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.

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.

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.

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.

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.

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.

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.

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.

Durvalumab has demonstrated significant efficacy in several types of malignancies, while large-scale real-world safety studies remain limited. This study aimed to systematically evaluate the safety of durvalumab through data mining of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We extracted reports of durvalumab as the primary suspected drug from the FAERS database (January 2017 to June 2024). Four disproportionality analysis algorithms were used to detect signals between durvalumab and adverse events (AEs). Durvalumab was recorded in 10,120 reports as the primary suspected drug. Of these, 43.6% of AEs occurred during the first month of treatment, with a median onset time of 40 days (IQR: 14-99 ). Among 181 potential signals, 64 were unexpected preferred terms not listed in the prescribing information, including cytokine release syndrome (CRS), pulmonary tuberculosis, radiation esophagitis, oesophageal fistula, oesophageal perforation, pleural effusion, pneumothorax, cerebral infarction, biliary tract infection, cholecystitis, psoriasiform dermatitis, portal vein thrombosis, acute cholangitis and pericarditis malignant. Serious adverse events accounted for 93.3% of cases. Males exhibited a significantly higher risk of experiencing serious outcomes compared to females (OR = 1.83, 95% CI: 1.52-2.19, P < 0.001). Older age groups demonstrated an elevated risk of severe outcomes relative to those under 65 years (65-74 years: OR = 1.52, 95% CI: 1.15-2.00, P = 0.003; ≥75 years: OR = 1.40, 95% CI: 1.02-1.92, P = 0.038). This study comprehensively assessed the safety of durvalumab and discovered potential new adverse event signals, which may provide critical support for risk identification and monitoring of durvalumab.

Neoadjuvant short-course radiotherapy (SCRT) followed by camrelizumab and chemotherapy has shown an encouraging pathological complete response rate (48.1%, primary endpoint) in patients with locally advanced rectal cancer (LARC). Here, we present the 3-year survival outcomes.

In this phase 2 trial, patients with previously untreated T3-4N0M0 or T1-4N + M0 rectal adenocarcinoma received 5 × 5 Gy SCRT over 5 days, followed by two cycles of camrelizumab (200 mg) and CAPOX regimen every 3 weeks after 1 week. Total mesorectal excision (TME) was scheduled 1 week after the completion of neoadjuvant treatment. The 3-year disease-free survival (DFS) and overall survival (OS) were evaluated in this analysis.

A total of 30 patients were enrolled, of whom 28 (93.3%) had microsatellite stable status (MSS) and 27 (90.0%) underwent TME. With a median follow-up of 40.8 months, the median DFS and OS were both not reached, with the 3-year DFS and OS rates of 80.2% (95% CI 58.6-91.3) and 93.3% (95% CI 75.9-98.3), respectively. Additionally, there was a trend toward improved 3-year DFS and OS in patients with pCR, postoperative pathological node-negative status (pN0), baseline negative circumferential resection margin as assessed by MRI, baseline negative extramural venous invasion and a PD-L1 combined positive score of 1 or higher, as compared with those without these characteristics.

Our data support the potential efficacy of neoadjuvant SCRT followed by camrelizumab and CAPOX regimen in LARC, as indicated by 3-year survival outcomes, suggesting that this may be an alternative therapeutic strategy, especially with the potential to address an unmet need for MSS patients.

www.

gov . NCT04231552.

Tumor-infiltrating CD8+ T cells are critical for anti-tumor immunity and positively associated with patient survival. However, the mechanisms governing CD8+ T cell infiltration remain incompletely elucidated, particularly those involving circular RNAs (circRNAs). In this study, we characterized circRNA expression profiles in four paired normal and tumor tissues of non-small-cell lung cancer (NSCLC) and identified that circFNDC3B, a circular transcript derived from exons 2 and 3 of the fibronectin type III domain containing 3B (FNDC3B) gene, as significantly upregulated in NSCLC tissues. Mechanistic investigations revealed that circFNDC3B directly binds to transcription factor II-I (TFII-I), forming an RNA-protein complex that competitively disrupts the interaction between TFII-I and STAT1. This sequestration abrogates the transcriptional activation of CXCL10 and CXCL11, two critical chemokines governing CD8+ T cell chemoattraction. Consequently, reduced CXCL10/11 expression significantly impairs CD8+ T cell infiltration into the tumor microenvironment. Consistently, the murine ortholog circFndc3b expression exhibits an inverse correlation with CD8+ T cell infiltration in tumors. Our study uncovers a crucial circRNA-mediated regulatory axis wherein circFNDC3B impedes anti-tumor immunity by suppressing chemokine-dependent CD8+ T cell recruitment, positioning circFNDC3B as a potential therapeutic target to enhance CD8+ T cell-mediated anti-tumor responses in NSCLC.

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.

The standard of care for unresectable locally advanced non-small cell lung cancer (LA-NSCLC) includes post-chemoradiotherapy durvalumab consolidation therapy. However, moderate symptomatic pneumonitis (Grade 2) constitutes a significant adverse event that frequently leads to treatment interruption and warrants careful consideration of re-administration. We evaluated the efficacy and safety of durvalumab re-administration after recovery from grade 2 pneumonitis.

This retrospective study included 208 patients with LA-NSCLC who received post-chemoradiotherapy durvalumab consolidation therapy at seven institutions between July 2018 and March 2022. Among them, 62 developed Grade 2 pneumonitis that led to treatment interruption and were stratified into the durvalumab re-administration (n = 33) and durvalumab non-re-administration (n = 29) groups. Survival outcomes were analyzed using the Cox proportional hazards model.

Participants in the durvalumab re-administration group had significantly longer progression-free survival (PFS; 32.0 months [95 % confidence interval (CI): 11.7-Not Available (NA)] vs. 5.3 months [95 % CI: 3.5-17.4], P = 0.003) and overall survival (OS; not reached [95 % CI: 29.0-NA] vs. 27.1 months [95 % CI: 12.1-NA], P = 0.012) than in the durvalumab non-re-administration group. Pneumonitis recurred in 30.3 % of the re-administration group, albeit without Grade ≥ 3 events. Multivariate analysis identified durvalumab re-administration as an independent predictor of improved survival, with hazard ratios of 0.31 (95 % CI: 0.15-0.65, P = 0.002) for PFS and 0.33 (95 % CI: 0.13-0.82, P = 0.017) for OS.

Durvalumab re-administration after grade 2 pneumonitis was associated with prolonged survival and a low recurrence rate of mild pneumonitis, which suggests that re-administration is a feasible, effective strategy with adequate monitoring.

The PACIFIC trial established chemoradiation followed by 1-year durvalumab consolidation as standard of care for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). This study aims to investigate therapeutic strategies and clinical outcomes after durvalumab failure in the real-world.

Patients with stage III LA-NSCLC from 23 Italian centres were retrospectively enrolled at durvalumab progression. Subsequent treatments (Sub-Tx) were prospectively collected and classified as follows:chemo-immunotherapy (subgroup-1), platinum-based chemotherapy (subgroup-2), non-platinum-based chemotherapy (subgroup-3), and targeted therapy (subgroup-4). Durvalumab progression free survival (Dur-PFS) and overall survival (Dur-OS), as well as outcomes of Sub-Tx (Sub-PFS and Sub-OS) were estimated by using the Kaplan-Meier approach.

A total of 122 patients were enrolled. Median Dur-PFS was 9.3 months (95 % CI: 7.1 - 11.4) and median Dur-OS 24.2 months (95 % CI: 18.7 - 29.7). Out of 93 patients receiving a Sub-Tx, 21.5 %, 43.0 %, 28.0 %, and 7.5 % were in the subgroup 1, 2, 3, and 4, respectively. Median Sub-PFS were 12.0, 4.1, 2.7, and 6.0 months, respectively. Patients who completed 12 months of durvalumab were 65.0 %, 27.5 %, 19.2 %, and 42.9 % across the four subgroups. In univariate analysis, the duration of durvalumab therapy was an independent factor for selecting Sub-Tx (p < 0.007). Median time to next treatment (TTNT) was 6.7 months with chemo-immunotherapy and 2.1 with chemotherapy (p = 0.009). Out of 15 patients with a TTNT > 1 year, 40 % were rechallenged with immunotherapy.

Platinum-based chemotherapy was the predominant treatment after durvalumab consolidation. Immunotherapy rechallenge was associated with the best survival outcome in selected cases, warranting further investigation.

The emergence of immune checkpoint inhibitors (ICIs) has revolutionized standard therapies for non-small cell lung cancer (NSCLC) [...].

The selective modulation of membrane proteins presents a significant challenge in drug development, particularly in cancer therapies. However, conventional small molecules and biologics often face significant hurdles in effectively targeting membrane-bound proteins, largely due to the structural complexity of these proteins and their involvement in intricate cellular processes. In light of these limitations, proximity-induced protein modulation has recently emerged as a transformative approach. It leverages molecule-induced proximity strategies to commandeer endogenous cellular machinery for precise protein manipulation. One of these modulatory strategies is protein degradation, wherein membrane-targeting degraders derived from proximity-induction approaches offer a unique therapeutic avenue by inducing the irreversible removal of key oncogenic and immune-regulatory proteins to combat cancer. This review explores the fundamental principles underlying proximity-driven membrane protein degradation, highlighting key strategies such as LYTACs, PROTABs, TransTACs, and IFLD that are reshaping targeted cancer therapy. We discuss recent technological advancements in the application of proximity-induced degraders across breast cancer, lung cancer, immunotherapy, and other malignancies, underscoring how these innovative approaches have demonstrated significant therapeutic potential. Lastly, while these emerging technologies offer significant promise, they still face substantial limitations, including drug delivery, selectivity, and resistance mechanisms that need to be addressed to achieve successful clinical translation.

To explore the efficacy and safety of neoadjuvant chemoradiotherapy (NCRT) plus sequential tislelizumab followed by surgery for esophageal squamous cell carcinoma (ESCC).

This single-arm, bicentric, phase 2 trial enrolled patients with resectable or potentially resectable thoracic ESCC to receive neoadjuvant radiotherapy (41.4 Gy in 23 fractions) with concurrent chemotherapy (albumin-bound paclitaxel, 50-100 mg/m2, and carboplatin, area under the curve of 2 mg/ml/min, once weekly, five times) plus sequential tislelizumab (200 mg Q3W, three cycles) followed by surgery. The primary endpoint was pathologic complete response (pCR) rate. The secondary endpoints included safety, R0 resection rate, major pathologic response (MPR) rate, disease-free survival (DFS), and overall survival (OS).

Of the 30 patients enrolled from January 2021 to October 2022, 24 (80.0 %) completed planned surgery and gained R0 resection (100 %). Among the 24 patients, nine (37.5 %) achieved pCR and 21 (87.5 %) achieved MPR. Ten patients (35.7 %) developed grade 3-4 toxicities during tislelizumab therapy, including lymphopenia (32.1 %), neutropenia (3.6 %), and thrombocytopenia (3.6 %). Grade 5 hematemesis occurred in two patients and both were attributed to aortic invasion. Three patients (12.5 %) developed grade 3 postoperative complications, including pulmonary infection (8.3 %) and hoarseness (4.2 %). After a median follow-up of 35.4 months, the 2-year OS and DFS rates were 83.3 % and 79.2 %, respectively.

Sequential tislelizumab after NCRT in ESCC is safe and feasible. Further study is warranted to validate the efficacy of this combination mode.

Quality of life (QoL) of patients with inoperable lung cancer can be negatively affected by both the disease and its treatment, generally consisting of (chemo)radiotherapy. The aim of this study was to prospectively assess QoL in patients with inoperable lung cancer, treated with (chemo)radiotherapy and to assess whether patient- and/or treatment-related characteristics were associated with poorer QoL.

This prospective cohort study evaluated QoL and patient-, tumor-, and treatment characteristics from inoperable lung cancer patients, treated with fractionated (≥40 Gy) (chemo)radiotherapy. Patients were evaluated at baseline, upon finishing radiotherapy, and 3 months, 6 months, 1 year, and yearly thereafter up to 5 years after radiotherapy. The QoL assessment consisted of questionnaires evaluating lung cancer-specific and treatment-related complaints using scale scores.

Compliance rates of the 574 analyzed patients ranged from 87 to 97 % during follow-up. Complaints increased after radiotherapy, as the QoL scale scores increased from median 8 (interquartile range, IQR 4-14) to 17 (IQR 4-25) after completing radiotherapy (P < 0.0004), indicating more complaints. From 3 months to 24 months of follow-up, scale scores returned to a median of 13, but were significantly higher compared to baseline (P < 0.0004). However, no clinically relevant differences compared to baseline were observed. Patients with pulmonary comorbidity and WHO scores ≥ 2 generally reported more complaints.

Patients experienced a temporary increase in complaints after finishing (chemo)radiotherapy, QoL returned to baseline level and remained stable up to five years of follow-up.

The etoposide-carboplatin and anti-PD-L1 combination has become the standard-of-care for patients with extensive-stage small cell lung cancer (ES-SCLC). This combinational strategy is well tolerated with manageable immune-related adverse effects (irAEs). In this report, we presented a rare immediate irAE after one course of anti-tumor treatment. The patient with ES-SCLC was treated with first-line etoposide-carboplatin chemotherapy and Durvalumab immunotherapy. After one cycle of indicated treatment, the patient developed persistent high-grade fever with extensive consolidation, surrounding by ground glass opacifications. The lesions did not respond to empirical antibiotics and the results for pathogen testing were negative. Histological analysis of biopsy sample yielded organizing pneumonia that was very likely to associate with Durvalumab treatment. The patient was therefore treated with prednisolone that resulted in a rapid radiological improvement. The reporting of this case is imperative for informing acute onset of irAE in patients with ES-SCLC treated with anti-PD-L1 immunotherapy. Differential diagnosis of infection, tumor progression and exacerbation of underlying illness should be considered before the initiation of prednisolone therapy.

The role of immunotherapy as systemic therapy for nonmetastatic non-small cell lung cancer (NSCLC) has evolved rapidly over the last decade. There are several well-conducted phase 3 clinical trials evaluating immunotherapy in the neoadjuvant, perioperative, adjuvant and nonoperative setting. In this narrative review, we summarize the data from these studies and discuss ongoing controversies in applying these data to clinical practice. These controversies relate to the value of the adjuvant component of perioperative immunotherapy, treatment of patients with PDL1 negative tumors, defining resectability, optimal use of operative versus nonoperative management, the role of stereotactic radiation therapy for very early lung cancers, and management of tumors with an oncogenic driver.