This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.

Lung cancer remains the leading cause of cancer-related mortality globally, with many patients diagnosed with advanced-stage disease. Treatment in this setting relies on systemic therapies, including chemotherapy, targeted therapy and immunotherapy. Immune-checkpoint inhibitors (ICIs), which promote or restore antitumour immunity by inhibiting immunosuppressive signalling pathways, are currently the most widely used immunotherapies in these patients. However, immune-related adverse events (irAEs) or disease progression often necessitate discontinuation of these agents, leaving many patients with limited subsequent treatment options. In this scenario, ICI rechallenge has emerged as a potential strategy. Despite this potential, evidence for ICI rechallenge after either disease progression or irAEs in patients with non-small-cell lung cancer is limited and evidence for those with small cell lung cancer seems to be non-existent. In this Review, we provide a comprehensive overview of the available data on ICI rechallenge in the context of both disease progression and irAEs, including a summary of current guidance on clinical management and detailed discussions of safety and efficacy. We also highlight important unanswered questions in an attempt to guide future research in this area.

Treatment of advanced mycosis fungoides (MF) and Sézary syndrome (SS) is a challenge. In this international, multicenter, open-label phase II trial, we assessed the efficacy and safety of anti-PD-L1 atezolizumab in stage IIB-IV refractory/relapsed MF and SS.

Patients received atezolizumab 1200 mg IV Q3w for up to 1 year unless progression or withdrawal. The main study endpoints were overall response rate (ORR), progression-free survival (PFS), time to next systemic treatment (TTNT), and overall survival (OS).

A total of 26 patients were enrolled from seven countries. Seventeen patients met the inclusion criteria. At a median follow-up of 36.6 months, the ORR was 15.4 % in the intention to treat (ITT) and 17.6 % in the per protocol (PP) population, respectively. In the PP group, 58.8 % of patients, and in the ITT group, 53.9 % of patients achieved partial response or stable disease as their best outcome. One complete response was observed after 1 year. Median PFS was 3 months (95 % CI 1.4-4.9) in PP and 3.1 months (95 % CI 2.4-4.0) in ITT. Median OS was not reached for PP and was 22.3 months (20.0-NE) for ITT. Median TTNT was 5.9 months (2.8-NE) in PP and 6.2 months (3.1-14.8) in ITT. The most common grade ≥ 3 adverse events were fatigue (23.1 %) and infections (15.4 %), with two sepsis-related deaths. Atezolizumab was primarily discontinued due to disease progression (50 %).

Atezolizumab shows moderate activity in pretreated refractory/relapsed MF and SS. Further studies are needed to identify reliable predictors of safety and treatment response.

Immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm of non-small cell lung cancer (NSCLC) over the last decade. Despite notable therapeutic advancements in responders, the response rate remains limited owing to the immunosuppressive tumor microenvironment (TME). Therefore, to improve the efficacy of ICIs, it is essential to explore alternative targets or signals that mediate immunosuppression. Immunoglobulin-like transcript (ILT) 5 is a negative regulator of immune activation in myeloid cells. However, the expression and function of ILT5 in NSCLC remain unknown. Here, we found that ILT5 was highly expressed in tumor-associated macrophages (TAMs) of NSCLC tissues and predicted poor patient survival. Functionally, ILT5 induces the M2-like polarization of TAMs, which subsequently decreases the density of T cells, and increases FOXP3+T cell accumulation, leading to an immunosuppressive TME. The combination of ILT5 expression with M2-like TAM density is a more reliable biomarker of patient survival than ILT5 expression alone. ILT5 knockout mitigates the reprogramming of TAM and T cell subsets toward immunosuppressive phenotypes and inhibits tumor growth in vivo. These findings highlight that ILT5 is a potential immunotherapeutic target and a promising prognostic biomarker for NSCLC.

The KRAS (Kirsten rat sarcoma viral oncogene homolog) gene is recognized as the most frequently mutated oncogene in advanced non-small cell lung cancer (NSCLC). The most prevalent mutation within this gene is G12C, formally known as KRAS G12C, which leads to the substitution of glycine with cysteine at position 12 of the KRAS protein [6].

Recent advancements in research have developed effective therapies designed to inhibit activated KRAS signaling. As a result, the first two accelerated FDA-approved KRAS inhibitors, sotorasib and adagrasib, have been successfully introduced to the market for locally advanced or metastatic KRAS G12C-mutated NSCLC who progressed after prior therapy. A second generation of KRAS inhibitors is currently being tested in clinical trials, and in combination with immunotherapy and chemotherapy.

Future research is crucial to determine the optimal timing for treatment with KRAS G12C inhibitors. Additional studies are needed to identify biomarkers that predict which patients will benefit most. This review discusses and analyzes both completed and ongoing clinical trials of first and second generation KRAS inhibitors. It also addresses mechanisms of resistance to KRAS inhibition, potential therapeutic strategies to overcome this resistance, biomarkers, side effects, and its role in central nervous system metastatic disease.

Although immune checkpoint inhibitors show great promise, not all patients respond and many do not achieve durable responses. Consequently, further investigations into potentially targetable molecules that regulate immune checkpoints are warranted. Previous studies in several cancers demonstrated that interferons produced by tumor-infiltrating leukocytes regulate immunosuppressive PD-L1, PD-L2 and IDO1 through JAK/STAT signaling. Here, we investigated a novel role for an immunosuppressive environmental chemical receptor, previously implicated in smoking-related cancers, in IFN signaling in human lung adenocarcinoma (LUAD) cells. Deletion of the aryl hydrocarbon receptor (AhR) from A549 LUAD cells significantly decreased baseline JAK2, STAT1, STAT3, IRF1 (a JAK/STAT target), PD-L1, PD-L2, and IDO1 expression. IFNγ and IFNα increased expression of JAK/STAT and immune checkpoint genes and proteins, but these increases were significantly diminished or absent in AhR-knockout cells. The AhR similarly controls IFN-induced, JAK/STAT-driven increases in multiple MHC class I- and class II-related genes. AhR control of type I and type II interferon signaling is mediated through up-regulation of a lncRNA, the IFN-stimulated non-coding RNA 1 (INCR1), and through repression of an RNA-binding protein, heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1), which sequesters JAK/STAT-related and immune checkpoint gene transcripts. The data suggest that the AhR is a key mediator of tumor immunosuppression through regulation of IFN-induced INCR1 and JAK/STAT signaling and, thereby, expression of immune checkpoints. However, that immunosuppression may be tempered by AhR control of MHC expression. Given the multiple roles of JAK/STAT signaling in the immune system, the results also suggest multiple levels on which the AhR may affect tumor immunity.

As machine learning (ML) continuously develops in cancer diagnosis and treatment, some researchers have attempted to predict the expression of programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) by ML. However, there is a lack of systematic evidence on the effectiveness of ML.

We conducted a thorough search across Embase, PubMed, the Cochrane Library, and Web of Science from inception to December 14th, 2023.A systematic review and meta-analysis was conducted to assess the value of ML for predicting PD-L1 expression in NSCLC.

Totally 30 studies with 12,898 NSCLC patients were included. The thresholds of PD-L1 expression level were < 1%, 1-49%, and ≥ 50%. In the validation set, in the binary classification for PD-L1 ≥ 1%, the pooled C-index was 0.646 (95%CI: 0.587-0.705), 0.799 (95%CI: 0.782-0.817), 0.806 (95%CI: 0.753-0.858), and 0.800 (95%CI: 0.717-0.883), respectively, for the clinical feature-, radiomics-, radiomics + clinical feature-, and pathomics-based ML models; in the binary classification for PD-L1 ≥ 50%, the pooled C-index was 0.649 (95%CI: 0.553-0.744), 0.771 (95%CI: 0.728-0.814), and 0.826 (95%CI: 0.783-0.869), respectively, for the clinical feature-, radiomics-, and radiomics + clinical feature-based ML models.

At present, radiomics- or pathomics-based ML methods are applied for the prediction of PD-L1 expression in NSCLC, which both achieve satisfactory accuracy. In particular, the radiomics-based ML method seems to have wider clinical applicability as a non-invasive diagnostic tool. Both radiomics and pathomics serve as processing methods for medical images. In the future, we expect to develop medical image-based DL methods for intelligently predicting PD-L1 expression.

Programmed cell death-ligand 1 (PD-L1) expression is used in treatment decision-making for patients with advanced non-small cell lung cancer, determining if immune checkpoint inhibitors (ICI) are recommended. Patient selection for ICI treatment can be improved by incorporating the host response. We developed and carried out multiple independent validations of a blood-based test designed to stratify outcomes for patients treated with atezolizumab.

A mass spectrometry-based test was developed from a cohort of patients treated with atezolizumab and validated in two clinical trials (n=269, 823) comparing atezolizumab with docetaxel. The test classifies patients as Good or Poor indicating better or worse outcomes, respectively. The prognostic and predictive power of the test was assessed and evaluated within PD-L1 subgroups. Protein enrichment methods were used to investigate the association of test classification with biological processes.

Approximately 50% of patients were assigned to each classification in all three cohorts. When treated with atezolizumab, the Good subgroup had superior outcomes in all cohorts. Overall survival (OS) HR (95% CI) for Good patients in each cohort was: 0.23 (0.12 to 0.44), 0.32 (0.21 to 0.51), and 0.52 (0.41 to 0.66) and persisted in all PD-L1 subgroups. The test was predictive of differential OS and progression-free survival in one cohort, but not in the other. Enrichment techniques indicated the test was associated with acute inflammatory response, acute phase response, and complement activation.

Aspects of host immune response to disease can be assessed from the circulating proteome and provide outcome stratification for patients treated with atezolizumab. Combining this information with PD-L1 measurements improves prediction of outcomes.

The safety of administering immune checkpoint inhibitors (ICIs) after talc pleurodesis, particularly the impact of talc on the development of immune-related interstitial lung disease (ILD), remains unclear.

We retrospectively analysed patients with primary lung cancer or malignant pleural mesothelioma who received ICIs within 90 days of talc pleurodesis at facilities participating in the Niigata Lung Cancer Treatment Study Group between November 2016 and June 2023.

A total of 52 cases were included, with 17 patients (32.7 %) developing ILD following ICI administration. The median time to ILD onset after ICI administration was 62 days. The median overall survival was 6 months in patients who developed ILD and 16.4 months in those who did not (P = 0.081). Among the five patients with pre-existing interstitial changes, four (80.0 %) developed ILD after ICI administration, identifying a high-risk subgroup.

A high incidence of ILD was observed in patients who received ICI therapy after talc pleurodesis. Additionally, overall survival tended to be shorter in patients who developed ILD.

The World Health Organization's (WHO) Reporting System for Lung Cytopathology intends to standardise the diagnosing and reporting of cytology specimens from the lung and aims at enhancing the communication between clinicians and (cyto)pathologists. It is closely connected to the 5th edition of the WHO Classification of Thoracic Tumours. The system includes five diagnostic categories, among them the 'Malignant' diagnostic category that incorporates both primary malignant tumours and metastases. Advancements in bronchoscopy have notably improved the diagnostic capacity of cytological specimens that represent the sole source of tumour material in approximately 40% of all lung carcinoma cases. An accurate diagnosis of malignancy and treatment-guiding classification into specific tumour types and subtypes can reliably be achieved with cytology specimens. They additionally serve as an excellent source for predictive immunocytochemistry (ICC) and molecular testing for targetable oncogenic alterations. This review article provides an overview of the key cytopathological features defining the 'Malignant' category of the WHO Reporting System for Lung Cytopathology for non-small cell carcinomas, neuroendocrine neoplasms and other specific carcinomas and malignancies which can be encountered in cytological specimens of the lung. It further describes the application of ancillary techniques, such as ICC and molecular testing, that have been successfully incorporated into different cytological sample types using various preparation methods.

The development of immune checkpoint inhibitors has changed treatment strategies for some patients with non-small cell lung cancer (NSCLC). However, resistance remains a major problem, requiring the elucidation of resistance mechanisms, which might aid the development of novel therapeutic strategies. The upregulation of CD155, a primary ligand of the immune checkpoint receptor TIGIT, has been implicated in a mechanism of resistance to PD-1/PD-L1 inhibitors, and it is therefore important to characterize the mechanisms underlying the regulation of CD155 expression in tumor cells. The aim of this study was to identify a Nectin that might regulate CD155 expression in NSCLC and affect anti-tumor immune activity. In this study, we demonstrated that NECTIN4 regulated the cell surface expression and stabilization of CD155 by interacting and co-localizing with CD155 on the cell surface. In a syngeneic mouse model, NECTIN4-overexpressing cells exhibited increased cell surface CD155 and resistance to anti-PD-1 antibodies. Of note, combination therapy with anti-PD-1 and anti-TIGIT antibodies significantly suppressed tumor growth. These findings provide new insights into the mechanisms of resistance to anti-PD-1 antibodies and suggest that NECTIN4 could serve as a valuable marker in therapeutic strategies targeting TIGIT.

Recent studies have promoted new insights into the biology of non-small cell lung cancer (NSCLC) and made considerable progress in the field of treatment, including targeted therapy for driver gene mutations. Immunotherapy (IO) is another breakthrough, which has achieved amazing clinical efficacy. However, the survival status of advanced NSCLC patients is still unsatisfactory. Drug resistance is an urgent problem to be solved in almost all anti-cancer treatment schemes. Nowadays, platinum based chemotherapy remains the standard treatment for patients with driver gene negative advanced NSCLC. Previous studies have shown that the reduction of intracellular accumulation of platinum drugs, DNA damage repair and the enhancement of detoxification effect all lead to platinum resistance. The mechanisms of tyrosine kinase inhibitors (TKIs) resistance include the emergence of secondary mutation, the activation of bypass signal pathways, the abnormality of downstream signal pathways and the transformation of phenotype. The mechanisms of immune checkpoint inhibitors (ICIs) resistance are more complex. A variety of cells, cytokines and metabolites participate in it to form an immunosuppressive microenvironment, resulting in the impairment of effector T cell function. Exosomes are small molecules secreted by a variety of cells. They can carry information such as miRNA, lncRNA, and protein, and play a pivotal role in signal transduction between cells. More and more studies show that exosomes are important transmitters in lung cancer cells, which can transfer drug resistance information from drug-resistant cells to sensitive cells. However, the underling specific mechanisms need to be further explored to find a new breakthrough for overcoming drug resistance of NSCLC.

In the phase 3 EMPOWER-Lung 1 study, first-line cemiplimab monotherapy provided significant survival benefit versus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. This exploratory subgroup analysis investigated the clinical outcomes of cemiplimab treatment in patients with advanced NSCLC with brain metastases.

Patients with advanced NSCLC were randomized (1:1) to cemiplimab 350 mg every 3 weeks or four cycles of platinum doublet chemotherapy (NCT03088540). Patients with symptomatic radiotherapy-treated brain metastases were eligible to enroll. Of the 565 patients with confirmed PD-L1 expression ≥50%, 69 (12%) had brain metastases at baseline.

Patients with brain metastases who received cemiplimab had a median overall survival (OS) of 52.4 months compared with 20.7 months for those who received chemotherapy (hazard ratio [HR], 0.40; p = .0031) and a median progression-free survival (PFS) of 12.5 versus 5.3 months (HR, 0.33; p = .0002), respectively. Patients without brain metastases had a median OS of 24.3 months with cemiplimab versus 12.5 months with chemotherapy (HR, 0.63; p < .0001); their median PFS was 6.5 months versus 5.2 months (HR, 0.55; p < .0001), respectively. Cemiplimab was associated with a significant improvement in global health status/quality of life in all patients, including those with brain metastases. The cemiplimab safety profile was generally similar in all patients.

In patients with advanced NSCLC with PD-L1 ≥50%, first-line cemiplimab monotherapy improved survival and patient-reported outcomes over chemotherapy for those who received prior radiotherapy for symptomatic brain metastases.

Immunotherapy based on programmed cell death protein receptor 1 and its ligand (PD-1/PD-L1) has become an important method for treating non-small cell lung cancer (NSCLC). Peptide-based and nanobody-based PET tracers offer potential advantages in PD-L1 detection, yet their comparative tumor uptake and biodistribution remain unclear. This study aimed to evaluate and compare [68Ga]Ga-DOTA-WL12 (a peptide-based tracer) and [68Ga]Ga-NOTA-RW102 (a nanobody-based tracer) in assessing PD-L1 expression in primary and metastatic NSCLC, providing insights for future radiotracer design and theranostic applications.

Ten patients diagnosed with NSCLC underwent [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 PET/CT scans, with four of these patients also receiving [18F]FDG PET/CT scans. The tracer uptakes, quantified by maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and target-to-background ratio (TBR), were compared between [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 PET/CT.

DOTA-WL12 and NOTA-RW102 exhibited favorable binding affinities with PD-L1, with equilibrium dissociation constant (KD) values of 0.2 nM and 0.0047 nM, respectively. Subsequent human studies revealed significant variations (P < 0.05) in the uptake of [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 across the liver (SUVmean: 20.43 ± 4.26 vs. 6.12 ± 1.36, p = 0.015), kidney (SUVmean: 2.40 ± 0.34 vs. 22.37 ± 2.88, P = 0.015), spleen (SUVmean: 2.44 ± 0.67 vs. 18.49 ± 3.90, P = 0.015), and lung background (SUVmean: 0.18 ± 0.12 vs. 1.09 ± 0.29, P = 0.015). Meanwhile, we found that the correlation between SUVmax and PD-L1 TPS was significantly stronger with [68Ga]Ga-DOTA-WL12 compared to [68Ga]Ga-NOTA-RW102 (P < 0.0001, r = 0.9471 vs. P = 0.0241, r = 0.5235).

The uptake of peptide-based [68Ga]Ga-DOTA-WL12 was more strongly correlated with PD-L1 TPS in primary and metastatic tumor lesions compared to [68Ga]Ga-NOTA-RW102. They also displayed different distribution, suggesting that peptide-based and nanobody-based radiotracers may have different clinical implications, particularly in radiotherapy.

This study assesses the impact of immune-oncology (IO) drugs' availability on cancer incidence-adjusted mortality rates from melanoma, lung, and renal cancers at population level in Italy between 2008 and 2019.

We conducted a retrospective study on cross-sectional time-series aggregated data collected from publicly available sources and IQVIA proprietary databases. Three fixed-effects regression models were used to estimate how IO availability affects incidence-adjusted mortality for each cancer type. Estimated deaths were compared with deaths in a scenario with no IO drugs availability. Finally, the number of averted deaths was valued using the human capital approach.

A 1% increase in IO availability reduces incidence-adjusted mortality rates for melanoma, lung, and renal cancers by 0.125% (95% CI: 0.138-0.112; p < 0.01), 0.011% (95% CI: 0.013-0.009; p < 0.01) and 0.005% (95% CI: 0.006-0.003; p < 0.01) between the introduction of the drug in the therapeutic area and 2019. This reduction resulted in total savings of € 49.0 million, € 61.3 million, and € 10.9 million in indirect costs due to premature mortality, respectively.

IO drugs introduction in Italy between 2008 and 2019 was associated with a significant decrease in deaths from each cancer and, consequently, in savings in indirect costs related to premature mortality.

Programmed death-ligand 1 (PD-L1) is a crucial immune checkpoint protein that tumors often exploit to evade immune surveillance. This study systematically screened a library of 1031 FDA-approved drugs using a high-throughput molecular dynamics approach to identify potential inhibitors targeting PD-L1. From this screening, five promising compounds-vorapaxar, delafloxacin, tenofovir disoproxil, pivmecillinam, and fursultiamine-showed significant binding affinities to PD-L1 and demonstrated cytotoxic activity against A549 lung tumor cells. These candidates were further evaluated through extended molecular dynamics simulations lasting up to 150 ns to assess their structural stability, residue fluctuations, and binding free energy. Among the identified compounds, pivmecillinam demonstrated the most favorable results, exhibiting stable binding interactions and a binding free energy of -18.01 kcal/mol, comparable to that of the known PD-L1 inhibitor BMS-1. These findings suggest that pivmecillinam has promising immunomodulatory potential and could serve as a candidate for further development in cancer immunotherapy. Overall, this study underscores the value of integrating high-throughput MD and experimental approaches for drug repositioning to identify novel therapeutic agents.

Programmed death ligand 1 (PD-L1) serves as a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC). This study aimed to identify the most suitable first-line treatment regimen for patients with PD-L1 expression <1% (PD-L1-negative) NSCLC by comparing nivolumab plus ipilimumab (NI), NI combined with chemotherapy (NICT), and pembrolizumab and chemotherapy (PCT).

We analyzed data from 141 patients with PD-L1-negative NSCLC treated with NI, NICT, or PCT at 14 Japanese institutions between December 2020 and November 2022. Propensity score analysis was employed to minimize selection bias, and Kaplan-Meier analysis and Cox proportional hazards regression were used to evaluate progression-free survival (PFS) and overall survival (OS).

Neither NI nor NICT demonstrated superior PFS or OS than PCT. Subgroup analyses revealed no significant differences between treatment groups across age, histological subtypes, or clinical features. Results from propensity score matching and inverse probability of treatment weighting were consistent with those observed in the overall cohort. Moreover, safety profiles showed that PCT was associated with the lowest rates of treatment discontinuation and immune-related adverse events requiring systemic corticosteroid therapy.

In patients with PD-L1-negative NSCLC, the efficacy of NI and NICT was not superior to that of PCT. Thus, we concluded that PCT could be a favorable treatment option for this patient population.

In updated analyses from the phase III POSEIDON study, after a median follow-up of >5 years, tremelimumab plus durvalumab and chemotherapy (T + D + CT) showed durable long-term overall survival (OS) benefit versus CT alone in first-line metastatic non-small-cell lung cancer (mNSCLC). In this article, we report the associations of tumor mutational burden (TMB) with outcomes of D with or without T in combination with CT versus CT alone.

A total of 1013 patients with EGFR/ALK wild-type mNSCLC were randomized (1 : 1 : 1) to T + D + CT, D + CT, or CT, stratified by programmed cell death-ligand 1 (PD-L1) tumor cell (TC) expression ≥50% versus <50%, disease stage (IVA versus IVB) and histology (squamous versus nonsquamous). Patient subgroups were defined by a range of blood TMB (bTMB) values, including at a prespecified cut-off of 20 mutations (mut)/megabase (Mb) and across further subdivisions by PD-L1 TC expression ≥1% or <1% and by tissue TMB (tTMB) values.

At the primary OS data cut-off (12 March 2021), at each bTMB or tTMB cut-off, the magnitude of OS benefit appeared greater among patients in the bTMB- or tTMB-high subgroups for the T + D + CT arm versus the CT arm but was similar between subgroups for the D + CT arm versus the CT arm. Updated OS analyses in the bTMB ≥20 and <20 mut/Mb subgroups, after median follow-up of >5 years (data cut-off 24 August 2023), were similar to those obtained at the primary OS data cut-off.

First-line treatment with T (limited course) plus D (until progression) and four cycles of CT consistently improved clinical outcomes versus CT alone in both bTMB-high and -low subgroups, and also in both high and low tTMB subgroups, in patients with mNSCLC. Benefit appeared greater in the TMB-high versus TMB-low subgroups; the addition of anti-cytotoxic T lymphocyte-associated antigen-4 to anti-PD-L1 and CT seemed to increase the magnitude of this difference.

Lung cancer remains the second leading cause of cancer-related morbidity and mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard first-line therapy for advanced NSCLC with EGFR mutations, offering significant improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to chemotherapy alone. Recent studies suggest that their effectiveness decreased with the emergence of acquired resistance, such as C797S and T790M. Immunotherapy alone also shows enhanced PFS and OS over chemotherapy; however, its applicability can be limited in cases with low programmed cell death ligand 1 (PD-L1) expression and result in immune-related adverse effects like those observed in retrospective, non-randomized studies. Emerging fourth-generation EGFR-TKIs, currently under clinical trials, show promising potential to address these resistance mechanisms. Advanced inhibitors, including BBT-176, BLU-945, and BLU-701, have effectively targeted resistant mutations and reduced disease progression. Studies have suggested that combining fourth-generation EGFR-TKIs with immunotherapies targeting novel pathways like LAG-3 and TIM-3 may enhance patient outcomes. Such combination regimens aim to optimize PFS, OS, and ORR while minimizing adverse effects and addressing the limitations of current therapies. This study explores the landscape of EGFR mutations, their clinical significance, and the integration of innovative fourth-generation EGFR-TKIs with immunotherapies, emphasizing the potential of precision medicine in advancing the management of EGFR-mutated NSCLC.

Quality control of immunohistochemistry (IHC) slides is crucial to ascertain accurate patient management. Visual assessment is the most commonly used method to assess the quality of IHC slides from patient samples in daily pathology routines. Control tissues for IHC slides are typically obtained from prior cases containing normal tissues or specific antigen-expressing disease samples, especially tumors. As such samples eventually run out, and tumors may be heterogeneous, constant expression levels from one control sample to the next cannot be guaranteed. With the increasing availability of standardized cell lines, the diagnostic use of these cell lines as alternatives to traditional laboratory-derived controls can be explored. Furthermore, stain quality of this cell line material can probably be better monitored with readout methods such as image analysis and artificial intelligence (AI) than with visual readout methods, in which accuracy is influenced by the training and experience of the pathologists and technicians. In this study, we present the results of our investigation into AI-measured stain quality of standardized cell lines designed as controls for HER2 and PD-L1 IHC stainings. Using 5 IHC autostainers from the same manufacturer and type, we quantified cell membrane expression levels of these cell lines after staining using Qualitopix, an AI algorithm for measuring stain quality control. Over a 24-month period of weekly AI measurements, we observed multiple unexpected variations, particularly in low- and medium-expressing cell lines. To further investigate these fluctuations, we assessed both interstainer variations and intrarun variations, revealing differences between the stainers and the slide slots within the stainers. To finalize our study, we performed HER2 and PD-L1 stainings on calibrator slides to measure the limit of detection to detect variance per stainer and slot. Our findings prompted extra maintenance from the manufacturer in one of the highly fluctuating stainers, which reduced variation. In conclusion, AI appears to be an effective approach to monitor the IHC stain quality of standardized control cell lines for therapeutic protein targets HER2 and PD-L1, and to trace the underlying errors. This may be crucial for accurate patient management.

Immune checkpoint inhibitors have improved survival in patients with non-small cell lung cancer (NSCLC). Whilst PD-L1 expression is a useful predictive biomarker, data on concordance of expression between primary tumor and nodal metastases in the surgical setting are sparse.

We assessed PD-L1 expression in paired primary tumor and involved lymph node samples from 451 consecutive patients with stage IIB-IIIB NSCLC who underwent curative lung resection and lymphadenectomy at our institution between 2009 and 2018, to assess intertumor heterogeneity. Clinical records were examined to determine survival outcomes, and relationship to PD-L1 expression was explored.

Using PD-L1 expression categories of < 1%, 1% to 49% and ≥ 50% there was heterogeneity of PD-L1 expression between the primary and corresponding lymph node metastases in 24% of cases with only moderate positive correlation (Spearman's coefficient 0.7). 46% of early-stage primary tumors expressed PD-L1, although only 11% demonstrated a high (> 50%) level. It was more common for PD-L1 expression to be higher in the primary tumor than its metastatic lymph node than the converse. PD-L1 expression irrespective of site, had no significant impact on disease-free or overall survival.

Our study confirms the heterogeneity of PD-L1 expression in early-stage NSCLC and suggests that a biopsy specimen from a single site may not be a comprehensive representation of PD-L1 expression. The proportion of tumours with high PD-L1 expression appears lower in early-stage NSCLC than in advanced disease.

Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.

The optimal management strategy for metastatic or advanced-stage non-small-cell lung cancer (NSCLC) after 2 years of immune checkpoint inhibitor (ICI) remains unclear.

We conducted a single-center retrospective observational study to characterize the management of patients who received at least 2 years of ICI in the first-line setting for a metastatic or advanced-stage NSCLC.

Among the 254 patients that received ICI in the first-line setting, 39 (15%) achieved 2 years of treatment (ICI in monotherapy, n = 14; ICI with chemotherapy, n = 25). ICI was discontinued after 2 years (<30 months) in 31 (79%) of the cases. During the first 2 years, 29 patients (74%) had no disease progression (2 complete radiological responses, 25 partial radiological responses, and 2 stable diseases) and 10 patients (26%) experienced at least one oligo-progression, which was treated with local ablative treatment (LAT), allowing continuation of ICI up to 2 years. A positron emission tomography (PET) scan was performed at 2 years for 37 patients (95%), revealing a complete metabolic response (CMR) in 16 individuals (43%). None of these patients progressed subsequently (median follow-up: 13 months). After 2 years of ICI, the 12-month progression-free survival was 100% in case of CMR versus 49% (95% CI, 29-91) in the absence of CMR (p = 0.00037).

A CMR at 2 years of ICI is associated with a favorable prognosis. Further studies are needed to better establish the role of PET scan at 2 years, the relevance of LAT and the optimal duration of ICI.

Breast cancer (BC) is the most prevalent malignancy among women and is associated with high mortality and significant clinical challenges. Although conventional treatments such as surgery, chemotherapy, and radiotherapy have significantly improved patient survival, their efficacy remains limited by severe side effects and treatment resistance. In recent years, advances in immunotherapy have underscored the pivotal role of immune cells in treating BC.

This systematic review summarizes the current knowledge on the roles of immune cells within the BC tumor microenvironment (TME), including their phenotypes, functions, and implications for immunotherapy. Following PRISMA guidelines, 71 studies published between 2010 and 2024 were analyzed. The results indicate that immune cell populations-such as tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs)-are integral to tumor progression and therapeutic response. However, their functional heterogeneity and plasticity remain key obstacles to the development of effective and personalized immunotherapeutic strategies.

Further research is needed to clarify the mechanisms governing immune cell behavior within the BC TME and to advance precision immunotherapy. Such insights will lay the foundation for individualized treatment approaches, ultimately improving patient outcomes and quality of life (QoL).

The current standard of care for advanced non-small cell lung cancer (NSCLC) without driver oncogenes is platinum-based chemotherapy together with immune checkpoint inhibition. However, most phase 3 trials of such combination therapy have excluded patients with renal impairment, with prospective data on its efficacy and safety in such patients thus being limited.

This multicenter, single-arm phase 2 study enrolled chemotherapy-naïve individuals with advanced nonsquamous NSCLC and renal impairment defined as a creatinine clearance (CCr) of 15 to <45 mL/min. Patients received four cycles of atezolizumab in combination with carboplatin plus nab-paclitaxel, followed by atezolizumab alone. The primary endpoint of the study was objective response rate as determined by Response Evaluation Criteria in Solid Tumors.

Twenty-five patients were enrolled from 13 centers. The median age was 78 years (range, 63-83 years). Median CCr was 38.0 mL/min (range, 19.0-44.3 mL/min). There were no treatment-related deaths or cases requiring hemodialysis. Worsening of chronic kidney disease to grade 4, defined as a CCr of <15 mL min-1 1.73 m-2, occurred in two patients (8 %), with the decreases in CCr being transient and both patients subsequently recovering. The objective response rate was 36.0 % (60 % confidence interval, 28.4-44.4 %), and the study did not meet its primary endpoint. Median progression-free survival and overall survival were 7.1 and 19.9 months, respectively.

Carboplatin plus nab-paclitaxel with atezolizumab is a potentially feasible treatment option for advanced nonsquamous NSCLC with renal impairment.

Despite advancements in systemic chemotherapy and immune checkpoint inhibitors (ICIs), advanced non-small cell lung cancer (NSCLC) continues to exhibit poor prognosis, underscoring an urgent need for safer and more effective therapeutic strategies. This study investigates the safety profile and biological effects of bronchial arterial infusion (BAI)-administered anti-PD-1 monoclonal antibody (aPD-1 mAb) using a preclinical beagle model and a clinical cohort of advanced NSCLC patients.

In preclinical evaluations, male beagles (n = 3/group) were randomized to receive 5 mg/kg aPD-1 mAb via BAI or intravenous routes (Venous group). Safety assessments included longitudinal imaging, biochemical analyses, and histopathological evaluation. Clinically, patients with advanced NSCLC meeting stringent inclusion criteria underwent BAI immunotherapy, with systematic monitoring of adverse events (AEs).

Both administration routes demonstrated comparable safety in canines, with no evidence of immune-related pneumonitis or structural lung alterations on CT or histology. Transient AEs (e.g., hematoma, lameness) resolved spontaneously. Pharmacokinetic analysis revealed similar systemic drug concentrations and tissue distribution between BAI and Venous groups (all p > 0.05). Biochemical profiling identified isolated mild LDH elevation in one BAI-treated canine. Notably, the BAI group exhibited significantly enhanced systemic IL-2 levels (80.15 ± 5.24 pg/mL vs. 66.47 ± 5.24 pg/mL in Venous groups, p = 0.001) at day 28, paralleled by elevated pulmonary IL-2 expression (626.90 ± 18.49 vs. 559.18 ± 45.61 pg/mg, p = 0.03). In the clinical cohort (n = 17; 94.1% male, mean age 61.6 ± 7.1 years), BAI immunotherapy was well-tolerated with mild AEs including nausea (n = 1), dyspnea (n = 1), atrial fibrillation (n = 1), and puncture-site hematoma (n = 1). No severe immune-related toxicities (e.g., pneumonitis) emerged during follow-up.

Our study suggest the preliminary safety and feasibility of delivering aPD-1 mAb via BAI in both canine models and NSCLC patients.

Non-small cell lung cancer (NSCLC) represents a formidable challenge in oncology due to its molecular heterogeneity and the dynamic suppressive nature of its tumor microenvironment (TME). Despite the transformative impact of immune checkpoint inhibitors (ICIs) on cancer therapy, the majority of NSCLC patients experience resistance, necessitating novel approaches to overcome immune evasion. This review highlights shared and subtype-specific mechanisms of immune resistance within the TME, including metabolic reprogramming, immune cell dysfunction, and physical barriers. Beyond well-characterized components such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, emerging players - neutrophil extracellular traps, tertiary lymphoid structures, and exosomal signaling networks - underscore the TME's complexity and adaptability. A multi-dimensional framework is proposed to transform cold, immune-excluded tumors into hot, immune-reactive ones. Key strategies include enhancing immune infiltration, modulating immunosuppressive networks, and activating dormant immune pathways. Cutting-edge technologies, such as single-cell sequencing, spatial transcriptomics, and nanomedicine, are identified as pivotal tools for decoding TME heterogeneity and personalizing therapeutic interventions. By bridging mechanistic insights with translational innovations, this review advocates for integrative approaches that combine ICIs with metabolic modulators, vascular normalizers, and emerging therapies such as STING agonists and tumor vaccines. The synergistic potential of these strategies is poised to overcome resistance and achieve durable antitumor immunity. Ultimately, this vision underscores the importance of interdisciplinary collaboration and real-time TME profiling in refining precision oncology for NSCLC, offering a blueprint for extending these advances to other malignancies.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) may serve as prognostic markers in non-small cell lung cancer (NSCLC). While prior studies suggest differences in overall survival (OS) based on irAE, their prognostic impact across various ICI regimens remains underexplored.

This retrospective study analyzed data from patients with advanced or recurrent NSCLC treated with ICIs between January 2018 and December 2022. Patients were categorized into three groups: severe irAEs (Grade 3-5), mild irAEs (Grade 1-2), and no-irAEs. OS was assessed across three regimens: anti-programmed cell death protein 1 (anti-PD-1) monotherapy, anti-PD-1/anti-programmed death-ligand 1 (anti-PD-L1) with chemotherapy (CT), and anti-PD-1 with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) ± CT.

Among the 256 patients included, 55 received anti-PD-1 monotherapy, 116 received anti-PD-1/L1 with CT, and 85 received anti-PD-1 with anti-CTLA-4 ± CT. For anti-PD-1 monotherapy, median OS (95 % confidence interval) was 38.3 (17.0-42.5) months in the mild irAE group, 16.1 (5.2-28.6) months in the severe irAE group, and 9.6 (12.3-37.1) months in the no-irAE group. In the anti-PD-1/L1 with CT group, median OS were 33.6 (14.2-40.3), 16.0 (1.84-not reached [NR]), and 17.7 (3.8-23.4) months, respectively. For anti-PD-1 with anti-CTLA-4 ± CT, median OS were 28.0 (21.8-NR), 10.9 (7.0-19.6), and 16.3 (8.7-23.4) months, respectively.

The relationship between irAE severity and OS was consistent across all ICI regimens, with patients experiencing mild irAEs demonstrating better OS across all ICI regimens.

This study aimed to evaluate the cost-effectiveness of Penpulimab versus placebo in treating metastatic squamous non-small cell lung cancer (NSCLC) from the perspective of Chinese payers. A three-state Markov model was developed to simulate clinical efficacy and cost consumption using Kaplan-Meier curves from clinical trials. The model considered only direct medical costs, with utility values derived from the published literature. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), and sensitivity analysis was performed to assess the impact of parameter uncertainty on the model's robustness. The base case analysis indicated that the Penpulimab group incurred higher costs ($33,592 vs. $9,351) than the placebo group, while also providing more quality-adjusted life years (QALYs) (3.30 vs. 2.11), resulting in an incremental cost-effectiveness ratio (ICER) of $20,389.38 per QALY. Sensitivity analyses revealed that the cost of Penpulimab, along with the utilities of progression-free survival (PFS) and progression of disease (PD), were the parameters that most significantly influenced the model's outcomes. From the perspective of Chinese payers, Penpulimab offers a cost-effectiveness advantage over placebo in treating metastatic squamous NSCLC.

Radiomics refers to the utilization of automated or semi-automated techniques to extract and analyze numerous quantitative features from medical images, such as computerized tomography (CT) or magnetic resonance imaging (MRI) scans. This study aims to develop a deep learning radiomics (DLR)-based approach for predicting programmed death-ligand 1 (PD-L1) expression in patients with non-small cell lung cancer (NSCLC). Data from 352 NSCLC patients with known PD-L1 expression were collected, of which 48.29% (170/352) were tested positive for PD-L1 expression. Tumor regions of interest (ROI) were semi-automatically segmented based on CT images, and DL features were extracted using Residual Network 50. The least absolute shrinkage and selection operator (LASSO) algorithm was used for feature selection and dimensionality reduction. Seven algorithms were used to build models, and the most optimal ones were identified. A combined model integrating DLR with clinical data was also developed. The predictive performance of each model was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve analysis. The DLR model, based on CT images, demonstrated an AUC of 0.85 (95% confidence interval (CI), 0.82-0.88), sensitivity of 0.80 (0.74-0.85), and specificity of 0.73 (0.70-0.77) for predicting PD-L1 status. The integrated model exhibited superior performance, with an AUC of 0.91 (0.87-0.95), sensitivity of 0.85 (0.82-0.89), and specificity of 0.75 (0.72-0.80). Our findings indicate that the DLR model holds promise as a valuable tool for predicting the PD-L1 status in patients with NSCLC, which can greatly assist in clinical decision-making and the selection of personalized treatment strategies.

Exosomes, characterized by their bilayer lipid structure, are crucial in mediating intercellular signaling and contributing to various physiological processes. Tumor cells produce distinct exosomes facilitating cancer progression, angiogenesis, and metastasis by conveying signaling molecules. A notable feature of these tumor-derived exosomes is the presence of programmed death-ligand 1 (PD-L1) on their surface. The PD-L1/programmed cell death receptor-1 (PD-1) signaling axis serves as a critical immune checkpoint, enabling tumors to evade immune detection and antitumor activity. The advancement of immunotherapy targeting the PD-1/PD-L1 pathway has significantly impacted the treatment landscape for non-small cell lung cancer (NSCLC). Despite its promise, evidence indicates that many patients experience limited responses or develop resistance to PD-1/PD-L1 inhibitors. Recent studies suggest that exosomal PD-L1 contributes to this resistance by modulating immune responses and tumor adaptability. This study reviews the PD-1/PD-L1 pathway's characteristics, current clinical findings on PD-L1 inhibitors in NSCLC, and exosome-specific attributes, with a particular focus on exosomal PD-L1. Furthermore, it examines the growing body of research investigating the role of exosomal PD-L1 in cancer progression and response to immunotherapy, underscoring its potential as a target for overcoming resistance in NSCLC treatment.

Malignant pleural effusion (MPE) remains a clinical issue since it is associated with advanced-stage cancers and dismal survival, with immunosuppressive tumor microenvironment (TME) and ineffective drug delivery. Conventional therapies such as thoracentesis and pleurodesis are for symptom relief but palliative, without inducing immunity and prolonging survival. Emerging new bioengineered drugs, synergizing with immunotherapies, offer a new paradigm by dual-targeting TME remodeling and immune activation. These technologies leverage nanotechnology, gene editing, and biomaterials to offer precise spatiotemporal control. This review illustrates the molecular mechanism of the immunosuppressive TME in MPE. It examines the newest bioengineering platforms-such as cytokine-encapsulated nanoparticles and oncolytic viruses-that can reactivate immune mechanisms. We highlight preclinical and clinical evidence of the effectiveness of combinatorial strategies in overcoming local immune tolerance and potential risks in adverse events. While the clinical transformation challenge remains, future directions necessitate cross-disciplinary convergence to engineer intelligent delivery vehicles and predictive biomarkers for patient stratification. By integrating immunotherapy with bioengineering, this strategy not only restores antitumor immunity but also portends a new epoch of precision medicine for MPE.

Phillyrin (PHN), derived from the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a kind of Chinese herbal medicine with the effect of clearing heat, and has been used in China for thousands of years in treating various tumors. However, the mechanism of its main components on non-small cell lung cancer (NSCLC) remains unclear. PHN is a distinct component extracted from Forsythia suspensa with promising anti-cancer activity against various tumor types. This study sought to elucidate the promising effects of PHN on NSCLC. Based on network pharmacology results, we identified potential PHN targets and pathways for NSCLC treatment. CCK-8 assay, wound healing assay, apoptosis assay, western blot, and in vivo experiments verified the inhibitory effect of PHN on NSCLC. Network pharmacology identified 160 potential PHN targets, 955 NSCLC-related targets, and 54 common targets, along with 132 pathways and 2 core genes. Biological experiments demonstrated that PHN significantly inhibited the growth and migration of A549 and LLC cells while promoting their apoptosis. Western blot analysis revealed down-regulation of AKT, HSP90AA1, and CDC37 expression, suggesting that PHN inhibits A549 and LLC cell proliferation by down-regulating the HSP90-AKT pathway. In vivo experiments confirmed that PHN significantly inhibited NSCLC growth with low toxicity. This study, using network pharmacology and biological experiments, verified the effectiveness of PHN against NSCLC through the HSP90-AKT pathway. These findings provide a foundation for further research and analysis.

Immunotherapy has revolutionized the diagnosis and treatment model for patients with advanced non-small cell lung cancer (NSCLC). Numerous clinical trials and real-world reports have confirmed that PD-L1 status is a key factor for the successful use of immunotherapy in NSCLC, by predicting clinical outcomes and identifying patients most likely to benefit from this treatment. Therefore, accurate and standardized evaluation of PD-L1 expression is crucial. Currently, PD-L1 testing in China faces several challenges, including a heavy pathologist workload, a shortage of highly trained pathologists plus the inadequate capacity of diagnostic laboratories, confusion around different scoring methods, cut-off values, and indications, and limited concordance between PD-L1 assays. In this review, we summarize the current status and limitations of PD-L1 testing for patients with NSCLC in China and discuss recent progress in artificial intelligence-assisted PD-L1 scoring. Our review aims to support improvements in clinical PD-L1 testing practice and optimization of the prognosis and outcomes of immunotherapy in this patient population.