Search Results (566)

Background: Several studies evaluated the role of variant allele frequency (VAF) as a clinical decision-making tool for targeted therapies. However, its predictive role for treatment response in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) remains debated. This study investigates the relationship between VAF and early tumor shrinkage (ETS) and deepness of response (DpR). We also explored the impact of previously undescribed compound uncommon EGFR mutations on osimertinib activity. Methods: We retrospectively analyzed data from patients with advanced EGFR-mutated NSCLC, treated with osimertinib. VAF was obtained through NGS. We calculated corrected VAF (cVAF) based on the percentage of tumor cells. ETS and DpR were assessed according to RECIST 1.1 criteria. Molecular modeling was performed to predict the impact of novel compound EGFR mutations on osimertinib binding and EGFR protein structure. Results: We included 16 patients, who met the eligibility criteria. We found no significant correlation between cVAF and ETS or DpR, suggesting that cVAF may not have a direct effect on early or late tumor response to osimertinib. Median cVAF was 14%. Median progression-free survival and overall survival were longer in patients with higher VAF, even though they were not statistically significant. We identified two previously unreported compound EGFR mutations: N771Y + L858R and L718V + K713R + L858R. Conclusions: This study demonstrates that cVAF of EGFR mutations is not significantly associated with ETS or DpR during osimertinib in mNSCLC patients. Survival does not appear to be influenced by cVAF either. The identification and structural characterization of novel compound EGFR uncommon mutations may explain the benefit experienced by patients. Full article

Modern medicine requires effective, continuous, and safe therapies, which largely depend on the targeted delivery and activity of the drug. This goal can be achieved by designing drug delivery systems with improved pharmacokinetic properties and enhanced drug transport to the affected tissue. Human serum albumin (HSA) is an attractive carrier for the synthesis of therapeutic nanoparticles, several of which have already been approved by the United States Food and Drug Administration (FDA). The success of Abraxane as an effective treatment for metastatic breast cancer and non-small cell lung carcinoma, the application of Optison in ultrasound imaging, and the use of Nanocoll as an agent for SPECT diagnostics in sentinel node localisation confirm the strong potential of albumin-based systems. Further benefits are expected in patients with soft tissue cancers, as LadRx is seeking FDA marketing approval for Aldoxorubicin. The future of oncology lies in theranostics, which combines a tumour-localising factor on one platform with a drug targeting cancer cells and a factor that activates the cytotoxicity of the drug after it reaches the target tissue. This article presents recent advancements in albumin-based nanoparticles for drug delivery, targeting, and imaging. It also briefly discusses methods of synthesis and surface modification of albumin nanocarriers to enable targeted delivery to pathological sites. Finally, it outlines the latest approaches in multimodal theranostic platforms, highlighting albumin’s potential to improve cancer therapy. Full article

Background and Objectives: Clinically meaningful drug–drug interactions may be overlooked in oncology. Proton pump inhibitors (PPIs) may modulate outcomes with immune checkpoint inhibitors (ICIs) by altering the gut microbiome, altering the immune milieu, and affecting transporter interactions. We evaluated whether concomitant PPI use affects survival among patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. Materials and Methods: We retrospectively included patients with metastatic NSCLC who received second-line nivolumab across five oncology centers (January 2020–June 2023). Patients were grouped as concomitant PPI users vs. non-users. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan–Meier method and compared with the log-rank test; multivariable Cox models assessed independent associations. Results: A total of 194 patients were screened, of whom 30 were excluded according to predefined criteria. The final analysis included 164 patients—85 PPI users and 79 non-users. Median OS was 26.1 months (95% CI 15.5–36.7) in PPI users and 29.3 months (22.2–36.4) in non-users; this difference was not statistically significant (p = 0.54). Median PFS was 6.2 months (3.7–8.6) in PPI users vs. 10.2 months (7.1–13.2) in non-users (p = 0.04). In multivariable analysis, absence of concomitant PPI use (No vs. Yes) was independently associated with longer PFS (HR = 0.52, 95% CI 0.24–0.89, p = 0.03), whereas PPI use was not associated with OS (HR = 0.96, 95% CI 0.67–1.61, p = 0.83). Conclusions: Concomitant PPI use during nivolumab therapy was associated with significantly shorter PFS and a numerical reduction in OS in real-world metastatic NSCLC. Where clinically feasible, the need for PPIs should be re-evaluated before and during ICI therapy. Full article

Background: Cancer-associated fibroblasts (CAFs) are key mediators of metastatic progression in non-small cell lung cancer (NSCLC). Fibroblast activation protein (FAP) serves as the hallmark of CAF activation. However, the upstream regulation of FAP remains elusive, limiting stroma-targeted therapy development. Methods: ⁶⁸Ga-FAP inhibitor (FAPI)-04 PET/CT imaging was performed on 61 NSCLC patients to evaluate the clinical significance of FAP. CAFs and normal fibroblasts (NFs) were isolated from patient tissues. Bioinformatic analysis and qRT-PCR were employed to screen and validate miRNAs. Functional assays (CCK-8, collagen contraction, wound healing, transwell co-culture) were utilized to investigate the role of miR-624-5p in regulating fibroblast activation and the effects on the metastatic potential of NSCLC cells. The targeting relationship between miR-624-5p and FAP was validated using FISH, dual-luciferase assay, and Western blotting. Results: ⁶⁸Ga-FAPI-04 uptake was higher in advanced NSCLC (p < 0.001) and correlated with tumor size, lymph node metastases, and distant metastases (p < 0.05). Isolated primary CAFs significantly enhanced the migration and invasion of A549 and PC9 cells compared to NFs (p < 0.001). We identified miR-624-5p as a significantly downregulated miRNA in CAFs (p < 0.001). Functionally, miR-624-5p overexpression inhibited CAF proliferation and collagen contraction (p < 0.01) and reduced the proliferation, migration, and invasion capabilities of A549 and PC9 cells (p < 0.001). Mechanistically, miR-624-5p bound to FAP mRNA and negatively regulated FAP expression (p < 0.001), thus suppressing CAF activation and tumor metastasis. Conclusions: Our findings establish miR-624-5p as a novel upstream regulator that suppresses FAP expression, consequently inhibiting CAF activation and its pro-metastatic function. Targeting the miR-624-5p/FAP axis represents a promising therapeutic strategy for NSCLC metastasis. Full article

The landscape of first-line treatment for metastatic non-small cell lung cancer (NSCLC) without actionable driver mutations is rapidly evolving, currently dominated by pembrolizumab-based regimens. This review discusses the unique molecular characteristics of cemiplimab, a newer anti-PD-1 antibody, and defines its optimal positioning against established standards. Cemiplimab is a fully human IgG4 monoclonal antibody distinguished by two key features: an engineered hinge-region mutation that prevents Fab-arm exchange, ensuring exceptional molecular stability which minimizes anti-drug antibody (ADA) risks associated with unstable molecules; and a unique interaction with PD-1 glycosylation sites, potentially enhancing binding efficacy. These structural advantages may be particularly relevant in histologies like squamous NSCLC, where accumulating somatic mutations drive high neoantigen loads and heightened immune responses, creating an environment historically prone to ADA formation. Based on data from the pivotal EMPOWER-Lung program, we highlight cemiplimab’s exceptional promise in specific populations. Firstly, in the EMPOWER-Lung 1 trial, cemiplimab monotherapy demonstrated extraordinary survival benefits in a pre-specified analysis of the distinct “ultra-high” PD-L1 expression subgroup (TPS ≥90%), potentially surpassing historical benchmarks. Secondly, cemiplimab displays consistent, robust efficacy in challenging-to-treat squamous histology, both as monotherapy for patients with high PD-L1 expression and in combination with chemotherapy for patients with PD-L1 < 50%. In conclusion, cemiplimab establishes a unique therapeutic niche for patients with squamous histology and ultra-high PD-L1 expression, likely driven by its distinct structural stability and reduced immunogenicity. Full article

Background/Objectives: Non-small-cell lung cancer (NSCLC) is a common disease with a high mortality rate and is often treated with immunotherapies; however, prognostic markers are required to identify patients who are most likely to benefit from these treatments. Therefore, we designed this study to assess the prognostic significance of the C-PLAN index, which includes performance status (PS) and C-reactive protein (CRP). Methods: A total of 560 patients were included in this multicenter study. Patients had been diagnosed with NSCLC and had received nivolumab therapy. The C-PLAN index, defined in 2022, is a score derived from the combination of PS, CRP, lactate dehydrogenase (LDH), albumin, and neutrophil–lymphocyte ratio (NLR). Patients were classified into good-, moderate-, and poor-prognosis groups according to the C-PLAN score. Results: The median metastatic overall survival was 25 months in the group with a C-PLAN score < 2 and 6 months in the group with a C-PLAN score ≥ 2 (p < 0.001). The median metastatic progression-free survival was 11 months in the group with a C-PLAN score < 2 and 3 months in the group with a C-PLAN score ≥ 2. Conclusion: This is the first comprehensive study demonstrating that the C-PLAN index can be used for prognostic purposes in immunotherapy. This score, which can be easily, economically, and practically calculated in outpatient clinics, can predict patient prognosis and determine who should receive longer durations of immunotherapy. Full article

Background/Objectives: Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer (NSCLC), is frequently diagnosed at advanced stages with distant metastasis, underscoring the need for effective prognostic biomarkers. Fibroblast growth factor 2 (FGF2), a multifunctional regulator, has shown to play contradictory roles in cancer progression. Methods: We analyzed three independent Gene Expression Omnibus (GEO) datasets (GSE19804, GSE18842, and GSE19188) to identify consistently dysregulated genes in LUAD. Functional enrichment (GO, KEGG, and cancer hallmark analysis), protein–protein interaction (PPI) network construction, and hub gene prioritization were performed using public bioinformatic tools. Survival analyses were conducted via the Kaplan–Meier Plotter. The expression of FGF2 was validated across multiple platforms, including TCGA, CPTAC, TNMplot, LCE, and the Human Protein Atlas. Functional assays (Transwell migration and wound healing) demonstrated that exogenous FGF2 significantly suppressed LUAD cell motility in vitro. Results: A total of 949 differentially expressed genes (DEGs) were commonly identified across datasets, with enrichment in cell adhesion and metastasis-related pathways. Among the 11 hub genes identified, FGF2 was consistently downregulated in LUAD tissues across all datasets and stages. Higher FGF2 expression was associated with longer overall and progression-free survival. In vitro, FGF2 treatment significantly suppressed the migration and wound healing abilities of LUAD cell lines. Conclusions: FGF2 is downregulated in LUAD and inversely associated with metastatic progression and poor prognosis. The observed reduction in cancer cell motility upon FGF2 treatment in vitro, together with its expression pattern, supports a potential tumor-suppressive role and suggests that FGF2 may serve as a candidate non-invasive biomarker for monitoring LUAD metastasis. Full article

Background: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive tumor for which the most effective systemic therapy remains uncertain. In metastatic LCNEC, chemotherapy approaches typically alternate between small-cell lung cancer (SCLC)-like and non-small-cell lung cancer (NSCLC)-like regimens. Emerging data indicate that treatment selection may be optimized through molecular subtype classification. This study aimed to evaluate the outcomes of SCLC-like and NSCLC-like chemotherapy (CT) regimens in relation to LCNEC molecular subtypes. Methods: This retrospective analysis included all patients diagnosed with LCNEC at Gaziantep University between January 2010 and October 2024. Individuals with available tumor tissue and complete clinical data were enrolled. LCNEC cases were categorized as SCLC-subtype or NSCLC-subtype according to the presence of TP53 and RB1 alterations. Platinum combined with etoposide, irinotecan, or topotecan was defined as SCLC-like CT, whereas platinum with taxanes or gemcitabine was considered NSCLC-like CT. Survival outcomes of both treatment types were compared across molecular subgroups using the Kaplan–Meier method. Results: Sixty-one patients met the inclusion criteria. The median overall survival (mOS) was 11.0 months (95% CI: 6.3–15.7). No significant difference in mOS was observed between SCLC-like and NSCLC-like regimens in the total cohort. When stratified by molecular subtype, patients with the SCLC subtype who received SCLC-like CT showed a longer mOS compared to those treated with NSCLC-like CT (15 [9.9–20.1] vs. 6 [3.9–8.1] months, respectively; p = 0.47), although this difference did not reach statistical significance. Conclusions: These findings suggest that molecular subclassification may help inform the choice of optimal systemic therapy in patients with LCNEC. Full article

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC. Full article

Background/Objectives: Brain metastases (BM) are a major challenge in the treatment of non-small cell lung cancer (NSCLC), particularly among patients with anaplastic lymphoma kinase rearrangements (ALK+ NSCLC), where incidence can reach up to 60% during the course of the disease. This study used in silico systems biology and artificial intelligence-based modeling to investigate the mechanistic effects of brigatinib, a second-generation ALK inhibitor, on metastatic processes in both primary tumors (PT) and established BM. Methods: We applied the Therapeutic Performance Mapping System (TPMS) technology, which integrates systems biology and artificial intelligence, to simulate the impact of brigatinib on metastasis-associated pathways in PT and BM of ALK+ NSCLC patients. Results: In these simulations, brigatinib was predicted to modulate a broad set of proteins implicated in metastasis in both PT and BM, acting mainly through IGF1R, EGFR, FLT3, and ROS1, in addition to its known target ALK. Conclusions: These results suggest brigatinib’s potential to impact key pathways involved in metastatic progression and intracranial disease control. Overall, this study provides insights into brigatinib’s multifaceted role in targeting metastatic processes in ALK+ NSCLC, underscoring its potential benefits in both PT and BM. Nonetheless, further experimental and clinical studies would confirm our results and the potential of in silico models reported here. Full article

Introduction: Intracranial stereotactic radiosurgery (SRS) is a specialised radiotherapy technique that plays an essential role in achieving local control of brain metastases and therefore optimising quality of life for many cancer patients. It also confers a survival benefit in selected patients. Rural and regional Australians may face significant challenges in accessing this treatment, as it is predominantly delivered at metropolitan institutions. We sought to assess the cost-effectiveness of a brain SRS service implemented using local resources at a North Queensland regional hospital from a societal perspective. Methods: We prospectively collected treatment costs and clinical outcomes for a consecutive cohort of patients who received SRS for intracranial metastatic lesions at a regional cancer centre since the implementation of the brain SRS program in September 2022. We compared the healthcare and non-healthcare costs (e.g., travel and informal care) with the costs that would have otherwise been incurred if patients were referred to metropolitan centres in the state capital. Clinical outcomes incorporated overall survival, intracranial disease control rates, and incidence of radiation necrosis. Clinical outcome data of the metropolitan centres were derived from the published literature. Results: A total of 34 patients received treatment during the study period. Their median age was 65 years (range: 49–78 years). Around 47% received adjuvant SRS following surgical resection, and the remaining 53% were treated for intact brain metastases. The predominant primary malignancy was non-small cell lung cancer. The mean total cost per course of brain SRS at a regional hospital was AUD 6690, including AUD 5754 for healthcare and AUD 1682 for non-healthcare costs, across 34 patients recruited between September 2022 and August 2024. This was AUD 760 less than that of a course of treatment delivered at a metropolitan hospital. Median survival among the cohort was 15.7 months, and eight patients (24%) developed radionecrosis; these were comparable to published data reported by Australian urban and international institutions. Conclusions: The implementation of a brain SRS service at regional cancer centres utilising existing infrastructure and local expertise has the potential to offer cost-effective treatment to rural and regional cancer patients. This approach improves access for patients who might otherwise face logistics barriers and competing life priorities when seeking treatment in metropolitan centres. Full article

Background and Objectives: This study aimed to evaluate the prognostic impact of baseline body composition measurements and changes in muscle and adipose tissue during treatment on overall survival (OS) in metastatic non-small cell lung cancer (NSCLC) patients treated with nivolumab. Materials and Methods: Eighty-eight metastatic NSCLC patients who were initiated on nivolumab between January 2022 and December 2024 were retrospectively analyzed. Body composition parameters were derived from baseline and 3-month ¹⁸F-FDG PET/CT scans at the L3 level, including psoas muscle index (PMI), skeletal muscle index (SMI), intramuscular adipose content (IMAC), and subcutaneous fat density (SFD). Treatment-related changes in body composition were evaluated, and survival analyses were performed using Kaplan–Meier estimates and Cox regression models. Results: Overall, 34.1% (n = 30) of patients were classified as sarcopenic. Median OS was significantly longer in non-sarcopenic patients (19 months vs. 5 months, p < 0.001). In univariate analysis, older age, higher comorbidity burden, liver metastasis, baseline sarcopenia, and adverse treatment-related changes in muscle and nutritional parameters were found to be associated with OS. In multivariate analysis, only unfavorable changes in skeletal muscle (ΔSMI; HR 3.39, p = 0.003) and subcutaneous fat radiodensity (ΔSFD; HR 2.45, p = 0.02) remained independent adverse prognostic factors. Baseline body composition parameters did not maintain their independence in multivariate models. Conclusions: Our study demonstrates that muscle loss or insufficient gain and unfavorable changes in subcutaneous fat radiodensity during nivolumab treatment more strongly predict overall survival compared to baseline measurements. These findings highlight the clinical importance of monitoring dynamic body composition throughout treatment, rather than static assessments, in NSCLC patients receiving immunotherapy. Full article

Background/Objectives: Recent preclinical studies suggest that acute exercise induces immune modulation, enhances tumor blood perfusion, and is associated with reduced tumor growth. Adding exercise to immunochemotherapy treatment (ICT) has been proposed as a strategy to increase treatment effectiveness. The ERICA trial (NCT04676009) aimed to assess the feasibility of acute aerobic exercise performed immediately before the administration of ICT in patients with metastatic non-small cell lung cancer (mNSCLC) and to explore hypothesis-generating outcomes related to physical fitness and patient-reported outcomes. Methods: Newly diagnosed mNSCLC patients were randomly assigned (2:1) to the exercise or control group. The exercise intervention included supervised acute exercise before each of four ICT cycles plus a 3-month home-based walking program with an activity tracker and step goals. The feasibility of the exercise protocol was assessed through adherence, acceptability, tolerability, and safety. Clinical, physical, and patient-reported outcomes were assessed at baseline and after 3 months. Results: Twenty-six patients (mean age 60.6 years; SD 10.65) participated, with an 87.5% acceptance rate. In the exercise group (n = 17), 80.9% of participants completed the acute exercise sessions, with a median interval of 38 min [IQR, 20–60] between exercise and ICT. No exercise-related adverse effects were reported. After 3 months, 60% of participants in the exercise group were classified as active and maintained their step goals. Self-reported measures suggest that maintaining physical fitness is favorable for reducing fatigue and insomnia, and therefore improving quality of life. Conclusions: Acute exercise performed immediately before each ICT administration in patients with mNSCLC appears feasible and safe. Full article

The PICO framework determines the scope of the Joint Clinical Assessment (JCA) under the EU HTA Regulation (EU HTAR), with PICO consolidation being a critical final step of the scoping process. Due to limited clarity on how consolidation works in practice, Health Technology Developers (HTDs) may simulate PICO scoping as a strategic tool to guide the development of robust JCA submissions. A review of 14 publications, representing 35 individual PICO exercises across 20 indications (74% in oncology), showed an average of 7 countries participating per exercise and 8 consolidated PICOs per analysis. A separate PICO scoping simulation focused on a first-line immuno-oncology treatment for metastatic non-small cell lung cancer (mNSCLC) generated 67 PICOs, reflecting the anticipated perspectives of 25 countries, largely driven by biomarker and histology-based sub-populations. The limited number of published examples and country participation restricts the ability to draw clear conclusions or confidently predict the output of PICO scoping in a real life JCA processes. The simulation also raised questions about whether all sub-populations should be included or consolidated further. Overall, there is a need for greater clarity in the JCA PICO scoping process, in particular the consolidation step, to facilitate high-quality evidence generation and support the EU HTAR to meet its goals of efficiency, transparency, and equity in health technology evaluation across Europe, along with more consistent patient access. Full article

Background/Objectives: AXL, a receptor tyrosine kinase of the TAM family, has emerged as a key target in cancer therapy due to its role in tumour growth, metastasis, immune evasion, and therapy resistance. SLC-391, a novel, orally bioavailable and selective AXL inhibitor, has demonstrated potent anti-tumour effects in preclinical studies. This first-in-human, open-label, multi-centre Phase I clinical trial (NCT03990454) was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of SLC-391 in patients with advanced solid tumours. Methods: Using a 3 + 3 design, SLC-391 was administered orally, either once daily (from 25 mg up to 175 mg QD) or twice daily (from 75 mg to 200 mg BID) in 21-day cycles. Results: Following single and repeated dosing, SLC-391 was generally well tolerated by subjects. The maximum tolerated dose (MTD) was not reached in this study. A total of 34/35 subjects experienced at least one TEAE. Three (8.6%) subjects experienced Grade 3 TRAEs that were considered related to SLC-391. Eight SAEs were reported in five (14.3%) subjects (seven Grade 3 SAEs and one Grade 2 SAE), in 150 mg QD (3/6, 50%), 175 mg QD (1/2, 50%), and 110 mg BID (1/3, 33.3%) cohorts. Four SAEs in three (8.6%) subjects led to dose interruption, drug withdrawal, or study discontinuation. Three DLTs were reported in two subjects: one subject experienced Grade 3 hematochezia (SUSAR/DLT) at 175 mg QD, and another subject experienced Grade 3 thrombocytopenia associated with Grade 1 hematuria at 200 mg BID. The median T_max was 2.0 h. Plasma concentrations following multiple doses generally increased with higher doses and appeared to reach steady state by Day 21 and were generally dose-proportional. Twelve (12) out of 35 subjects with solid tumours achieved stable disease according to RECIST or mRECIST (mesothelioma), with durations of stable disease lasting up to 318 days on SLC-391 monotherapy. The clinical benefit rate was 34.3%. Conclusions: This first study of SLC-391 in adult subjects with advanced solid tumours demonstrated that a total daily dose of 300 mg (150 mg BID) of SLC-391 monotherapy was generally well tolerated, with no DLTs or SAEs observed at this dose. The drug’s promising safety profile, along with stable disease reported for several subjects with advanced solid tumours, provides a strong rationale for the phase 1b/2a clinical investigation of SLC-391 in combination with pembrolizumab in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) (NCT05860296). Full article