Management Of Non-small Cell Lung Cancer Research Articles

Locally advanced/metastatic non-small-cell lung cancer in Lebanon: focus on ALK tyrosine kinase inhibitors.

Treatment of non-small-cell lung cancers (NSCLC) has evolved over the last decade. According to studies, the use of targeted therapies has significantly increased the life expectancy of patients. Moreover, ALK-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes. In Lebanon, translating recommendations into clinical practice remains challenging. A Lebanese expert panel of oncologists was convened to describe the management paradigm and the clinical evidence supporting the optimal use of next-generation TKIs in patients with ALK-rearranged NSCLC and to provide an expert overview of local challenges and recommendations for optimizing the management of advanced NSCLC in Lebanese patients. The experts agreed that these recommendations should be part of a healthcare strategy to be implemented at the national level.

Tocilizumab for Advanced Non-Small-Cell Lung Cancer With Concomitant Cachexia: An Observational Study.

Cancer cachexia significantly contributes to morbidity and mortality in patients with non-small-cell lung cancer (NSCLC). Inflammatory pathways mediated by interleukin-6 (IL-6) play a crucial role in the development of cancer cachexia. This study aimed to investigate the use of tocilizumab in the management of NSCLC with coexisting IL-6-elevated cachexia. In this retrospective study, data were collected from patients with NSCLC and concurrent IL-6-elevated cachexia who received either tocilizumab plus antitumour therapy or antitumour therapy alone. The primary endpoints were overall survival (OS) and improved modified Glasgow Prognostic Score (mGPS) at Week 12. The secondary endpoints included changes from baseline over 12 weeks in body weight, albumin, C-reactive protein (CRP) and mGPS. Qualitative improvements in patient self-rated appetite and fatigue were reported as exploratory analysis. The study included 49 patients diagnosed with NSCLC and IL-6-elevated cachexia, Eastern Cooperative Oncology Group performance status of 2-4. Of these, 26 received tocilizumab in combination with antitumour therapy, and 23 received antitumour therapy alone. The majority of these patients were male (87.8%). Baseline characteristics were almost identical between the two groups. The tocilizumab group demonstrated a significantly longer median OS compared to the control group (15.1 vs. 3.2 months; hazard ratio 0.18, 95% confidence interval 0.08-0.38; p < 0.001). The rate of patients surviving with mGPS improvement at Week 12 was significantly higher in the tocilizumab group than in the control group (risk difference 0.88, 95% confidence interval 0.75-1.00; p < 0.001). Over the 12-week period, significant improvements were observed in body weight, albumin, CRP and mGPS in the tocilizumab group compared to the control group (body weight: 5.15 ± 0.53 kg vs. -5.69 ± 0.76 kg, p = 0.041; albumin: 5.89 ± 0.70 g/L vs. -2.97 ± 0.71 g/L, p < 0.001; CRP: -91.50 ± 7.15 mg/L vs. 9.47 ± 13.69 mg/L, p < 0.001; mGPS: -1.61 ± 0.15 vs. 0.03 ± 0.08, p < 0.001). The tocilizumab group also displayed significantly higher rates of improvement in appetite and fatigue (both p < 0.001). The incidence of Grade 3 or higher adverse events was 34.6% in the tocilizumab group compared to 78.3% in the control group. Tocilizumab-related adverse events were observed in three patients (11.5%), including two cases of neutropenia and one case of skin and subcutaneous tissue infection. Tocilizumab demonstrated significant benefits in survival and various clinical parameters, including body weight, albumin, CRP, mGPS and symptom burden in patients with NSCLC and concurrent IL-6-elevated cachexia. Given the existing unmet medical need for effective interventions for cancer cachexia, tocilizumab may be considered as a potential treatment option.

Enhancing DOX efficacy against NSCLC through UDCA-mediated modulation of the TGF-β/MAPK autophagy pathways

Lung carcinoma, predominantly manifested as non-small cell lung cancer (NSCLC), significantly contributes to oncological mortality, underscoring an imperative for novel therapeutic paradigms. Amidst this context, the present investigation delineates the synergistic potentiation of doxorubicin (DOX)—a canonical chemotherapeutic—by Ursodeoxycholic acid (UDCA), a compound with a historical pedigree in hepatobiliary medicine, now repositioned within oncological pharmacotherapy due to its dichotomous cellular modulation—affording cytoprotection to non-malignant epithelia whilst eliciting apoptotic cascades in neoplastic counterparts. This study, through a rigorous methodological framework, elucidates UDCA’s capacity to inhibit NSCLC cellular proliferation and induce apoptosis, thereby significantly amplifying DOX’s chemotherapeutic efficacy. Notably, the co-administration of UDCA and DOX was observed to attenuate DOX-induced autophagy via the modulation of the TGF-β/MAPK signaling axis, a pathway pivotal in mediating cellular survival and autophagic mechanisms. Such findings not only underscore the therapeutic potential of UDCA as a chemosensitizer but also illuminate the molecular underpinnings of its modulatory effects, thereby contributing to the corpus of knowledge necessary to surmount chemoresistance in NSCLC. The implications of this research are twofold: firstly, it offers a compelling evidence base for the clinical reevaluation of UDCA in combinatory chemotherapeutic regimens; secondly, it posits a novel mechanistic insight into the modulation of chemotherapeutic efficacy and resistance. Collectively, these insights advocate for the expedited clinical translation of UDCA-DOX synergy, potentially heralding a paradigm shift in the management of NSCLC, thereby addressing a critical lacuna in contemporary oncological therapy.

How to Keep Up With Molecular Testing and Targeted Therapies in Lung Cancer.

Until the early 2000s, advanced or metastatic non-small cell lung cancer (NSCLC) was treated as a single disease with all histologic subtypes treated alike with standard chemotherapy agents. Over the past two decades, the treatment paradigms for advanced NSCLC have changed dramatically with the discovery of multiple targeted therapies that are now approved for the treatment of NSCLC tumors with specific oncogene drivers or molecular alterations. Molecular testing has become integrated and critical for the clinical management of advanced NSCLC. The discovery and success of these targeted therapies have reshaped the classification of NSCLC on the basis of molecular classification and enabled a personalized approach in thoracic oncology. In this review, we discuss recent developments in the molecular profiling of NSCLC, and approved and emerging targeted therapies for the treatment of NSCLC.

Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover

Non-small cell lung cancer (NSCLC) is a prevalent and fatal malignancy with a significant global impact. Recent advancements have introduced targeted therapies like tyrosine kinase inhibitors (TKIs) such as osimertinib, which have improved patient outcomes, particularly in those with EGFR mutations. Despite these advancements, acquired resistance to TKIs remains a significant challenge. Hence, one of the current research priorities is understanding the resistance mechanisms and identifying new therapeutic targets to improve therapeutic efficacy. Herein, we identified high expression of c-Met in osimertinib-resistant NSCLC cells, and depletion of c-Met significantly inhibited the proliferation of osimertinib-resistant cells and prolonged survival in mice, suggesting c-Met as an attractive therapeutic target. To identify effective anti-tumor agents targeting c-Met, we screened a compound library containing 641 natural products and found that only xanthohumol exhibited potent inhibitory effects against osimertinib-resistant NSCLC cells. Moreover, combination treatment with xanthohumol and osimertinib sensitized osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. Mechanistically, xanthohumol disrupted the interaction between USP9X and Ets-1, and inhibited the phosphorylation of Ets-1 at Thr38, promoting its degradation, thereby targeting the Ets-1/c-Met signaling axis and inducing intrinsic apoptosis in osimertinib-resistant NSCLC cells. Overall, the research highlights the critical role of targeting c-Met to address osimertinib resistance in NSCLC. By demonstrating the efficacy of xanthohumol in overcoming resistance and enhancing therapeutic outcomes, this study provides valuable insights and potential new strategies for improving the clinical management of NSCLC.

B-356 Siemens CYFRA 21-1: an assay for measurement of cytokeratin fragment 21-1

Abstract Background Cytokeratins are structural proteins forming the subunits of epithelial intermediary filaments. The soluble fragment of cytokeratin 19, cytokeratin fragment 21-1 (CYFRA 21-1), can be found in the blood of lung cancer patients, primarily those with non-small cell lung cancer (NSCLC). CYFRA 21-1 is the preferred biomarker in the management of NSCLC, particularly squamous cell and large cell carcinoma subtypes. An assay for CYFRA 21-1 on Siemens ADVIA Centaur® XPT and Siemens Atellica® IM (Siemens CYFRA) is being developed and analytical performance is being presented. Methods The Siemens CYFRA 21-1 assay (in development) is a one-step chemiluminescent microparticle immunoassay (CMIA) for the quantitative determination of CYFRA 21-1 in human serum and plasma. The specimen is incubated with paramagnetic microparticles coated with the monoclonal antibody (mAb) BM19.21 and acridinium-labeled mAb KS19.1 conjugate on the Siemens ADVIA Centaur XPT System and Siemens Atellica IM System. After incubation and washing, Acid and Base reagents are added. The resulting relative light units (RLUs) are directly proportional to the amount of CYFRA 21-1 in the sample allowing for the quantitative determination of CYFRA 21-1 in the specimen. Results The following performance were determined using 3 unique lots of reagents and calibrators with the calibration range for the assay being 0.00 to 100.00 ng/mL. For the ADVIA Centaur XPT and Atellica IM systems were shown to be equivalent within 4%. The limit of blank (LoB), limit of detection (LoD), and limit of quantitation at 20% CV (LoQ) were determined and met the goal of ≤ 1.00 ng/mL. Linearity according to CLSI EP06 Ed2 was demonstrated for a range of 0.66 through 100.00 ng/mL. A Precision study of 2 controls and 5 panels spanning the range of the assay demonstrated a total %CV ≤ 8% at all levels. In the sample tube type study, a matrix comparison of 61 matched serum and plasma samples were evaluated. Passing-Bablock slopes of &amp;lt; 5% and r &amp;gt; 0.99 were observed when evaluating samples within the measurement range for plasma (LiHep, LiHep separator, K2EDTA and K3EDTA) tubes and serum separator tubes (SST) compared to the Red Top serum samples. Six endogenous substances were evaluated for interference in the CYFRA 21-1 assay. The average percent difference between test and control samples for all endogenous interferents was &amp;lt; 10%. Percent difference in the presence of 20 potentially interfering drugs was ≤ 4.0%. Conclusions The Siemens CYFRA 21-1 assay currently in development is a sensitive and precise assay for the quantitative determination of CYFRA 21-1 in human serum and plasma.

Exploring immunotherapy efficacy in non-small cell lung cancer patients with BRAF mutations: a case series and literature review.

The use of immunotherapy in treatment of non-small cell lung cancer (NSCLC) patients with the BRAF gene mutations is an area of active research and is an item of clinical trials. While BRAF mutations are relatively infrequent in NSCLC patients, comprising approximately 1-3% of cases, the V600E substitution stands out as the most prevalent subtype of BRAF mutations. The presence of this mutation in cancer cells qualifies the patients for first-line therapy with BRAF and MEK inhibitors. This study aims to evaluate the efficacy of immunotherapy in NSCLC patients with BRAF mutations. We presented a series of seven NSCLC cases with BRAF mutations, four of whom received immunotherapy or chemoimmunotherapy. We observed benefit from immunotherapy in all patients, but its duration depended on comorbidities and the presence of brain metastases. Utilization of the next generation sequencing (NGS) technique causes high detection frequency of BRAF mutations (4.7% of patients), although mutations other than V600E may predominate (4 out of 7 patients). In patients receiving immune checkpoint inhibitors (ICIs)-based therapy, the median progression-free survival (PFS) was 17 months from the start of immunotherapy, the overall objective response rate (ORR) was 50%, and disease control was achieved in all patients. Immunotherapy can benefit NSCLC patients with BRAF mutations, though its efficacy is affected by comorbidities and brain metastases. The use of NGS enhances mutation detection, highlighting the need for personalized treatment approaches in NSCLC management. The varying responses to treatments among the patients emphasize the complexity of NSCLC management and the necessity for a personalized approach.

Stage III NSCLC treatment options: too many choices.

Stage III nonsmall cell lung cancer (NSCLC) represents a wide range of tumour (T1 to T4) and nodal (N0 to N3) components, requiring variable management and a multidisciplinary approach. Recent advancements in minimally invasive techniques, molecular biology and novel drug discoveries have accelerated the refinement of stage III NSCLC management. The latest developments in staging include the forthcoming update of the nodal component in the 9th TNM (tumour-node-metastasis) edition, which emphasises the critical role for endobronchial ultrasonography in mediastinal staging. Recent treatment developments include the use of immunotherapy and targeted molecular therapy in both the neoadjuvant and adjuvant setting, either in combination with other modalities or used alone as consolidation. Surgical and radiotherapy advancements have further enhanced patient outcomes. These developments have significantly improved the prognosis for patients with stage III NSCLC. Fast-changing recommendations have also brought about a challenge, with clinicians facing a number of options to choose from. Therefore, a multimodal approach by a multidisciplinary team has become even more crucial in managing stage III NSCLC.

Non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is one of the most frequent cancer types and is responsible for the majority of cancer-related deaths worldwide. The management of NSCLC has improved considerably, especially in the past 10 years. The systematic screening of populations at risk with low-dose CT, the implementation of novel surgical and radiotherapeutic techniques and a deeper biological understanding of NSCLC that has led to innovative systemic treatment options have improved the prognosis of patients with NSCLC. In non-metastatic NSCLC, the combination of various perioperative strategies and adjuvant immunotherapy in locally advanced disease seem to enhance cure rates. In metastatic NSCLC, the implementation of novel drugs might prolong disease control together with preserving quality of life. The further development of predictive clinical and genetic markers will be essential for the next steps in individualized treatment concepts.

Molecular Markers, Immune Therapy, and Non-Small Cell Lung Cancer-State-of-the-Art Review for Surgeons.

Background: Lung cancer is a leading cause of cancer deaths in the United States. An increasing understanding of relevant non-small cell lung cancer (NSCLC) biomarkers has led to the recent development of molecular-targeted therapies and immune checkpoint inhibitors that have revolutionized treatment for patients with advanced and metastatic disease. The purpose of this review is to provide surgeons with a state-of-the-art understanding of the current medical and surgical treatment trends and their implications in the future of management of NSCLC. Materials and Methods: A systematic search of PubMed was conducted to identify English language articles published between January 2010 and March 2024 focusing on molecular markers, tumor targeting, and immunotherapy in the diagnosis and treatment of NSCLC. Case series, observational studies, randomized trials, guidelines, narrative reviews, systematic reviews, and meta-analyses were included. Results: There is now increasing data to suggest that molecular-targeted therapies and immune therapies have a role in the neoadjuvant setting. Advances in intraoperative imaging allow surgeons to perform increasingly parenchymal-sparing lung resections without compromising tumor margins. Liquid biopsies can noninvasively detect targetable mutations in cancer cells and DNA from a blood draw, potentially allowing for earlier diagnosis, personalized therapy, and long-term monitoring for disease recurrence. Conclusions: The management of NSCLC has advanced dramatically in recent years fueled by a growing understanding of the cancer biology of NSCLC. Advances in medical therapies, surgical techniques, and diagnostic and surveillance modalities continue to evolve but have already impacted current treatment strategies for NSCLC, which are encompassed in this review.

Innovations in Early Lung Cancer Detection: Tracing the Evolution and Advancements in Screening.

Lung cancer mortality rates, particularly non-small cell lung cancer (NSCLC), continue to present a significant global health challenge, and the adoption of lung cancer screening remains limited, often influenced by inequities in access to healthcare. Despite clinical evidence demonstrating the efficacy of annual screening with low-dose computed tomography (LDCT) and recommendations from medical organizations including the U.S. Preventive Services Task Force (USPSTF), the national lung cancer screening uptake remains around 5% among eligible individuals. Advancements in the clinical management of NSCLC have recently become more personalized with the implementation of blood-based biomarker testing. Extensive research into tumor-derived cell-free DNA (cfDNA) through fragmentation offers a novel method for improving early lung cancer detection. This review assesses the screening landscape, explores obstacles to lung cancer screening, and discusses how a plasma whole genome fragmentome test (pWGFrag-Lung) can improve lung cancer screening participation and adherence.

Revamping Non-Small Cell Lung Cancer Treatments in Stages II and III: Preparing Healthcare for Cutting-Edge Immuno-Oncology Regimens.

Non-small cell lung cancer (NSCLC) poses a significant challenge in clinical oncology, necessitating continual refinement of treatment approaches in stages II and III. Recent advancements have highlighted the potential of neoadjuvant therapy in optimising patient outcomes. Biomarker testing guides neoadjuvant therapy decisions, including epidermal growth factor receptor (EGFR) mutation and programmed death-ligand 1 (PD-L1) expression testing. Neoadjuvant therapy aims to improve oncological outcomes by treating micrometastatic disease and assessing tumour response before surgery. Disease-free survival is a surrogate endpoint for overall survival in both neoadjuvant and adjuvant settings. Multidisciplinary collaboration is crucial for individualised treatment planning and optimising patient care. The management of NSCLC requires a comprehensive approach, integrating expertise across disciplines and tailoring treatment strategies to individual patient needs. Neoadjuvant therapy shows promise in improving long-term outcomes, with biomarker testing guiding treatment decisions. Challenges such as defining borderline resectability and differentiating pseudoprogression highlight the need for ongoing research and collaboration.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. ClinicalTrials.gov number, NCT03849768.

Comparison of Nivolumab with Docetaxel in the Treatment of Advanced Squamous Cell Non-small Cell Lung Cancer

Lung squamous-cell carcinoma poses a significant global health challenge with limited treatment options available. Immune checkpoint inhibitors, particularly nivolumab, have revolutionized cancer therapy, especially in non-small cell lung cancer (NSCLC). Nivolumab, targeting the PD-1 protein, exhibits promise in treating advanced squamous-cell NSCLC. This article critically examines nivolumab’s development and compares its efficacy with docetaxel in this context. Nivolumab’s effectiveness lies in its ability to block the PD-1/PD-L1 immune checkpoint pathway, reinvigorating the immune response against cancer cells. Clinical trials reveal higher overall survival rates and fewer adverse events (AEs) with nivolumab compared to docetaxel, alongside improvements in patient-reported outcomes and mental well-being. However, limitations exist, primarily stemming from clinical trial data’s potential mismatch with real-world scenarios. Short trial durations hinder long-term outcome analysis and delay AE evaluations. Furthermore, the comparison is restricted to nivolumab and docetaxel, overlooking other Food and Drug Administration-approved monoclonal antibodies. Addressing these limitations are crucial for enhancing the utility of these evaluations in clinical decision-making and guiding future research in advanced squamous-cell NSCLC management. Nivolumab emerges as a promising treatment option, offering superior efficacy and safety over traditional chemotherapy, yet its real-world efficacy warrants further exploration.

Personalizing Therapy Outcomes through Mitogen-Activated Protein Kinase Pathway Inhibition in Non-Small Cell Lung Cancer.

Lung cancer (LC) is a highly invasive malignancy and the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) as its most prevalent histological subtype. Despite all breakthroughs achieved in drug development, the prognosis of NSCLC remains poor. The mitogen-activated protein kinase signaling cascade (MAPKC) is a complex network of interacting molecules that can drive oncogenesis, cancer progression, and drug resistance when dysregulated. Over the past decades, MAPKC components have been used to design MAPKC inhibitors (MAPKCIs), which have shown varying efficacy in treating NSCLC. Thus, recent studies support the potential clinical use of MAPKCIs, especially in combination with other therapeutic approaches. This article provides an overview of the MAPKC and its inhibitors in the clinical management of NSCLC. It addresses the gaps in the current literature on different combinations of selective inhibitors while suggesting two particular therapy approaches to be researched in NSCLC: parallel and aggregate targeting of the MAPKC. This work also provides suggestions that could serve as a potential guideline to aid future research in MAPKCIs to optimize clinical outcomes in NSCLC.

Analysis of the resistance profile of real-world alectinib first-line therapy in patients with ALK rearrangement-positive advanced non-small cell lung cancer using organoid technology in one case of lung cancer.

Alectinib has achieved excellent therapeutic efficacy in anaplastic lymphoma kinase (ALK) fusion gene-positive non-small cell lung cancer (NSCLC) patients, however, patients eventually develop resistance to it. Exploring the gene variant mapping after alectinib resistance provides a basis for the whole management of ALK-positive advanced NSCLC. This study aimed to characterize the mutation profiles of real-world ALK rearrangement-positive advanced NSCLC patients after first-line alectinib treatment resistance. The research also investigated the treatment options and coping strategies after resistance. Clinical data of patients with advanced NSCLC who received first-line alectinib treatment in the First Affiliated Hospital of Guangzhou Medical University between November 2018 and April 2022 were collected. Moreover, next-generation sequencing (NGS) data of the patient's baseline and post-resistance tissues were gathered. One patient underwent lung cancer organoid culture and drug sensitivity testing. Out of 35 first-line alectinib-treated patients with advanced NSCLC, 31 are presently in progression-free survival (PFS; 4.3-35.0 months). Four patients experienced progressive disease, and all of them were sequentially treated with ceritinib. Tissue NGS results before sequential treatment in three patients indicated an echinoderm microtubule-associated protein-like 4-ALK fusion that remained at the original baseline, and the PFS for ceritinib treatment was 0.5-1.3 months. One patient developed acquired resistance mutations in the structural domain of ALK protein kinase (V1180L and E1161D), and the PFS for ceritinib treatment was 6.7 months. For one patient who maintained original baseline ALK rearrangement positive without acquired mutation after progression of ceritinib resistance, lung cancer-like organ culture with sequential brigatinib and lorlatinib led to a PFS of 3.2 and 1.9 months, respectively, which aligned with the corresponding drug susceptibility testing results for this patient. For ALK rearrangement-positive patients, blind sequencing of other second-generation tyrosine kinase inhibitors (TKIs) or third-generation lorlatinib may not guarantee satisfactory tumor suppression following first-line second-generation ALK-TKI alectinib administration for treatment progression. NGS testing of patients' blood or tissue samples after disease progression may provide insight into the etiology of alectinib resistance. Patient-sourced drug sensitivity testing of lung cancer-like organs selects drug-sensitive medications based on NGS results and provides a reference for subsequent drug therapy for patients after drug resistance, particularly those who remain ALK rearrangement-positive at baseline.

Efficacy and safety of personalized optimal PD-(L)1 combinations in advanced NSCLC: a network meta-analysis.

Programmed death 1 (PD-1)/programmed death 1 ligand 1 (PD-L1)-directed immunotherapy has revolutionized the treatments for advanced non-small cell lung cancer (NSCLC), whereas the optimal therapeutic combinations remain uncertain. Our study encompassed phase II/III randomized controlled trials (RCTs) that involved anti-PD-(L)1-based therapies for stage-IV NSCLC. The primary outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and incidences of adverse events. Subgroup analyses were conducted by treatment lines, PD-L1 expression levels, histological types, and metastatic sites. Our analysis incorporated 38 publications, covering 14 therapeutic combinations and involving 18 048 participants. PD-(L)1+chemotherapy (CT), PD-(L)1+ cytotoxic T lymphocyte-associated antigen-4 (CTLA4) +CT, and PD-(L)1+ T-cell immunoglobulin and ITIM domain were notably effective in prolonging OS. Overall, PD-(L)1+CT and PD-(L)1+CT+ vascular endothelial growth factor (VEGF) were significantly beneficial for PFS and ORR. As for the subsequent-line treatments, incorporating radiotherapy can enhance PFS and ORR (ranked fourth among enrolled treatments). For patients with PD-L1 <1%, PD-(L)1+CT+VEGF and PD-(L)1+CTLA4+CT were favorable approaches. Conversely, in patients with PD-L1 ≥50%, PD-(L)1+CT represented an effective treatment. Patients with nonsquamous cell carcinoma or liver metastases might benefit from the addition of VEGF. In cases of squamous cell carcinoma or brain metastases, the combination of PD-(L)1+CTLA4+CT yielded superior benefits. This study underscores the enhanced efficacy of combination immunotherapies over monotherapy. It highlights the necessity for personalized treatment, considering individual factors. These insights are vital for clinical decision making in the management of advanced NSCLC.

Assessment of PD-L1 Expression in Non-Small Cell Lung Cancers Using [68Ga]Ga-DOTA-WL12 PET/CT.

Assessing programmed death ligand-1 (PD-L1) expression in non-small cell lung cancer (NSCLC), particularly in metastatic cases, remains challenging. In this study, surface plasmon resonance (SPR) analysis and [68Ga]Ga-DOTA-WL12 micro-PET/CT imaging are performed. [68Ga]Ga-DOTA-WL12 PET/CT and [18F]FDG PET/CT are performed on a cohort of 20 patients with NSCLC. Semi-quantitative assessments include SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and target-to-background ratio (TBR). DOTA-WL12 exhibits robust PD-L1 binding with a KD value of 0.2nM. Subsequent human studies reveal significant correlations between PD-L1 expression and the [68Ga]Ga-DOTA-WL12 SUVmax in primary and metastatic lesions, surpassing the [18F]FDG results (r = 0.8889, p <0.0001 vs r = 0.0469, p = 0.8127). Notably, [68Ga]Ga-DOTA-WL12 imaging discerned SUVmax and TBR differences between PD-L1 TPS ≤1% and PD-L1 TPS > 1% groups (p all <0.001). In an NSCLC patient with brain metastases, [68Ga]Ga-DOTA-WL12 shows a SUVmean of 0.04 in the brain background, with TBR values of 17 and 23, underscoring its potential for detecting brain metastases. The study provides initial evidence for the clinical utility of [68Ga]Ga-DOTA-WL12 PET/CT for lesion detection, immunotherapy selection, and therapeutic efficacy evaluation in PD-L1-expressing NSCLC, demonstrating its potential as a valuable tool in NSCLC research and management.

Inhibition of non-small cell lung cancer metastasis by knocking down APE1 through regulating myeloid-derived suppressor cells-induced immune disorders.

Non-small cell lung cancer (NSCLC) represents a highly immunogenic malignancy. Immunologic tolerance facilitated by myeloid-derived suppressor cells (MDSCs) is implicated in primary or secondary resistance mechanisms in NSCLC. The potential role of APE1 in regulating NSCLC metastasis by targeting MDSCs remains uncertain. This study utilized a plasmid, Plxpsp-mGM-CSF, to induce elevated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in A549 cells. Tumor transplantation experiments involved A549, A549+GM-CSF, and A549+GM-CSF-siAPE1 cell lines. Evaluation encompassed MDSCs, Treg cells, IgG, CD3, and CD8 levels. Notably, lung cancer tissues and cells displayed markedly reduced APE1 expression. siAPE1 transfection significantly curtailed tumor growth compared to the A549+GM-CSF group. APE1 knockdown orchestrated immune system modulation in lung tumor mice, characterized by diminished MDSCs but augmented Treg cells, IgG, CD3, and CD8. Additionally, APE1 knockdown led to reduced levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12) and a concurrent upregulation of the anti-MDSC cytokine IL-1ra. Furthermore, APE1 knockdown impeded cell viability in both A549 and H1650 cells. Transplantation of A549-GM-CSF amplified MDSC levels, fostering accelerated tumor growth, while mitigating MDSC levels through APE1 knockdown hindered tumor progression and alleviated inflammatory infiltration in lung cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach for lung cancer prevention and treatment, presenting novel insights for NSCLC management.

Promising Combinatorial Therapeutic Strategies against Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) presents a complex and diverse disease, exhibiting variations at individuals' cellular and histological levels. This complexity gives rise to different subtypes and genetic mutations, posing challenges for accurate diagnosis and effective treatment. Nevertheless, continuous progress in medical research and therapies is continually shaping the landscape of NSCLC diagnosis and management. The treatment of NSCLC has undergone significant advancements in recent years, especially with the emergence of targeted therapies that have shown remarkable efficacy in patients with actionable mutations. This has ushered in the era of personalized medicine in NSCLC treatment, with improvements in molecular and immunohistochemical techniques contributing to enhanced progression-free survival. This review focuses on the latest progress, challenges, and future directions in developing targeted therapies for NSCLC, including tyrosine kinase inhibitors (TKIs), DNA-damaging agents, immunotherapy regimens, natural drug therapy, and nanobodies. Furthermore, recent randomized studies have demonstrated enhanced overall survival in patients receiving different targeted and natural drug therapies.