Minimal residual disease (MRD) negativity is a well-established prognostic marker in multiple myeloma (MM), yet the clinical relevance of MRD response timing and duration remains unclear, particularly in real-world settings. We retrospectively analyzed 1048 newly diagnosed MM patients from the National Longitudinal Cohort of Hematological Diseases in China (NICHE) between 2012 and 2023, with a total of 5406 MRD assessments. A longer time to best MRD response (> 6 months) was significantly associated with improved progression-free and overall survival, especially among those with persistent MRD positivity but stable low-level disease burden. Early responders were more likely to exhibit high tumor burden and high-risk cytogenetic abnormalities. Notably, a prolonged MRD duration (≥ 36 months) predicted favorable outcomes regardless of MRD negativity status. Integrating response timing and duration identified a "Late + Durable" MRD pattern consistently associated with the best prognosis, even in patients with persistent MRD positivity, high-risk cytogenetics, or without ASCT. These findings highlight the prognostic significance of longitudinal MRD monitoring beyond single-timepoint assessments. A slow but durable MRD response may overcome adverse biological features and support individualized risk stratification, therapeutic decisions, and long-term disease monitoring in MM.

e19571 Background: The treatment of newly diagnosed multiple myeloma (NDMM) has evolved rapidly over the past two decades. We aimed to describe temporal trends in treatment patterns and clinical outcomes among patients in China. Methods: This retrospective cohort study utilized electronic medical record data from the National Longitudinal Cohort of Hematological Diseases in China. Eligible patients were ≥18 years at diagnosis and received ≥ 4 cycles induction therapy. Patients were excluded if previously treated for MM. Patients were followed until death, study end (June 30, 2023), or last follow-up via telephone. OS and PFS were estimated by Kaplan–Meier methods. Age group stratified Cox proportional hazards regression was performed to identify prognostic factors for survival. Results: A total of 1,622 patients were included. Median age was 57.0 years, and 18.4% were aged >65 years. Most patients were male. At diagnosis, 41.8% had ISS stage III disease. IgG was the predominant subtype, and high-risk cytogenetic abnormalities were present in 24.1% of patients. Induction therapy shifted from mainly chemotherapy to proteasome inhibitor–based regimens by 2009, and to PI+IMiD-based combinations by 2019. By 2023, about 60% of patients received PI+IMiD-based induction and 30% received anti-CD38 antibody–based induction. Utilization of autologous stem cell transplantation (ASCT) also increased steadily over time, ranging from 22% to 48% annually. With median follow-up of 35.6 months, survival improved steadily over time: median PFS increased from 32.3 months (95% CI: 26.7–38.9) in 2008–2012 to 33.6 months (95% CI: 30.7–36.7) in 2013–2017, and to 48.0 months (95% CI: 44.6–52.5) in 2018–2023, while median OS rose from 78.5 months to 85.6 months to not reached. Advanced ISS stage and high-risk cytogenetics were linked to poorer clinical outcomes. In contrast, ASCT and the use of PI+IMiD-based or CD38 antibody–based induction regimens independently correlated with improved PFS and OS. Among patients aged >65 years, treatment pattern shifts were similar to those in the overall cohort, with increasing use of PI+IMiD-based and anti-CD38 antibody–based induction in recent years. Since 2016, roughly 10% of older patients received ASCT. Improvements in PFS and OS across time periods were likewise observed in this age group as well. Conclusions: Over two decades, NDMM treatment in China has transitioned from chemotherapy-based regimens to widespread use of PI+IMiD combinations and increasing use of anti-CD38 antibodies, and expanding application of ASCT. These advances have driven meaningful improvements in PFS and OS across the study period. Similar trends were observed among patients aged >65 years. Continued efforts to expand access to novel agents and optimize treatment strategies are essential to sustain and accelerate these gains.

ABSTRACT In patients with small cell lung cancer (SCLC), nutritional status is a key determinant of disease progression, treatment tolerance, and prognosis. The prognostic nutritional index (PNI), reflecting both immune and nutritional conditions, is widely used to evaluate prognostic risk, but its longitudinal monitoring is often limited by incomplete clinical data in real‐world settings. This study aimed to propose a decision‐support framework for predicting future nutritional status and improving risk screening in SCLC patients with missing data. Using PNI values and related variables from the first four follow‐up time points to predict the PNI at the fifth time point (PNI5) and evaluated the impact of different missing data imputation strategies on predictive performance. Missing PNI values were imputed using mean imputation, multiple imputation (MI), Kalman filtering, k‐nearest neighbors (KNN), and XGBoost imputation. Predictive models were developed with two machine learning algorithms: random forest (RF) and XGBoost. The RF model demonstrated better overall performance, and MI combined with RF achieved the best predictive accuracy (MAE: 2.952; RMSE: 3.727). Predicted PNI values were further translated into risk categories using a predefined threshold (PNI = 45), with overall accuracy of 93.33%, PPV 95.24%, and NPV 92.59%. Importantly, the model enabled risk assessment in patients with incomplete laboratory data, covering previously unassessable cases and reducing monitoring gaps. This study highlights the importance of appropriate imputation strategies in and provides a practical tool for continuous nutritional risk assessment and early identification of high‐risk patients in SCLC.

Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) represent a distinct and highly aggressive malignancy characterized by SMARCA4 deficiency, poor prognosis, and resistance to chemotherapy. The lack of clarity regarding the regulatory mechanisms underlying this disease has hindered the development of standardized treatment guidelines. In this study, we analyzed clinical samples and found significantly elevated levels of cancer stem cell markers, including SOX2, CD34, c-Myc, and EpCam, in thoracic SMARCA4-UT, which were further confirmed in SMARCA4-deficient non-small cell lung cancer (NSCLC) cells. Furthermore, SMARCA4 knockdown in NSCLC cells promoted cell proliferation, migration, invasion, and tumorsphere formation in vitro, as well as enhanced tumor growth in a mouse model in vivo. RNA sequencing analysis of SMARCA4-deficient cells revealed the upregulation of a subset of genes, including Wnt10A, and activation of Wnt signaling. This was validated through SMARCA4-ChIP-seq and SMARCA4-ChIP-PCR analyses, Wnt activity reporter assays, and subcellular distribution analysis of β-catenin. Subsequent studies using a small molecule Wnt inhibitor in SMARCA4-deficient cells and thoracic SMARCA4-UT patient-derived organoids demonstrated induction of apoptosis, inhibition of cell stemness, and suppression of tumor cell growth. These results suggest the potential for developing a novel therapeutic strategy targeting cancer stem cells for the treatment of thoracic SMARCA4-UT.

The 2025 IMS-IMWG consensus genomic staging (CGS) system has improved genomic risk stratification in newly diagnosed multiple myeloma (NDMM), yet does not capture whether high-risk clones have acquired a disseminated phenotype. We investigated whether circulating tumor cells (CTC) refine CGS and enable longitudinal residual disease monitoring. We retrospectively analyzed 631 MM patients from the NICHE cohort (NCT04645199) who underwent CTC assessment across disease phases. Among 410 patients assessed at diagnosis, CTC were detectable in 63.9% and correlated with both bone marrow plasma cell infiltration and accumulation of high-risk cytogenetic abnormalities. In 359 NDMM patients with adequate follow-up, a cohort-derived CTC threshold of 0.38% independently predicted inferior progression-free survival (PFS) after multivariable adjustment. Importantly, CTC refined prognostic stratification specifically within the CGS high-risk subgroup. Patients with CGS high-risk/CTC-high disease had the shortest PFS, thereby defining a disseminated genomic high-risk phenotype comprising 12.4% (39/314) of evaluable NDMM patients. In follow-up cohorts, detectable CTC were associated with inferior outcomes in 127 patients assessed during non-progressive disease states, whereas combined CTC and bone marrow minimal residual disease assessment stratified outcomes in 120 patients with paired measurements. Overall, CTC-integrated CGS supports minimally invasive baseline risk stratification and longitudinal disease monitoring.

Immune checkpoint inhibitors (ICIs) have improved outcomes in non-small cell lung cancer (NSCLC), yet reliable biomarkers to predict clinical response remain limited. This study aimed to identify and validate a clinically practical biomarker reflecting neoantigen-driven immunogenicity and associated with ICI efficacy in NSCLC. We conducted a multi-phase study integrating unbiased discovery, clinical validation, and preliminary mechanistic exploration. Multi-omics profiling of a prospective NSCLC cohort (n = 28) integrated genomics, transcriptomics, and proteomics to identify fibrinogen alpha chain (FGA) as a top candidate. FGA was evaluated by quantitative immunohistochemistry in a training (n = 93) and independent validation (n = 78) cohort of patients with advanced NSCLC treated with ICIs. Multiplex immunofluorescence characterized FGA‑associated immune biology, and in vitro transcriptomic analysis explored transcriptional programs associated with FGA exposure. FGA expression positively correlated with tumor neoantigen expression (r = 0.618, p < 0.001). In the training cohort, high FGA was associated with significantly prolonged progression-free survival (median PFS: 25.8 vs. 5.2 months; adjusted HR = 0.44, p = 0.003) and higher objective response rate (50.0

Abstract Background Research on the efficacy of first-line osimertinib in non-small cell lung cancer (NSCLC) patients with different epidermal growth factor receptor (EGFR) exon 19 deletion (19del) mutation sites is limited. This study aimed to evaluate whether different EGFR 19del subtypes are associated with differential clinical outcomes in patients with EGFR-mutant NSCLC receiving first-line osimertinib therapy. Methods This study included 106 NSCLC patients with stage IIIb–IV disease from the CAPTRA-Lung database, confirmed to have EGFR 19del mutations through next-generation sequencing (NGS) and receiving first-line osimertinib. Patients were categorized based on mutation frequencies (common E746_A750del mutation or other uncommon subtypes), the deletion start codon for the EGFR 19del (E746 or L747), and the number of deleted nucleotides (15-nucleotide deletion [15n-del] or non-15n-del). Clinical characteristics, objective response rate (ORR) and progression-free survival (PFS) were compared between these subgroups. Results A total of 19 EGFR 19del mutation subtypes were identified. The most frequent mutation site for exon 19 deletion was E746_A750del, accounting for 56.6% of cases (n = 60), followed by L747_P753delinsS (9.4%, n = 10), L747_T751delinsP (6.6%, n = 7), and L747_A750delinsP (4.7%, n = 5). Patients in the non-15n-del group had a higher prevalence of baseline brain metastases compared with those in the 15n-del group (41.7% vs. 22.9%; P = 0.044). No associations were found between ORR and PFS of first-line osimertinib treatment and mutation frequencies, the deletion start codon for the EGFR 19del, and the number of deleted nucleotides. However, certain subtypes, particularly L747_A750delinsP, showed a trend toward a shorter PFS compared with the common E746_A750del subtype, although these differences did not reach statistical significance (12.3 months vs. 24.3 months; P = 0.100). Conclusions Overall, EGFR 19del subtypes showed comparable responses to first-line osimertinib. However, the trend toward poorer outcomes in the L747_A750delinsP subtype suggests potential heterogeneity that warrants confirmation in larger cohorts with longer follow-up.

e20119 Background: Optimizing the sequence of immunotherapy (IT) and stereotactic radiotherapy (SRT) in metastatic non-small cell lung cancer (NSCLC) may enhance survival, yet site-specific efficacy remains undefined. We investigated the impact of IT followed by SRT (IT→SRT) versus SRT followed by IT (SRT→IT) sequencing on overall survival (OS) in NSCLC patients with brain metastases (BrMs) or bone metastases using National Cancer Database (NCDB) data. Methods: This retrospective cohort study included 3,158 adults with Stage IV NSCLC diagnosed between 2015 and 2022 who had either brain metastases (n = 2,475) or bone metastases (n = 683). All patients received both SRT and IT, started 10–66 days apart. Patients were grouped by treatment sequence: SRT→IT or IT→SRT. Confounding was addressed using inverse-probability-of-treatment weighting (IPTW) and overlap weighting (OW) derived from propensity scores. OS was evaluated using Kaplan–Meier estimation and Cox proportional-hazards models within each metastasis site. Missing covariates were handled with multiple imputation by chained equations (25 datasets), and hazard ratios (HRs), 95% confidence intervals (CIs), and p values were combined across imputations using Rubin’s rules. Results: In the brain-metastasis cohort, 2,061 patients received SRT→IT and 414 received IT→SRT. Median OS was 27.4 months with SRT→IT versus 23.3 months with IT→SRT. The MI-pooled unweighted Cox model yielded an HR of 1.13 (95% CI 0.98–1.30; p = 0.081) for IT→SRT versus SRT→IT, while IPTW weighting produced a similar but statistically significant association (HR 1.10, 95% CI 1.02–1.19; p = 0.012); OW estimates were directionally similar but less precise (HR 1.10, 95% CI 0.90–1.35; p = 0.341). In the bone-metastasis cohort, 520 patients received SRT→IT and 163 received IT→SRT. IT→SRT was associated with longer survival (median OS 22.7 vs 15.5 months). The MI-pooled unweighted Cox HR for IT→SRT versus SRT→IT was 0.81 (95% CI 0.64–1.01; p = 0.064), with a statistically significant effect under IPTW weighting (HR 0.79, 95% CI 0.68–0.91; p = 0.001) and a directionally consistent but less precise OW estimate (HR 0.80, 95% CI 0.58–1.10; p = 0.165). Conclusions: Treatment-sequencing effects in metastatic NSCLC appear to be site specific. In patients with brain metastases, SRT→IT was associated with modestly longer OS, with sequence effects sensitive to the weighting approach. In patients with bone metastases, IT→SRT was associated with substantially longer OS, corresponding to an approximate 20% relative reduction in mortality in IPTW-weighted analyses. These findings support consideration of metastasis-site biology when determining the sequencing of IT and SRT and highlight the need for prospective trials explicitly designed to evaluate site-tailored multimodality strategies.

Immunotherapy has fundamentally transformed the management of lung cancer. For unresectable, locally advanced non-small cell lung cancer (LA-NSCLC) and limited-stage small-cell lung cancer (LS-SCLC), the current standard of care is platinum-based concurrent chemoradiotherapy (cCRT) followed by consolidation immune-checkpoint blockade, a sequence that significantly prolongs progression-free and overall survival. Attempts to deliver immunotherapy concurrently with cCRT have not improved efficacy in randomized trials and have raised additional safety concerns. Induction chemotherapy plus immunotherapy followed by cCRT is biologically rational and feasible, but definitive benefit awaits phase III confirmation. Optimal sequencing, the most effective immunotherapeutic agents, and the best radiotherapy schedules remain active research priorities. The biological rationale for combining radiotherapy and chemotherapy with immunotherapy rests on their capacity to increase tumor immunogenicity, such as by releasing neoantigens, enhancing major histocompatibility complex-I (MHC-I) expression, and promoting dendritic-cell activation, thereby amplifying subsequent T-cell-mediated cytotoxicity. Yet the same cytotoxic stimuli concurrently elicit lymphodepletion, expand regulatory T cells, and trigger pro- inflammatory cytokine cascades that can blunt antitumor immunity. Consequently, the net therapeutic benefit depends on meticulous optimization of sequencing, fractionation, and dosing to harness immunostimulatory efects while minimizing immunosuppressive sequelae. Circulating tumor DNA, metabolic imaging parameters, and real-time immune-profiling are being integrated into non-invasive biomarker platforms that track response and guide post-concurrent chemoradiotherapy (cCRT) immunotherapy decisions. The next generation of curative-intent therapy will be defined by multidisciplinary, patient-centred treatment plans that combine advanced radiotherapy techniques to reduce toxicity, novel agents such as bispecific antibodies or antibody-drug conjugates, biomarker-driven precision medicine, and proactive adverse-event management.

Background:The efficacy of first-line immune checkpoint inhibitor (ICI)-based therapy remains to be established for patients with advanced non-small cell lung cancer (NSCLC) harboring specific driver mutations for which effective first-line targeted therapies are unavailable. This study aims to examine the outcomes of first-line ICIs for advanced NSCLC with gene alterations in China and explore predictive factors of survival in this cohort. Methods:This retrospective study analyzed pathologically diagnosed advanced NSCLC with KRAS, insensitive EGFR, HER2, MET, BRAF, RET, NTRK, or non-driver gene alterations that received first-line ICIs at Peking Union Medical College Hospital (PUMCH) in China between January 2017 and June 2023. Clinical, genomic, and serological information before first-line treatment was collected from an electronic medical database. Best overall response, progression-free survival (PFS), and overall survival (OS) were evaluated. Results:There are 138 patients enrolled, including 96 with driver gene alterations and 42 with non-driver alterations. Driver gene alterations were insensitive EGFR (n=14), KRAS (n=45), HER2 (n=8), MET (n=2), BRAF (n=11), RET or NTRK (n=5), and concurrent driver genes (n=11). The objective response rate (ORR) was 44.9%, the median PFS was 11.3 months, and the median OS was 24.4 months. Survival was similar among different gene alteration subgroups. However, those with KRAS [14.6 months, 95% confidence interval (CI): 9.7-not reached (NR)] had longer PFS, while EGFR (7.97 months, 95% CI: 6.13-NR) and MET (7.4 months, 95% CI: not calculable) showed an inferior PFS. Programmed death ligand 1 (PD-L1) ≥50% was a consistent protective factor in univariate [hazard ratio (HR) 0.402, 95% CI: 0.196-0.827, P=0.01] and multivariate (HR 0.409, 95% CI: 0.186-0.903, P=0.03) Cox regression models, and PFS varied significantly among patients with PD-L1 <1%, 1-49%, and ≥50% (7.97 vs. 11.27 vs. 11.77 months, P=0.04). In KRAS mutant NSCLC, patients with KRAS G12C mutations exhibited longer PFS (19.9 vs. 10.3 months, P=0.71) and OS (NR vs. 14.2 months, P=0.36) compared to non-G12C mutations. Similarly, KRAS mutant patients with TP53 co-mutation had numerically prolonged PFS (25.9 vs. 10.5 months, P=0.16) and OS (NR vs. 20.4 months, P=0.06), compared to those without TP53 co-mutation. Conclusions:Among different gene alteration subgroups for advanced NSCLC, the efficacy of first-line ICIs did not differ with statistical significance, with high PD-L1 expression as a predictive factor for better survival. In KRAS mutant patients, KRAS G12C mutation or TP53 co-mutation might indicate improved survival.

Antibody imprinting is well recognized, yet its long-term dynamics and epitope specificity remain poorly understood. Here, we studied individuals sequentially infected with SARS-CoV-1 (SARS-1) and SARS-CoV-2 (SARS-2) over two decades and found durable imprinting of antibody responses following SARS-2 BF.7 breakthrough infection. Approximately 60% of isolated monoclonal antibodies were SARS-1 imprinted and targeted conserved receptor-binding domain regions, whereas 37% overcame imprinting to recognize the SARS-2 receptor-binding motif overlapping the ACE2-binding site. Notably, some SARS-1-only antibodies retained germline-like features and neutralizing activity 20 years after infection. One exceptionally imprinted broadly neutralizing antibody, THZ937, protected hamsters against contact and airborne transmission of Omicron EG.5.1, demonstrating the functional relevance of durable imprinted antibodies. Together, these findings define the remarkable longevity and molecular basis of antibody imprinting and provide insights for pan-sarbecovirus vaccine design.

8567 Background: PD-1/L1 inhibitors have become a part of 1L treatment for EGFR/ALK wild-type NSCLC. However, >60% patients (pts) develop AR associated with T cell exhaustion and defective antigen presentation. Doc remains a mainstay for pts who relapse after anti-PD-1/L1 therapy, while multiple late-stage clinical trials have failed in comparison. Plin is a first-in-class, brain-penetrating dendritic cell maturation agent with clinically validated potential to restore antigen presentation/T cell function after AR to PD-1/L1 inhibitors. Plin also reduces severe neutropenia and thereby increases Doc tolerability. In a global phase 3 study (Dublin-3, n=559), Plin/Doc outperformed Doc with significant OS/PFS/ORR benefits, doubling of 2-/3-year OS rates, and 80% reduction in G4 neutropenia (p<0.0001). The aim of this study was to assess the efficacy/safety of Plin/Doc plus Pemb in mNSCLC after anti-PD-1/L1 based therapy. Methods: This single-arm phase 2 trial (NCT05599789; Study 303) enrolled 47 pts after immediate progression on anti-PD-1/L1 alone or combined with platinum doublets. Pts received Plin 30mg/m2, Doc 75mg/m2 and Pemb 200mg, on Day 1 in 21-day cycles. The primary/secondary endpoints at the median follow-up of 20.6 months (mo) are tabulated. For immunophenotyping, whole blood from baseline and post treatment were analyzed by flow cytometry. Results: At the data cutoff date of 31-Dec-2025, cORR was 18.2% with 79.5% DCR. mPFS was 7.0 mo, and mDoR at 9.3 mo. While mOS was 34 mo, the 24-mo OS rates were 64.3% (ITT), 71.1% (NSQ), and 52.0% (SQ). In all endpoints assessed, prior Pemb exposure did not reduce the efficacy of this regimen. Whole blood analysis indicated that activated CD4+/CD8+ T cells and proliferating Ki67+CD8 T cells were significantly increased post two cycles of treatment. Also observed were concurrent elevations of Ki67+B cells and CD38+NK cells. Conclusions: Plin/doc plus Pemb shows promising efficacy in mNSCLC with AR to anti-PD-1/L1 confirmed by immune activation post-treatment. TRAEs were manageable. These findings along with DUBLIN-3 support a global confirmatory study in EGFR/ALK wild-type NSQ NSCLC following progression on anti-PD1/L1 based therapy. Clinical trial information: NCT05599789 . Efficacy endpoints. Endpoint* ITT(N=47) NSQ(N=30) SQ(N=17) Primary endpoint cORR (RECIST 1.1) 18.2% 13.8% 26.7% Secondary endpoints mPFS (RECIST 1.1) 7.0 mo 7.7 mo 5.5 mo mOS 34 mo (not reached) 34 mo mDoR (RECIST 1.1) 9.3 mo (not reached) 9.1 mo DCR (PR+SD > 4 mo) 79.5% 82.8% 73.3% 12-mo OS rate 78.2% 80.0% 74.8% 24-mo OS rate 64.3% 71.1% 52.0% *cORR/DoR/DCR: 44 evaluable pts; PFS/OS & follow-up duration: ITT.

BackgroundImmune checkpoint inhibitor-associated myocarditis is an uncommon but potentially fatal cardiovascular toxicity of cancer immunotherapy. Early risk stratification remains challenging, and readily available biomarkers are needed. We investigated whether early changes in absolute lymphocyte count (ALC) were associated with major adverse cardiovascular events (MACE) and overall survival in patients with immune checkpoint inhibitor-associated myocarditis.MethodsThis retrospective cohort study included 60 patients diagnosed with immune checkpoint inhibitor-associated myocarditis. Absolute lymphocyte count was measured serially during the first 9 days after corticosteroid initiation. A Day-9 landmark design was used to assess associations between lymphocyte dynamics and subsequent outcomes. The primary endpoint was 60-day major adverse cardiovascular events, and the secondary endpoint was 1-year overall survival. Cox regression, Kaplan–Meier analysis, receiver operating characteristic analysis, and restricted cubic spline modeling were performed.ResultsAmong 60 patients, 28 (46.7%) developed MACE in 60 days. Patients who developed MACE had persistently lower ALC levels and impaired early lymphocyte recovery. Day-9 ALC demonstrated good discrimination for MACE (AUC = 0.816) and remained independently associated with lower risk after multivariable adjustment (HR 0.33, 95% CI 0.14–0.81; p = 0.016). The association between Day-9 ALC and MACE risk was nonlinear, with lower estimated risk at higher ALC levels. Faster lymphocyte recovery was also independently associated with lower MACE risk (HR 0.07 per 0.1 × 109/L/day, 95% CI 0.01–0.44; p = 0.004). Both lower Day-9 ALC and impaired recovery were associated with worse 1-year overall survival.ConclusionsIn patients with immune checkpoint inhibitor-associated myocarditis, lower Day-9 absolute lymphocyte count and slower early lymphocyte recovery were associated with adverse cardiovascular events and mortality. Serial absolute lymphocyte count assessment may provide a simple and clinically accessible approach for early risk stratification, although external validation is needed.

INTRODUCTION:Leptomeningeal metastasis (LM) is a devastating complication of lung cancer. We investigated the clinical and molecular evolution of LM in the modern targeted-therapy era and factors associated with post-LM survival. METHODS:We retrospectively analyzed 201 patients with cytologically confirmed lung cancer LM diagnosed between November 2012 and May 2026. Patients were classified by LM diagnosis date (2012-2016 vs. 2017-2026). Intervals from lung cancer and Stage IV diagnosis to LM were compared using the Mann-Whitney U test. Paired primary tumor and cerebrospinal fluid (CSF) molecular profiles were assessed in 80 patients. Overall survival (OS) was evaluated using Kaplan-Meier and prespecified multivariable cox analyses. RESULTS:Adenocarcinoma accounted for 93.0% of cases. The intervals from lung cancer and Stage IV diagnosis to LM were longer in the later cohort (23.7 vs. 13.8 months, p < 0.001; 17.4 vs. 10.4 months, p = 0.002). Unadjusted OS from LM diagnosis did not differ significantly between eras (9.8 vs. 11.3 months, p = 0.864). Tissue-CSF driver discordance occurred in 7/80 patients (8.75%). In multivariable analysis, later diagnostic era, smoking, and ECOG PS ≥ 2 were associated with higher mortality (adjusted HR, 1.826, p = 0.014; 1.847, p = 0.014; and 1.674, p = 0.007, respectively), whereas post-LM third-generation EGFR-TKI exposure was associated with lower mortality (adjusted HR, 0.385; p < 0.001). CONCLUSION:The later era was associated with a longer interval to LM diagnosis but no statistically significant improvement in unadjusted post-LM OS. Adjusted associations require cautious interpretation because of residual confounding and post-baseline treatment bias. CSF profiling may provide clinically relevant information beyond primary tumor genotyping.

BACKGROUND:Neoadjuvant chemoimmunotherapy improves outcomes in resectable non-small cell lung cancer (NSCLC), yet the spatial immune features associated with treatment response remain unclear. METHODS:In this single-arm phase II trial (NCT05383716), patients with resectable NSCLC received neoadjuvant pembrolizumab plus platinum-based chemotherapy, followed by surgery and adjuvant immunotherapy. The primary endpoint was major pathological response (MPR). Digital spatial profiling was performed on resected tumors and paired draining lymph nodes from 22 patients, with additional tumor samples collected for validation. RESULTS:Among 80 enrolled patients, 55 underwent surgery, achieving an MPR rate of 37.5% and a pathological complete response rate of 26.3%. Grade 3-4 treatment-related adverse events occurred in 26.3% of patients. Spatial transcriptomics showed that MPR tumors were enriched for T- and B-cell activation pathways and infiltration of CD8+ T cells, B cells, plasma cells, and T-follicular helper cells, whereas non-MPR tumors exhibited stress adaptation and immune suppression signatures. Two immune phenotypes were identified within MPR samples: myeloid-enriched (ME) and lymphoid-enriched (LE) subtypes. The LE subtype was associated with improved response and survival in validation cohorts, whereas higher ME scores showed a trend toward poorer survival. An 18-gene LE signature was developed as a potential biomarker for adjuvant immunotherapy benefit. CONCLUSION:Neoadjuvant pembrolizumab plus chemotherapy demonstrated encouraging efficacy and manageable safety in resectable NSCLC. Spatial profiling identified distinct immune phenotypes associated with response and may inform patient stratification for adjuvant therapy.

12016 Background: Checkpoint inhibitor pneumonitis (CIP) stands out as a remarkable complication during ICIs therapy. Severe CIP represents a potentially life-threaten immune-related adverse event (irAE) with limited evidence from clinical trials that guides therapeutic interventions. Ruxolitinib, a selective JAK1/2 inhibitor, effectively attenuates cytokine-release syndrome and show significant anti-fibrotic in mouse lung with BLM model. We conducted a multicenter, investigator-initiated, open-label, phase 2 randomized controlled trial to evaluate the efficacy and safety of add-on ruxolitinib for patients with severe CIP management with corticosteroids. Methods: Patients with malignant who were suffered from CTCAE grade (G) 3 or G4 CIP after ICIs therapy were screened. Enrolled CIP patients were randomly assigned 1:1 to control group (only glucocorticoids) or ruxolitinib group (glucocorticoids plus ruxolitinib). Initiated dosage of glucocorticoids was no less than prednisone 1 mg/kg/day (or same steroid equivalent dose) with subsequent tapering off. In ruxolitinib group, enrolled patients were add-on ruxolitinib (5 mg twice daily for 2 weeks, followed with 5 mg daily for 2 weeks). The primary end point was the proportion of patients with a prednisone daily dosage of no more than 10mg and improvement to G1 CIP at week 8. Continuous variables were analyzed using a mixed-effects model for repeated measures with treatment group, study visit and treatment-by-visit interaction. Results: From April 2023 to November 2025, a total of 60 eligible patients were recruited and randomly assigned to control group and ruxolitinib group. There were 52 cases of G3 CIP and 8 cases of G4 CIP. There were more patients in the ruxolitinib group improved to G1 CIP and received ≤prednisone 10mg daily at 8 th week than in the controlled group (20cases/66.7% vs 11cases/36.7%, p = 0.0379 ). This effect was more significant in the 2 nd and 4 th week. Two patients in ruxolitinib group and 4 patients in the control group died within eight weeks. The repeated measures analysis using a generalized linear mixed model demonstrated a significant overall treatment effect, ie. add-on ruxolitinib was associated with significantly higher odds of clinical improvement (adjusted OR = 5.12, 95% CI 1.06 - 24.64; p = 0.04). A total of 13 G3 or higher treatment-related AEs (TRAEs) occurred (7 cases in control group and 6 cases in ruxolitinib group), including 9 cases of infectious diseases. Conclusions: Add-on ruxolitinib for malignant patients with severe CIP management with glucocorticoids show with higher resolution rates and earlier response trends than only glucocorticoids treatment. And there were no different adverse events between them. Add-on ruxolitinib with glucocorticoids might be a promising proposed treatment for patients with severe CIP. Clinical trial information: NCT05899725 .

Background: Immune checkpoint inhibitor (ICI)-based treatment regimens have become the standard of care for first-line treatment of NSCLC. Once progressed, it is not recommended to continue using ICI monotherapy, and the efficacy of chemotherapy is limited (ORR ∼10% with doc), so there is a high unmet clinical need. Plin is a selective immunomodulating microtubule-binding agent which promotes dendritic cell maturation and enhances anti-tumor T cell response, and have the potential to overcome immunotherapy resistance as a novel regimen in combination with pemb and doc. This phase 2 study was aimed to evaluate the efficacy and safety of pemb plus plin and doc in pts with metastatic NSCLC who had progressed after ICI. Methods: In this investigator-initiated, single-arm, open-label, phase 2 trial, metastatic NSCLC pts who acquired resistance after ICI treatment were enrolled (Clinical trial information: NCT05599789). Participants received pemb 200 mg D1, plin 30 mg/m2 D1 and doc 75 mg/m2 D1 intravenously for a 21-day cycle. The primary endpoint was investigator-based ORR per RECIST 1.1. The secondary endpoints included PFS, OS, DoR and toxicity. Kaplan-Meier method is used for OS, PFS, and DOR analysis. The study intends to enroll 47 patients with a formal interim analysis at 19 patients enrolled. Findings: 38 pts were enrolled and 35 pts evaluable ITT population were analyzed at data cutoff on 10/10/2024. Median follow-up was 8.8 months (M) and median age was 68.0 (50-83) with 77.1% male and 22.9% female. 65.7% were current or former smokers. Histology included 60% with non-squamous, 40% with squamous cell carcinoma. Confirmed ORR was 18.2%. DCR was 89.7% (defined as PR and SD > 4 M), median DoR was 11.4 M, median PFS was 8.3 M (current 6 M PFS rate was 70.4%, 12 M PFS rate was 42.7%), and OS had not been reached. 48.6% of pts experienced G3 or higher treatment-related AEs. Interpretation: With good tolerability, pemb plus plin and doc in pts with metastatic NSCLC who progressed after clinical benefit to ICI demonstrated promising efficacy.

Objective:This study aimed to delineate the occurrence and duration of the symptoms of coronavirus disease 2019 (COVID-19) in patients with lung cancer to provide supporting data for clinical research and epidemic prevention and control. Methods:This prospective longitudinal study was conducted in a tertiary hospital in China, comprising 697 outpatients and inpatients with lung cancer seeking medical care between March and April 2023. The enrolled patients completed questionnaires during the visit, with subsequent follow-up by telephone at 6 months after the patients' first infection. The questionnaire covered general patient information, disease characteristics, and SARS-CoV-2 infection and vaccine status. The details of COVID-19 treatment included the diagnostic method, infection time, and lung cancer treatment for up to three months after infection. This study also investigated the symptoms and duration of COVID-19. Results:Among 697 patients, 591 (84.79%) had a history of COVID-19, 165 patients (27.92%) were not vaccinated, and 339 (57.36%) received the recommended ≥ 3 doses of the COVID-19 vaccine, yielding a 72.08% overall vaccination rate. The predominant symptoms of the initial SARS-CoV-2 infection included fever (79.53%), muscle pain (49.24%), cough (48.22%), sore throat (46.02%), and fatigue (35.36%). Patients who were infected with COVID-19 after the lung cancer diagnosis and received systematic treatment exhibited significant differences in muscle pain (χ2 ​= ​11.808, P = 0.038), sore throat (χ2 ​= ​14.368, P ​= ​0.013), nasal congestion (χ2 ​= ​12.934, P ​= ​0.024), and chest tightness/pain (χ2 ​= ​12.218, P ​= ​0.032). The symptom analysis indicated that the duration of symptoms was significantly longer in unvaccinated than in vaccinated patients with lung cancer experiencing a first-time COVID-19, especially for fever (χ2 ​= ​21.268, P ​= ​0.001) and palpitations (χ2 ​= ​17.797, P ​= ​0.007). The six-month follow-ups in this study revealed that 12.01% of patients with lung cancer experienced a second infection. Patients with lung cancer reinfected with COVID-19 exhibited fever (χ2 ​= ​16.780, P ​= ​0.005), muscle pain (χ2 ​= ​28.489, P ​= ​0.000), sore throat (χ2 ​= ​21.915, P ​= ​0.001), rhinorrhea (χ2 ​= ​20.783, P ​= ​0.002), cough (χ2 ​= ​19.129, P ​= ​0.004), expectoration (χ2 ​= ​16.105, P ​= ​0.013), shortness of breath (χ2 ​= ​26.461, P ​= ​0.000), palpitations (χ2 ​= ​17.065, P ​= ​0.004), chest tightness/pain (χ2 ​= ​13.108, P ​= ​0.041), fatigue (χ2 ​= ​21.593, P ​= ​0.001), reduced activity tolerance (χ2 ​= ​35.476, P ​= ​0.000), headache (χ2 ​= ​16.003, P ​= ​0.001), hypogeusia (χ2 ​= ​42.511, P ​= ​0.000), hyposmia (χ2 ​= ​20.650, P ​= ​0.002), and diarrhea (χ2 ​= ​9.397, P ​= ​0.024) revealed significant differences in comparison with the first-time COVID-19 infection in patients with lung cancer. Conclusions:Our analysis suggests that COVID-19 has a high infection rate in patients with lung cancer, but the duration of different symptoms varies. Patients with a first SARS-CoV-2 diagnosis who had previously been treated for oncology experienced less severe pain-related symptoms than patients with lung cancer diagnosed after infection. COVID-19 vaccines have demonstrated protective effects by mitigating symptom severity following a second infection. Suggest that we should further explore ways to reduce the morbidity, severity, and mortality of COVID-19 while ensuring adherence to patients' standard treatment plans.