ObjectivesCirculating cytokines/chemokines are linked to checkpoint inhibitors (ICIs) in non‐small cell lung cancer (NSCLC). The tumor‐immune microenvironment (TIME) plays a significant role in modulating a broad range of cytokines and chemokines. This study aimed to explore the crosstalk between circulating cytokines/chemokines and TIME, related to ICIs outcomes.MethodsWe conducted a prospective cohort study of 81 participants with advanced or recurrent NSCLC who received ICIs. Pretreatment comprehensive 27 cytokines/chemokines analysis, immunohistochemistry (IHC) for CD8, Treg/FOXP3, and PD‐L1(22C3) TPS, and RNA sequencing were conducted. Demographic characteristics were integrated in the analysis to define the crosstalk of significant TIME‐related signatures. Circulating neutrophil‐to‐lymphocyte ratio (NLR) and IHC tumor‐infiltrated neutrophil density were evaluated to correlate systemic and local inflammatory states with ICIs response.ResultsPretreatment plasma IL‐6 and IL‐8 were the significant cytokines correlated with surrogate ICIs responses and ICIs progression‐free survival (PFS). Despite several correlations between cytokines/chemokines and CD8+ TILs, Treg/FOXP3+ TILs, neither pretreatment IL‐6 nor IL‐8 was correlated with intra‐tumoral or stromal Treg/FOXP3+ TILs, CD8+ TILs, and PD‐L1. Four active neutrophil‐related gene signatures overlapped and were significantly correlated with better ICIs outcomes and lower IL‐6 levels. Among 69 genes in 4 neutrophil‐related gene signatures, the overexpression of TREM1, SORL1, and HSD17B11 significantly contributed and inversely correlated with CIBERSORT memory B cells. Clinically, the stratification by low levels of IL‐6/IL‐8 and low NLR identified a subgroup with significantly improved survival outcomes, whereas IHC tumor‐infiltrated neutrophil counts did not show a similar association.ConclusionOur study reveals a potential mechanistic axis linking circulating IL‐6 and IL‐8 to tumor‐associated neutrophils, memory B cells, and therapeutic response. These findings underscore the crucial role of synergistic treatment in augmenting the efficacy of ICIs. The crosstalk between neutrophils and B cells in the orchestration of ICIs therapy for NSCLC was further elucidated through the roles of HSD17B11, SORL1, and TREM1.

Targeting driver mutations in lung cancer with interstitial pneumonia: A nationwide study in Japan.

Although various therapeutic options are available for advanced or recurrent non-small cell lung cancer (NSCLC), the optimal criteria for selecting combination therapies involving anti-programmed death-1 (PD-1) or anti-programmed death ligand-1 (PD-L1) antibodies with anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies remain unclear. Clinical trials suggest potential benefits of the treatment with anti-CTLA-4 antibodies in NSCLC with PD-L1 <1%; however, concerns persist regarding the increased risk of immune-related adverse events (irAEs). Therefore, identifying reliable biomarkers to guide the use of anti-CTLA-4 antibodies is crucial. We performed immunohistochemical staining to assess intratumoral tumor-infiltrating lymphocytes (iTILs) and stromal tumor-infiltrating lymphocytes (sTILs) expressing CD8 or FOXP3 using surgically obtained specimens. The association between these cells and the clinical efficacy of the treatment with nivolumab plus ipilimumab was evaluated using univariate and multivariate analyses in NSCLC patients with PD-L1 <1%. Kaplan-Meier analysis was conducted to assess survival outcomes. Univariate analysis revealed a significant correlation between progression-free survival and sTIL infiltration, but not iTIL infiltration. Patients who responded to therapy exhibited significantly higher CD8+ and lower FOXP3+ iTIL infiltration, as reported previously. Notably, responders also demonstrated significantly higher infiltration of both CD8+ and FOXP3+ sTILs. Moreover, high stromal infiltration of CD8+ T cells was significantly associated with prolonged overall survival, while high FOXP3+ sTILs infiltration showed a trend toward improved overall survival. Despite the increased risk of irAEs, patients with high stromal infiltration of CD8+ and FOXP3+ T cells may derive meaningful clinical benefit from anti-CTLA-4 antibody therapy. Assessing these immune parameters could aid in appropriate patient selection and contribute to optimizing therapeutic outcomes.

BackgroundDrugs for systemic therapy to advanced or recurrent non-small cell lung cancer (NSCLC) are determined by the type of driver oncogenes and programmed death-ligand 1 (PD-L1) immunostaining. In this study, we investigated the potential for artificial intelligence to assist in detecting epidermal growth factor receptor (EGFR) mutation, which is one of the most frequent and important driver oncogenes, and predicting the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in patients with NSCLC.MethodsWe built an ensemble model that combined machine learning models (logistic regression, Bernoulli naive Bayes and Gaussian naive Bayes) for clinical information and tumor characteristics analysis, and a deep convolutional neural network for analyzing computed tomography (CT) images. The convolutional neural network was trained from scratch on our imaging dataset. Clinical and imaging features were analyzed separately within their respective models and subsequently integrated in the ensemble framework. The models were trained to predict EGFR mutation and the response of EGFR-TKI using cross-entropy loss. The performance of the proposed model was evaluated by 5-fold cross-validation.ResultsOne hundred and fifty consecutive evaluable patients were included in this study. Among them, 61 patients had EGFR mutation, including 59 patients with common EGFR mutation and 2 patients with uncommon EGFR mutation. The ensemble model predicted EGFR mutation with an area under the curve (AUC) of 0.88 [95% confidence interval (CI): 0.79–0.97]. Each sub-model integrated into the ensemble model predicted EGFR mutation with AUC of 0.83 (95% CI: 0.71–0.95), 0.88 (95% CI: 0.79–0.97), 0.87 (95% CI: 0.79–0.94), and 0.84 (95% CI: 0.72–0.96) for logistic regression, Bernoulli naive Bayes, Gaussian naive Bayes and deep neural network respectively. The predictive accuracy of the ensemble model was 0.56. Specifically, the ensemble model reported that the predictive accuracy of the Del19 EGFR mutation was higher than that of the L858R EGFR mutation, with overall response rate predictive accuracy (AUC) of 0.67 versus 0.52, and disease control rate AUC of 0.88 versus 0.53.ConclusionsThe ensemble model demonstrated strong performance in predicting EGFR mutations and showed higher predictive treatment response for EGFR exon 19 deletions than for L858R mutations. These findings suggest that ensemble learning may enhance the non-invasive prediction of EGFR mutation status and EGFR genotype-specific therapeutic outcomes in NSCLC, although further validation in larger cohorts is warranted.

The optimal management of patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) after progression on osimertinib includes cytotoxic chemotherapy. Continuing osimertinib therapy beyond progressive disease (PD) is occasionally adopted in real-world practice; however, evidence for its efficacy is limited. In this multi-institutional retrospective study, we evaluated whether osimertinib continuation beyond PD could improve survival compared with the best supportive care (BSC) in such patients. We retrospectively reviewed patients with EGFR-mutated advanced or recurrent NSCLC treated with osimertinib between March 2016 and September 2025 at three Japanese community hospitals. Patients with radiological progression or intolerable adverse events after osimertinib treatment were included Patients were classified into three groups: (1) osimertinib beyond PD, (2) BSC, and (3) chemotherapy after osimertinib. Overall survival (OS) was compared among the groups using Kaplan-Meier and Cox regression analyses adjusted for time-to-treatment failure (TTF). Of the 309 patients treated with osimertinib, 126 met the inclusion criteria. The median age of the patients was 77 years, and 23% had poor performance status (≥ 2). Osimertinib beyond PD was administered to 21 patients (16.7%), BSC to 36 patients (28.6%), and chemotherapy to 69 patients (54.8%). The median OS after osimertinib failure was 8.8, 2.6, and 15.5 months in the beyond PD, BSC, and chemotherapy groups, respectively (p < 0.001). In multivariate analysis, beyond PD was associated with significantly longer OS than BSC (hazard ratio: 0.34, 95% confidence interval: 0.18-0.66, p < 0.001), even after adjusting for TTF. In real-world settings involving elderly and frail patients, osimertinib continuation beyond PD was associated with improved survival compared with BSC alone. Although chemotherapy remains the preferred strategy when feasible, osimertinib continuation beyond PD may represent a reasonable treatment option for patients who are ineligible for further cytotoxic therapy. In the absence of other guiding biomarkers, TTF may help clinicians identify patients most likely to benefit from continued TKI administration.

BackgroundAlthough immunotherapy has revolutionized lung cancer treatment, its effectiveness as a single agent in the second-line setting is limited by low response rates and the small number of patients who benefit from it, despite its demonstrating superior overall survival compared to standard chemotherapies. This study aimed to determine whether the timing of nivolumab administration, specifically before or after 1 PM, influences treatment efficacy, thereby exploring its potential role in overcoming drug resistance.Material/MethodsThis single-center retrospective study included 54 patients with stage IV or recurrent non-small cell lung cancer who received nivolumab as second-line therapy between January 2021 and January 2025. Patients were categorized into 2 groups based on whether they received all treatment protocols before or after 1 PM, and treatment outcomes were subsequently compared.ResultsPatients treated before 1 PM showed statistically significant improvements in treatment response compared to those treated after 1 PM. However, no significant differences were found in progression-free survival or immune-related adverse effects.ConclusionsOur study indicates that the timing of nivolumab administration can affect treatment outcomes, with earlier administration potentially leading to better responses. This observation aligns with the growing body of evidence suggesting that circadian rhythms play a significant role in cancer biology and treatment efficacy. Understanding the mechanisms behind these effects could lead to more effective treatment strategies and improved patient outcomes. Further research is needed to elucidate the underlying mechanisms and validate these findings in larger, prospective studies. Despite the lack of clear guidelines, our findings, along with other studies, suggest earlier immunotherapy administration may be beneficial.

Selpercatinib is the current standard of care for patients with recurrent or advanced RET fusion-positive non-small cell lung cancer (RET-NSCLC). However, real-world data on selpercatinib for RET-NSCLC are extremely limited, particularly in the Japanese population. This retrospective multicenter study enrolled 27 patients who were pathologically diagnosed with RET-NSCLC and started selpercatinib treatment between September 2021 and June 2024. Patients who had previously received other molecular-targeted drugs were excluded. Of the patients, 10 had received prior treatment and 17 had not. As of August 31, 2024, the median follow-up period was 12.0months (range 0.5-31.5months). The objective response rate (ORR) was 100% (8/8 cases) in the previously treated group and 81% (13/16 cases) in the treatment-naïve group. The median progression-free survival (PFS) was 13.3months (95% confidence interval [CI] 0.5-not evaluable [NE]) in the previously treated group and 23.5months (95% CI 5.7-NE) in the treatment-naïve group. The median overall survival was 25.4months (95% CI 0.5-NE) in the previously treated group and not reached (95% CI NE-NE) in the treatment-naïve group. No significant differences were observed in any of these comparisons. The most frequent grade 3 adverse event (AE) was increased ALT (n = 11, 41%), followed by increased AST (n = 7, 26%). In Japanese patients treated with selpercatinib, efficacy in whole patients was similar to the worldwide population, whereas AEs (especially liver dysfunction) was more severe than worldwide population. This result highlights the need for careful dose management strategies for Japanese patients.

966eP Investigation of driver gene alterations in stage IV or recurrent non-small cell lung cancer at our institution

1036P Efficacy of immune checkpoint inhibitor combination chemotherapy in patients with recurrent non-small cell lung cancer after durvalumab consolidation following chemoradiotherapy: A multicenter retrospective study (NEJ066)

Taletrectinib [DOVBLERON ® (China); IBTROZITM (USA)] is an oral, potent, next-generation proto-oncogene tyrosine-protein kinase-1 (c-Ros oncogene-1; ROS1) inhibitor developed by Nuvation Bio China Ltd., a Nuvation Bio Inc. company, for the treatment of advanced ROS1-positive non-small cell lung cancer (NSCLC). Taletrectinib received its first approval on 20 December 2024 in China for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC who have previously been treated with ROS1 inhibitors. Subsequently, taletrectinib was approved on 3January 2025 in China and on 11June 2025 in the USA for the treatment of adults with locally advanced or metastatic ROS1-positive NSCLC, and then on 19September 2025 in Japan for the treatment of adults with unresectable advanced and/or recurrent ROS1-positive NSCLC. Additional global filings for taletrectinib are underway. This article summarizes the milestones in the development of taletrectinib leading to these first approvals.

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and glioblastoma (GBM). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent GBM and NSCLC. After determining the maximum tolerated dose, adults with recurrent GBM were treated in two expansion cohorts: (a) non-surgical cohort (6/12 patients thus far): EGFRvIII mutation, first recurrence; food-effect study included (b) surgical cohort (6/6 patients), any EGFR mutation, any recurrence; window-of-opportunity study (WOO) included. Among these 12 patients, median age = 60 years; 50% female; 58% ECOG 0). All patients received prior radiation and temozolomide. After the WOO or food-effect study, patients were dosed at 120 mg BID (5 days on, 2 days off), and escalated to 160 mg BID (5 days on, 2 days off) based on tolerability. Common adverse events (&amp;gt;40%) are comparable to other EGFR inhibitors (acneiform rash, diarrhea, fatigue, xerosis, pruritis). Treatment-related grade 3+ adverse events were limited to lymphopenia (n = 1). WSD0922-Fu exposure in the fed state exceeded the fasted state (median plasma Cmax and AUC0-24h are 1.6x and 1.3x, respectively) with a delayed Tmax (6.0 vs 1.8 hours). For the WOO, time between last dose administered to tumor collection ranged between 4 - 13.5 hours. Median tumor WSD0922-Fu concentration was 0.76 µg/g; estimated median unbound tumor concentration was 24.9 ng/g and within expectations for pharmacodynamic effect. Median brain/plasma ratio = 0.59; median unbound brain/unbound plasma = 0.88. Enrollment to the non-surgical cohort is ongoing, so formal efficacy data remain immature. However, examples of clinical efficacy will be shown along with data on recurrence patterns. Phase 2 clinical trial development is in progress.

ObjectiveTo evaluate the clinical efficacy, safety, and changes in the immune status of advanced non-small cell lung cancer (NSCLC) patients with disease progression after chemoradiotherapy treated with CT-guided 125I radioactive seed implantation.Materials and methodsFrom January 2016 to June 2022, 34 NSCLC patients who progressed after radiotherapy and chemotherapy were studied retrospectively. There were 34 evaluable lesions, and 125I seeds were implanted into the lesions under CT guidance. The study’s endpoints were as follows: short-term clinical efficacy, quality of life score, and adverse reaction status assessment, with patients being collected for immune status assessment.ResultsThe average postoperative follow-up period was 16.58 ± 7.41 months. The 1-year postoperative survival rate was 76.47% (26/34), the 2-year postoperative survival rate was 58.82% (20/34), and the median overall survival was 16 (6–24) months (95% CI: 13.7–18.3). The 1-year progression-free survival (PFS) rate after the operation was 61.76% (21/34), the 2-year PFS rate was 41.18% (14/34), and the median PFS was 12.5 (1–24) months (95% CI: 10.8–16.2). Postoperative pneumothorax occurred in 11.76% of patients, minor bleeding in 5.88%, and pneumonia in 2.94%, all of which improved after symptomatic treatment. Compared with the preoperative results, the percentages of CD3+ and CD4+ T lymphocytes in the treatment group increased 1, 2, 3, and 6 months after surgery; the percentage of NK cells increased 3 and 6 months after surgery. The positive immune factor levels of IL-2 and TNF-α were increased at 2, 3, and 6 months after surgery; γ-IFN levels were increased at 1, 2, 3, and 6 months after surgery; IL-4 levels were decreased at 3 and 6 months after surgery; and IL-10 levels were decreased at 6 months after surgery. TH17 (IL-17) levels decreased at 1, 2, 3, and 6 months after surgery.ConclusionCT-guided 125I particle therapy may be an effective treatment for NSCLC that has progressed following radiotherapy and chemotherapy. Local treatments improve patients’ quality of life and reduce tumor burden. CT-guided 125I radioactive seed implantation may improve the immune status of patients with recurrent or progressive NSCLC after radiotherapy and chemotherapy and may enhance the antitumor immune response.

Image-Guided Thermal Ablation in Patients With Locally Recurrent Non-Small Cell Lung Cancer After Stereotactic-Beam Radiation Therapy.

Immune checkpoint inhibitor-induced interstitial lung disease with and without CTLA-4 regimen in non-small cell lung cancer patients and PD-L1<1%: A multicenter, retrospective study.

ABSTRACTBackgroundEmerging evidence indicates that baseline use of certain concomitant drugs may affect the efficacy of immune checkpoint inhibitors (ICIs), including PD‐1, PD‐L1, and CTLA‐4 inhibitors, in patients with cancer. However, most previous studies have evaluated individual drug classes in isolation, without considering potential interactions among multiple drugs.AimsThis study aimed to evaluate the individual and combined effects of commonly prescribed concomitant drugs on the efficacy and safety of ICI‐based therapy in patients with non‐small cell lung cancer (NSCLC).MethodsWe conducted a retrospective analysis of 124 patients with advanced or recurrent NSCLC who received first‐line ICI‐based treatments at a single institution. Drug exposure at treatment initiation was assessed for proton pump inhibitors (PPIs), low‐dose aspirin, non‐steroidal anti‐inflammatory drugs, statins, biguanides, antibiotics, and probiotics. Associations with progression‐free survival (PFS), overall survival (OS), and immune‐related adverse events (irAEs) were analyzed using multivariate Cox regression models.ResultsPPI use was independently associated with shorter PFS (HR: 2.44, p < 0.001) and OS (HR: 2.04, p = 0.01). In contrast, low‐dose aspirin use was independently associated with longer PFS (HR: 0.31, p = 0.01). Patients receiving both PPIs and aspirin had longer PFS and OS compared to those receiving PPIs alone, although the differences were not statistically significant. No consistent associations were observed for other drugs. The incidence of irAEs was not significantly affected by concomitant drug use.ConclusionPPI use at baseline may be associated with reduced efficacy of ICI therapy in NSCLC patients. In contrast, low‐dose aspirin use was independently associated with improved PFS, and may potentially mitigate the negative effects of PPIs. These findings underscore the importance of considering concomitant drug use when initiating ICI treatment. Prospective studies are needed to validate these observations and clarify underlying mechanisms.

BackgroundCombination immunotherapy has become a standard first-line treatment for advanced non-small cell lung cancer (NSCLC). However, its application in patients with checkpoint inhibitor-related pneumonitis (CIP) remains challenging due to the risk of treatment-related pulmonary toxicity. While first-line outcomes in CIP patients are increasingly reported, data on the efficacy and safety of subsequent therapies are lacking. This study aimed to evaluate treatment patterns, survival outcomes, and the risk of pulmonary toxicity associated with second-line therapy in NSCLC patients with prior CIP after first-line immunotherapy.MethodsThis retrospective study analyzed 159 patients with advanced or recurrent NSCLC treated with first-line combination immunotherapy at Fukuoka University Hospital between January 2019 and March 2024, including those who had previously received molecular targeted therapy for driver gene mutations. Patients were stratified based on baseline CIP status. Among them, 91 patients (19 prior CIP and 72 non-prior CIP) who received second-line therapy were evaluated for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and drug-induced pneumonitis onset during second-line treatment.ResultsBaseline CIP was present in 32 patients (20.1%). The transition rate to second-line therapy was 73% in the prior CIP group and 64% in the non-prior CIP group, with no statistically significant difference observed between the two groups (P=0.49), indicating that the presence of prior CIP did not clearly affect the likelihood of receiving secondary therapy. PFS following second-line treatment was similar between patients with and without prior CIP. However, OS tended to be shorter in the prior CIP group (6.4 vs. 10.3 months), although the difference was not statistically significant (P=0.07), a trend that persisted after propensity score matching. Drug-induced pneumonitis development during second-line therapy occurred more frequently in patients with prior CIP (26% vs. 3%, P<0.01).ConclusionsSecond-line cytotoxic chemotherapy following combination immunotherapy may be associated with shorter survival and increased pulmonary toxicity in NSCLC patients with prior CIP. Careful clinical decision-making, multidisciplinary consultation, and close monitoring are essential when initiating second-line treatment in this population.

Establishing the suitability of initiating immune checkpoint inhibitor (ICI) therapy in patients with lung cancer and coexisting interstitial pneumonia (IP) is challenging. Real-world evidence on the efficacy and safety of ICIs in such patients is urgently needed to inform clinical practice. This retrospective study evaluated the effects of ICI administered to 79 patients with advanced or recurrent non-small cell lung cancer (NSCLC) and programmed death ligand 1 (PD-L1) tumor proportion scores of 1-49%, who had pre-existing IP. These patients received first-line therapy comprising an ICI with chemotherapy or chemotherapy alone at 18 institutions in Japan between March 2017 and June 2022. Twelve patients received ICI plus chemotherapy (chemoimmunotherapy group) as first-line treatment, and 67 received chemotherapy alone (chemotherapy group). Only brain metastases were significantly more frequent in the chemoimmunotherapy group; no other differences in patient backgrounds between the two groups were observed. Overall survival (OS) and progression-free survival did not differ between the two groups. After propensity score matching, chemoimmunotherapy significantly prolonged OS compared to chemotherapy alone (25.3 months vs. 9.6 months, p=0.033), without significant differences in incidences of severe adverse events, including pneumonitis. In the analysis of patients who received ICI up to second-line treatment, ICI therapy was associated with prolonged OS compared to non-ICI treatment (29.8 months vs. 16.3 months, p=0.012). Early use of immunotherapy for patients with advanced NSCLC with low PD-L1 expression and coexisting IP may improve prognosis.

Improving reirradiation of recurrent non-small cell lung cancer through non-coplanar beam arrangements☆

Leveraging readily available clinical data with machine learning to predict first-line immunotherapy outcomes in non-small cell lung cancer.

The prognosis of patients with non-small cell lung cancer (NSCLC) remains poor. This phase II clinical trial investigated the efficacy of dendritic cell (DC) vaccination using Wilms' tumor 1 (WT1) and/or mucin 1 (MUC1) peptides - universal tumor-associated antigens - in combination with chemotherapy in patients with advanced-stage NSCLC. Additionally, we examined whether single nucleotide polymorphisms (SNPs) in immune checkpoint genes could serve as prognostic markers for survival. Forty-four eligible patients with metastatic, unresectable or recurrent NSCLC were enrolled. DCs were administered intradermally every two to four weeks in combination with chemotherapy. Following the seventh vaccination, four patients achieved a partial response and 15 patients had stable disease. The median progression-free survival (PFS) and overall survival (OS) from the initiation of DC vaccination were 6.7 months and 12.3 months, respectively. Log-rank analysis revealed that neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, prognostic nutritional index (PNI) and the programmed cell death 1 (PD-1) rs36084323 SNP were significantly associated with both PFS and OS. Cox regression analysis identified the PD-1 rs36084323 SNP and PNI as independent prognostic factors for both PFS and OS. DC vaccination with WT1 and/or MUC1 peptides combined with salvage chemotherapy appears to be a promising treatment strategy for patients with advanced or relapsed NSCLC. The PD-1 rs36084323 SNP, along with PNI, was identified as an independent prognostic factor, suggesting its potential utility as a biomarker for selecting appropriate candidates for this treatment approach.