence on treatment outcomes is poorly understood, it likely holds the key to effective, personalized treatment regimens. Here we profiled an adjuvant chemotherapy (n=61) as well as a second line immunotherapy (n=42) NSCLC cohort by the Phenocycler CODEX technology (highplex spatial proteomics) to investigate the association between immune composition and patient outcome. We applied a panel of 38 markers to delineate naïve, memory, cytotoxic and hyperactivated T cell states, as well as B cells, Tregs and myeloid lineage innate immune cell types. Our study sought to understand the heterogeneity of tumour-immune composition across patients and investigate the spatial neighbourhoods and clusters that these cells inhabit within TMA cores. We used Phenoplex™ software for tissue segmentation (into classes for tumor, stroma, artifacts, blood vessels, etc.), cellular segmentation, and cellular phenotyping based on thresholds for each marker, and then performed spatial analyses (distances, interactions, neighborhoods) using SpatialMap1 to identify cellular motifs associated with clinical phenotypes. Our study has identified spatial features associated with immune contexture linked to therapy outcome in both chemotherapy and immunotherapy modalities. Taken together, our study demonstrates the utility of spatial proteomics to identify cellular features associated with outcome to therapy in lung cancer. 1) Trevino A, Ivison G, Hamel S, Chiou A (2022). SpatialMap: Analysis of Spatial Biology Data. R package version 0.4.57. Citation Format: James Monkman, Afshin Moradi, Connor O'Leary, Zhenqin Wu, Steven Hamel, David Mason, Fabian Schneider, James Robert Mansfield, Aaron Meyer, Ken O'Byrne, Arutha Kulasinghe. Immune profiling of immunotherapy and adjuvant chemotherapy pretreatment NSCLC tissues by CODEX. [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 4627.

Abstract 3396: Discovery of BDTX-1535, a novel 4th generation, irreversible, potent, wild type sparing EGFR MasterKey inhibitor that targets oncogenic kinase domain mutations as well as extracellular domain alterations for the treatment of NSCLC and GBM

Abstract Acquired resistance to 3rd generation EGFR inhibitors used in the treatment of NSCLC is common. While the EGFR C797S substitution is a frequently reported post-osimertinib resistance mutation, real world evidence indicates the emergence of additional EGFR alterations that can drive drug resistance: kinase domain mutations (e.g., S768I), extracellular domain alterations (e.g., EGFRvIII, A289X), and EGFR amplification. Moreover, while osimertinib targets the classical EGFR mutations, primary NSCLC tumors are also driven by other oncogenic kinase domain mutations including G719X, S768I, and L861Q, which confer de novo (intrinsic) resistance to 3rd generation EGFR TKIs. A family of extracellular domain alterations occurs in nearly 50% of GBM patients, and these alterations are clinically resistant to all current generation inhibitors. Real world data in GBM demonstrate these EGFR alterations often co-occur and persist throughout treatment with current standard of care therapy. Of critical importance is the observation that the oncogenic isoform of EGFR in GBM is a covalent homo-dimer which can be formed and paradoxically activated by the binding of reversible 1st generation EGFR inhibitors. There is a significant clinical need to develop a potent CNS penetrant EGFR inhibitor that would target both acquired and intrinsic resistance mutations expressed in NSCLC and co-occurring EGFR alterations in GBM. An effective inhibitor should meet four design principles; 1) potent and selective against a broad family of intracellular, extracellular EGFR oncogenic alterations and amplification, 2) wild type EGFR sparing, 3) irreversible to avoid paradoxical activation, and 4) CNS penetrant. BDTX-1535 is a 4th generation irreversible CNS penetrant EGFR MasterKey inhibitor targeting a family of oncogenic EGFR extracellular domain alterations and amplification in GBM patients and EGFR resistance mutations in NSCLC. BDTX-1535 meets all four criteria for a highly effective EGFR inhibitor and was designed using the MAP Discovery Engine to target the activated conformations used by oncogenic EGFR to drive tumorigenesis. BDTX-1535 achieves potent anti-tumor activity against EGFR alterations and amplification across models including NSCLC and GBM PDX and intracranial tumors. BDTX-1535 is currently in a phase I clinical study in patients with NSCLC and GBM harboring sensitive EGFR alterations (NCT05256290). Citation Format: Matthew O'Connor, Matthew Lucas, Sherri Smith, Anthony Trombino, Sudharshan Eathiraj, Elizabeth Buck. Discovery of BDTX-1535, a novel 4th generation, irreversible, potent, wild type sparing EGFR MasterKey inhibitor that targets oncogenic kinase domain mutations as well as extracellular domain alterations for the treatment of NSCLC and GBM [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 3396.

Abstract 554: The role of Mycobacterium w as a novel treatment for osteosarcoma

Abstract Osteosarcoma (OS) is the most common malignant primary tumor of bone and occurs in adolescents and young adults as well as in the elderly. Despite a number of large clinical trial efforts, metastatic sarcoma remains a lethal disease, and there have been no meaningful advances in therapy or improvements in patient outcomes for decades. Mycobacterium w (Mw, also known as Mycobacterium indicus pranii) is a non-pathogenic strain of mycobacterium which has been used as an immunomodulator against leprosy, tuberculosis and several cancers and is approved for treatment of NSCLC along with chemotherapy in India. Mw promotes a Th1 immune response and its administration in tumor bearing animals is associated with an increase in total number of tumor infiltrating immune cells (TIIC) with decrease in FOXP3 and PD-1 expressing TIIC in pancreatic cancer and melanoma. Previous studies in our lab have shown that Mw promotes mature dendritic cell and activated CD8+ T cell accumulation within the tumor microenvironment in a mouse model of pancreatic cancer. We compared the effects Mw with standard of care doxorubicin on OS tumor progression in a subcutaneous K7M2 syngeneic mouse model. Mw treatment was more effective at tumor inhibition than doxorubicin. Immunohistochemistry analyses of OS tumors revealed an increase in macrophages following Mw treatment. We aim to further analyze the tumor immune microenvironment using a panel of 28 antibodies to determine alterations due to Mw treatment. With these results we hope to show that Mw is a promising candidate for further development as a therapy for OS. Citation Format: Kirsten Stefan, Arpit Dheeraj, Dhanir Tailor, Sushil Kumar, Wenqi Li, Rajiv Modi, Manjul Joshipura, Bakulesh Khamar, Lara E. Davis, Sanjay V. Malhotra. The role of Mycobacterium w as a novel treatment for osteosarcoma [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 554.

Abstract 4832: Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC

Abstract Non-small cell lung cancer (NSCLC) is a highly aggressive disease with a dismal prognosis associated with high rates of treatment resistance and disease recurrence. High-dose stereotactic body radiation therapy (SBRT) is the standard of care for locally advanced non-resectable NSCLC. However, as discovered more than six decades ago, tumor hypoxia is a significant barrier to effective radiation therapy. In the last decade, immunotherapy targeting immune checkpoints such as programmed cell death 1 (PD-1) has been introduced as first-line NSCLC treatment, yet long-term disease control occurs in less than 25% of patients. Therefore, understanding the mechanisms of the treatment resistance is essential to address the need for novel synergistic therapies to sensitize refractory NSCLC tumors to anti-cancer treatment. Tumor hypoxia has been associated with treatment resistance for decades, yet its role in the clinical management of NSCLC remains largely unexplored. The basis of tumor hypoxia has traditionally been attributed to the oxygen supply deficit as malformed tumor vasculature fails to meet the high demand of the rapidly proliferating tumor mass. However, our preliminary analysis of NSCLC patient datasets in the Cancer Genome Atlas (TCGA) revealed a significant correlation between high-level expression of nuclear genes encoding mitochondrial subunits essential for oxidative phosphorylation (OXPHOS) and the expression of validated hypoxia-regulated genes (Buffa hypoxia score). The oxygen-consumption expression signature was implemented in software that enables the calculation of numerous tumor microenvironment expression signatures, called tmesig. Furthermore, we have observed a direct positive correlation between the hypoxia expression signatures levels in NSCLC patient samples and the copy number amplification (CNA) of essential OXPHOS genes. Because mitochondrial function consumes up to 90% of available cellular oxygen, its activity may indirectly regulate oxygen availability in the tumor microenvironment by rapidly consuming oxygen upon its delivery to the tumor. Mechanistically, this leads to the hypothesis that OXPHOS gene amplification drives mitochondrial function, which may, in turn, promote tumor hypoxia and treatment resistance in NSCLC. Citation Format: Martin Benej, Katarina Benejova, McKenzie Kreamer, Jinghai Wu, Syed Ashraf, Caroline Wheeler, Rebecca Hoyd, Daniel Spakowicz, Nicholas C. Denko. Copy number amplification of OXPHOS genes drives tumor hypoxia in NSCLC. [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 4832.

Abstract 2566: Blocking the functional domain of TIP1 upregulates midkine via the β-catenin/Wnt signaling pathway

Abstract Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortalities world-wide. Targeted therapy has been a growing topic of investigation to improve therapeutic efficacy for NSCLC. A few targeted therapies that exploit aberrant protein expression profiles have been approved for NSCLC. However, marginal improvement in efficacy observed with these therapeutic approaches highlights the need for discovery of additional therapeutic targets. Tax interacting protein 1 (TIP1) is a molecular target that is overexpressed on the surface of various cancers and correlates with poor overall patient survival. The functional domain of TIP1 (PDZ domain) caps the C-terminus of many cellular proteins that regulate cell signaling, cancer development, and progression. We found that antibodies against the PDZ domain of TIP1 induced cytotoxicity of lung cancer cells but not normal cells. A quantitative mass spectrometry-based approach identified a ten-fold increase in Midkine protein expression on blockade of TIP1. Midkine is a heparin-binding growth factor that is involved in cancer progression, therapy resistance, and immune suppression. This study tested the hypothesis that Midkine is upregulated by the anti-PDZ/TIP1 antibody via the β-catenin/Wnt signaling pathway, which subsequently modulates downstream signaling mechanisms. In co-immunoprecipitation studies we found a direct interaction of TIP1 with β-catenin on the cell surface. Anti-TIP1 antibody treatment led to nuclear translocation of β-catenin in NSCLC cells. We used a luciferase based TOPFlash/FOPFlash reporter assay to study the transcriptional activity of the canonical β-catenin/Wnt pathway following TIP1 blockade. Reporter assays showed a three to four-fold increase (p<0.0001) in the transcriptional activity of β-catenin following TIP1 blockade in NSCLC cells. Genetic silencing of β-catenin inhibited Midkine mRNA transcription (p<0.005), protein induction and its extracellular release (p<0.0001) following anti-TIP1 antibody treatment. In conclusion, the mechanism of Midkine release following TIP1 blockade involves the β-catenin/Wnt signaling pathway. Ongoing studies are evaluating the dual-targeting of TIP1 and Midkine for enhanced efficacy of NSCLC treatment. Citation Format: Minakshi Saikia, Abhay K. Singh, Nathan Cheung, Dennis E. Hallahan, Vaishali Kapoor. Blocking the functional domain of TIP1 upregulates midkine via the β-catenin/Wnt signaling pathway [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 2566.

182P CD27-IgD- B cells might portray an exhausted B cell phenotype resulting in lack of response to checkpoint inhibitor treatment in NSCLC

182P CD27-IgD- B cells might portray an exhausted B cell phenotype resulting in lack of response to checkpoint inhibitor treatment in NSCLC

95 - Assessing the impact of the pharmacist independent prescriber as part of the multi-disciplinary care of patients receiving adjuvant treatment for NSCLC

95 - Assessing the impact of the pharmacist independent prescriber as part of the multi-disciplinary care of patients receiving adjuvant treatment for NSCLC

67 - Trends in the use of first line systemic anti-cancer treatment for NSCLC between 2012 and 2022

67 - Trends in the use of first line systemic anti-cancer treatment for NSCLC between 2012 and 2022

Histone Deacetylase 6 Inhibition Exploits Selective Metabolic Vulnerabilities in LKB1 Mutant, KRAS Driven NSCLC

IntroductionIn KRAS-mutant NSCLC, co-occurring alterations in LKB1 confer a negative prognosis compared with other mutations such as TP53. LKB1 is a tumor suppressor that coordinates several signaling pathways in response to energetic stress. Our recent work on pharmacologic and genetic inhibition of histone deacetylase 6 (HDAC6) revealed the impaired activity of numerous enzymes involved in glycolysis. On the basis of these previous findings, we explored the therapeutic window for HDAC6 inhibition in metabolically-active KRAS-mutant lung tumors. MethodsUsing cell lines derived from mouse autochthonous tumors bearing the KRAS/LKB1 (KL) and KRAS/TP53 mutant genotypes to control for confounding germline and somatic mutations in human models, we characterize the metabolic phenotypes at baseline and in response to HDAC6 inhibition. The impact of HDAC6 inhibition was measured on cancer cell growth in vitro and on tumor growth in vivo. ResultsSurprisingly, KL-mutant cells revealed reduced levels of redox-sensitive cofactors at baseline. This is associated with increased sensitivity to pharmacologic HDAC6 inhibition with ACY-1215 and blunted ability to increase compensatory metabolism and buffer oxidative stress. Seeking synergistic metabolic combination treatments, we found enhanced cell killing and antitumor efficacy with glutaminase inhibition in KL lung cancer models in vitro and in vivo. ConclusionsExploring the differential metabolism of KL and KRAS/TP53-mutant NSCLC, we identified decreased metabolic reserve in KL-mutant tumors. HDAC6 inhibition exploited a therapeutic window in KL NSCLC on the basis of a diminished ability to compensate for impaired glycolysis, nominating a novel strategy for the treatment of KRAS-mutant NSCLC with co-occurring LKB1 mutations.

The Role of Pembrolizumab (Keytruda) in Treating Non-small Cell Lung Cancer

Lung cancer also cause causes most of the cancer death cases around the world. In 2020, 1,796,144 people from all the world were estimated to die because of it. Lung cancer is responsible for one-fourth of all cancer death cases. There are many risk factors for lung cancer, including air pollution and cigarettes. Genes also play an important role in the pathogenesis of lung cancer. There are many types of treatment for it nowadays and they are used in different stages or different combinations. Treatment of NSCLC is influenced by the patient's overall health status, tumor stage, and pathological type. However, most of them have lots of side effects, such as bone marrow suppression, liver and kidney damage, etc. Compared to those treatments, immune checkpoint inhibitors less side effects. Pembrolizumab (Keytruda) is one of the inhibitors, which has a good performance in treating the NSCLC. Pembrolizumab inhibits the binding of PD-1 to PD-L1 and has shown good results in many clinical experiments. However, it also has limitations. As a result, this paper will introduce non-small cell lung cancer, Pembrolizumab (Keytruda), and its function in treating this disease.

Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients With NSCLC

IntroductionAccording to mechanisms of adaptive immune resistance, tumor immune microenvironment (TIME) is classified into four types: (1) programmed death-ligand 1 (PD-L1)–negative and tumor-infiltrating lymphocyte (TIL)–negative (type I); (2) PD-L1–positive and TIL-positive (type II); (3) PD-L1–negative and TIL-positive (type III); and (4) PD-L1–positive and TIL-negative (type IV). However, the relationship between the TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among patients with advanced NSCLC. MethodsOn the basis of RNA-sequencing and immunohistochemistry data from the ORIENT-11 study, we optimized the TIME classification model and evaluated its predictive value for the efficacy of immunotherapy plus chemotherapy. ResultsPD-L1 mRNA expression and immune score calculated by the ESTIMATE method were the strongest predictors for the efficacy of immunotherapy plus chemotherapy. Therefore, they were determined as the optimized definition of the TIME classification system. When compared between combination therapy and chemotherapy alone, only the type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved progression-free survival (PFS) (hazard ratio = 0.12, 95% confidence interval: 0.06–0.25, p < 0.001) and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.13–0.55, p < 0.001). In the combination group, the type II subpopulation had a much longer survival time, not even reaching the median PFS or overall survival, but the other three subpopulations were susceptible to having similar PFS. In the chemotherapy group, there was no marked association between survival outcomes and TIME subtypes. ConclusionsOnly patients with both high PD-L1 expression and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens.

A Systematic Review of Progress toward Unlocking the Power of Epigenetics in NSCLC: Latest Updates and Perspectives

Epigenetic research has the potential to improve our understanding of the pathogenesis of cancer, specifically non-small-cell lung cancer, and support our efforts to personalize the management of the disease. Epigenetic alterations are expected to have relevance for early detection, diagnosis, outcome prediction, and tumor response to therapy. Additionally, epi-drugs as therapeutic modalities may lead to the recovery of genes delaying tumor growth, thus increasing survival rates, and may be effective against tumors without druggable mutations. Epigenetic changes involve DNA methylation, histone modifications, and the activity of non-coding RNAs, causing gene expression changes and their mutual interactions. This systematic review, based on 110 studies, gives a comprehensive overview of new perspectives on diagnostic (28 studies) and prognostic (25 studies) epigenetic biomarkers, as well as epigenetic treatment options (57 studies) for non-small-cell lung cancer. This paper outlines the crosstalk between epigenetic and genetic factors as well as elucidates clinical contexts including epigenetic treatments, such as dietary supplements and food additives, which serve as anti-carcinogenic compounds and regulators of cellular epigenetics and which are used to reduce toxicity. Furthermore, a future-oriented exploration of epigenetic studies in NSCLC is presented. The findings suggest that additional studies are necessary to comprehend the mechanisms of epigenetic changes and investigate biomarkers, response rates, and tailored combinations of treatments. In the future, epigenetics could have the potential to become an integral part of diagnostics, prognostics, and personalized treatment in NSCLC.

Abstract PD11-01: PD11-01 Evaluation of the PD-1 Inhibitor Cemiplimab in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab (Cemi) is a PD-1 inhibitor approved for the treatment of NSCLC, cutaneous basal, and squamous cell cancer. Here, we report current efficacy rates of Cemi in combination with paclitaxel followed by AC. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included paclitaxel 80 mg/m2 IV weekly x 12 and Cemi 350 mg IV given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MRI imaging; and imaging response (at 3 weeks, 12 weeks and prior to surgery) were used along with accumulating pCR data to continuously update and estimate pCR rates for trial arms. Analysis was modified intent to treat. Patients who switched to non-protocol therapy count as non-pCR. The goal is to identify (graduate) regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within responsive signatures. Cemi was eligible to graduate in 3 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemi being superior to the dynamic control. Results: 60 HER2- patients (28 HR+ and 32 HR-) received Cemi arm treatment. The control group included 357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemi graduated in HR-/HER2- signature. Estimated pCR rates (as of June 2022) are summarized in the table. Immune-related endocrine disorders include: hypothyroid (14.5%), adrenal insufficiency (10%), hyperthyroid (4.8%),) and thyroiditis (3.2%). Only one grade 3 adrenal insufficiency was observed. All immune related AE’s were manageable. Additional biomarker analyses are ongoing and will be presented at the meeting. Response predictive subtypes (Immune+ vs Immune-) and additional predictive biomarkers were assessed. Associations with pCR will be presented at SABCS. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Anti-PD-1 therapy with Cemi resulted in a higher predicted pCR rate in HR-/HER2- 55 rate% disease compared to control at 29%. Immune-mediated AE’s were observed. This data is consistent with previously published data using check point inhibitors in early-stage HR-/HER2- breast cancer. Estimated pCR rates Citation Format: Erica Stringer-Reasor, Rebecca A. Shatsky, Jo Chien, Anne Wallace, Judy C. Boughey, Kathy S. Albain, Hyo S. Han, Rita Nanda, Claudine Isaacs, Kevin Kalinsky, Zahi Mitri, Amy S. Clark, Christos Vaklavas, Alexandra Thomas, Meghna S. Trivedi, Janice Lu, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van ’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. PD11-01 Evaluation of the PD-1 Inhibitor Cemiplimab in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-01.