Programmed cell death-1 (PD-1) inhibitors and programmed cell death ligand 1 (PD-L1) inhibitors are considered effective alternatives for the primary treatment of recurrent metastatic cancers. However, they can induce various adverse events affecting multiple organ systems, potentially diminishing patients' quality of life, and even leading to treatment interruptions. Adverse events related to PD-1/PD-L1 inhibitors differ from those associated with CTLA-4 inhibitors and are more commonly observed in the treatment of solid tumors. This study aimed to address the knowledge gap regarding adverse events related to PD-1/PD-L1 inhibitors. A visual bibliometric network was constructed using VOSviewer, CiteSpace, R software, and the Web of Science Core Collection (WoSCC) to quantitatively analyze this research field. Future research directions were also explored. The USA ranked first in publication count and total citations. Over time, publication types transitioned from case reports to clinical trials. Research on for nivolumab was the most prevalent. The spectrum of cancers treated by PD-1/PD-L1 inhibitors expanded beyond melanoma and lung cancer to include renal cell carcinoma, esophageal cancer, and others. Common adverse events included pneumonitis, myasthenia gravis, and vitiligo. There was a significant increase in multi-phase clinical trials and studies related to biomarkers. This study offers valuable insights for potential collaborators and institutions, highlighting trends in the study of adverse events related to PD-1/PD-L1 inhibitors. The management of these adverse events has become more refined and standardized. Biomarker research and multi-phase clinical trials are likely to be key areas of focus in future studies.

Immunotherapy is firmly established as a treatment regimen in various solid tumors, driven by its exceptional benefits in a selected group of patients. Despite widespread adoption of immune checkpoint blockade (ICB) across diverse solid tumors, the quest for a clinically informative biomarker for long-term benefit remains unmet.

A total of 49 patients with metastatic NSCLC treated with ICB were included. Long-term (LTR) and short-term responders (STR) were defined as those with a response to ICB lasting more than 24 months or less than 6 months, respectively. Longitudinal blood specimens were collected before ICB treatment initiation and early-on treatment. Plasma ctDNA next-generation sequencing panel (NGS) and serum proteomics were performed. GeoMx DSP on baseline tumor tissue was performed in a subset of patients.

Our analysis revealed specific characteristics of LTR compared with STR, namely higher PD-L1 in tumor cells (p = 0.005) and higher incidence of irAEs (p = 0.001). Genomic features associated with lack of benefit from ICB included co-occurring mutations in KRAS/STK11 and TP53/KMT2D (p < 0.05). At a baseline, LTR patients exhibited higher serum levels of proteins related with apoptosis (CASP8, PRKRA), chemotaxis, immune proteasome, processing of MHC class I (S100A4, PSMD9, RNF41) and immune homeostasis (HAVCR1, ARG1) (p < 0.05). Protein spatial profiling of tumor samples showed higher levels of proteins linked with the presence of immune cells (CD45), T cells (CD8), antigen presentation (HLA-DR) and immune regulation proteins (PD-L1, IDO1) within the tumor and tumor stroma component (p < 0.05) in LTR patients. Serum longitudinal analysis identified a set of proteins that presented distinct dynamics in LTR compared to STR, making them interesting candidates to evaluate as early predictors of treatment efficacy.

Our multimodal analysis of patients with metastatic NSCLC treated with ICB identified clinicopathological and immunological features associated with long-term benefits. The presence of preexisting antitumor immunity emerged as a strong predictor of long-term benefits, providing insights for potential biomarkers and therapeutic strategies for enhancing ICB outcomes in metastatic NSCLC.

The combination of thoracic radiotherapy and immunotherapy (radioimmunotherapy) has shown significant antitumor efficacy but is associated with increased cardiotoxicity, the mechanisms of which remain poorly understood.

A total of 72 male C57BL/6 J mice were employed to establish the radioimmunotherapy-induced cardiac injury model, with 18 mice allocated to each of four groups, including the IR group (single-dose 16 Gy cardiac irradiation), ICI group (PD-1 inhibitor 200 μg every 3 days), iRT group (16 Gy cardiac irradiation combined with PD-1 inhibitor), and Control group (IgG). Cardiac function and myocardial senescence were assessed at 28 days, 3 months, and 5 months post-intervention. Additionally, myocardial tissue transcriptomics, non-targeted metabolomics, and acetylated proteomics were performed at 28 days post-intervention, integrated with molecular experiments to investigate the mechanisms of cardiomyocyte senescence. H9C2 cardiomyocytes with FABP3 K45 acetylation-mimetic (K45Q), empty vector (EV), and non-acetylatable (K45R) mutant were used for functional validation.

Combined radioimmunotherapy significantly exacerbated cardiac dysfunction and cardiomyocyte senescence in murine models, manifested with elevated serum levels of cardiac injury biomarkers of cTnI and NT-proBNP, reduced LVEF and LVFS, aggravated myocardial histopathological changes characterized by enhanced inflammatory infiltration, interstitial edema, and myocardium structure disorder in iRT group compared to the other three groups. Concomitantly, compared with other groups, the senescence-associated markers (p16, p21, and SASP factors) in the myocardial tissues of the iRT group were markedly upregulated from 28 days to 5 months. By integrating transcriptomic and non-targeted metabolomics analyses, as well as molecular experiments, we revealed that radioimmunotherapy resulted in dysregulated myocardial metabolism by suppressing ATP production, promoting lipid droplet accumulation, mitochondrial dysfunction, and fatty acid metabolism alterations, particularly involving long-chain polyunsaturated fatty acid (PUFAs) metabolism. Acetylome profiling identified a significant increase in FABP3 K45 acetylation (log2FC = 8.73, P < 0.05) in iRT vs. Control group, with acute-phase elevation (28 days, P < 0.001) and chronic-phase reduction (3 months, P < 0.001). Functional validation in H9C2 cardiomyocytes demonstrated that, compared to EV and K45R groups, FABP3 K45Q attenuated cellular senescence, enhanced mitochondrial oxidative phosphorylation, fatty acid metabolism, and ATP production, while attenuated ROS generation, lipid droplet accumulation, and glycolysis. Metabolomic analysis also revealed the acetylation of FABP3 K45 was significantly associated with the synthesis or accumulation of PUFAs, such as arachidonic acid and linoleic acid, which may alleviate cardiomyocyte senescence by enhancing energy supply and blocking the synthesis of inflammatory mediators.

FABP3 K45 acetylation mitigates radioimmunotherapy-induced cardiomyocyte senescence and metabolic dysfunction, revealing a novel regulatory mechanism that links post-translational modifications to cardiac cellular homeostasis under combined radioimmunotherapy.

This review aims to provide an updated overview of the diagnosis, risk factors, and treatment strategies for immune checkpoint inhibitor (ICI) pneumonitis, with a particular emphasis on its underlying pathophysiology.

Recent advances, such as single-cell RNA sequencing of bronchoalveolar lavage fluid and the identification of biomarkers, including autoantibodies, are enhancing our understanding of ICI-related pneumonitis. These findings suggest that both cell-mediated and humoral mechanisms contribute to the pathophysiology of the condition.

Pneumonitis can significantly limit the efficacy of life-saving cancer treatments, such as ICIs. Although corticosteroids are the first-line treatment according to guidelines, steroid-refractory pneumonitis remains common and is associated with high mortality. Emerging data is providing a more detailed understanding of the dysregulated immune response responsible for pneumonitis, which may guide the development of targeted therapies and direct future research efforts.

Advances in radiation delivery have expanded the scope of stereotactic body radiation therapy (SBRT) in lung cancer treatment, as it offers better local control, shorter treatments, and enhanced immunostimulation. This review summarizes recent literature regarding SBRT's role in nonoperable and operable early-stage, locally advanced, central, and oligometastatic nonsmall cell lung cancer (NSCLC), and its mixed results with immunotherapy.

Recent studies demonstrate SBRT achieves excellent local control in inoperable early-stage NSCLC and is being explored as an alternative to surgery for operable cases. Additionally, SBRT can be done safely in central tumors if strict dose limits to normal structures are observed. SBRT shows promise in locally advanced disease, as consolidative local therapy for oligoprogressive and oligometastatic disease and in combination with immune checkpoint inhibitors. Advances in adaptive radiation therapy and novel fractionation schedules, including ultra-hypofractionation and personalized approaches, further refine SBRT's role in lung cancer management, with more practice changing clinical trials on the horizon.

SBRT provides durable and well tolerated treatment for patients with localized and metastatic lung cancer. With ongoing trials exploring its synergy with immunotherapy and its applicability in operable patients and large tumors, SBRT is poised to play an even greater role in personalized lung cancer treatment.

Follow-up investigations in locally advanced stage non-small cell lung cancer (NSCLC) patients treated with radiochemotherapy (RCHT) regularly focus around lung toxicity. However, Cardiac Adverse Events (CAE) can occur much earlier in patients than originally anticipated with serious repercussions for patient quality-of-life and survival.Therefore, here we investigated spatial dependencies of dose within the heart and their correlation with toxicity, with dosimetric parameters of sub-regions of the heart at the focus of this analysis.Additionally, we aimed to explore the connection between cardiac toxicity and pulmonary toxicity.

Patient treatment plans with dosimetric data for the lungs and the heart, as well as toxicity data for 502 NSCLC patients treated with either passively scattered proton therapy (PSPT), intensity modulated radiation therapy (IMRT), three-dimensional conformal radiation therapy (3DCRT) or volumetric arc therapy (VMAT) with or without chemotherapy was retrospectively retrieved from prospective clinical studies of three international centers. Cardiac toxicity data was not available for all patients. Data was randomly split into a training set (336) and validation set (166). Statistical analyses were performed using binomial logistic regression.

In univariate modeling, the Mean Lung Dose (MLD) significantly predicted CAE grade ≥ 3 in the training-set (pMLD = 0.02, AUCtrain = 0.69), which was confirmed in validation (AUCval, = 0.77). No suitable candidates for the construction of multivariate models could be identified. Parameters of the heart and its subregions did not significantly predict CAE grade ≥ 3 in the investigated cohorts. No parameters were found to significantly predict CAE grade ≥ 2 or RP. Finally, no spatial dependency was found in the investigated toxicity data.

The pulmonary dosimetric parameter MLD successfully predicted CAE grade ≥ 3 in a cohort treated with either photons or protons. Cardiac dosimetric parameters as well as spatial parameters did not perform similarly. No parameters were found to significantly predict RP in the investigated cohorts.

Consolidative PD-L1 inhibitors after concurrent chemoradiotherapy (cCRT) have become standard care in locally advanced non-small cell lung cancer (LA-NSCLC). However, the correlation between immune-related adverse event (irAE) characteristics and patient outcomes remains unclear.

This retrospective study enrolled LA-NSCLC patients who received consolidative PD-L1 inhibitors after CRT at four cancer centers. Patients who received CRT alone were also included for comparison. Associations between irAE characteristics, frequency, timing, affected systems, and severity, and progression-free survival (PFS) and overall survival (OS) were assessed. Tumor immune microenvironment (TIME) features were analyzed to identify subpopulations at higher risk of severe irAEs.

Among 107 patients, 59 (55.1%) developed irAEs; 89.8% were grade 1-2 and 10.2% grade 3-4. Patients with irAEs had significantly longer PFS than those without. Late-onset, single-system, endocrine, and mild irAEs predicted better PFS. In contrast, patients with severe irAEs had worse survival than those without ICI consolidation. TIME analysis revealed that severe irAEs were associated with higher CD103+CD8+ T cells infiltration. A > 1.545% cutoff for CD103+CD8+ T cells may help identify patients less likely to benefit from PD-L1 inhibitor consolidation.

Occurrence of irAEs, particularly late-onset, single-system, or grade 1-2 correlated with greater benefit from consolidative PD-L1 inhibitors in LA-NSCLC. Conversely, severe irAEs predict poorer survival, even compared to no ICI consolidation. Elevated CD103+CD8+ T cell infiltration may serve as a biomarker to identify patients at risk of severe irAEs who may not benefit from immunoconsolidation therapy.

Tumor-associated macrophage (TAM) heterogeneity significantly influences the tumor microenvironment, positioning TAM inhibition as a promising anticancer strategy. Although several TAM subsets have been described, their functional roles remain unclear. In this study, we identified a distinct subset of CD9hiCD63hiCD206+Class IIlo hypoxic TAMs, located near tumors. These TAMs engage in trogocytosis, acquiring tumor membrane fragments, and cross-dress major histocompatibility complex (MHC)/tumor antigen epitopes. These processes facilitate their recognition by cytotoxic T lymphocytes, enhancing antitumor immune responses. We further found CH25H as a key regulator of TAM cross-dressing, with its inhibition associated with the activity of HIF1-α and VHL. These findings highlight the potential of modulating TAMs as an innovative immunotherapy strategy.

Combining radiotherapy with immune checkpoint inhibitors is a promising approach to improve the effectiveness of cancer treatment. However, the success rates of these clinical studies are limited. It is essential to determine the optimal irradiation scheme that maximizes the therapeutic effect by taking into account the balance between the positive and negative effects of radiation on immunity. In this context, we developed a mathematical mechanistic model that simulates (1) the balance between effector and exhausted cytotoxic T-lymphocytes (CTLs), (2) the number of neoantigens released by high-dose irradiation, and (3) the impact of radiation on draining lymph nodes (DLNs) for systemic anti-tumor immunity, and tested whether this mathematic model fits in several animal experiments. Our mechanistic model reproduced the anti-tumor effects of several cancer treatment models for combination therapies with radiation, immune checkpoint inhibitors, and/or a metabolic modulator. Furthermore, this mechanistic model simulated that tumor suppression in distant metastatic foci, known as the abscopal effect, was dysregulated by hypofractionated high-dose irradiation or by the direct radiation exposure on DLN. The mechanistic model successfully reproduced tumor control under various treatment conditions with appropriate parameters, indicating that it may be useful for optimizing immunoradiotherapy prescriptions.

This real-world study aimed to investigate the efficacy of early radiotherapy (RT) in ES-SCLC patients treated with first-line chemo-immunotherapy.

ES-SCLC patients were enrolled from August 2018 to October 2023. Patients who received early radiotherapy before disease progression were defined as Early RT group, while the others, named Salvage and Non-RT (S&N RT) group. Propensity score matching (PSM) with a 1:1 ratio was performed to balance the baseline characteristics.

In this study, 375 patients with ES-SCLC treated with first-line chemo-immunotherapy were enrolled. The median PFS was 11.4 months of the Early RT group compared to 6.1 months of the S&N RT group (HR = 0.59, 95%CI 0.45-0.77; p < 0.001). The median OS was 23.8 months of the Early RT group versus 18.0 months of the S&N RT group (HR = 0.50, 95%CI 0.34-0.73; p = 0.004). The survival benefit persisted in the PSM cohort. Furthermore, survival was significantly improved in Early RT group compared to Salvage RT group (p = 0.028), while Salvage RT group had a similar survival with Non-RT group (p = 0.868). The risk of adverse events was tolerable. The multivariate analysis also demonstrated that early radiotherapy was an independently positive predictor for PFS and OS.

Administering early radiotherapy significantly improved both PFS and OS in patients with ES-SCLC treated with first-line chemo-immunotherapy with tolerable adverse events, while salvage radiotherapy did not improve survival. This finding warrants further validation through prospective randomized studies.

The incidence of radiation pneumonitis (RP) has decreased significantly compared to historical series, mainly due to improved radiotherapy techniques and patient selection. Nevertheless, some patients still develop RP. This guideline provides user-friendly flowcharts to address common clinical practice questions regarding RP. We summarize the current state of the art regarding the mechanisms, risk factors, diagnosis and treatment of RP. Dosimetric constraints to minimize the incidence of RP, as well as risk factors for developing RP, such as idiopathic pulmonary fibrosis (IPF) were identified. The combination of radiotherapy and medication as a risk factor for the development of RP was reviewed. RP remains a diagnosis of exclusion, but an algorithm for reaching the diagnosis has been proposed. Finally, practical approaches to the treatment of RP are outlined.

In recent years, targeted therapy and immunotherapy have been demonstrated to improve survival in non-operable, non-small cell lung cancer (NSCLC) patients. The results of salvage lung resection in patients with initially unresectable advanced NSCLC after immune checkpoint inhibitor (ICI) or Target Therapy (TT) treatment remain unclear. This study aimed to define the outcomes of patients undergoing salvage surgery in a multi-center real-life setting.

An international multicenter retrospective cohort study was conducted. Patients included in the study were judged inoperable, according to a multidisciplinary tumor board decision, before being submitted to ICI or TKI treatment. The rate of complications, the overall survival (OS), and progression-free survival (PFS) were compared. Crude and Multivariable-adjusted analysis were conducted.

Nighty-eight patients affected by NSCLC were included in the study. Most patients were female (N = 50-51 %), and the median age at surgery was 62 years. While ICI was performed in 29 patients (30 %), TT was done in 45 (46 %), and ICI plus chemotherapy in 24 (24 %). The inoperability was determined by metastatic disease in 43 cases (44 %), N2-N3 advanced disease in 18 (18 %), local invasiveness in 10 (10 %), a combination of local invasiveness and N-status in 26 (27 %), and other reasons in 1 case (1 %). Overall, the complication rate was 30 %, the mortality rate was 1 %, and the median LOS was 6 days. No residual lung disease (ypT0) was observed in 30 patients (31 %). The 5-year OS was 74 %, while the 5-year PFS was 44 %. Performing sublobar resections was an independent adverse prognostic factor in the multivariable analysis for survival (P < 0.01), while the pathological complete response (pCR) was an independent prognostic predictor of improved survival (P = 0.025). On multivariable analysis performing a sublobar resection (P < 0.01), an increasing ypT stage (P < 0.01), and postoperative therapy (P < 0.01) were independent prognostic predictors, correlating with impaired disease progression.

Patients selected for Salvage Surgery after ICI or TT have reasonable post-operative and long-term outcomes. In this context, Salvage Surgery could be proposed in selected patients after a careful multidisciplinary evaluation.

Immune checkpoint inhibitor-induced type 1 diabetes mellitus (ICI-T1DM) is a rare adverse reaction associated with durvalumab. Among the adverse reactions to durvalumab, the incidence of new-onset diabetes is relatively rare, occurring in ~0.2% of cases. The present study reports the case of a 62-year-old woman who developed ICI-T1DM following two cycles of durvalumab, presenting with thirst, polydipsia and polyuria. Laboratory examinations (glycated hemoglobin and glutamic acid decarboxylase antibody), along with consultations from an endocrinologist, led to the patient being diagnosed with ICI-T1DM. Immunotherapy was discontinued, and insulin replacement therapy was initiated. Blood glucose levels were closely monitored using a subcutaneous meter. The onset of diabetic ketoacidosis (DKA) was prevented due to timely treatment. In conclusion, medical oncologists need to be aware that durvalumab, an immunotherapy agent, can induce ICI-T1DM. Therefore, regular monitoring of blood glucose levels and collaborative consultations with endocrinologists are essential for an accurate diagnosis when elevated blood sugar levels are detected. The prompt diagnosis of ICI-T1DM is crucial to prevent the occurrence of DKA.

Consolidation immunotherapy with immune checkpoint Inhibitor (ICI) Durvalumab is an effective treatment for inoperable stage III non-small cell lung cancer (NSCLC) patients with a PD-L1 expression ≥ 1% after definitive curative concurrent chemoradiotherapy (CCRT). While this approach is widely used as standard therapy, it carries an increased risk of immune-related and radiation-induced pneumonitis. Currently, there is no data on pneumonitis in patients receiving CCRT with an overall dose of 70 Gy (Gy) compared with the standard protocol of 60 Gy ± 10% in this setting.

This study analyzed retrospective data from 39 patients with unresectable NSCLC treated with CCRT. Patients received either 70 Gy (n = 29) or lower than 70 Gy total dose (n = 10) in 2 Gy fractions. Cases of pneumonitis were further classified as RI‑P (Radio-induced Pneumonitis) and ICI‑P (ICI Pneumonitis) based on clinical and radiological findings.

Of the 39 patients, 15 (38.5%) developed pneumonitis, with 10 out of 29 (34.5%) in the 70 Gy group and five out 10 (50%) in the < 70 Gy group. There was no significant difference in pneumonitis and in occurrence of ICI‑P vs. RI‑P (26.7% vs. 73.3%) within both groups. The 70 Gy group showed a significant benefit in mortality (p = < 0.001). Overall survival (OS) differed significantly between groups (p =0.028).

70 Gy radiation dose for CCRT followed by durvalumab is a safe regimen and may provide clinical benefits in NSCLC patients compared to lower doses. Pneumonitis incidence aligns with previous literature. The higher dose is associated with improved overall survival, and reduced disease progression, potentially due to a longer consolidation time.

Consolidative radiation is increasingly regarded as an effective treatment for oligometastatic and oligoprogressive non-small cell lung cancer (NSCLC). This systematic review examines the clinical evidence on the significance of consolidative radiation in improving outcomes in NSCLC, including progression-free survival and overall survival. Innovations in radiotherapy, including stereotactic body radiotherapy and intensity-modulated radiotherapy, have enhanced the accuracy and effectiveness of local control in oligometastatic disease. This paper analyzes the integration of consolidative radiotherapy with systemic agents, including immunotherapy and targeted therapy, along with the application of biomarkers such circulating tumor DNA for patient selection. Our findings indicate that consolidative radiotherapy could benefit some patients with controlled oligometastatic NSCLC following systemic therapy, emphasizing the importance of proper patient selection. Additional research is necessary to optimize treatment combinations and develop biomarkers for better patient stratification in consolidative radiotherapy.

The effectiveness of neoadjuvant immuno-chemotherapy in stage III non-small cell lung cancer (NSCLC) patients undergoing definitive concurrent/sequential chemo-radiotherapy (CRT) is not well established.

This retrospective study involved stage III NSCLC patients treated at the Third Xiangya Hospital and Xiangxi Autonomous Prefecture People's Hospital. We compared prognosis, dosimetric outcomes, and radiation pneumonitis incidence between those receiving neoadjuvant immuno-chemotherapy and those undergoing immunotherapy maintenance after CRT. Tumor assessments were conducted on patients administered 2-4 cycles of immuno-chemotherapy, and diagnostic CT images of 54 patients were analyzed for treatment impact.

A total of 76 patients received neoadjuvant immuno-chemotherapy followed by CRT, while 68 received immunotherapy after CRT. The median progression-free survival (PFS) for the neoadjuvant group was 29.3 months compared to 13.4 months for the maintenance group (p < 0.001). Median overall survival (OS) was not reached for the neoadjuvant group, while it was 37.4 months for the maintenance group (p = 0.004). Uni-variable analysis indicated neoadjuvant immuno-chemotherapy as an independent OS prognostic factor. The disease control rate was 99.09 %, and significant reductions in tumor volume and radiation doses to healthy tissues were observed post-treatment.

Our findings suggest neoadjuvant immuno-chemotherapy improves prognosis for stage III NSCLC patients and effectively reduces tumor volume and organ-at-risk radiation exposure, warranting further phase III trials.

Chemoradiotherapy (CRT) followed by durvalumab is the standard of care for unresectable locally advanced NSCLC. Limited prospective data have been reported on intensity-modulated radiotherapy (IMRT)-adapted CRT in the immunotherapy era.

In this multicenter prospective observational study, patients underwent IMRT-adapted CRT (platinum-doublet chemotherapy plus 60 Gy IMRT in 30 fractions under a prespecified radiation protocol), followed by consolidative durvalumab. The primary outcome was the durvalumab introduction rate within 42 days post-CRT.

Thirty-two patients with unresectable locally advanced NSCLC were enrolled between November 2019 and February 2021. Among the 28 evaluable cases, durvalumab was introduced in 24 (85.7%, 90% confidence interval: 70.2%-95.0%) of 28 patients after CRT, achieving the primary end point. All 29 patients who received IMRT completed the scheduled 60 Gy radiotherapy dose. One year of durvalumab treatment was completed in 12 of 24 patients (50%). In the 24 patients who were durvalumab-introduced, the median progression-free survival and overall survival were 20.9 (95% confidence interval: 6.9-not evaluable) months and not reached, respectively. Two-year progression-free survival and overall survival rates were 44% and 73%, respectively. Among the 29 patients in the safety analysis set, there were no treatment-related deaths or grade 4 nonhematological adverse events. Pneumonitis grade 1 was observed in 13 patients (45%), grade 2 in seven (24%), and grade 3 in one (3%).

High durvalumab introduction rate was reported after the completion of IMRT-adapted CRT under a prespecified radiation protocol. Its efficacy has been suggested, with favorable safety profiles, including a low incidence of severe pneumonitis.

University Hospital Medical Information Network database ID: UMIN000038366.

Immune checkpoints are crucial in regulating the activation of cell-mediated and humoral immune responses. However, cancer cells hijack this mechanism to evade the immune surveillance and anti-cancer response. Typically, receptors like PD-1 and CTLA4, expressed on immune cells, prevent the activation and differentiation of T cells. They also inhibit the development of autoimmune reactions. However, ligands such as PD-L1 for the receptor PD-1 are also expressed on the surface of cancer cells that help prevent the activation of anti-cancer immune responses by blocking the signalling pathways mediated by PD-1 and CTLA4. Immune checkpoint inhibitors (ICIs) have promising therapeutic efficacy for treating several cancers by activating T cells and their differentiation into effector cells against tumours. Nonetheless, hyperactivated immune cells usually contribute to detrimental issues, also known as immune-related adverse effects (IrAE). IrAEs have been observed in multiple organs, leading to neurological issues, colitis, endocrine dysfunction, renal issues, hepatitis, pneumonitis, and dermatitis. The interplay between hyperactivated T cells and Treg cells helps in orchestrating the development of autoimmunity. Moreover, the crosstalk between proinflammatory interleukins and the development of autoantibodies also mediates the multiorgan effects of ICIs in cancer patients. IrAEs are generally managed by terminating the ICI therapy, reducing the ICI dose, and by using corticosteroids to subvert inflammation. Therefore, the present review aims to delineate the impacts of ICIs on the development of autoimmune diseases and inflammatory outcomes in cancer patients. In addition, mechanistic insight involving immune cells, cytokines, and autoantibodies for ICI-mediated IrAEs will also be discussed with updated findings in this field.

Definitive concurrent chemoradiotherapy (CRT) is the primary curative-intent treatment option for unresectable locally advanced nonsmall-cell lung cancer (NSCLC). Completion of CRT is generally required for eligibility for consolidation durvalumab, which significantly improves survival. We sought to establish CRT completion rates at a comprehensive cancer center.

265 patients were treated with concurrent CRT over the decade 2012-2022, during which durvalumab became available. 63% were male, median age was 67, and 91% had performance status 0-1. All patients were recruited into the AURORA prospective cohort study which captured baseline demographics and comorbidities, and prospectively updated treatment and outcome data at subsequent hospital visits. Data were analyzed retrospectively to evaluate CRT completion rates, reasons for noncompletion, and survival outcomes. Survival was also analyzed based on durvalumab availability and administration.

CRT was completed as planned by 246/265 (93%) patients. Reasons for noncompletion included treatment related toxicity (n = 6/19), unrelated illnesses (n = 7/19), local disease progression (n = 2/19), and distant progression (n = 4/19). Median overall survival (OS) was 2.2 years (95% CI, 1.7-2.8) for the entire cohort and 1.0 years (95% CI, 0.2-1.5) for those who ceased CRT early. No specific baseline characteristics predicted noncompletion of CRT. Consolidation durvalumab was associated with improved OS (HR 0.39; 95% CI, 0.21-0.72, P = .002).

With appropriate supportive care, most patients initially considered suitable for CRT could complete it and access consolidation durvalumab. Consolidation durvalumab was associated with improved survival in this "real-world" stage III NSCLC cohort.

We report a case of lung squamous cell carcinoma with bronchomediastinal fistula and mediastinitis caused by aggressive locoregional recurrence following bronchoscopic tumour debulking, chemoradiotherapy and durvalumab. Despite initial tumour regression, rapid regrowth led to airway penetration and infection, highlighting the challenges of managing central airway-invasive relapses.

Neoadjuvant chemoimmunotherapy has been successfully used in patients with resectable non-small-cell lung cancer (NSCLC). However, its application to potentially resectable IIIA/IIIB NSCLC remains controversial. This retrospective study aims to evaluate the efficacy and safety of neoadjuvant chemoimmunotherapy followed by conversion surgery in patients with potentially resectable stage III NSCLC, focusing on conversion rate and survival benefits. Patients with 'potentially resectable' stage IIIA/IIIB NSCLC who were deemed unsuitable for complete (R0) resection at initial diagnosis were retrospectively identified. After 2-4 cycles of treatment, all patients were reevaluated for surgical resectability. Data on patient characteristics, radiological and pathological responses, and survival outcomes were collected. In total, 148 patients were included in the final analysis. Upon the completion of neoadjuvant therapy, 105 patients were considered suitable for conversion surgery. Three patients refused surgery, and 102 patients ultimately underwent surgery, yielding a conversion rate of 70.9% and a resection rate of 68.9%. The rate of complete (R0) resection was 100%, with a major pathological response (MPR) of 64.7% and a pathologic complete response (pCR) of 41.2%. Postoperative complications were observed in nine patients (8.8%), and there was no surgery-related mortality within 30 days. The median progression-free survival (PFS) was 19.1 months in the non-surgery group, and the overall survival (OS) was not reached. In the 102 patients who underwent conversion surgery, both the median PFS and OS were not reached, accompanied by 2-year OS and PFS rates of 87.3% and 78.4%, respectively. Our findings showed that neoadjuvant chemoimmunotherapy expanded the opportunities for conversion surgery in potentially resectable cases. Subsequent conversion surgery is safe and has the potential for significant survival benefits.

This study evaluated the efficacy and safety of thoracic radiotherapy (TRT) after first-line chemotherapy or chemoimmunotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC), focusing on the impact of different TRT timing strategies (consolidative vs. salvage) on survival. A total of 54 ES-SCLC patients treated between January 2019 and July 2022 were retrospectively analyzed. Patients receiving consolidative TRT (cTRT) within 3 months after first-line treatment completion were compared to those receiving salvage TRT (sTRT) following disease progression. Primary endpoints included overall survival (OS), progression-free survival (PFS), locoregional-free survival (LRFS), and distant metastasis-free survival (DMFS); safety was a secondary endpoint. The cTRT group (n=41) showed significantly longer median OS (26.6 vs. 14.8 months, P=0.048), PFS (12.9 vs. 3.5 months, P< 0.0001), and DMFS (10.7 vs. 3.4 months, P= 0.0044) than the sTRT group (n=13). Multivariate analysis identified cTRT as an independent favorable prognostic factor. No significant differences in OS or LRFS were found between high-dose (≥50 Gy) and low-dose (<50 Gy) TRT. Hematologic and respiratory toxicities were the most common adverse events, with acceptable tolerability. In conclusion, consolidative TRT after chemoimmunotherapy significantly improves survival outcomes in ES-SCLC patients, and low-dose TRT may be a suitable option.

This study aimed to investigate the safety and efficacy of programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibody-based therapy in treating patients with advanced non-small cell lung cancer (NSCLC) according to different PD-L1 expression statuses in a real-world setting.

This retrospective, multicenter, observational study enrolled adult patients who received PD-1/PD-L1 antibody-based therapy in China and met the following criteria: (1) had pathologically confirmed, unresectable stage III-IV NSCLC; (2) had a baseline PD-L1 tumor proportion score (TPS); and (3) had confirmed efficacy evaluation results after PD-1/PD-L1 treatment. Logistic regression, Kaplan-Meier analysis, and Cox regression were used to assess the progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) as appropriate.

A total of 409 patients, 65.0% (n = 266) with a positive PD-L1 TPS (≥1%) and 32.8% (n = 134) with PD-L1 TPS ≥50%, were included in this study. Cox regression confirmed that patients with a PD-L1 TPS ≥1% had significantly improved PFS (hazard ratio [HR] 0.747, 95% confidence interval [CI] 0.573-0.975, P = 0.032). A total of 160 (39.1%) patients experienced 206 irAEs, and 27 (6.6%) patients experienced 31 grade 3-5 irAEs. The organs most frequently associated with irAEs were the skin (52/409, 12.7%), thyroid (40/409, 9.8%), and lung (34/409, 8.3%). Multivariate logistic regression revealed that a PD-L1 TPS ≥1% (odds ratio [OR] 1.713, 95% CI 1.054-2.784, P = 0.030) was an independent risk factor for irAEs. Other risk factors for irAEs included pretreatment absolute lymphocyte count >2.5 × 109/L (OR 3.772, 95% CI 1.377-10.329, P = 0.010) and pretreatment absolute eosinophil count >0.2 × 109/L (OR 2.006, 95% CI 1.219-3.302, P = 0.006). Moreover, patients who developed irAEs demonstrated improved PFS (13.7 months vs. 8.4 months, P <0.001) and OS (28.0 months vs. 18.0 months, P = 0.007) compared with patients without irAEs.

A positive PD-L1 TPS (≥1%) was associated with improved PFS and an increased risk of irAEs in a real-world setting. The onset of irAEs was associated with improved PFS and OS in patients with advanced NSCLC receiving PD-1/PD-L1-based therapy.

Patients with borderline resectable or unresectable stage III non-small cell lung cancer (NSCLC) with T4 and/or N2-N3 involvement face limited treatment options and poor outcomes. Neoadjuvant chemoimmunotherapy has shown promise in improving resectability and pathological responses.

To evaluate the efficacy of neoadjuvant programmed cell death 1 protein (PD-1) or programmed cell death 1 ligand 1 (PD-L1) blockade combined with chemotherapy in enhancing surgical outcomes and pathological responses in patients with T4 and/or N2-N3 stage III NSCLC.

This multicenter cohort study analyzed data from patients treated between February 2018 and January 2024 with neoadjuvant PD-1/PD-L1 inhibitors plus chemotherapy at academic and tertiary care centers across the US and Italy. Pathological and survival outcomes were assessed. Patients with stage III NSCLC and T4 and/or N2-N3 involvement were included. Data were collected from February 2018 to January 2024.

Neoadjuvant PD-1/PD-L1 blockade combined with platinum-based chemotherapy.

Pathological complete response (pCR), major pathological response, surgical resectability, and event-free survival (EFS).

Of 112 patients, 58 (51.8%) were female, and the median (range) age was 66 (41-84) years. A total of 84(75.0%) underwent surgical resection, achieving a pCR rate of 29.0% (24 of 83 with available final pathology) and a major pathological response rate of 42.2% (35 of 83). Patients with both PD-L1 expression of 50% or more and high tumor mutational burden achieved the highest pCR rate (4 of 9 [44.4%]; P = .03). Conversely, covariants in KRAS/STK11 or KRAS/KEAP1 were associated with lack of pCR. Patients with single-station or multistation N2/N3 disease exhibited comparable pathological outcomes. The median EFS for all resected patients was 52.6 months (95% CI, 27.8 to not reached), and this was significantly longer in patients with pCR (not reached vs 27.8 months [95% CI, 19.5 to not reached]; P < .001).

In this study, neoadjuvant PD-1/PD-L1 blockade combined with chemotherapy resulted in high pathological response rates and surgical resectability in patients with T4 and/or N2-N3 stage III NSCLC. This approach offers a viable treatment option for patients with borderline resectable or unresectable NSCLC but requires further validation through prospective studies.

The PACIFIC trial showed that immune checkpoint inhibitors (ICI) administered after concurrent chemoradiotherapy (cCRT) significantly improve survival in stage III unresectable non-small cell lung cancer (NSCLC). However, the optimal timing of ICI administration with cCRT is still debated, with concerns about increased risks of adverse effects, particularly radiation-induced pneumonitis (RP), from combining radiotherapy and immunotherapy.

A search of multiple databases identified studies on stage III unresectable NSCLC patients receiving cCRT and ICI. A meta-analysis was performed utilizing the meta package in R software. Furthermore, data from 170 patients treated at Shandong Cancer Hospital and Institute between 2019 and 2023 were analyzed to assess RP following cCRT and ICI treatment.

The meta-analysis revealed that the incidences of ≥grade 2 RP were 25.3%, 24.3%, and 45.3% in the ICI following cCRT group, the ICI concurrent with cCRT group, and the ICI prior to cCRT group, respectively. The ICI prior to cCRT group exhibited significantly elevated rates. In the clinical retrospective study, ≥grade 2 RP was more prevalent in the ICI concurrent with cCRT group (HR: 2.258, 95% CI: 1.135-4.492, p = 0.020) and the ICI prior to cCRT group (HR: 2.843, 95% CI: 1.453-5.561, p = 0.002) compared with the ICI following cCRT group. Furthermore, a shorter interval between treatments correlates with an increased incidence of RP.

Advancing the timing of ICI administration is associated with an increased incidence of ≥grade 2 RP following cCRT in patients with stage III unresectable NSCLC.

Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review focuses on the evasive attributes of the TME. Immune evasion mechanism in TME include immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations and overexpression of immune checkpoint molecules such as PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA and their interactions within the TME. In addition, this review focuses on the overcoming resistance by targeting immunosuppressive cells, normalizing tumor blood vessels, blocking two or three checkpoints simultaneously, combining vaccines, oncolytic viruses and metabolic inhibitors with ICIs or other therapies. This review also focuses on the necessity of finding predictive markers for the stratification of patients and to check response of ICIs treatment. It remains to be made certain by new research and intelligent innovations how these discoveries of the TME and its interplay facilitate ICI treatment and change the face of cancer treatment.

The treatment landscape of non-small-cell lung cancer (NSCLC) is evolving rapidly, driven by advances in the development of targeted agents and immunotherapies. Despite this progress, some patients have suboptimal responses to treatment, highlighting the need for new therapeutic strategies. In the past decade, the important role of the tumour microenvironment (TME) in NSCLC progression, metastatic dissemination and response to treatment has become increasingly evident. Understanding the complexity of the TME and its interactions with NSCLC can propel efforts to improve current treatment modalities, overcome resistance and develop new treatments, which will ultimately improve the outcomes of patients. In this Review, we provide a comprehensive view of the NSCLC TME, examining its components and highlighting distinct archetypes characterized by spatial niches within and surrounding tumour nests, which form complex neighbourhoods. Next, we explore the interactions within these components, focusing on how inflammation and immunosuppression shape the dynamics of the NSCLC TME. We also address the emerging influences of patient-related factors, such as ageing, sex and health disparities, on the NSCLC-TME crosstalk. Finally, we discuss how various therapeutic strategies interact with and are influenced by the TME in NSCLC. Overall, we emphasize the interconnectedness of these elements and how they influence therapeutic outcomes and tumour progression.

Chemoradiotherapy (CRT) followed by durvalumab (CRT → durvalumab) is standard of care to treat patients with unresectable, stage III non-small cell lung cancer (NSCLC). The RELEVANCE study was designed to provide real-world effectiveness and safety data for CRT → durvalumab in Canadian settings.

RELEVANCE was a retrospective, observational, multicenter chart review that included adult patients with unresectable, stage III NSCLC treated with CRT alone or CRT → durvalumab at 5 Canadian cancer centers. Key outcomes included treatment patterns, adverse events of special interest (AESI), and overall survival (OS).

487 patients were included (144 CRT alone; 343 CRT → durvalumab). Median follow-up was 43.1 and 35.8 months for the CRT alone and CRT → durvalumab groups, respectively. The most frequently observed regimen included radiotherapy dose 54-66 Gy and radiosensitizing carboplatin. Median treatment duration was 1.5 months (CRT alone) and 13.4 months (CRT → durvalumab), and 47 % of patients completed a full course of durvalumab. Median OS and 3-year OS rate were 21.3 months and 32 % for CRT alone and 44.6 months and 56 % for CRT → durvalumab. Exploratory analysis by programmed cell death-ligand 1 (PD-L1) expression status of the CRT → durvalumab group noted 3-year OS rates of 69 %, 44 %, and 39 % in the PD-L1 ≥ 50 % (high), 1 %-49 % (intermediate), and < 1 % (negative) populations, respectively (32 %, 38 %, and 24 % for CRT alone, respectively). PD-L1 high expression was associated with lower risk of death vs. PD-L1 negative expression (P < 0.05). The most common AESI with CRT → durvalumab was pneumonitis. Median OS for patients who completed durvalumab was not reached and was 41.3 months among patients who discontinued durvalumab due to AEs.

Results validate the treatment benefit and safety of the PACIFIC regimen in real-world Canadian settings. Among patients who received CRT → durvalumab, there was a correlation between increasing PD-L1 status and improved OS; however, shorter OS was observed in patients discontinuing durvalumab early due to AEs.

Real-world Canadian RELEVANCE study validates effectiveness and safety of durvalumab in patients with unresectable, stage III NSCLC.

Approximately 20% to 30% of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) experience disease relapse despite definitive chemoradiotherapy. The programmed cell death 1 (PD-1) blockade camrelizumab has demonstrated considerable value in recurrent or metastatic NPC, while its role in locoregionally advanced NPC is unclear.

To evaluate the efficacy and safety of adjuvant camrelizumab for patients with locoregionally advanced NPC.

Randomized, open-label, multicenter, phase 3 clinical trial conducted from August 2018 to November 2021 at 11 centers in China and enrolling 450 patients with T4N1M0 or T1-4N2-3M0 NPC who had completed induction-concurrent chemoradiotherapy. The final date of follow-up was March 20, 2024.

Patients were randomized (1:1) to receive adjuvant camrelizumab (200 mg intravenously once every 3 weeks for 12 cycles; n = 226) or observation (standard therapy group; n = 224).

The primary end point was event-free survival (freedom from distant metastasis, locoregional relapse, or death due to any cause). Secondary end points included distant metastasis-free survival, locoregional relapse-free survival, overall survival, safety, and health-related quality of life.

Among the 450 participants (mean age, 45 [SD, 10] years; 24% women), after a median follow-up of 39 (IQR, 33-50) months, the camrelizumab group had a 3-year event-free survival rate of 86.9%, whereas the standard therapy group had a rate of 77.3% (stratified hazard ratio, 0.56; 95% CI, 0.36-0.89; P = .01). Grade 3 or 4 adverse events were reported in 23 patients (11.2%) in the camrelizumab and 7 (3.2%) in the standard therapy group. Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab, occurring in 85.8% of patients at grade 1 or 2, while 2% of patients had grade 3 or 4 events. There was no significant deterioration in quality of life associated with camrelizumab treatment.

Adjuvant PD-1 blockade with camrelizumab significantly improved event-free survival with manageable toxicities, highlighting its potential role in the management of locoregionally advanced NPC.

ClinicalTrials.gov Identifier: NCT03427827.

Tumor Area Positivity (TAP) score is an emerging score measuring programmed death-ligand 1 (PD-L1) expression in tumors. However, the availability of concordance data between TAP score and other immunohistochemistry scoring methods is limited. We investigated concordance between TAP score and combined positive score (CPS) and the relationship between PD-L1 status and clinical outcomes using gastric/gastroesophageal junction adenocarcinoma (GC/GEJC) and esophageal squamous cell carcinoma (ESCC) samples from patients subsequently treated with tislelizumab. Baseline tissue samples from RATIONALE-305 (GC/GEJC; NCT03777657), RATIONALE-302 (ESCC; NCT03430843), and RATIONALE-306 (ESCC; NCT03783442) were assessed for PD-L1 expression using an investigational-use only version of the VENTANA PD-L1 (SP263) CDx Assay. PD-L1 status was scored per protocol by TAP score and post-hoc by TAP score and CPS depending on the cutoff used. Concordance and correlation of both scores with clinical and safety outcomes were analyzed. Across all trials, agreement between TAP score and CPS was significant at PD-L1 cutoffs of ≥1%/≥1, ≥5%/≥5, and ≥10%/≥10 (Cohen's Kappa, 0.64-0.85). Similar outcomes for overall survival (OS), progression-free survival, objective response rate, and duration of response were observed between TAP score- and CPS-defined PD-L1-positive subgroups at analogous PD-L1 cutoffs. OS hazard ratios (HRs) in the PD-L1-high subgroups were similar between protocol-defined TAP score and the same numeric CPS value (OS HR [95% confidence interval]: RATIONALE-305, 0.72 [0.59-0.88] and 0.73 [0.60-0.89]; RATIONALE-302, 0.52 [0.35-0.76] and 0.54 [0.37-0.78]; RATIONALE-306, 0.63 [0.45-0.89] and 0.58 [0.42-0.81], respectively). Safety outcomes were generally comparable between all PD-L1 subgroups. In conclusion, TAP score and CPS are clinically comparable immunohistochemistry measures of PD-L1 expression in tislelizumab-treated patients with GC/GEJC or ESCC.