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Biomedicine & Pharmacotherapy =... Dec 2023Lung cancer accounts for a relatively high proportion of malignant tumors. As the most prevalent type of lung cancer, non-small cell lung cancer (NSCLC) is characterized... (Review)
Review
Lung cancer accounts for a relatively high proportion of malignant tumors. As the most prevalent type of lung cancer, non-small cell lung cancer (NSCLC) is characterized by high morbidity and mortality. Presently, the arsenal of treatment strategies encompasses surgical resection, chemotherapy, targeted therapy and radiotherapy. However, despite these options, the prognosis remains distressingly poor with a low 5-year survival rate. Therefore, it is urgent to pursue a paradigm shift in treatment methodologies. In recent years, the advent of sophisticated biotechnologies and interdisciplinary integration has provided innovative approaches for the treatment of lung cancer. This article reviews the cutting-edge developments in the nano drug delivery system, molecular targeted treatment system, photothermal treatment strategy, and immunotherapy for lung cancer. Overall, by systematically summarizing and critically analyzing the latest progress and current challenges in these treatment strategies of lung cancer, we aim to provide a theoretical basis for the development of novel drugs for lung cancer treatment, and thus improve the therapeutic outcomes for lung cancer patients.
Topics: Humans; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Immunotherapy; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37979378
DOI: 10.1016/j.biopha.2023.115891 -
CA: a Cancer Journal For Clinicians 2023Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens.... (Review)
Review
Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Etoposide; Combined Modality Therapy; Antineoplastic Combined Chemotherapy Protocols; Biological Products
PubMed: 37329269
DOI: 10.3322/caac.21785 -
Journal of Hematology & Oncology Jun 2023Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are,... (Review)
Review
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a poor prognosis. Initial responses to standard-of-care chemo-immunotherapy are, unfortunately, followed by rapid disease recurrence in most patients. Current treatment options are limited, with no therapies specifically approved as third-line or beyond. Delta-like ligand 3 (DLL3), a Notch inhibitory ligand, is an attractive therapeutic target because it is overexpressed on the surface of SCLC cells with minimal to no expression on normal cells. Several DLL3-targeted therapies are being developed for the treatment of SCLC and other neuroendocrine carcinomas, including antibody-drug conjugates (ADCs), T-cell engager (TCE) molecules, and chimeric antigen receptor (CAR) therapies. First, we discuss the clinical experience with rovalpituzumab tesirine (Rova-T), a DLL3-targeting ADC, the development of which was halted due to a lack of efficacy in phase 3 studies, with a view to understanding the lessons that can be garnered for the rapidly evolving therapeutic landscape in SCLC. We then review preclinical and clinical data for several DLL3-targeting agents that are currently in development, including the TCE molecules-tarlatamab (formerly known as AMG 757), BI 764532, and HPN328-and the CAR T-cell therapy AMG 119. We conclude with a discussion of the future challenges and opportunities for DLL3-targeting therapies, including the utility of DLL3 as a biomarker for patient selection and disease progression, and the potential of rational combinatorial approaches that can enhance efficacy.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Ligands; Neoplasm Recurrence, Local; Membrane Proteins; Intracellular Signaling Peptides and Proteins
PubMed: 37355629
DOI: 10.1186/s13045-023-01464-y -
Signal Transduction and Targeted Therapy Aug 2023Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel targeting LAG-3 drugs have also been approved in clinical application. With... (Review)
Review
Immune-checkpoint inhibitors (ICBs), in addition to targeting CTLA-4, PD-1, and PD-L1, novel targeting LAG-3 drugs have also been approved in clinical application. With the widespread use of the drug, we must deeply analyze the dilemma of the agents and seek a breakthrough in the treatment prospect. Over the past decades, these agents have demonstrated dramatic efficacy, especially in patients with melanoma and non-small cell lung cancer (NSCLC). Nonetheless, in the field of a broad concept of solid tumours, non-specific indications, inseparable immune response and side effects, unconfirmed progressive disease, and complex regulatory networks of immune resistance are four barriers that limit its widespread application. Fortunately, the successful clinical trials of novel ICB agents and combination therapies, the advent of the era of oncolytic virus gene editing, and the breakthrough of the technical barriers of mRNA vaccines and nano-delivery systems have made remarkable breakthroughs currently. In this review, we enumerate the mechanisms of each immune checkpoint targets, associations between ICB with tumour mutation burden, key immune regulatory or resistance signalling pathways, the specific clinical evidence of the efficacy of classical targets and new targets among different tumour types and put forward dialectical thoughts on drug safety. Finally, we discuss the importance of accurate triage of ICB based on recent advances in predictive biomarkers and diagnostic testing techniques.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Melanoma; Combined Modality Therapy; Drug Delivery Systems
PubMed: 37635168
DOI: 10.1038/s41392-023-01522-4 -
International Journal of Molecular... Aug 2023Laryngeal cancer is a very common tumor in the upper aero-digestive tract. Understanding its biological mechanisms has garnered significant interest in recent years. The... (Review)
Review
Laryngeal cancer is a very common tumor in the upper aero-digestive tract. Understanding its biological mechanisms has garnered significant interest in recent years. The development of laryngeal squamous cell carcinoma (LSCC) follows a multistep process starting from precursor lesions in the epithelium. Various risk factors have been associated with laryngeal tumors, including smoking, alcohol consumption, opium use, as well as infections with HPV and EBV viruses, among others. Cancer development involves multiple steps, and genetic alterations play a crucial role. Tumor suppressor genes can be inactivated, and proto-oncogenes may become activated through mechanisms like deletions, point mutations, promoter methylation, and gene amplification. Epigenetic modifications, driven by miRNAs, have been proven to contribute to LSCC development. Despite advances in molecular medicine, there are still aspects of laryngeal cancer that remain poorly understood, and the underlying biological mechanisms have not been fully elucidated. In this narrative review, we examined the literature to analyze and summarize the main steps of carcinogenesis and the risk factors associated with laryngeal cancer.
Topics: Humans; Laryngeal Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Risk Factors; Alcohol Drinking
PubMed: 37629093
DOI: 10.3390/ijms241612913 -
Critical Reviews in Oncology/hematology Oct 2023Non-small cell lung cancer (NSCLC) stages I-III were previously predominantly treated with surgery and chemotherapy. With the advent of Checkmate-816, neoadjuvant... (Review)
Review
Non-small cell lung cancer (NSCLC) stages I-III were previously predominantly treated with surgery and chemotherapy. With the advent of Checkmate-816, neoadjuvant nivolumab and chemotherapy was FDA approved for the treatment of resectable NSCLC. There are several ongoing trials evaluating other neoadjuvant combinations of chemotherapy and immunotherapy as well as targeted therapies towards driver mutations. Here, we review previous clinical trials and discuss current ongoing trials' potential benefits and challenges.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Neoadjuvant Therapy; Nivolumab; Immunotherapy
PubMed: 37532102
DOI: 10.1016/j.critrevonc.2023.104080 -
JAMA Oncology Sep 2023MET inhibitors have recently demonstrated clinical activity in patients with MET exon 14 (METex14)-skipping non-small cell lung cancer (NSCLC); however, data with longer...
IMPORTANCE
MET inhibitors have recently demonstrated clinical activity in patients with MET exon 14 (METex14)-skipping non-small cell lung cancer (NSCLC); however, data with longer follow-up and in larger populations are needed to further optimize therapeutic approaches.
OBJECTIVE
To assess the long-term efficacy and safety of tepotinib, a potent and highly selective MET inhibitor, in patients with METex14-skipping NSCLC in the VISION study.
DESIGN, SETTING, AND PARTICIPANTS
The VISION phase 2 nonrandomized clinical trial was a multicohort, open-label, multicenter study that enrolled patients with METex14-skipping advanced/metastatic NSCLC (cohorts A and C) from September 2016 to May 2021. Cohort C (>18 months' follow-up) was an independent cohort, designed to confirm findings from cohort A (>35 months' follow-up). Data cutoff was November 20, 2022.
INTERVENTION
Patients received tepotinib, 500 mg (450 mg active moiety), once daily.
MAIN OUTCOMES AND MEASURES
The primary end point was objective response by independent review committee (RECIST v1.1). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
RESULTS
Cohorts A and C included 313 patients (50.8% female, 33.9% Asian; median [range] age, 72 [41-94] years). The objective response rate (ORR) was 51.4% (95% CI, 45.8%-57.1%) with a median (m)DOR of 18.0 (95% CI, 12.4-46.4) months. In cohort C (n = 161), an ORR of 55.9% (95% CI, 47.9%-63.7%) with an mDOR of 20.8 (95% CI, 12.6-not estimable [NE]) months was reported across treatment lines, comparable to cohort A (n = 152). In treatment-naive patients (cohorts A and C; n = 164), ORR was 57.3% (95% CI, 49.4%-65.0%) and mDOR was 46.4 (95% CI, 13.8-NE) months. In previously treated patients (n = 149), ORR was 45.0% (95% CI, 36.8%-53.3%) and mDOR was 12.6 (95% CI, 9.5-18.5) months. Peripheral edema, the most common treatment-related adverse event, occurred in 210 patients (67.1%) (35 [11.2%] experienced grade ≥3 events).
CONCLUSIONS AND RELEVANCE
The findings from cohort C in this nonrandomized clinical trial supported the results from original cohort A. Overall, the long-term outcomes of VISION demonstrated robust and durable clinical activity following treatment with tepotinib, particularly in the treatment-naive setting, in the largest known clinical trial of patients with METex14-skipping NSCLC, supporting the global approvals of tepotinib and enabling clinicians to implement this therapeutic approach for such patients.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02864992.
Topics: Aged; Female; Humans; Male; Carcinoma, Non-Small-Cell Lung; Exons; Follow-Up Studies; Lung Neoplasms
PubMed: 37270698
DOI: 10.1001/jamaoncol.2023.1962 -
Frontiers in Endocrinology 2023No existing comprehensive Mendelian randomization studies have focused on how obesity affects respiratory diseases.
BACKGROUND
No existing comprehensive Mendelian randomization studies have focused on how obesity affects respiratory diseases.
METHODS
BMI and waist circumference, mainly from the UK Biobank, and 35 respiratory diseases from the FinnGen Biobank were subjected to Mendelian randomization analyses. In this study, the inverse variance weighting method was used as the predominant analysis method and was complemented by MR-Egger and weighted median methods. Horizontal pleiotropy and potential outliers were detected by employing the MR-PRESSO method.
RESULTS
This study indicated that obesity rises the possibility of acute upper respiratory infections (BMI: OR=1.131, p<0.0001; WC: OR=1.097, p=0.00406), acute sinusitis (BMI: OR=1.161, p=0.000262; WC: OR=1.209, p=0.000263), acute pharyngitis (WC: OR=1.238, p=0.0258), acute laryngitis and tracheitis (BMI: OR=1.202, p=0.0288; WC: OR=1.381, p=0.00192), all influenza (BMI: OR=1.243, p=0.000235; WC: OR=1.206, p=0.0119), viral pneumonia (WC: OR=1.446, p=0.000870), all pneumoniae (BMI: OR=1.174, p <0.0001; WC: OR=1.272, p <0.0001), bacterial pneumoniae (BMI: OR=1.183, p=0.000290; WC: OR=1.274, p<0.0001), acute bronchitis (BMI: OR=1.252, p <0.0001; WC: OR=1.237, p=0.000268), acute unspecified lower respiratory infection (BMI: OR=1.303, p=0.000403), chronic tonsils and adenoids diseases (BMI: OR=1.236, p <0.0001; WC: OR=1.178, p=0.000157), chronic laryngotracheitis and laryngitis (WC: OR=1.300, p=0.00785), COPD (BMI: OR=1.429, p <0.0001; WC: OR=1.591, p <0.0001), asthma (BMI: OR=1.358, p <0.0001; WC: OR=1.515, p <0.0001), necrotic and suppurative conditions of lower respiratory tract (WC: OR=1.405, p=0.0427), pleural effusion (BMI: OR=1.277, p=0.00225; WC: OR=1.561, p<0.0001), pleural plaque (BMI: OR=1.245, p=0.0312), other diseases of the respiratory system (BMI: OR=1.448, p <0.0001; WC: OR=1.590, p <0.0001), and non-small cell lung cancer (BMI: OR=1.262, p=0.00576; WC: OR=1.398, p=0.00181). This study also indicated that obesity decreases the possibility of bronchiectasis (BMI: OR=0.705; p=0.00200).
CONCLUSION
This study revealed that obesity increases the risk of the majority of respiratory diseases (including 20 of all 35 respiratory diseases) and that obesity decreases the risk of bronchiectasis.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Laryngitis; Mendelian Randomization Analysis; Lung Neoplasms; Respiratory Tract Infections; Bronchiectasis
PubMed: 37711902
DOI: 10.3389/fendo.2023.1197730 -
Cancer Medicine Jul 2023To improve the understanding of special types of tumors, we summarized and analyzed the clinicopathological features and prognostic factors of SMARCA4-deficient...
PURPOSE
To improve the understanding of special types of tumors, we summarized and analyzed the clinicopathological features and prognostic factors of SMARCA4-deficient non-small cell lung cancer (SMARCA4-dNSCLC).
METHODS
We selected 105 patients with SMARCA4-dNSCLC and 221 patients with SMARCA4-intact non-small cell lung cancer (SMARCA4-iNSCLC) by performing immunohistochemical analysis of 1520 NSCLC samples, and we assessed the patients' clinicopathological features and survival state.
RESULTS
(1) SMARCA4-dNSCLC was significantly associated with older age, male sex, smoking history, larger invasive tumor size, higher tumor proliferation index (Ki-67), more adrenal metastases, more lymph node metastases, and few EGFR mutations (p < 0.05). The tumors were mostly negative for thyroid transcription factor-1 (TTF-1), CD34, and p40 and positive for cytokeratin 7 (CK7) in immunohistochemistry (IHC). Nineteen SMARCA4-dNSCLC patients mostly had TP53, SMARCA4, and LRP1B mutations, and 48% of them had SMARCA4 frameshift mutations. SMARCA4-dNSCLC patients have a worse prognosis than SMARCA4-iNSCLC patients (HR: 0.27; 95% CI: 0.17-0.45). The overall survival (OS) of patients with stage III SMARCA4-dNSCLC was worse than that of patients with SMARCA4-iNSCLC, and the OS of stage IV SMARCA4-dNSCLC patients was also worse than that of SMARCA4-iNSCLC patients (p < 0.01). (2) Multivariate regression analysis showed that sex (HR: 4.12; 95% CI: 1.03-16.39) and smoking history (HR: 2.29; 95% CI: 1.04-5.02) had significant effects on the survival time of SMARCA4-dNSCLC patients. In SMARCA4-dNSCLC patients without distant metastases (stage I-III), patients with stage N2 or N3 lymph node metastases (HR: 6.35; 95% CI: 1.07-37.47) had a poor prognosis. Among patients with SMARCA4-dNSCLC who were treated and had distant metastases (stage IV), male patients and patients treated with immunotherapy combined with chemotherapy showed a longer median overall survival (mOS).
CONCLUSION
SMARCA4-dNSCLC has unique clinicopathological features and a shorter survival prognosis than SMARCA4-iNSCLC. The efficacy of immunotherapy combined with chemotherapy needs to be observed for longer periods.
Topics: Humans; Male; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; DNA Helicases; Lung Neoplasms; Lymphatic Metastasis; Nuclear Proteins; Prognosis; Transcription Factors
PubMed: 37184108
DOI: 10.1002/cam4.6083 -
Nature Medicine Oct 2023Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of... (Randomized Controlled Trial)
Randomized Controlled Trial
Circulating tumor DNA (ctDNA) has shown promise in capturing primary resistance to immunotherapy. BR.36 is a multi-center, randomized, ctDNA-directed, phase 2 trial of molecular response-adaptive immuno-chemotherapy for patients with lung cancer. In the first of two independent stages, 50 patients with advanced non-small cell lung cancer received pembrolizumab as standard of care. The primary objectives of stage 1 were to ascertain ctDNA response and determine optimal timing and concordance with radiologic Response Evaluation Criteria in Solid Tumors (RECIST) response. Secondary endpoints included the evaluation of time to ctDNA response and correlation with progression-free and overall survival. Maximal mutant allele fraction clearance at the third cycle of pembrolizumab signified molecular response (mR). The trial met its primary endpoint, with a sensitivity of ctDNA response for RECIST response of 82% (90% confidence interval (CI): 52-97%) and a specificity of 75% (90% CI: 56.5-88.5%). Median time to ctDNA response was 2.1 months (90% CI: 1.5-2.6), and patients with mR attained longer progression-free survival (5.03 months versus 2.6 months) and overall survival (not reached versus 7.23 months). These findings are incorporated into the ctDNA-driven interventional molecular response-adaptive second stage of the BR.36 trial in which patients at risk of progression are randomized to treatment intensification or continuation of therapy. ClinicalTrials.gov ID: NCT04093167 .
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Antibodies, Monoclonal, Humanized; Progression-Free Survival
PubMed: 37814061
DOI: 10.1038/s41591-023-02598-9