BACKGROUND:Daily low-dose carboplatin with concurrent thoracic radiotherapy is the standard treatment for older patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) in Japan. METHODS:This open-label phase 3 trial was conducted at 38 institutions in Japan. Patients aged ≥ 75 years with LA-NSCLC were randomly assigned (1:1) to receive daily carboplatin (30 mg/m2) or weekly carboplatin (area under the curve, 2 mg·min/mL) plus nab-paclitaxel (30 mg/m2) with thoracic radiotherapy. Durvalumab maintenance therapy was recommended after treatment completion. The primary endpoint was overall survival, which was used to assess the non-inferiority of weekly carboplatin plus nab-paclitaxel compared to daily low-dose carboplatin. RESULTS:From December 2020 to March 2024, 124 patients were enrolled (carboplatin arm, 61 and carboplatin plus nab-paclitaxel arm, 63). In the planned interim analysis, the Bayesian predictive probability indicating the non-inferiority of carboplatin plus nab-paclitaxel compared with carboplatin in the final analysis was 8.0%, leading to early study termination for futility. The median overall survival was not estimable in the carboplatin arm; the estimated value in the carboplatin plus nab-paclitaxel arm was 26.1 months (hazard ratio, 1.56; 95% confidence interval, 0.79-3.11; p = 0.200). Two treatment-related and seven non-cancer-related deaths occurred in the carboplatin plus nab-paclitaxel arm. Patients in the carboplatin arm had better quality of life than those in the carboplatin plus nab-paclitaxel arm at 6 weeks (odds ratio, 0.39; 95% confidence interval, 0.18-0.81; p = 0.012). CONCLUSIONS:Daily low-dose carboplatin with concurrent thoracic radiotherapy remains the standard treatment for older patients with unresectable LA-NSCLC in Japan.

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.

8573 Background: Pembrolizumab is a standard 1st line treatment for advanced non–small cell lung cancer (NSCLC) with high PD-L1 expression (tumor proportion score [TPS] ≥50%); however, durable benefit is achieved in only a subset of patients. Prior pembrolizumab-based combination strategies (e.g., anti-TIGIT) have inconsistently improved outcomes over pembrolizumab monotherapy in this setting. Epidermal growth factor receptor (EGFR) signaling may promote immune evasion by stabilizing PD-L1 expression and shaping an immunosuppressive tumor microenvironment, providing a rationale for combining the anti-EGFR antibody necitumumab with pembrolizumab. We therefore evaluated the efficacy and safety of necitumumab plus pembrolizumab in treatment-naive patients with PD-L1–high advanced NSCLC. Methods: K-TAIL-202 (jRCT2031200248) was an open-label, multicenter, single-arm phase II study conducted in Japan. Eligible patients were aged ≥20 years with unresectable stage III/IV or recurrent NSCLC, PD-L1 TPS ≥50% (22C3), ECOG PS 0–1, and ≥1 measurable lesion. Patients received necitumumab 800 mg IV on days 1 and 8 plus pembrolizumab 200 mg IV on day 1 every 3 weeks for up to 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed objective response rate (ORR) per RECIST v1.1; secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. The study assumed an expected ORR of 54.8% and a threshold ORR of 39.0% (one-sided α = 0.10; 80% power), requiring enrollment of 50 patients. Results: Between December 2020 and March 2023, 50 patients were enrolled (median age, 72 years). The ORR was 68.0% (95% CI, 53.3–80.5) and the disease control rate was 78.0% (95% CI, 64.0–88.5). Complete response, partial response, stable disease, progressive disease, and not evaluable status were observed in 2.0%, 66.0%, 10.0%, 12.0%, and 10.0% of patients, respectively, meeting the primary endpoint. Median PFS was 16.0 months (95% CI, 9.0–24.0), with a 24-month PFS rate of 35.9%. Median OS was not attained (95% CI, 38.0 months–not estimable), and the 24-month OS rate was 71.3%. The most treatment-emergent adverse events included acneiform dermatitis (66.0%), hypomagnesemia (60.0%), and pneumonitis (12.0%). One grade 5 cardiac arrest occurred in 1 patient (2.0%), for which a causal relationship to study treatment could not be ruled out. Conclusions: At final analysis, first-line necitumumab plus pembrolizumab demonstrated durable antitumor activity and encouraging long-term survival as a chemotherapy-free regimen in patients with PD-L1–high advanced NSCLC. Toxicities were consistent with the known profiles of EGFR-targeted antibodies and PD-1 inhibitor therapy, underscoring the need for careful monitoring. These findings warrant further confirmation in a randomized phase III clinical trial. Clinical trial information: jRCT2031200248.

BACKGROUND:Radiation-induced esophagitis (RE) is common during thoracic radiotherapy for NSCLC. We assessed its clinical impact and developed a model to predict grade ≥ 2 acute RE in patients with unresectable stage III NSCLC undergoing concurrent chemoradiotherapy, using the Japan Lung Cancer Society integrated phase II-III database. METHODS:We retrospectively analyzed clinical and laboratory data from 1288 patients across 8 randomized trials (1999-2016). We evaluated associations between RE and survival outcomes and identified predictors of grade ≥ 2 acute RE using LASSO regression. RESULTS:Grade 2 RE occurred in 15% and grade 3 in 2.0%. Grade ≥ 2 RE was not significantly associated with progression-free survival (PFS; HR 0.98, 95% confidence interval [CI] 0.72-1.34) or overall survival (OS; HR 1.20, 95% CI 0.82-1.75). Grade ≥ 3 RE was significantly associated with worse PFS (HR 1.62, 95% CI 1.12-2.35) but not with OS (HR 1.22, 95% CI 0.58-2.60). Eight variables independently predicted grade ≥ 2 RE: female sex, T stage < 4, N3 status, adenocarcinoma histology, primary tumor in the left upper lobe, cisplatin use, white-blood-cell count < 11 × 109/L, and hemoglobin ≤ 12 g/dL. The model achieved a c-statistic of 0.85 (95% CI, 0.81-0.88). CONCLUSION:In this national clinical-trial cohort, grade ≥ 2 RE was not associated with worse OS, but grade ≥ 3 RE was associated with worse PFS in patients receiving concurrent chemoradiotherapy for unresectable stage III NSCLC. The 8-variable model provides a practical tool for predicting grade ≥ 2 RE and may facilitate tailored supportive care.

Spontaneous hemothorax, defined as bleeding into the pleural cavity without trauma or coagulopathy, is rare. Especially, it is uncommon in patients with primary epithelial lung cancer. We report a rare autopsy case of lung adenocarcinoma harboring both an anaplastic lymphoma kinase (ALK) rearrangement and a tumor protein p53 (TP53) mutation, in which hemothorax led to the formation of a giant pleural hematoma.A 75-year-old man with stage IVB lung adenocarcinoma presented with mediastinal and cervical lymph node metastases and right pleural effusion at diagnosis. Molecular testing revealed an ALK rearrangement and a TP53 mutation. He was treated sequentially with alectinib, lorlatinib, and brigatinib. After disease progression and treatment-related complications, he presented to the emergency department with acute dyspnea and a rapid decrease in hemoglobin level. Contrast-enhanced computed tomography showed encapsulated fluid retention with faint high attenuation in the right pleural cavity, and magnetic resonance imaging findings were consistent with a hematoma. Given his poor performance status and the absence of active bleeding on imaging, invasive intervention was not performed. Despite supportive management, he died one week after admission from respiratory failure and hemodynamic deterioration.Autopsy revealed a giant pleural hematoma above the diaphragm, surrounded by pleural metastases. Although no definite source vessel was identified, active bleeding from a metastatic pleural lesion was observed, suggesting persistent tumor-related hemorrhage as the cause of the hemothorax.This case represents an extremely rare presentation of ALK-rearranged lung adenocarcinoma complicated by spontaneous hemothorax. Neither ALK rearrangement nor TP53 mutation has been directly linked to hemothorax, but the aggressive biological behavior associated with this molecular profile may have contributed to the catastrophic pleural bleeding. In lung cancer patients, rapid pleural fluid accumulation with hyperdense imaging findings should raise suspicion for hemothorax.

BACKGROUND:Patients with hematologic malignancies frequently require diagnostic bronchoscopy for the evaluation of pulmonary complications, but thrombocytopenia complicates procedural safety and decision-making. We aimed to identify a platelet count threshold associated with increased intraprocedural bleeding risk during bronchoscopy with biopsy or brushing in this population. METHODS:We conducted a single-centre retrospective cohort study of adults with hematologic malignancies who underwent diagnostic bronchoscopy between 2010 and 2023. Bleeding was graded according to the Nashville Bleeding Scale (grade 1-4). Among procedures including transbronchial lung biopsy (TBLB) and/or endobronchial brushing, receiver operating characteristic (ROC) curve analysis was used to identify the platelet count cut-off associated with grade 2-4 bleeding. RESULTS:Overall, 122 bronchoscopies were performed in 117 patients; 16 procedures (13.1%) were complicated by grade 2-4 bleeding. Among the 89 procedures involving TBLB and/or brushing, the optimal platelet count cut-off for predicting grade 2-4 bleeding was 8.2 × 104/μL (area under the ROC curve 0.73, 95% CI 0.59-0.88; sensitivity 85.7%; specificity 65.7%). No procedure-related deaths occurred. TBLB yielded a pathological diagnosis in 22.4% (17/76) of procedures, while brushing cytology was diagnostic in 3.6% (2/55). Organizing pneumonia was the most frequent histopathological diagnosis, followed by lung cancer and fungal infection. CONCLUSIONS:In patients with haematologic malignancies and thrombocytopenia, bronchoscopy with biopsy or brushing provides clinically useful diagnostic information but carries an increased bleeding risk at lower platelet counts. A platelet count of approximately 8.2 × 104/μL may serve as a reference point indicating increased bleeding risk at lower counts during TBLB and brushing, rather than a definitive "safe" threshold. However, given the limited number of bleeding events, this should be regarded as an exploratory finding requiring validation in larger, prospective studies.

BACKGROUND:Epidermal growth factor receptor (EGFR) exon 19 deletion subtypes may be associated with differential survival outcomes following EGFR-tyrosine kinase inhibitor treatment. However, evidence remains scarce, particularly regarding osimertinib, and the underlying biological mechanisms are poorly understood. We aimed to compare survival outcomes among EGFR exon 19 deletion subtypes in patients with non-small cell lung cancer (NSCLC) treated with osimertinib. METHODS:In this multicenter retrospective study, patients with NSCLC were stratified according to exon 19 deletion subtypes. Whole-exome sequencing data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange registry and Memorial Sloan Kettering Clinicogenomic Harmonized Oncologic Real-World Dataset were analyzed to investigate co-occurring genomic alterations. RESULTS:Overall, 111 patients with advanced EGFR exon 19 deletion-positive NSCLC were analyzed and 86.5% received osimertinib as first-line therapy. Patients with non-E746_A750del (n = 25) had shorter progression-free survival (PFS) than those with E746_A750del (n = 86) (median: 14.3 vs. 20.6 months; p < 0.05). Among non-E746_A750del subtypes, L747_A750delinsP (n = 4) had a particularly poor prognosis, with significantly worse survival than those with E746_A750del (median PFS: 3.5 vs. 20.6 months; p < 0.001, and median overall survival: 11.8 vs. 48.5 months; p < 0.001). In public database analyses, non-E746_A750del had a higher rate of RBM10 co-mutations, whereas L747_A750delinsP was characterized by frequent CDKN2A/B homozygous deletions and MYC amplifications. CONCLUSIONS:Non-E746_A750del was associated with poorer outcomes, with L747_A750delinsP potentially being a high-risk subtype. Differences in co-occurring genomic alterations may contribute to the prognostic heterogeneity among exon 19 deletion subtypes.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, high-grade, neuroendocrine carcinoma with an aggressive clinical course, and there are few treatment options for relapsed and refractory cases. Tarlatamab, a first-in-class, bispecific T-cell engager targeting delta-like ligand 3 (DLL3) and CD3, holds promise as a therapeutic option for previously treated cases of small-cell lung cancer, but clinical data on LCNEC are exiguous. We report herein a 69-year-old, male patient. He underwent a left upper lobe partial resection for stage pT1bN0M0 LCNEC. Three years later, a recurrence with left pleural thickening, multiple liver metastases, and a marked elevation of pro-gastrin-releasing peptide developed. The patient had received five lines of systemic therapy over 2.5 years. Comprehensive genomic profiling revealed a high tumor mutational burden but no actionable targets. With approval from the institutional ethics committee, tarlatamab therapy was begun as sixth-line therapy. The patient experienced manageable grade 1 cytokine release syndrome. After two cycles, computed tomography demonstrated a partial response with a 40

Background Clinical trials of immune-checkpoint inhibitors (ICIs) have shown a characteristic long-term survival plateau in non-small-cell lung cancer (NSCLC), yet long-term real-world Asian data on nivolumab are limited. We analyzed a consecutively enrolled post-marketing surveillance (PMS) cohort of Japanese patients treated with nivolumab to evaluate long-term overall survival (OS). Methods All patients who started nivolumab monotherapy for previously treated NSCLC between December 2015 and February 2017 and were registered in the nationwide PMS programme were eligible. Survival status was updated through December 2023. OS was estimated with the Kaplan–Meier method, and annual survival rates and 95 % confidence intervals (CIs) were calculated. Individual patient data for the CheckMate 017/057 trials were reconstructed from published Kaplan-Meier curves and compared with the PMS cohort to assess concordance. Results Of 834 registered patients, 832 were evaluable for OS. With a median follow-up of 80.6 months, median OS was 10.23 months (95 % CI 9.11–11.51). Yearly OS rates were 44.9 % (1 year), 26.1 % (2 years), 16.9 % (3 years), 12.8 % (4 years), 9.4 % (5 years), 7.8 % (6 years) and 6.6 % (7 years), demonstrating a sustained tail effect on the Kaplan–Meier curve. ECOG performance status 0–1, earlier treatment line and lower clinical stage were associated with superior survival. OS in the PMS and reconstructed CheckMate cohorts was nearly identical (hazard ratio [HR] 1.01; 95 % CI 0.89–1.14; p = 0.933). In a subgroup matching CheckMate eligibility criteria (ECOG 0–1, second-line, stage IIIB/IV), the PMS cohort showed longer OS (HR 0.78; 95 % CI 0.63–0.97; p = 0.023). Conclusions This study provides one of the longest Asian real-world cohorts with at least seven years of follow-up and supports the presence of durable long-term survival after nivolumab treatment in routine clinical practice.

INTRODUCTION:Immune checkpoint inhibitors (ICIs) have enabled durable responses in a subset of patients with advanced NSCLC; however, the clinical trajectories and patterns of late disease progression among long-term survivors remain poorly characterized. METHODS:This multicenter retrospective study enrolled patients with advanced NSCLC who received ICI-containing therapy between January 2015 and April 2020. Long-term beneficiaries (LTBs) were defined as patients who achieved both an overall survival (OS) of more than or equal to 4 years and a time to next cytotoxic chemotherapy of more than or equal to 4 years. We performed 4-year landmark analyses, characterized late progression (first radiographic progression ≥4 y from ICI initiation), and evaluated cause-specific mortality using competing risk analysis. RESULTS:Of 3144 patients, 537 (17%) survived more than or equal to 4 years, and 295 (9.4%) were LTBs (median follow-up: 68.6 mo); only 8.1% were lost to follow-up at the data cutoff. ICI was initiated as first-line therapy in 63% of the patients. Among the 235 LTBs without progression at 4 years, 66% discontinued ICI. The lung cancer-specific OS rates were 97.8% and 88.0% at 6 and 8 years, respectively. Late progression occurred in 26 patients (11.1%); all had less than or equal to five lesions, and 84.6% demonstrated indolent progression with growth speeds less than or equal to 10 mm/mo. Local therapy was selected in 42% of the patients after progression. Of 22 deaths more than or equal to 4 years post-ICI, only seven (32%) were lung cancer related, whereas 15 (68%) were from other causes, including secondary malignancies. Competing risk analysis revealed that other-cause mortality consistently exceeded lung cancer-related mortality. CONCLUSIONS:LTBs without progression at 4 years achieved durable control, with lung cancer-specific OS approaching 90% at 8 years of follow-up. Late progression is uncommon, limited in extent, and often treated locally. The predominance of non-lung cancer-related mortality underscores the importance of comprehensive survivorship care.

PURPOSE:This study investigated the efficacy and safety of pembrolizumab and necitumumab as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) who had ≥50% programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS:This nonrandomized, multicenter, open-label, single-arm phase II trial included patients with previously untreated advanced NSCLC who had a PD-L1 tumor proportion score of ≥50%. Patients received pembrolizumab and necitumumab every 3 weeks for up to 35 cycles. The primary endpoint was the investigator-assessed objective response rate (ORR). The secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS:The sample comprised 50 patients (38 men, 12 women; median age: 72 years, range: 51-90 years). The ORR was 76.0% (95% confidence intervals: 61.9-86.9; P < 0.0001), with complete and partial response rates of 2.0% and 74.0%, respectively. Moreover, 10.0% and 8.0% of the patients had stable and progressive disease, respectively, whereas 6.0% could not be evaluated. The median PFS was 15.7 months, whereas the median OS was not reached at the time of analysis. The most common treatment-related adverse events were rash (64.0%) and hypomagnesemia (60.0%). Grade 3 interstitial lung disease occurred in five patients (10.0%), and grade 5 cardiac arrest occurred in one patient (2.0%). CONCLUSIONS:The pembrolizumab and necitumumab combination exhibited a promising ORR of 76.0% with a manageable safety profile in patients with NSCLC who had high PD-L1 expression. These findings highlight the need for further research on this regimen for patients with advanced NSCLC who have high PD-L1 expression.

A 57-year-old man presented with endobronchial tuberculosis (EBTB). He had a history of using inhaled corticosteroids (ICS) for years since asthma was diagnosed during childhood. The present case was remarkable in that ICS alone may have affected the onset and progression of the EBTB. In addition, diagnosing the patient’s condition apparently was challenging because he had atypical epidemiology, diagnostic imaging findings, and sites of occurrence for tuberculosis.The CT images revealed no cavitation, which is reported to be relatively specific and typical for tuberculosis. And then, it demonstrated mixed shadows indicating consolidation in the lower lobe and tree-in-bud, which are not specific. And the patient had no other risk factors of tuberculosis but prolonged ICS use. Tuberculosis was also cited as the differential diagnosis based on the chronic clinical course, bronchial wall calcification, and the tree-in-bud sign on imaging, not being highly suspected overall. To understand the clinical condition, we performed bronchoscopy. As a result, EBTB and pulmonary tuberculosis were diagnosed.Even when findings are largely atypical for tuberculosis, it should be strongly considered in the differential diagnosis when any typical elements, which are sometimes not specific, are encountered. It is also because EBTB is reported to be extremely transmissible owing to its high rate of bacterial shedding. Moreover, the recognition of the risk of reactivation especially in patients with asthma using ICS will also be important in the future although the possibility that ICS can affect it has been discussed for a long time.

e20712 Background: Molecular targeted therapies have transformed the management of non–small cell lung cancer (NSCLC) with actionable genomic alterations. However, direct comparisons of treatment outcomes across different genomic subtypes within a single real-world cohort remain limited. We evaluated the relative efficacy and safety of targeted therapies across major actionable genomic alterations in a large Japanese real-world population. Methods: This multicenter retrospective study included 810 consecutive Japanese patients with advanced or recurrent NSCLC harboring actionable genomic alterations who received molecular targeted therapy between 2017 and 2023. Patients were classified into three genomic groups: EGFR mutations (Group A, n = 659), fusion oncogenes involving ALK/ROS1/RET (Group B, n = 106), and other actionable alterations including MET exon 14 skipping, BRAF V600E, and KRAS G12C (Group C, n = 45). Treatment outcomes, including objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety, were analyzed using Kaplan–Meier methods and multivariable Cox regression. Results: The median follow-up was 24.9 months overall (Group A 25.6, Group B 27.3, Group C 16.1). A total of 580 progression events and 398 deaths were observed. ORR differed significantly among groups (74.1% in Group A, 85.8% in Group B, and 68.9% in Group C; P = 0.014). Median PFS was 17.5 months in Group A, 42.5 months in Group B, and 9.2 months in Group C (P < 0.001). Median OS was not reached in Group B, compared with 39.3 months in Group A and 22.7 months in Group C (P < 0.001). In multivariable analyses adjusting for clinical covariates, genomic subgroup remained independently associated with both PFS and OS, with fusion-driven tumors demonstrating consistently superior outcomes. EGFR-mutated tumors showed intermediate outcomes, whereas Group C exhibited limited efficacy and higher treatment discontinuation due to adverse events. Conclusions: In this large Japanese real-world cohort, a clear hierarchy of therapeutic benefit across actionable genomic alterations was observed. Fusion oncogene–driven NSCLC derived exceptional and durable benefit from targeted therapy, EGFR-mutated tumors demonstrated intermediate outcomes, and MET exon 14 skipping, BRAF V600E, and KRAS G12C mutations remained associated with limited efficacy and higher toxicity. These findings underscore the clinical importance of genomic subtype–based treatment strategies and highlight unmet needs in selected molecular subsets.

Introduction: Resistance to EGFR tyrosine kinase inhibitors is influenced by tumor-intrinsic and-extrinsic factors. We investigated the impact of tumor cell histology and tumor microenvironment on the efficacy of osimertinib. Methods: We evaluated surgically resected adenocarcinoma from patients treated with first-line osimertinib at the National Cancer Center Hospital East (2016-2023), evaluating clinicopathologic characteristics, tumor cell histology, podoplanin expression in cancer-associated fibroblasts (CAFs) identified by immunohistochemistry, and outcomes. We also investigated HGF mRNA expression levels, using The Cancer Genome Atlas Program and Singapore Oncology Data Portal cohorts. Results: The study included 93 patients. Solid (n = 19) versus non-solid predominant (n = 74) histology was not associated with worse disease-free survival after surgery (p = 0.12), but was significantly associated with worse progression-free survival (PFS) and overall survival following osimertinib treatment (p = 0.026, p = 0.004). Similarly, highpodoplanin (n = 31) versus low-podoplanin (n = 62) expression in CAFs was not associated with worse disease- free survival after surgery (p = 0.65), but was significantly associated with worse PFS and showed a trend towards worse overall survival following osimertinib treatment (p < 0.001, p = 0.11). In the multivariable analysis, solid predominant histology and high-podoplanin expression in CAFs were independently associated with worse PFS. In the cohorts of The Cancer Genome Atlas Program and Singapore Oncology Data Portal, EGFR-mutated lung adenocarcinoma with solid predominant histology or high-podoplanin expression exhibited significantly higher HGF expression. Conclusions: Solid predominant histology and highpodoplanin expression in CAFs predicted osimertinib resistance, potentially guiding the selection of patients for more intensive treatments beyond osimertinib monotherapy. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

Intravesical Bacillus Calmette-Guerin (BCG) therapy is the standard treatment for non-muscle-invasive bladder cancer. While it is effective, it sometimes causes a disseminated BCG infection, which is often difficult to diagnose microbiologically. We report herein a 73-year-old, male patient in whom a persistent fever, dyspnoea, and jaundice developed after he received his tenth round of intravesical BCG therapy. Chest computed tomography revealed diffuse micronodules, and lung and liver biopsies demonstrated multiple, well-formed, non-caseating granulomas. Despite negative microbiological test results, a disseminated BCG infection was suspected. Antimycobacterial therapy was started but discontinued after 2 weeks due to a drug-induced eruption. The clinical and radiological findings continued to improve without further treatment. The present case highlights the importance of a detailed assessment of radiological and histopathological findings for the diagnosis and management of diffuse lung diseases, including complications related to intravesical BCG therapy.

BACKGROUND:EGFR exon 19 insertions (EGFRex19ins) are rare EGFR mutations. Their clinical-genomic characteristics and outcomes with EGFR-tyrosine kinase inhibitors (TKIs) remain uncertain. METHODS:We evaluated the clinical-genomic characteristics and outcomes of EGFR-TKIs for EGFRex19ins in the multi-institutional prospective lung cancer genomic screening project (LC-SCRUM-Asia). We also studied preclinical Ba/F3 models expressing EGFR-K745_E746insIPVAIK (Ba/F3-IPVAIK) to investigate their sensitivity to 1st-, 2nd-, 3rd-generation, and EGFR exon 20 insertion-active TKIs. RESULTS:In LC-SCRUM-Asia, 16,204 NSCLC patients were enrolled from March 2015 to December 2023. EGFRex19ins were detected in 13 samples (0.1 % of NSCLC). The median age was 72 years (range, 38-80); most patients were female (77 %), had adenocarcinoma (92 %), and were never-smokers (62 %). Twelve patients (93 %) had EGFR-K745_E746insIPVAIK, while one (7 %) had EGFR-K745_E746insVPVAIK. The most frequent co-mutation was TP53 (62 %); no patients had other driver alterations. Six patients (46 %) tested positive for EGFR exon 19 deletions with PCR-based Cobas EGFR test, likely due to cross-reactivity arising from sequence homology. Twelve patients received EGFR-TKIs; five (42 %) experienced partial response. In the preclinical study, Ba/F3-IPVAIK showed the highest sensitivity to 2nd-generation EGFR-TKIs compared to other EGFR-TKIs. Structural studies supported these consistent results. When broken down by EGFR-TKI generations, response rates for 1st-, 2nd-, and 3rd-generation TKIs were 50 % (1/2), 80 % (4/5), and 0 % (0/5), respectively. The median PFS for 1st-, 2nd-, and 3rd-generation TKIs were 8.7 (95 % CI, 7.4-NR), 14.7 (95 % CI, 8.0-NR), and 4.4 (95 % CI, 3.4-NR) months, respectively. CONCLUSION:Our preclinical, structural, and clinical findings indicate 2nd-generation EGFR-TKIs are more effective for EGFRex19ins compared to other TKIs.

BACKGROUND:Immune checkpoint inhibitor plus chemotherapy (ICT) is the standard treatment for extensive-stage small cell lung cancer (ES-SCLC). We previously reported that oligometastasis (OM) is a predictor of ICT efficacy, however, the relationship between ICT efficacy and OM in older patients remains unknown. Therefore, this study examined the efficacy of ICT in the older patients including the influence of OM. METHODS:We enrolled patients with ES-SCLC who received ICT as first-line treatment between September 2019 and June 2022. Patient characteristics and treatment efficacy were compared between older (≥75 years) and non-older (<75 years) patients. RESULTS:We enrolled 228 patients, including 42 older patients. The prevalence of synchronous oligometastasis (SOM) at the start of first-line treatment was 21.0 % and 21.4 % (p = 1.0) in the older and non-older groups, respectively. The progression-free survival (PFS) with first-line therapy was 5.4 and 4.5 months (p = 0.55) and overall survival (OS) was 11.5 and 12.6 months (p = 0.74) for the SOM and non-SOM subgroups in the older group, respectively. For second-line treatment, PFS was 4.5 and 6.3 months (p = 0.79), and OS after second-line initiation was 16.0 and 13.2 months (p = 0.55) in oligoprogression (OP) and non-OP patients in the older group, respectively. CONCLUSIONS:The frequencies of SOM and OP were not significantly different between older and non-older patients. Although the small number of older patients in this study makes it impossible to conclude definitively, we did not observe a significant prognostic prolongation in older patients with OM as in non-older patients.

INTRODUCTION:Immunotherapy has transformed the treatment for NSCLC. Nevertheless, reliable biomarkers for treatment selection remain scarce. Gut microbiota has emerged as a potential biomarker, but its role in chemoimmunotherapy for NSCLC is unclear. METHODS:The phase III trial (JCOG2007, NIPPON) compared pembrolizumab plus platinum doublet chemotherapy (PC) with nivolumab and ipilimumab plus platinum doublet chemotherapy (NIC) in treatment-naive patients with advanced NSCLC without driver gene alterations. As an ancillary biomarker study, 270 patients with baseline fecal samples were analyzed for gut microbiota composition from 295 patients enrolled. 16S ribosomal DNA sequencing was performed for the diversity and differential abundance analysis. RESULTS:The beta diversity analysis of the overall cohort (n = 270) revealed distinct microbial structures between the subpopulations defined by whether overall survival (OS) exceeds 12 or 18 months. Subsequent linear discriminant analysis effect size analysis identified specific bacterial genera that differed between the subpopulations, with Fusicatenibacter, Butyricicoccus, and Blautia being enriched in patients with longer OS. Regarding adverse events (AEs), lower microbial alpha diversity and the presence of certain taxa were linked to a higher risk of serious (≥grade 4) AEs. In addition, favorable genera, including Fusicatenibacter and Butyricicoccus, were associated with a lower risk of serious AEs. Last, regimen-specific analysis demonstrated that higher abundance of Fusicatenibacter and Butyricicoccus was linked to better OS in the NIC arm compared with that in the CP arm (hazard ratio for OS = 0.56 and 0.52, respectively). Conversely, the higher abundance of Prevotellaceae NK3B31 was associated with higher mortality risk in the NIC arm (hazard ratio for OS = 2.33). CONCLUSIONS:Gut microbiota may serve as a biomarker for chemoimmunotherapy in advanced NSCLC. Differences in microbial diversity and specific bacterial genera were associated with prognosis and serious AEs, with potential regimen-specific effects. These findings support integrating gut microbiota profiling into clinical practice to optimize first-line treatment strategies.

8524 Background: Pembrolizumab-based chemo-immunotherapies (Pembro) and nivolumab plus ipilimumab-based immunotherapies with or without 2 cycles of chemotherapies (Nivo+Ipi) have improved survival in patients with advanced NSCLC compared to the conventional chemotherapy. However, biomarkers to support appropriate choice in these immunotherapies remain unclear. Methods: From 2019 to 2023, this multicenter, observational study retrospectively reviewed advanced NSCLC patients who received first-line Pembro or Nivo+Ipi and had evaluable PD-L1 expression status on tumor cells (tumor proportion score [TPS], 22C3) and immune cells (immune cell [IC] score, SP142). Survival curve comparisons between treatments were conducted using restricted mean survival time (RMST) estimation in place of Log-rank test, when the proportional hazard assumption was not met. Additionally, the genomic and expression profiles associated with TPS and IC score were assessed using whole-exome sequencing and RNA sequencing in available NSCLC samples. Results: A total of 198 patients were included (Pembro/Nivo+Ipi: 137/61). In the Pembro cohort, patients with high TPS (≥ 50%) had significantly longer progression-free survival (PFS) than those with low TPS (< 50%) (median PFS [mPFS, months]: 8.1 vs. 7.1, P = 0.02; hazard ratio [HR] = 0.59 [0.38–0.92]), while no significant difference in PFS was observed based on IC score (high vs. low: mPFS 7.4 vs. 6.8, P = 0.11, HR = 0.72 [0.49–1.07]). In the Nivo+Ipi cohort, PFS did not significantly differ by TPS (high vs. low: mPFS 4.0 vs. 4.0, P = 0.26; HR = 0.51 [0.16–1.68]), whereas patients with high IC score (≥ 1) had significantly longer PFS than those with low IC score (= 0) (mPFS: 7.7 vs. 2.8, P = 0.04; HR = 0.53 [0.28–0.98]). A durable PFS benefit of Nivo+Ipi over Pembro was observed only in patients with low TPS/high IC score (mPFS: 12.4 vs. 6.6; Schoenfeld individual test: P < 0.05; RMST Nivo+Ipi /RMST Pembro [2 years] = 1.5, P = 0.049, Table). Sequence analyses revealed that tumors with low TPS/high IC score had significantly higher tumor mutational burden (TMB) than other tumors (median TMB: 18.2 vs. 1.9 [/mb]; P < 0.001) and showed distinct enrichment in antigen presentation and T-cell receptor signaling pathways. Conclusions: Nivolumab plus ipilimumab-based immunotherapies demonstrated superior durable response compared to pembrolizumab-based chemo-immunotherapies in patients with low TPS/high IC score. PD-L1 phenotypes based on TPS and IC score could guide the optimal selection of immunotherapies for advanced NSCLC patients. Efficacy comparison in patients with low TPS (< 50%)/high IC score (≥ 1). Treatments mPFS (months) PFS rate at 2 years RMST at 2 years RMST Nivo+Ipi /RMST Pembro at 2 years P value Pembrolizumab-based chemo-immunotherapies 6.6 6% 8.5 1.5 [1.0–2.3] 0.049 Nivolumab plus ipilimumab-based immunotherapies 12.4 41% 12.9