Myofibroblast differentiation is a pivotal event in idiopathic pulmonary fibrosis (IPF) and is driven by TGF-β1-dependent PTEN destabilization; however, the intermediate regulators remain incompletely defined. We tested three lung fibroblast cell lines (one normal and two IPF-derived) and identified the phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 2 (PREX2)-membrane-associated guanylate kinase inverted 2 (MAGI2) as a critical regulator of myofibroblast differentiation. Loss-of-function analysis of MAGI2 in normal human lung fibroblasts revealed a shift toward a myofibroblast phenotype characterized by abundant α-SMA expression. In vitro experiments revealed increased PREX2 expression and decreased MAGI2 expression in IPF-derived lung fibroblasts compared with those in normal lung fibroblasts. Consistent with this finding, in vivo experiments using bleomycin-induced murine pulmonary fibrosis revealed PREX2 upregulation in contrast to MAGI2 downregulation with the progression of lesions. Notably, PREX2 depletion in IPF-derived cells enhanced MAGI2 expression, mitigating TGF-β1-induced α-SMA expression. Conversely, PREX2 overexpression promoted myofibroblast differentiation, as evidenced by MAGI2 downregulation followed by marked α-SMA expression. The PREX2-targeting suppressive miR-338-3p upregulated MAGI2 expression in vitro and ameliorated bleomycin-induced murine pulmonary fibrosis in vivo. Immunohistochemical staining of PREX2 on lung samples obtained from patients with IPF delineated that PREX2 was exclusively expressed in the fibroblastic foci of IPF-affected lungs. Fluorescence immunostaining revealed PREX2 colocalization with α-SMA in myofibroblasts within fibroblastic foci, corroborating our hypothesis. These findings suggest that MAGI2 acts as a negative regulator of myofibroblast differentiation by stabilizing PTEN, whereas PREX2 is aberrantly expressed in the fibrotic milieu, negatively modulating MAGI2, thereby accelerating pulmonary fibrosis.

Introduction: Although the efficacy of molecular targeted therapies varies across actionable genomic alterations in NSCLC, comparisons within a single real-world cohort remain limited. Methods: We conducted a retrospective multi-institutional study of 810 consecutive Japanese patients with advanced or recurrent NSCLC harboring actionable genomic alterations who received molecular targeted therapy from 2017 to 2023. Patients were classified into the following three genomic groups: EGFR mutations (group A), ALK/ROS1/RET fusion oncogenes (group B), and others, including MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations (group C). Treatment efficacy and safety were compared across the groups. Results: Treatment outcomes differed between the subgroups. Group B demonstrated the highest objective response rate (85.8%) and the longest median real-world progression-free survival (rwPFS; 42.5 mo); median overall survival (OS) was not reached. Group A had intermediate outcomes. Group C exhibited the shortest rwPFS (9.2 mo), poorer OS, and higher rates of treatment discontinuation due to adverse events. Such hierarchical differences were observed in patients with baseline central nervous system metastases and in those receiving first-line treatment. In multivariate analysis, genomic subgroup remained associated with rwPFS and OS, with fusion-driven tumors maintaining superior outcomes irrespective of other factors. Conclusions: This large real-world analysis yielded a hierarchy of therapeutic benefits across actionable genomic alterations in NSCLC. Patients with fusion-driven tumors benefited from targeted therapy, whereas those with EGFR-mutated tumors had intermediate outcomes. Treatment of patients with MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations had limited efficacy and higher toxicity, underscoring the need for improved therapeutic strategies.

Background:The combination of an anti-programmed death-ligand 1 (PD-L1) antibody with etoposide and either carboplatin or cisplatin (platinum-etoposide) has become the first-line treatment for patients with extensive-stage small-cell lung cancer (ES-SCLC). Although previous studies have examined the relationship between geriatric assessments and treatment efficacy, the association with treatment tolerability in elderly patients with ES-SCLC remains insufficiently understood. We aimed to evaluate the association between low body mass index (BMI)-a component of geriatric assessment-and treatment tolerability. Methods:We conducted a retrospective analysis of patients aged ≥65 years with ES-SCLC who received anti-PD-L1 antibody plus platinum-etoposide at a single center between August 2019 and April 2024. Tolerability was defined as the completion of four cycles of anti-PD-L1 antibody combined with platinum-etoposide. We also assessed treatment efficacy and safety profiles. Results:A total of 71 patients were included, with a median age of 73 years (range: 65-91 years). Of these, 51 patients (72%) were male, and 54 (76%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1. Sixteen patients (23%) showed a low BMI (<19 kg/m2), whereas 55 (77%) showed a non-low BMI. Tolerability was achieved in 8 patients (50%) with low BMI compared with 44 patients (80%) with non-low BMI. There were no significant differences in overall survival, progression-free survival, or the incidence of grade ≥3 adverse events among the two groups. In multivariate analysis, low BMI and ECOG-PS ≥2 were independently associated with reduced treatment tolerability [odds ratio (OR): 0.24, 95% confidence interval (CI): 0.06-0.88, P=0.03; OR: 0.13, 95% CI: 0.04-0.48, P<0.01, respectively]. Conclusions:Low BMI and poor performance status were independently associated with decreased tolerability to anti-PD-L1 antibody combined with platinum-etoposide in elderly patients with ES-SCLC. These findings underscore the importance of incorporating geriatric assessments into treatment decision-making for this population.

8528 Background: EGFR blockade enhances tumor antigen presentation and may potentiate PD-1 inhibition. This phase I/II study evaluated the safety and efficacy of adding necitumumab to pembrolizumab plus platinum-based chemotherapy in patients with previously untreated advanced squamous non–small cell lung cancer (NSCLC), a population with limited biomarker-driven treatment options. Methods: Patients received necitumumab (400–800 mg on days 1 and 8), pembrolizumab (200 mg on day 1), nab-paclitaxel (100 mg/m² on days 1, 8, and 15), and carboplatin (AUC 5 on day 1) every 3 weeks for four cycles, followed by necitumumab plus pembrolizumab maintenance. Phase I used a standard 3+3 dose-escalation design. Per protocol amendment, patients treated at the recommended dose (RD) in phase I (n = 6) and all phase II patients (n = 6) were pooled for efficacy analyses (n = 12). Tumor assessments were performed every 6 weeks per RECIST v1.1. Primary endpoints were safety and objective response rate (ORR). Data cutoff was September 14, 2025. Results: Twenty-one patients were enrolled, including 15 in phase I (400 mg, n = 6; 600 mg, n = 3; 800 mg, n = 6). One dose-limiting toxicity (DLT) occurred in the 800 mg cohort, which was determined as the RD and maximum tolerated dose (MTD). Among the 12 patients treated at the RD, the ORR was 75.0% (9/12; 95% CI, 42.8–94.5), with partial response in 9 patients, stable disease in 1 patient, and progressive disease in 2 patients. The disease control rate was 83.3%. The 24-week survival rate was 95.2%. Median progression-free survival and overall survival were not reached at the time of analysis. The most frequent adverse events (AEs) in 21 patients were hypomagnesemia (66.7%), acneiform dermatitis (66.7%), neutropenia (61.9%), decreased appetite (52.4%), anemia (52.4%), constipation (47.6%), stomatitis (42.9%), and leukopenia (42.9%). Grade 3 and 4 AEs occurred in 66.7% and 28.6% of patients, respectively, with no grade 5 events. Conclusions: The addition of necitumumab to pembrolizumab and platinum-based chemotherapy demonstrated manageable toxicity and resulted in a high ORR in patients with untreated squamous NSCLC. These findings support the potential activity of EGFR blockade–based immunochemotherapy and warrant further clinical investigation. Clinical trial information: 2031210387.

Background:Previous studies have reported an association between expression of thyroid transcription factor 1 (TTF-1) and the efficacy of immune checkpoint inhibitors (ICIs), cytotoxic chemotherapy, and immunochemotherapy in patients with advanced non-squamous non-small cell lung cancer (NS-NSCLC). However, the relationship between TTF-1 expression and the efficacy of cytotoxic chemotherapy in patients with NS-NSCLC with idiopathic interstitial pneumonias (IIPs) remains unclear. This study aimed to evaluate the relationship TTF-1 expression and the efficacy of platinum-doublet chemotherapy in patients with NS-NSCLC with coexisting IIPs. Methods:This retrospective study reviewed 120 patients with NSCLC complicated by IIPs who were treated at Nippon Medical School Hospital in Japan between January 2010 and December 2024. We analyzed the efficacy and safety of carboplatin and either paclitaxel or nanoparticle albumin-bound (nab-) paclitaxel for NS-NSCLC with IIPs. Results:In the total cohort, 51 patients were evaluated for TTF-1 expression status and administered carboplatin plus (nab-) paclitaxel as first-line therapy. TTF-1 expression was observed in 32 patients (63%). Twenty-five patients (49%) exhibited a usual interstitial pneumonia (UIP) pattern. The overall response rate (ORR) was significantly higher in the TTF-1-positive group compared to the TTF-1-negative group (62.4% vs. 31.6%, P=0.045). Median overall survival (OS) and progression-free survival (PFS) were also significantly longer in the TTF-1-positive group than in TTF-1-negative group (11.3 vs. 8.2 months, P=0.007; 8.4 vs. 4.4 months, P<0.001). TTF-1 negativity was identified as an independent prognostic factor associated with inferior OS and PFS in multivariate analysis. Furthermore, the TTF-1-negative group had a significantly higher incidence of lung cancer development in the setting of underlying interstitial pneumonia (IP) (P<0.001), suggesting that decreased TTF-1 expression may be involved in the pathogenesis of lung cancer arising from IIPs. Conclusions:TTF-1 expression is an independent prognostic factor in patients with NS-NSCLC complicated by IIPs who received carboplatin plus (nab-) paclitaxel. TTF-1 expression may represent a valuable biomarker for characterizing the disease subtypes and guiding therapeutic strategies in lung cancer with coexisting IIPs.

BACKGROUND:Non-invasive methods for detailed evaluation of airway pathology in asthma, including structural airway abnormalities, remain limited, and accurate assessment is still insufficient. The MostGraph, which utilizes the impulse oscillation system (IOS), allows non-invasive measurement of airway resistance and reactance. This study evaluated its utility in distinguishing airway pathology between bronchial asthma (BA) and cough variant asthma (CVA), with a focus on peripheral airway involvement. METHODS:In this cross-sectional study, 383 patients with stable respiratory symptoms for over three months were enrolled (203 BA, 180 CVA). All patients underwent spirometry, IOS assessment using the MostGraph, blood tests, and fractional exhaled nitric oxide (FeNO) measurement. RESULTS:Body composition was comparable between groups, although BA patients were older. BA showed significantly greater airway obstruction (%FEV1/predicted FEV1) and peripheral impairment (V50/V25, MMF). R5-R20 values were higher in BA than CVA before and after bronchodilator use. In BA, R5, R20, and R5-R20 correlated significantly with %FEV1; in CVA, only R5 and R20 did. R5-R20 showed no correlation (R = -0.11, P = 0.14). Inspiratory R5-R20 was not correlated in CVA (Pre-BD: R = -0.048, P = 0.53; Post-BD: R = -0.13, P = 0.091), while all parameters correlated in BA. Fres was significantly higher in BA both pre- and post-bronchodilator (P < 0.0001). CONCLUSION:MostGraph indices, when integrated with spirometry, may offer a valuable non-invasive approach for characterizing peripheral airway abnormalities that may reflect remodeling-related changes in BA and support airway monitoring in asthma management. TRIAL REGISTRATION:UMIN-CTR Clinical Trial (UMIN000054006). (https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000061647).

9044 Background: To date, osimertinib has been commonly used as a first-line treatment for EGFR mutated advanced NSCLC. However, the issue of what constitutes effective treatment after osimertinib failure remains．We evaluated treatment with afatinib plus chemotherapy for EGFR mutated NSCLC resistant to osimertinib. Methods: Patients (pts) with EGFRm (Del19 or L858R) after failure of osimertinib treatment were assigned to a regimen of afatinib 20mg daily combined with carboplatin AUC5 mg/ml/min and pemetrexed 500mg/m2 every 3 weeks followed by maintenance treatment with afatinib plus pemetrexed until disease progression or unacceptable toxicity was noted. The primary endpoint was rate of PFS at 6 months after initiation of treatment (6M-PFSR). The threshold was set at 35% and the expected value at 60% (two-sided P-value of 5% and power of 80%). Thirty-one patients were required, and the target number of patients was set at 35 after accounting for ineligible cases. Secondary endpoints were PFS, OS, ORR, DOR, and Safety. In this study, blood samples were collected before and after study treatment and at the time of PD to examine biomarkers using CAPP-SEQ. This biomarker study is ongoing. Results: Between June 7, 2020 and January 19, 2022, 36 pts were enrolled. One patient was found to meet the exclusion criteria, and the efficacy was analyzed in the other 35 patients. The mean age was 70 years, 60% were women, and 54.3% were nonsmokers. The 6M-PFSR, the primary endpoint, was 57.1%. The confidence interval of 39.3%-71.5% exceeded the threshold of 35%, and the study met its primary endpoint. Notably, 24.1% of pts had a long-term PFS of 1 year or longer. ORR was 48.6%, DCR was 88.6%, median PFS was 8.2M, median DOR was 5.6 M, and median OS was not reached. By mutation type, ORR were similar for Del19 and L858R (46.7% and 50.0%, respectively), but median PFS tended to be longer for Del19 compared to L858R (9.6M and 5.2M, respectively). Pts who responded to previous osimertinib therapy (CR and PR: n = 29) tended to have longer mPFS compared to non-responders (SD, PD, and NE: n = 6) (8.5M and 5.8M, respectively). Adverse events due to TKI and chemotherapy were observed. Diarrhea (52.8%), anorexia (44.4%), fatigue (33.3%), and paronychia (36.1%) were the most frequent adverse events, and these adverse events were predictable and manageable. Interstitial pneumonia developed in three patients (8%), one of whom was the only death in the study. Conclusions: The combination of afatinib and the platinum doublet showed satisfactory efficacy with manageable adverse events in tumors refractory to osimertinib, and met its primary endpoint. OS follow-up and biomarker analyses are still ongoing. This regimen is expected to be a candidate for second-line therapy after osimertinib. Clinical trial information: jRCTs021200005 .

Idiopathic pulmonary fibrosis (IPF) is a progressive disease often complicated by pulmonary hypertension (PH), leading to a worse prognosis. In this study, we use the term “secondary PH” to refer to PH that develops as a complication of IPF (i.e., IPF-PH), and “the ERPE (Exercise-Responsive PAP Elevation) group, defined as patients without resting PH but with potential PAP elevation during exertion, indicating early pulmonary vascular stress.” This study aimed to evaluate the impact of pulmonary vascular resistance (PVR) on the clinical course, activities of daily living (ADL), and exercise tolerance in IPF patients. Additionally, we sought to determine whether PVR influences prognosis within a short-term period of just two years. This exploratory single-center study was conducted as an interim analysis of a prospective trial targeting patients with IPF complicated by secondary PH or ERPE. The analysis included 49 IPF patients who received conventional IPF management without pulmonary arterial hypertension (PAH)-specific therapies and completed a two-year follow-up. Pulmonary circulation parameters, including PVR and pulmonary artery pressure (PAP), were assessed via right heart catheterization. Lung function, ADL, and exercise tolerance were also evaluated. Statistical analyses were performed to assess the association between PVR and prognosis. Higher PVR was significantly associated with poorer prognosis and worsening restrictive lung impairment. PVR correlated with modified Medical Research Council (mMRC) scores (Spearman’s ρ = 0.47, p = 0.0007) and 6-minute walk distance (Spearman’s ρ = -0.41, p = 0.0042). Proportional hazard analysis identified PVR as a significant predictor of overall survival (hazard ratio [HR]: 1.28, 95

Lung cancer, one of the most common cancers, is a leading cause of cancer-related deaths worldwide. While the incidence of lung cancer in non-smokers (LCINS) has been rising due to the overall decline in smoking rates, non-smokers account for about 10%–20% of all lung cancer cases [1]. Primary factors associated with LCINS include exposure to carcinogens, such as radon, second-hand smoke, and other indoor air pollutants. Despite these known factors, many of the lung cancer cases among non-smokers cannot be definitively linked to established environmental risks. Research indicates that LCINS differs from smoking-related lung cancer in terms of genetic mutations, tumour mutational burden (TMB), and chromosomal abnormalities, suggesting it is a distinct disease entity. A deeper understanding of the genetic alterations common in LCINS and its genomic landscape could lead to the identification of new molecular targets and improve outcomes for non-smokers. LCINS is more prevalent in women and Asians and is often diagnosed at a younger age than smoking-related lung cancer. The most common histological type of LCINS is adenocarcinoma. Unlike lung cancers in smokers, which are caused by a combination of genetic mutations and environmental exposure, LCINS is primarily driven by specific genetic mutations. Key mutations in LCINS involve driver genes, such as KRAS, EGFR, BRAF, and ALK fusions [2]. These alterations distinguish LCINS from smoking-related lung cancer and contribute to its unique biology and tumour microenvironment (TME) [3]. Recent studies have provided insights into the molecular characteristics of LCINS. A comprehensive genomic analysis of 160 LUAD (lung adenocarcinoma) samples revealed a potential role for germline variants in DNA repair genes, such as BRCA1, BRCA2, FANCG, FANCM, MSH6, and POLD1, in the development of LCINS [4]. Additionally, passive exposure to cigarette smoke was found to contribute to the pathogenesis of some non-smoker LUADs. LCINS tumours also exhibit a higher prevalence of targetable driver alterations in the RTK/RAS/RAF signalling pathway compared to smokers. These tumours can be categorised into immune 'cold' and 'hot' subtypes. The cold subtype, which lacks immune markers like PD-L1 and is depleted of immune cells, suggests immune evasion mechanisms. In contrast, hot tumours show a more active immune response. LCINS tumours have lower TMBs than those in smokers and often harbour mutations in genes like CTNNB1, which is involved in Wnt signalling. This signalling pathway helps tumours evade immune detection and may explain the relatively poor response to immunotherapy in non-smokers compared to smokers. High-coverage whole genome sequencing (WGS) of 232 LCINS cases identified three distinct subtypes of LCINS based on somatic copy number alterations [5]. Subtype 1 (piano) tumours were characterised by slow tumour growth and fewer mutations, with KRAS mutations being the most common. KRAS mutations promote the proliferation of bronchioalveolar stem cells and contribute to tumour growth. Subtype 2 (mezzo-forte) tumours display mutations in EGFR, which is associated with faster tumour growth. Subtype 3 (forte) tumours grew the fastest and showed characteristics similar to lung cancers in smokers. This subtype was dominated by whole-genome doubling (WGD) and had a low TMB with a high proportion of subclonal mutations, indicating significant intra-tumour heterogeneity. Interestingly, no major differences were found in the mutational profiles of passive versus non-passive smokers. The median TMB in LCINS tumours is significantly lower than in smokers, and TMB is associated with clinical factors such as stage, histology, and age [2, 6]. Moreover, female patients are more likely to have EGFR mutations than males. Mutations in EGFR and KRAS commonly occur together, and co-occurring mutations in RBM10 and TP53 are also frequently observed in EGFR-altered tumours. Additionally, significant co-occurring patterns were identified between RBM10 and PIK3CA, as well as between TP53 and ERBB2. In tumours with oncogene fusions, particularly those with TP53 mutations, SETD2 mutations were also enriched. The majority of LCINS tumours (54.3%) exhibit alterations in the RTK-RAS pathway, with EGFR being the most commonly altered gene (30.6%), followed by KRAS (7.3%), ALK (6%), MET (4.3%), ERBB2 (3.9%), ROS1 (2.6%), and RET (1.3%). Most previous reports have focused on European descent (EUR) populations, but genetic alterations in non-smokers vary by ethnicity [2, 7]. Lung adenocarcinoma patients of East Asian descent (EAS) had fewer genomic alterations and more stable genomes than those of EUR. EGFR mutations were more frequent in EAS, while EUR showed more KRAS and other driver mutations. TMB was lower in non-smokers than smokers in both groups, and EGFR and KRAS mutations were mutually exclusive. A study conducted in Taiwan analysed the molecular attributes of LCINS in a cohort of 83% non-smokers, combining genomic, proteomic, and phosphoproteomic data [7]. The analysis revealed that age and gender influence mutagenesis in LCINS, with younger females showing a high prevalence of APOBEC-related mutations and older females having more environmentally driven mutagenic signatures. Approximately 85% of the patients had EGFR mutations, followed by TP53 (33%) and RBM10 (20%). Proteomics-informed classification helped distinguish clinical characteristics of early-stage patients with EGFR mutations. Ongoing efforts to understand the genomic and epigenomic factors driving LCINS will facilitate the development of targeted therapies tailored to non-smokers. This could lead to better survival outcomes for this group. LCINS remains a significant public health challenge, and further research into its incidence, aetiology, and biology is critical. Prospective data collection on mutation status, smoking history, and environmental exposures is essential to improve our understanding of this complex disease and to develop more effective treatments for non-smokers (Figure 1). AM has received honoraria from AstraZeneca, Nippon Kayaku, Merck Biopharma, Takeda Pharmaceutical, Kyowa Kirin, and Pfizer. MS has received grants and contracts from any entity from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Boehringer Ingelheim, Nippon Kayaku, and Kyowa Kirin; honoraria from AstraZeneca, MSD K.K, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Pfizer, Novartis, Takeda Pharmaceutical, Kyowa Kirin, Nippon Kayaku, Daiichi-Sankyo Company, Merck Biopharma, and Amgen inc.

Background:Managing malignant pleural effusion (MPE) with pleurodesis is essential for symptom relief and minimizing the need for repeated thoracentesis. Interstitial lung disease (ILD) is one of the most common complications associated with advanced lung cancer. However, the efficacy and safety of pleurodesis for MPE secondary to lung cancer with ILD remains unclear. This study aimed to evaluate the efficacy and safety of pleurodesis in this population. Methods:This study was a single-center retrospective analysis. The cases of pleurodesis in patients with MPE secondary to lung cancer complicated with ILD at Nippon Medical School Hospital (Tokyo, Japan) between January 2010 and December 2022 were included. Results:Of the 26 lung cancer patients with ILD who underwent pleurodesis were analyzed. Fourteen patients received talc and 12 patients received minocycline, respectively. Talc was used in 10 out of 14 patients with drug-induced ILD and radiation-induced lung injury (RILI). In contrast, minocycline was used in 10 out of 12 patients with idiopathic interstitial pneumonias (IIPs). One month after pleurodesis, the efficacy for pleural adhesions was 64.3% and 50.0% in the talc and minocycline groups. The presence of a partially expanded lung before pleurodesis was a predictive factor for failure [odds ratio: 7.00, 95% confidence interval (CI): 1.20-40.83, P=0.04]. When excluding the patients presenting partially expanded lung, the efficacy rate was 77.8% and 71.4% in the talc and minocycline groups. One case of grade 5 acute respiratory distress syndrome (ARDS) was observed in each group. All cases developing ARDS had been treated with systemic prednisolone against ILDs presenting ground glass opacity and consolidation within 6 months before pleurodesis. Conclusions:Pleurodesis is considered to be one of the treatment options against MPE in patients with ILD. However, two cases of ARDS were observed; thus, clinicians should carefully consider the indication of pleurodesis in the patients who had the recent onset of ILD and were treated with systemic prednisolone.

Background: Skin disorders are major adverse events associated with necitumumab plus gemcitabine and cisplatin (Neci + GC) administration. However, the prognostic effect of skin disorders in patients with lung squamous cell carcinoma (LSCC) administered Neci + GC is unclear. Objectives: We examined this prognostic effect in patients with LSCC, and the usefulness of minocycline administration. Design: This was a sub-analysis of the retrospective multicenter NINJA study. Methods: We performed a landmark survival analysis according to the presence of skin disorders at Day 30 of treatment and examined the usefulness of minocycline for treating skin disorders. Results: Among the 93 patients, 62 (66.7%) had a skin disorder at Day 30. Nineteen, 30, and 13 patients experienced Grade 1, 2, and 3 skin disorders, respectively. The overall survival (OS) and progression-free survival (PFS) of patients with skin disorders at Day 30 were longer than those of patients without skin disorders (median OS: 434 vs 278 days, p = 0.0201; median PFS: 148 vs 82 days, p = 0.0835). Multivariable analysis showed that a skin disorder at Day 30 was an independent prognostic factor for both OS ( p = 0.0044) and PFS ( p = 0.0514). Of the 62 patients with skin disorders at Day 30, 38 (61.3%) were taking minocycline, and their time to treatment failure (TTF) was better than that in patients not taking minocycline (median TTF: 148 vs 101 days, p = 0.0495). Conclusion: A skin disorder within 30 days was a favorable prognostic factor for patients with LSCC administered Neci + GC. Additionally, minocycline administration may be beneficial in patients who develop skin disorders within 30 days.

BACKGROUND:Diuretics are commonly used to reduce renal dysfunction during cisplatin-based chemotherapy; however, reports suggest that renal function is unaffected when diuretics are not administered. This phase II trial evaluated the effectiveness and safety of a short hydration method without diuretics. METHODS:Patients were included if they were aged 20-74 years, had a thoracic malignancy for which a cisplatin-based regimen (dose: ≥60 mg/m2) was indicated, and had adequate renal function. All patients received cisplatin-based chemotherapy using a short hydration method without diuretics. The primary endpoint was the proportion of patients without grade 2 or higher elevations in creatinine levels during the first cycle of cisplatin. RESULTS:Forty-six patients were enrolled between June 2019 and April 2022. The patients included 38 men and 8 women with a median age of 64 years (range: 45-74 years). Of these, 13 patients received adjuvant chemotherapy, 19 received chemoradiotherapy, 1 received chemotherapy for post-surgical recurrence, and 13 received chemotherapy for advanced disease. The median number of chemotherapy cycles was 3 (range: 1-4). A total of 93.5% (43/46) of the patients completed cisplatin-based chemotherapy without grade 2 or higher creatinine elevation during the first cycle, and 84.8% (39/46) of participants, including those who discontinued treatment, did not show grade 2 or higher creatinine elevation after all cycles of cisplatin-based chemotherapy. CONCLUSIONS:Short hydration without diuretics is safe for patients receiving cisplatin-containing chemotherapy. Randomized trials with or without diuretics in this setting are warranted.

Acute exacerbation (AEx) of interstitial pneumonia is the most common lethal adverse event related to the pharmacological treatment of patients with lung cancer complicated with interstitial pneumonia. Although small cell lung cancer (SCLC) is linked to poor prognosis, it exhibits good response to chemotherapy. Few previous research studies have investigated the safety and efficacy of treatment for advanced SCLC complicated with idiopathic interstitial pneumonia (IIP). We conducted a single-arm phase II study to evaluate the safety and efficacy of carboplatin plus etoposide for the treatment of patients with SCLC complicated with IIP. Chemotherapy-naïve patients with advanced SCLC complicated with IIP were enrolled. Patients received carboplatin every 21–28 days at a dose of area under the curve 4–6 on day 1 and etoposide at a dose of 80–100 mg/m2 on days 1–3. Thirty-one patients were enrolled between December 2009 and December 2022. A median of four cycles of carboplatin plus etoposide were administered. Acute exacerbation of idiopathic interstitial pneumonia was not observed; the rate of AEx was 0

BACKGROUND AND OBJECTIVE:The optimal treatment modality for interstitial lung disease (ILD) associated with anti-aminoacyl-tRNA synthetase (ARS) antibodies remains controversial. This study aimed to compare the efficacy and safety of pulse corticosteroid therapy with that of conventional corticosteroid therapy in patients with anti-ARS ILD. METHODS:This retrospective cohort study included 62 patients with anti-ARS ILD. Patients were divided into two groups: Those who received pulse corticosteroid therapy (500-1000 mg of methylprednisolone intravenously for three days) and those who received conventional corticosteroid therapy. Primary outcomes included initial treatment response at one year and disease recurrence. Secondary outcomes were alterations in pulmonary function tests, KL-6 levels, prednisolone dose, and adverse events. RESULTS:Both the pulse corticosteroid therapy group and the conventional therapy group had similar rates of initial treatment improvement (90.3 % vs. 77.4 %, p = 0.301), with no significant differences in recurrence-free survival. Improvements in pulmonary function tests were comparable between the two groups. At 12 months, the mean daily prednisolone dose was 3.9 mg in the pulse therapy group compared with 6.0 mg in the conventional therapy group. The pulse corticosteroid therapy group also experienced fewer adverse events (25.8 % vs. 61.3 %, p = 0.010). CONCLUSION:Pulse corticosteroid therapy provides similar treatment efficacy, earlier reduction in corticosteroid dosage, and a lower incidence of adverse events compared to conventional therapy in patients with anti-ARS ILD. These findings highlight the potential benefit of a steroid-sparing strategy, suggesting that pulse corticosteroid therapy may be considered an effective and safer option in managing this condition.

8596 Background: Osimertinib is commonly used as a first-line treatment for EGFR-mutated advanced NSCLC. However, the optimal treatment following osimertinib failure remains unclear. This study evaluated afatinib plus chemotherapy for EGFR-mutated NSCLC resistant to osimertinib. Initial findings were presented at ASCO2023, and this report provides final data, including blood NGS analysis. Methods: Patients (pts) with EGFR mutations (Del19 or L858R) after osimertinib failure were treated with afatinib (20 mg daily) combined with carboplatin (AUC5 mg/mL/min) and pemetrexed (500 mg/m² every 3 weeks), followed by maintenance therapy with afatinib plus pemetrexed until progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (6M-PFSR). Secondary endpoints included PFS, OS, ORR, DOR, and safety. Blood samples were collected before and during treatment, and at progression, to evaluate biomarkers using CAPP-SEQ. Results: Between June 7, 2020, and January 19, 2022, 36 pts were enrolled. One pt met exclusion criteria, leaving 35 pts for efficacy analysis. The mean age was 70 years; 60% were women, and 54.3% were nonsmokers. The median observation period was 29.1 months (cutoff date: January 18, 2024). The primary endpoint, 6M-PFSR, was 57.1% (95% CI, 39.3–71.5), exceeding the threshold of 35%. Notably, 28.6% of pts achieved long-term PFS of ≥1 year. ORR was 51.4%, DCR was 88.6%, median PFS was 8.2 months, median DOR was 5.6 months, and median OS was 22.5 months. By mutation type, ORRs were similar for Del19 and L858R (46.7% and 55.0%, respectively), but median PFS was longer for Del19 than for L858R (9.6 vs. 5.2 months). Pts who had responded to prior osimertinib (CR/PR, n=29) had longer median PFS than non-responders (SD/PD/NE, n=6) (8.5 vs. 5.8 months). Adverse events (AEs) from TKI and chemotherapy were common but manageable. The most frequent AEs were diarrhea (52.8%), anorexia (47.2%), fatigue (36.1%), and paronychia (36.1%). Interstitial pneumonia occurred in 3 pts (8.3%), with one treatment-related death. In plasma NGS analysis, clearance of EGFR mutations during treatment was a key predictive factor. Pts without EGFR mutation clearance had shorter PFS and OS compared to those with clearance (PFS: 5.7 vs. 12.0 months; OS: 15.7 vs. 34.4 months). Efficacy was observed even in pts with p53 mutations, a known resistance factor. MET gene amplification was detected in 4 pts upon resistance. Conclusions: Afatinib combined with platinum-based chemotherapy demonstrated satisfactory efficacy and manageable toxicity in pts with tumors refractory to osimertinib. EGFR mutation clearance during treatment was predictive of therapeutic outcomes. This regimen may be a promising second-line option after osimertinib failure. Clinical trial information: 021200005 .

ABSTRACT Introduction Noninvasive evaluation of airway conditions is considered useful in the management of COPD, although assessing airway remodeling remains difficult in routine clinical practice. The impulse oscillometry system used in this study allows separate analysis of inspiratory and expiratory phases, offering detailed insights into airway function. This study examined the effects of inhaled corticosteroids (ICSs) on airway remodeling and assessed the utility of this system in COPD management. Methods Stable COPD patients on LAMA/LABA for over a year were assessed by spirometry and impulse oscillometry at baseline and after 48 weeks of ICS/LAMA/LABA therapy. Symptoms, imaging, and blood tests were also evaluated. Results Among 52 patients (mean baseline %FEV1/predicted: 56.9% ± 22.1%), all had one to two moderate exacerbations in the past year despite LAMA/LABA therapy. Significant correlations were observed between spirometry and MostGraph (e.g., baseline FEV1 vs. R5: r = −0.54). Although spirometry showed no significant changes, Fres improved significantly (−2.11 ± 0.35, p < 0.0001), with reductions in both expiratory and inspiratory phases. Conclusions Fres measured by MostGraph significantly improved after ICS addition, whereas no significant changes were observed in spirometry or resistance parameters. Fres also showed significant correlations with FEV1, suggesting that it may capture airway changes not detected by spirometry. These findings support further investigation into its role as a noninvasive marker in COPD. Trial Registration UMIN‐CTR Clinical Trial: UMIN000040764 (https://upload.umin.ac.jp/cgi‐open‐bin/ctr_e/ctr_view.cgi?recptno=R000042394)

Background: The clinical impact of hypomagnesemia induced by necitumumab plus gemcitabine and cisplatin (GCN) as a second-line or later therapy is unclear. Objective: We aimed to evaluate the clinical characteristics and survival impact of hypomagnesemia induced by this therapy. Design: This was a sub-analysis of the retrospective multicenter NINJA study. Methods: Among the 93 patients enrolled in the NINJA study, this subanalysis included 75 patients with baseline serum magnesium concentrations. Results: The incidence of grade ⩾2 hypomagnesemia was 18.0% in the patients with normal baseline serum magnesium concentrations and 42.8% in those with low concentrations ( p = 0.073). The discontinuation rates of GCN treatment owing to hypomagnesemia in each group were 0% and 7.1%, respectively ( p = 0.187). The number of necitumumab doses and severity of hypomagnesemia were positively correlated ( r = 0.389, p < 0.001). Patients who developed hypomagnesemia in fewer than 21 days after the first dose of GCN ( n = 12) had significantly poorer progression-free survival (PFS) than those without the condition ( n = 63; median: 4.1 vs 4.4 months, p = 0.048). A similar trend was observed for OS (median: 9.7 vs 15.7 months, p = 0.062). These results were maintained after multivariate analyses (PFS: hazard ratio (HR) 2.46, p = 0.014; OS: HR 2.78, p = 0.021). Conclusion: GCN as a second-line or later therapy may be tolerable regardless of the patient’s baseline serum magnesium concentration. On the other hand, early serum magnesium reduction with this therapy is associated with a poor prognosis. However, caution should be needed because our results lacked sufficient information for confounding variables other than those analyzed here that may influence the correlation between hypomagnesemia and survival.

Recently, immune checkpoint inhibitors (ICIs) have been increasingly applied in the treatment of small cell lung cancer (SCLC). While their development has enhanced treatment options for SCLC, the effectiveness of immunotherapy remains limited due to the low expression of Programmed Cell Death Ligand 1 (PD-L1) and the emergence of immunotherapy resistance. As a result, there is a pressing need for new biomarkers to guide SCLC treatment. We obtained four microarray datasets from GEO (Gene Expression Omnibus) database and screened differentially expressed genes (DEGs). After the establishment of protein-protein interaction network through Cytoscape, key hub genes were selected via a volcano plot. To validate these results, we used an independent dataset as a test cohort. We also analyzed differences in immune cell infiltration between normal and SCLC samples. Lastly, we identified a marker gene associated with immune cell infiltration and validated its role in SCLC through in vitro experiments. We screened GEO gene expression database for DEGs, which are immune-related genes, in SCLC. A PPI network analysis revealed seven overexpressed hub genes (AURKB, BIRC5, TOP2A, TYMS, PCNA, UBE2C, AURKA) in the SCLC cohort, which were significantly more expressed than in normal cells. Correlation analysis between immune cells and the seven hub genes showed that BIRC5 expression was inversely correlated with monocytes. In SCLC cell lines such as SBC5 and SBC3, downregulation of BIRC5 using siRNA induced apoptosis and inhibited cell activity, tumor invasiveness and proliferative potential. Furthermore, treatment with a BIRC5 inhibitor (YM155) reduced SCLC cell viability and increased apoptosis. Co-culture experiments with SBC3 and monocytes (e.g., THP1) led to decreased BIRC5 expression in SBC3 cells. We identified AURKB, BIRC5, TOP2A, TYMS, PCNA, UBE2C, and AURKA genes as potential immune-related therapeutic targets for SCLC. In particular, high BIRC5 expression promotes SCLC progression and may influence the immune microenvironment of the tumor by affecting monocytes. Akihiko Miyanaga, Yang Yunchu, Kuniko Matsuda, Takehiro Tozuka, Aya Fukuizumi, Kakeru Hisakane, Naomi Onda, Susumu Takeuchi, Koichiro Kamio, Kazuo Kasahara, Masahiro Seike. Immune-associated genes as potential therapeutic targets in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5687.