This study investigated the role of anlotinib in restoring osimertinib sensitivity in EGFR-mutant non-small cell lung cancer (NSCLC) by targeting the Wnt/β-catenin/YAP signaling and PD-L1 expression. Using osimertinib-resistant HCC827 cells with high PD-L1 expression, a stable PD-L1 knockdown line (Sh-PD-L1) was generated through lentiviral vectors. Resistance was induced by stepwise exposure to osimertinib, and the two constructed resistant cell lines were named OR (osimertinib-resistant) and Sh-PD-L1-OR (PD-L1 knockdown osimertinib-resistant) cell lines. Functional assays, including wound healing, Transwell, and MTT, along with Western blot analysis, were conducted in both cell and animal models. Sh-PD-L1 significantly reduced PD-L1 and EGFR expression (P < 0.001), decreased cell viability, and lowered IC50 values compared to parental cells (P < 0.001). In OR, PD-L1 expression was elevated, and PD-L1 knockdown in the Sh-PD-L1-OR group reduced both PD-L1 and EGFR levels (P < 0.001), enhanced YAP inhibition, and reversed Wnt/β-catenin signaling activation (P < 0.05). Anlotinib treatment reduced cell viability, migration, and invasion, with enhanced effects in the Sh-PD-L1-OR group (P < 0.001). It decreased p-EGFR, PD-L1, and YAP expression while activating GSK3β and reducing β-catenin phosphorylation (P < 0.05). In vivo, anlotinib reduced tumor growth in Sh-PD-L1-OR models (P < 0.01), with decreased expression of EGFR, PD-L1, YAP, and β-catenin. These findings suggest that high PD-L1 expression promotes osimertinib resistance through activation of YAP and Wnt/β-catenin, and that anlotinib combined with osimertinib can reverse resistance by restoring GSK3β activity, activating the Hippo pathway, and inhibiting β-catenin signaling.

The aim of this study was to assess the value of C-X-C motif chemokine receptor 4 (CXCR4) targeted positron emission tomography/computed tomography ([18F]AlF-NOTA-QHY-04 PET/CT) imaging in spleen for prediction of degree of myelosuppression in patients with small cell lung cancer (SCLC) before therapy. 59 patients with SCLC underwent [18F]AlF-NOTA-QHY-04 PET/CT scanning before treatment. The maximum, mean, and peak standard uptake value (SUVmax, SUVmean, SUVpeak), metabolic tumor volume (MTV) and total lesion CXCR4 expression (TLC) of spleen at baseline were acquired. Chemotherapy-based treatment was administered for limited-stage and extensive-stage SCLC. The most severe degree of myelosuppression during the treatment was recorded. Patients were identified as mild and severe myelosuppression. Potential predictors were identified and validated through intergroup difference analysiis, ROC curve assessment, and ordinal regression analysis. Patients with severe myelosuppression exhibited significantly higher splenic uptake values (SUVmax, SUVmean, SUVpeak and TLC) compared to those with mild myelosuppression (all p < 0.05). Regions of interest (ROI) curve analysis identified that higher metabolic parameters, including SUVmax (AUC = 0.853, p < 0.0001), SUVmean (AUC = 0.885, p < 0.0001), SUVpeak (AUC = 0.821, p < 0.0001), TLC (AUC = 0.753, p = 0.0016), were significantly associated with more severe myelosuppression. Multivariate analysis identified SUVmax (p = 0.007) and age (p = 0.005) as significant independent predictors of treatment-related myelosuppression severity. Our findings suggest that baseline splenic [18F]AlF-NOTA-QHY-04 PET/CT parameters, particularly SUVmax, may help identify patients with small cell lung cancer who are at high risk of severe treatment-related myelosuppression, with older age serving as an additional clinical risk factor.

BACKGROUND AND PURPOSE:We evaluated whether using the tracer [18F] AlF-NOTA-FAPI-04. in positron emission tomography/computed tomography (PET/CT) could predict pathologic complete response (pCR) rates in patients receiving neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC). MATERIALS AND METHODS:We prospectively evaluated 60 patients with histopathologically confirmed primary rectal cancer (20 referred for surgery and 40 for nCRT) who provided pretreatment [18F] AlF-NOTA-FAPI-04 PET/CT scans to detect FAP on tumor surfaces. Among those 40 patients, 26 provided a second [18F] AlF-NOTA-FAPI-04 PET/CT scan after the 10th radiotherapy fraction to assess changes in FAPI uptake variables. Correlations between baseline PET variables and markers of cancer-associated fibroblasts (CAFs) were assessed with Spearman's rank test. Relationships between pathologic remission and potential predictors were assessed with logistic regression. RESULTS:The FAPI PET variables maximum and mean standardized uptake values (SUVmax, SUVmean) were positive correlated with FAP expression (p < 0.05). Receiver operating characteristic curve analysis identified SUVmean (area under the curve [AUC] = 0.869, p < 0.001; cutoff value 6.02; sensitivity 100%; specificity 74.2%) and SUVmax (AUC = 0.810, p = 0.005; cutoff value 11.46; sensitivity 77.8%; specificity 80.6%), both for the primary tumor, as predicting pCR. Multivariate logistic regression showed that SUVmean was an independent predictor of good response (odds ratio = 0.295, 95% confidence interval [CI] 0.113-0.772, p = 0.013). Changes in FAPI uptake variables were not correlated with radiotherapy response. CONCLUSIONS:[18F] AlF-NOTA-FAPI-04 PET/CT uptake variables reflected the expression of CAF-related biomarkers. Higher baseline SUVmean on [18F] AlF-NOTA-FAPI-04 PET/CT scans was associated with poor response to nCRT for LARC.

Background Patients with unresectable stage III non-small cell lung cancer (NSCLC) have an unmet need for new therapies that improve survival. This phase III trial investigated the safety and efficacy of concurrent ociperlimab and tislelizumab plus concurrent chemoradiotherapy (cCRT) in treatment-naïve patients with stage III NSCLC.Methods In this phase III, multicenter, randomized, multiarm, open-label trial, patients with unresectable stage III NSCLC received concurrent ociperlimab plus tislelizumab and cCRT, followed by ociperlimab plus tislelizumab (arm A), tislelizumab and cCRT, followed by tislelizumab (arm B), or cCRT, followed by durvalumab (arm C) (NCT04866017). Objectives were to compare progression-free survival (PFS), overall survival (OS), objective response rate (ORR), duration of response, disease control rate, clinical benefit rate, time to death or distant metastasis (TTDM), and safety and tolerability for arms A versus C, B versus C, and A versus B.Results 63 patients were randomized to arms A (N=22), B (N=19), and C (N=22) prior to early trial termination. In A, B, and C, respectively, 95.5% (21/22), 84.2% (16/19), and 95.5% (21/22) were current or former smokers, and 68.2% (15/22), 73.7% (14/19), and 68.2% (15/22) had PD-L1 expression in tumor cells of ≥1%. Median PFS (95% CI) was not reached (NR) (6.3–not estimable (NE)) in A, 15.0 months (7.4 to NE) in B, and 10.4 months (5.7 to NE) in C. Median OS and TTDM were NR in any arm. ORR (95% CI) was 68.2% (45.1%–86.1%) in A, 68.4% (43.4%–87.4%) in B, and 59.1% (36.4%–79.3%) in C; all responses were partial responses. Treatment-emergent adverse events (TEAEs) occurred in all patients; in arms A, B, and C, respectively, pneumonitis occurred in 18.2% (4/22), 5.6% (1/18), and 9.1% (2/22) of patients, and interstitial lung disease occurred in 13.6% (3/22), 11.1% (2/18), and 0% of patients, of which the majority of events for each were grade 1/2. Grade ≥3 treatment-related TEAEs occurred in 68.2% (15/22), 66.7% (12/18), and 68.2% (15/22) of patients in arms A, B, and C, respectively.Conclusions There was a trend toward improved efficacy when adding tislelizumab with or without ociperlimab to cCRT followed by tislelizumab with or without ociperlimab compared with cCRT followed by durvalumab; however, efficacy data were for descriptive purposes only. No unexpected or new safety signals were identified.

TPS8133 Background: LS-SCLC is a highly aggressive malignancy with poor prognosis. Positioning effective consolidation strategies is a key focus to improve long-term patient outcomes. Prominently, immune checkpoint inhibitors (ICIs) have emerged as consolidation therapy after cCRT or sCRT for LS-SCLC. QL1706 is a bifunctional antibody against both programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte antigen 4, and iparomlimab (QL1604) is an anti-PD-1 agent. In previous studies, both QL1706 and QL1604 demonstrated manageable safety profiles. Notably, QL1706 also showed encouraging preliminary anti-tumor signals in SCLC, which indicated the potential as consolidation therapy (Zhao et al. 2023; Huang et al. 2023). This trial aims to compare the efficacy and safety of QL1706 and QL1604 as consolidation therapy in pts with LS-SCLC without progression after cCRT or sCRT. Methods: In this multicenter double-blind double-dummy randomized controlled phase 3 trial (NCT06789796), pts with pathologically-confirmed LS-SCLC per AJCC 8 th edition are recruited. Pts are eligible if aged ≥18 years, with adequate organ function, ECOG PS scored 0 or 1, and do not have disease progression after completion of the requested cCRT or sCRT. Prophylactic cranial irradiation (PCI) is permitted before randomization. Approximately 636 pts are planned to be randomized 1:1 to receive either QL1706 (at 5 mg/kg) plus QL1604 placebo or QL1604 (at a fixed dose of 200 mg or at 3 mg/kg for pts weighing <40 kg) plus QL1706 placebo via intravenous infusion on day 1 in a 21-day cycle. Treatment will be continued until disease progression, intolerable toxicity, initiation of new anti-tumor treatment, withdrawal of informed consent, loss to follow-up, trial termination, or up to 24 months, whichever occurs first. Randomization is stratified by disease stage (I/II vs. III), receipt of PCI (yes vs. no), and the type of CRT (cCRT vs. sCRT). The co-primary endpoints are progression-free survival (PFS) per RECIST v1.1 assessed by blinded independent central review (BICR), and overall survival (OS). Secondary endpoints are investigator-assessed PFS, 1-year and 2-year PFS rates assessed by BICR and investigator, objective response rate, disease control rate, duration of response, 1-year and 2-year OS rates, safety, pharmacokinetics, and immunogenicity. Exploratory endpoints are biomarker assessments and their relationship to efficacy and prognosis, as well as patient-reported outcomes. Overall two-sided Type I error (α=0.05) controlled by fixed-sequence testing: BICR assessed PFS will be tested first, followed by OS if significant. An interim analysis is planned. The study will be conducted across around 79 sites in China, and enrollment is ongoing. Clinical trial information: NCT06789796 .

INTRODUCTION:Radioresistance remains a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Transcription factor AP-2α (TFAP2A) has been implicated in tumor progression, but its role in NSCLC radioresistance and translational therapeutic relevance remain unclear. METHODS:Bioinformatics analyses of TCGA and GEO datasets were used to identify transcription factors associated with NSCLC radioresponse. TFAP2A expression was evaluated in NSCLC tissues by immunohistochemistry. The functional role of TFAP2A was investigated using gain- and loss-of-function experiments in NSCLC cells, xenograft models, and patient-derived NSCLC organoids. Mechanistic studies included RNA sequencing, DNA damage repair assays, dual-luciferase reporter assays, chromatin immunoprecipitation, BRCA1 rescue experiments, and extended DNA damage response pathway validation. Structure-based virtual screening, surface plasmon resonance analysis, clonogenic survival assays, and xenograft experiments were performed to assess TFAP2A-targeted radiosensitization. RESULTS:TFAP2A was overexpressed in NSCLC tissues and was associated with poor prognosis and reduced radiotherapy response. TFAP2A knockdown enhanced radiosensitivity by reducing post-irradiation proliferative recovery, increasing apoptosis, inducing G2/M accumulation, and impairing DNA damage repair, whereas TFAP2A overexpression promoted radioresistance. TFAP2A directly bound to the BRCA1 promoter and transcriptionally activated BRCA1. BRCA1 restoration partially rescued the radiosensitizing effects and G2/M accumulation induced by TFAP2A knockdown. Extended validation of representative DNA damage response pathways and additional RNA-seq-derived repair candidates further supported BRCA1 as a principal downstream effector in this model. Patient-derived NSCLC organoids confirmed that TFAP2A knockdown enhanced radiosensitivity in a clinically derived ex vivo model. Pharmacological validation identified Dephospho-CoA as a candidate TFAP2A-binding compound that enhanced radiotherapy response in clonogenic assays and xenograft models. CONCLUSIONS:TFAP2A promotes NSCLC radioresistance by transcriptionally activating BRCA1 and enhancing DNA damage repair. The TFAP2A/BRCA1 axis may serve as a predictive biomarker and therapeutic target for overcoming radioresistance, and TFAP2A-targeted radiosensitization warrants further preclinical development.

Additional data on DGAT1 deficiency-induced intratumoral lymphocyte infiltration and immune response.

The introduction of immune checkpoint inhibitors(ICIs)has substantially improved therapeutic outcomes in patients with non-small cell lung cancer(NSCLC)but marked inter-indi-vidual variability in treatment response persists1.Increasing evidence indicates that the gut microbiota has a critical role in regulating antitumor immune responses through the gut-organ axis,thereby influencing the efficacy and toxicity of systemic anticancer therapies2.Among microbiota-mod-ulating strategies,antibiotics and probiotics have attracted considerable interest.Nevertheless,the clinical impact of antibiotics and probiotics on treatment outcomes in NSCLC has not been comprehensively and systematically evaluated.Against this background,a meta-analysis was performed to determine the associations between antibiotic exposure or probiotic supplementation and clinical outcomes in patients with NSCLC,focusing on the objective response rate(ORR),progression-free survival(PFS),and overall survival(OS).

PURPOSE:Concurrent chemoradiation therapy is the standard therapy for limited-stage small cell lung cancer (LS-SCLC) but induces cancer therapy-induced thrombocytopenia (CTIT), which leads to treatment delays. This study aims to assess the efficacy and safety of prophylactic recombinant human thrombopoietin (rhTPO) in preventing CTIT in this patient population. METHODS AND MATERIALS:This prospective, multicenter, phase II trial was conducted across 14 Chinese centers. LS-SCLC patients receiving etoposide plus cisplatin or carboplatin chemotherapy with concurrent radiation therapy were given subcutaneous rhTPO (300 IU/kg/d) on days 1-5, 8-12, and 15-19 during radiation therapy. rhTPO treatment was stopped if platelet count reached ≥300 × 109/L or increased by ≥100 × 109/L from baseline. Primary endpoints were the nadir and peak platelet count. RESULTS:From March 8, 2024, to October 10, 2024, 56 LS-SCLC patients were enrolled. During the rhTPO treatment period, nadir platelet count (×109/L) was 128.54 ± 54.15, and peak platelet count reached 409.23 ± 173.50. Overall incidence of CTIT was 33.9% (19/56), including 8.9% (5/56) grade 3, and no grade 4-5 events. A total of 78.9% of patients (15/19) experienced platelet count recovery to ≥100 × 109/L during the rhTPO treatment period. Median time for platelet count recovery from <100 × 109/L to ≥100 × 109/L was 8 days (95% CI, 6-14). Multivariable logistic regression analysis revealed that low baseline platelet count (<150 × 109/L) was an independent risk factor for developing CTIT (odds ratio, 4.26; 95% CI, 1.08-16.78; P = .038). No patients required platelet transfusions or experienced radiation therapy interruptions, and only one patient required a reduction in the dose of chemotherapy throughout the entire study. Moreover, no serious adverse events were reported. rhTPO-related adverse reactions were infrequent and predominantly grade 1 (eg, transient platelet elevation). CONCLUSIONS:Prophylactic rhTPO during concurrent chemoradiation therapy for patients with LS-SCLC demonstrated a potential benefit in maintaining platelet counts with a low incidence of CTIT. These findings support further investigation of rhTPO as a preventive strategy for high risk CTIT patients.

Stage III non-small cell lung cancer (NSCLC) presents marked heterogeneity under evolving therapeutic paradigms. Real-world evidence on current treatment practices and outcomes remains limited. The MOOREA study aimed to evaluate real-world molecular testing, treatment patterns, and clinical outcomes of treatment-naïve Chinese patients with stage III NSCLC. MOOREA is a prospective, multicenter Chinese study enrolling patients with untreated stage III NSCLC (16 July 2019 to 28 February 2022) from 28 hospitals. Patients were consecutively enrolled. The primary endpoint was treatment pattern of cohort 1 (C1; unresectable stage III NSCLC), and the secondary endpoints included molecular testing pattern, progression-free survival (PFS), overall survival (OS) of C1, and treatment pattern of cohort 2 (C2; resectable stage III NSCLC). In total, 486 patients were analyzed (C1: 379; C2: 107). Molecular testing rates were: EGFR (20.0

ABSTRACT Stereotactic body radiation therapy (SBRT) is effective for early‐stage non‐small cell lung cancer (NSCLC), but the treatment of ultra‐central NSCLC (UCNLC) near critical structures remains challenging. This retrospective study analyzed 66 patients with stage I–II unresectable UCNLC who underwent SBRT at Shanghai Pulmonary Hospital (2020–2023). UCNLC was defined by planning target volumes (PTVs) abutting/overlapping vital structures (proximal bronchial tree, esophagus, heart, great vessels, pulmonary vessels) or internal target volumes (ITVs) within 1 cm of these organs. Tailored SBRT plans with non‐uniform PTV margins were used in 45.5% of cases, enabling 53.3% of patients to receive a biologically effective dose ≥ 100 Gy. With a median follow‐up of 32.2 months, the median progression‐free survival (PFS) was 42.9 months; 1‐ and 3‐year PFS rates were 93.9% and 68.8%, respectively. Median local control (LC) and overall survival (OS) were not reached, with 1‐ and 3‐year LC rates of 98.5% and 84.6%, and OS rates of 98.5% and 88.7%, respectively. Toxicities were predominantly grade 1–2, with only one grade 3 pneumonitis. Larger ITV predicted poorer LC and PFS, whereas T stage independently predicted PFS and OS. Therefore, a non‐uniform PTV strategy maintained clinical efficacy without compromising safety, supporting its application in UCNLC management.

The advancement of precision medicine depends critically on well-defined molecular targets. Pathologically activated fibroblasts drive disease progression in cancer, fibrosis and chronic inflammation through sustained inflammation, extracellular matrix remodeling and pathological microenvironment formation. Among available markers, fibroblast activation protein (FAP) stands out due to its selective overexpression in diseased tissues versus minimal expression in healthy organs. This unique profile makes FAP a promising target for molecular imaging and targeted therapy, enabling precision theranostics across both oncological and nononcological diseases. FAP-targeted theranostics originated from the lead compound PT-100, which established the core pharmacophore. Subsequent key advance was the replacement of the boronic acid warhead with a cyano group, along with the introduction of fluorine and quinoline moieties, yielding the UAMC-1110 scaffold. This scaffold exhibits improved bioactivity and favorable pharmacokinetics. Systematic modification of the quinoline side chain and conjugation with chelators have allowed efficient radiolabeling, positioning radiolabeled FAP inhibitors as promising tools for precision theranostics. However, continued optimization of UAMC-1110-derived probes to enhance their stability, affinity, tumor retention, and cellular uptake, together with integration into advanced strategies such as nanomedicine, remains essential not only for refining FAP-targeted precision medicine but also for expanding its applications beyond oncology to nononcological diseases. Unlike previous reviews, this Account organizes the field around a unified chemical design language, following a "rational design-pharmacokinetics-translational validation" paradigm. After delineating the core biological functions of FAP-expressing fibroblasts in disease pathogenesis, we systematically examine the rapid advancement of radionuclide-labeled FAPIs, including optimization of linkers, chelators, and albumin-binding moieties, along with multimerization strategies, which significantly enhanced the pharmacokinetic profiles. Key innovations in the field include three strategic approaches. First, the albumin-binding therapeutic agent [177Lu]Lu-EB-FAPI achieves prolonged tumor retention and promising efficacy. Second, multimerization strategies have yielded bivalent and tetrameric FAPI constructs, which exhibit superior tumor accumulation. Third, heterodimeric probes such as [68Ga]Ga-FAPI-RGD and [68Ga]Ga-FAPI-LM3 enable dual targeting of FAP along with integrin αvβ3 or somatostatin receptor SSTR2, thereby addressing tumor heterogeneity and enhancing lesion detectability. Subsequently, the application scope of FAPI-based imaging has been expanded from oncology to nononcological diseases. The value of this technique in visualizing dynamic remodeling processes across key pathologic conditions has been established, offering quantitative assessment beyond the reach of standard modalities. Furthermore, we review recent advances in diverse FAP-targeted therapeutic strategies, including nanomaterials, CAR-T cells, and vaccines, and offer a forward-looking perspective on both the potential and the ongoing challenges of FAP as a cross-disease precision theranostic platform.

Fibroblast activation protein (FAP), a key biomarker of activated fibroblasts in pathological tissue remodeling, is up-regulated in injured myocardium, driving cardiac fibrosis and adverse ventricular dysfunction. FAP's specificity for activated fibroblasts enables its use as a target for non-invasive molecular imaging, risk stratification and therapeutic efficacy. Radiolabeled FAP inhibitors (FAPIs), allow positron emission tomography to visualize fibroblast activity in myocardial infarction, non-ischemic cardiomyopathies, heart failure, atherosclerosis, and cardiotoxicity. Therapeutically, FAP-targeted strategies such as 177Lu-FAPI, chimeric antigen receptor-engineered natural killer cells and T cells, FAP vaccines show promise in mitigating fibrosis. The integration of FAP-targeted imaging and therapy offers a paradigm for precision medicine in cardiac fibrosis management. Here we synthesize current translational and clinical evidence for FAPI PET tracers in cardiovascular disease and succinctly outline emerging FAP-targeted anti-fibrotic strategies.

BACKGROUND:Extensive-stage small cell lung cancer (ES-SCLC) carries a poor prognosis. Although first-line chemoimmunotherapy (IO+ChT) is standard, evidence in elderly patients (≥70 years) and the role of thoracic radiotherapy (TRT) remain limited. METHODS:We retrospectively analyzed 1,276 ES-SCLC patients, including 350 elderly patients, treated with first-line therapy. To reduce TRT-related bias, a 4-month landmark analysis and propensity score matching (PSM; n = 780) were performed. Overall survival (OS) and progression-free survival (PFS) were primary endpoints. RESULTS:IO+ChT significantly improved OS compared with chemotherapy alone in the overall cohort and in elderly patients (both p < 0.01). In the matched elderly cohort, TRT markedly prolonged OS (HR = 0.56, p < 0.001) and emerged as the strongest independent prognostic factor. A significant interaction between TRT and immunotherapy was observed (pinteraction < 0.001), with survival benefits predominantly in patients receiving TRT. TRT was associated with increased mild hematologic toxicity but no excess severe adverse events or pneumonia. CONCLUSION:First-line IO+ChT confers survival benefit in ES-SCLC, including elderly patients. The receipt of consolidative TRT is associated with potentially favorable survival outcomes and an acceptable safety profile, suggesting that integrated treatment strategies may be considered in fit elderly patients, pending prospective validation.

Ferroptosis, a form of regulated cell death driven by lipid peroxidation, has emerged as a promising mechanism in cancer therapy. However, the lack of clinically viable ferroptosis inducers has precluded its therapeutic evaluation in patients. In this study, we demonstrated that inhibition of diacylglycerol O-acyltransferase 1 (DGAT1) induces a ferroptosis-like phenotype in cancer cells and enhances the efficacy of immune checkpoint blockade (ICB) therapy. In human cancer cohorts, low DGAT1 expression correlated with improved prognosis and elevated ferroptosis-associated gene signatures. In murine models, both genetic knockout and pharmacologic inhibition of DGAT1 enhanced ICB therapy efficacy by promoting increased infiltration of cytotoxic T lymphocytes. Mechanistically, DGAT1 inhibition reduced lipid droplet accumulation, triggering elevated lipid peroxidation, mitochondrial dysfunction, and reactive oxygen species production. These events culminated in glutathione peroxidase 4 depletion and ferroptosis. Given the availability of clinical-stage DGAT1 inhibitors, these findings provide a strong rationale for repurposing these agents as ferroptosis inducers to improve responses to cancer immunotherapy. SIGNIFICANCE:DGAT1 inhibition promotes ferroptosis by reducing lipid droplet accumulation, increasing lipid peroxidation, and inducing mitochondrial dysfunction, ultimately enhancing sensitivity to immune checkpoint blockade and offering a promising strategy for improving cancer treatment.

PURPOSE:Intestinal low-dose irradiation (ILDR) may enhance immunotherapy efficacy by modulating the gut microbiota and metabolism; however, its role in metastatic non-small cell lung cancer (mNSCLC), particularly in the first-line setting, remains unclear. EXPERIMENTAL DESIGN:This multicenter retrospective and prospective study included patients with mNSCLC receiving first- and second-line programmed cell death protein 1 (PD-1) inhibitors along with abdominopelvic radiotherapy between 2018 and 2025. Patients were stratified by the mean intestinal radiation dose into <1 Gy, 1 to 3 Gy, and >3 Gy groups, and treatment outcomes were compared. The blood and fecal samples were subjected to multiomics profiling. RESULTS:A total of 309 patients were included in the retrospective analysis. Optimal efficacy was observed with a small intestinal mean radiation dose (SIMRD) of 1 to 3 Gy, showing longer progression-free survival (PFS, 10.2 months) and overall survival (OS, 22.8 months; P < 0.01), which was consistent across subgroups. Compared with 1 to 3 Gy, SIMRD >3 Gy [hazard ratio (HR) = 4.87; P < 0.001] and <1 Gy (HR = 1.85; P < 0.001) independently predicted worse OS. Prospective results confirmed the best disease control rate (P = 0.041) and PFS (P = 0.046) with SIMRD of 1 to 3 Gy. Responders were enriched in Bacillota, Clostridia, and indole derivatives, particularly indole-3-carboxylic acid. Moreover, the 1 to 3 Gy group exhibited increased circulating macrophage inflammatory protein-3α and reduced circulating α4β7+ regulatory T cells. CONCLUSIONS:ILDR influences the efficacy of PD-1 blockade in patients with mNSCLC, particularly when SIMRD is maintained within the 1 to 3 Gy range, likely through modulation of the gut microbiota-metabolite-immune axis. See related commentary by Deutsch et al., p. 3420.

3036 Background: The prognosis of G/GEJA remains poor, especially in late line patients (pts). mPFS for G/GEJA pts who received ≥ 2 prior lines of standard therapy is 1.6 - 2.6 months (mos). XNW27011 is a novel antibody-drug conjugate (ADC) targeting CLDN18.2, a promising therapeutic target that is aberrantly expressed in patients with G/GEJA. Methods: This phase 2 study aims to evaluate the efficacy and safety of XNW27011. Adult pt with advanced solid tumors who has failed standard therapy or is intolerable to available standard therapy/without available standard therapy, and with CLDN18.2 expression in ≥5% tumor cells (TC) with IHC staining ≥2+ (IHC≥2+, TC≥5%, EPR19202) were enrolled, including G/GEJA pts. All patients had measurable disease (RECIST v1.1) and ECOG 0-1. Patients received XNW27011 at 2.4-4.8 mg/kg Q3W. Endpoints included ORR for efficacy, TRAE events for safety and PK parameters. Results: As of Dec 29, 2025, a total of 86 eligible G/GEJA pts were enrolled at 2.4-4.8 mg/kg. IHC≥2+, TC≥20% was chosen as the CLDN18.2 expression criteria for further development of XNW27011. Here, we report the results in G/GEJA pts with CLDN18.2 expression of IHC≥2+, TC≥20%. Safety: 71 enrolled pts had CLDN18.2 expression of IHC≥2+, TC≥20%. The median age was 57.0 years, 87.3% of the pts had received ≥2 lines of systemic therapy, 85.9% of the pts had received immune checkpoint inhibitors. The common TRAEs (≥20%) included anemia, nausea, white blood cell count decreased, decreased appetite, neutrophil count decreased, vomiting, weight loss, hypoalbuminemia, asthenia, platelet count decreased, lymphocyte count decreased and hypokalemia. Efficacy: At 3.0 mg/kg, 26 patients were evaluable for efficacy, with 23 and 3 pts had received ≥2 and 1 prior lines of systemic therapy, respectively. The median follow-up(mFU) was 11.3 mos, cORR and cDCR were 65.4% and 84.6%, respectively. mPFS was 5.7 mos and mOS was 11.7 mos. Among the 23 pts who had ≥2 prior lines of therapy, the mPFS was 6.8 mos and mOS was 11.9 mos, with the mFU of 11.5 mos. Notably, one patient previously treated with CLDN18.2-targeted therapy still demonstrated durable clinical benefit, with PFS of 11.3 mos and still remains on treatment as of data cutoff date. Pharmacokinetics: At doses from 0.6 - 6.0 mg/kg in pts with solid tumors including G/GEJA, XNW27011 exposure (C max and AUC 0-∞ ) increased in an approximately dose proportional manner with a half-life of 5~7 days. Across all dose levels, circulating blood payload concentrations were low with 3.3% ADA positive rate. Conclusions: XNW27011 demonstrated promising anti-tumor activity and a manageable safety profile in CLDN18.2-positive G/GEJA. A pivotal phase 3 study evaluating XNW27011 as a ≥3 line therapy in G/GEJA pts is currently ongoing. Clinical trial information: NCT06792435 .

This single-center retrospective study evaluated radiation pneumonitis (RP) in 209 treatment-naive EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving first-line third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs) plus thoracic radiotherapy (TRT), with concurrent defined as any overlap of ≥ 1 day between EGFR-TKI and TRT, at Shandong Cancer Hospital and Institute between January 2019 and September 2024, excluding concurrent chemotherapy and anti-angiogenic therapy. RP was diagnosed by chest computed tomography (CT), clinical symptoms, and irradiated field concordance, while infectious pneumonia and tumor progression were excluded by laboratory tests and serial imaging. Grade ≥ 2 RP occurred in 43.54% of patients (22.01% grade 2, 21.53% grade 3; no grade 4/5 RP), with osimertinib showing the highest rates of grade ≥ 2 and grade 3 RP, followed by aumolertinib and furmonertinib. For grade ≥ 2 RP, patients receiving aumolertinib or furmonertinib had a lower observed risk than those receiving osimertinib, while ipsilateral lung V5 ≥ 35.93% and gross tumor volume (GTV) ≥ 12.62 mL were independent risk factors. For grade 3 RP, an inverse association between smoking history and RP risk was observed, whereas ipsilateral lung V30 ≥ 24.61% and GTV ≥ 14.56 mL were associated with increased risk. Median progression-free survival (PFS) was 26.70 months, with no significant difference among the three TKIs. In this cohort, first-line third-generation EGFR-TKI plus TRT was associated with frequent but generally manageable RP. TKI type, ipsilateral lung V5/V30, and GTV were key predictors of RP, although the dosimetric thresholds and drug-specific differences identified in this cohort require external validation.

To further explore relative biological effectiveness (RBE) variability, the RBE of different intracerebral cells at various irradiation (IR) dosages and time were determined in this study. A total of 120 rabbits were randomly divided into proton groups (0, 10, 20, 30, 40 Gy, RBE) (n = 3) and photon groups (0, 10, 20, 30, 40 Gy) (n = 3). The rabbits were sacrificed at 2, 4, 6, 8 weeks after brain IR. Neuronal survival, identified via Hematoxylin and Eosin (H&E) staining, and immunohistochemical detection of neurofilament (NF), Olig2, and CD68 in the hippocampus and thalamus, were analyzed. Dose- and time-dependent RBE curves were fitted using the LQ model. Proton IR showed higher neuronal survival at 4-, 6-, and 8-weeks post 10 Gy, 20 Gy, 30 Gy IR (p < 0.05) compared to photon IR. Oligodendrocyte populations in photon group at 4-, 6-, and 8-weeks post 10 Gy IR and 6-, 8-weeks post 20 Gy were consistently higher than proton subgroups (p < 0.05). While proton IR showed higher microglial activation which was observed only at 4-weeks post 30y IR. Proton RBE for neurons and oligodendrocytes remained below 1.1 but exceeded 1.1 for microglial activation. These findings demonstrate the dose- and time- dependent nature of proton RBE and suggest brain tissue tolerates higher proton IR doses compared to photon IR, which fully confirmed the biological advantages of proton IR. These will help clinicians more precisely set the organ limit at risk and tailor radiotherapy plans.