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Introduction Bronchoscopic lung volume reduction with endobronchial valves (EBV) is an effective procedure for patient with severe emphysema to improve lung function, exercise tolerance, dyspnoea and quality of life. Optimisation of patient and treatment lobe selection is essential for successful EBV outcomes. While clinical selection criteria are rigorous, many centres use a multidisciplinary team and rely on previous clinical experience for the selection process. To aid objective clinical decision making, we present a mathematical model to facilitate patient and target lobe selection. Methods A multidisciplinary team reviewed quantitative high-resolution computed tomography (HRCT) analysis from 119 patients to select candidates for EBV and to select a treatment lobe. Two logistic regression models, (1) candidacy for EBV placement and (2) target-lobe selection, were developed based on the normalised distributions of the four quantitative HRCT variables (fissure completeness score, per cent of voxel density with HU < −910 and HU < −950, and lobar volumes) across all five lung lobes. An external cohort of 50 patients (25 candidates and 25 non-candidates) was used to validate the prediction model. Results Performance measures of the training cohort demonstrated an area under the curve (AUC) of 0.91, accuracy of 81%, sensitivity of 93% and specificity of 78% compared with the multidisciplinary teams’ target lobe selection. The validation cohort demonstrated an AUC of 0.89, accuracy of 84%, sensitivity of 88% and specificity of 83% compared with the multidisciplinary team decision making. Conclusions Endobronchial valve lung volume reduction remains a potent palliative measure to improve quality of life in patients with hyperinflated emphysema. Our model for target lobe selection harnesses the multidisciplinary experience at a tertiary care centre to objectively select candidates and target lobes to assist clinicians’ decision making. Future studies investigating prediction of lobar collapse and functional improvement after target lobe selection using our model are needed.

SUMMARY Tuberculosis induces diverse lesions, such as necrotic pneumonia, contributing to disease progression and transmission. Despite advances in understanding the role of ATP-gated P2RX7 ion channels in developing severe forms of tuberculosis, the regulation of this important signaling pathway remains unclear. Herein, we show that the ectonucleotidase CD39 plays an essential regulatory role in TB progression by preventing lung tissue damage, bacterial dissemination, and excessive inflammatory responses. Mechanistically, through its enzymatic activity on the cellular surface, CD39 protects infected macrophages from undergoing necrotic death mediated by P2RX7 activation. We proposed that by protecting macrophages from P2RX7-mediated cell death and bacterial dissemination, CD39 prevents the development of necrotic lesions. Altogether, these findings uncover a significant role for CD39 as an essential component of the molecular regulation underlying the development of severe tuberculosis. GRAPHICAL ABSTRACT Brief In tuberculosis, necrotic granuloma-like structures release extracellular ATP (eATP), which triggers P2RX7-mediated immune cell death. CD39 degrades eATP, preventing P2RX7 activation and promoting macrophage survival, thereby limiting inflammation, tissue damage, and bacterial dissemination.

BACKGROUND: Patients with lung disease, sleep apnea, and chronic thromboemboli can develop pulmonary hypertension, currently classified as group 3 or 4. Many of these patients also have risk factors for heart failure with preserved ejection fraction (HFpEF), but the optimal approach to identify the disease overlap remains unclear. METHODS: Pretest probability for HFpEF was determined using the HFpEF-ABA (age, body mass index, atrial fibrillation) algorithm among adjudicated group 3 or 4 patients at risk for pulmonary hypertension in the PVDOMICS study (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Patients were stratified by current resting right heart catheterization criteria, and in a separate analysis, stratified only by HFpEF-ABA probability into low (<25%), intermediate, and high (≥75%) HFpEF probability groups. RESULTS: Among 598 patients with group 3 disease, 27% (n=161) had elevated pulmonary capillary wedge pressure (PCWP) with postcapillary pulmonary hypertension even at rest, which was associated with the highest exercise PCWP. However, regardless of this resting PCWP-based classification, a larger subset had intermediate-to-high HFpEF-ABA probabilities (32% [n=197] high and 57% [n=358] intermediate HFpEF probability). High HFpEF probability in group 3 disease was associated with higher resting and dynamic PCWP response to NO, fluid, and exercise ( P <0.0001 for all). These changes were comparable with more traditionally defined HFpEF without pulmonary vascular disease (n=61) but less severe than those with combined precapillary and postcapillary pulmonary hypertension HFpEF (n=31; interaction P =0.006). Increasing HFpEF probability in group 3 disease was associated with worse left heart remodeling, quality of life, 6-minute walk distance, and peak VO 2 ( P <0.0001 for all). Findings were replicated in group 4 disease (n=102). CONCLUSIONS: Quantifying pretest probability for HFpEF in patients with sleep apnea, lung disease, or chronic thromboemboli identifies a progressive gradient for dynamic PCWP abnormalities with worse functional status and quality of life. These subclinical left heart abnormalities are not universally detectable by resting right heart catheterization alone and call for further study of whether strategies to prevent or treat HFpEF might improve functional status in these patients with high risk of occult HFpEF.

e20629 Background: Lung cancer (LC) and respiratory failure (RF) are major contributors to mortality in adults globally. Understanding long-term mortality trends across demographic, racial, geographic, and socio-economic groups is crucial to addressing disparities and improving outcomes. This study examines national mortality patterns for LC and RF in the United States from 1999 to 2023, providing critical insights into changes over time and identifying key disparities in age-adjusted mortality rates (AAMRs). Methods: A descriptive analysis of mortality data from the CDC WONDER database (1999-2023) identified deaths due to LC (ICD-10 code C34) and RF (ICD-10 code J96) in adults aged 25+. AAMRs per 100,000 population were calculated and stratified by gender, race/ethnicity, region, state, and urban-rural classification. Temporal trends were analyzed with Joinpoint regression to compute APCs and 95% CIs. Statistical significance was set at p<0.05. The study followed STROBE guidelines. Results: From 1999 to 2023, a total of 456,325 adult deaths (age 25-85+) were attributed to Lung cancer and Renal failure. Age-adjusted mortality rates (AAMRs) for lung cancer (LC) and respiratory failure (RF) decreased from 1999 to 2010 (APC = -1.2, 95% CI: -1.6 to -0.9), followed by an increase from 2010 to 2023 (APC = 1.4, 95% CI: 1.1 to 1.7). Gender trends revealed a steady decline for men, while women's Age-Adjusted Mortality Rates (AAMr) initially decreased, then increased from 2011-2023 (APC: 2.0, 95% CI: 1.7 to 2.5). Non-Hispanic White populations experienced a rapid increase in age-adjusted mortality rates from 2014 to 2017 (APC: 2.7; 95% CI: 0.9 to 3.3), while other racial/ethnic groups exhibited varied trends with declines, increases, and stabilizations. Geographically, AAMRs were highest in the Northeast (8.6; 95% CI: 8.5 to 8.7) and lowest in the Midwest (7.1; 95% CI: 7.0 to 7.1). Metropolitan areas saw declining trends until 2006, stabilizing briefly, and increasing thereafter. Non-metropolitan areas experienced notable increases post-2009 (APC = 2.3, 95% CI: 1.8 to 3.1). State-level disparities revealed Mississippi with the highest AAMR (14.0; 95% CI: 13.7 to 14.4) and Wisconsin with the lowest (3.7; 95% CI: 3.5 to 3.8). These findings highlight significant demographic, racial, and geographic variations in LC and RF mortality trends. Conclusions: LC and RF-related mortality rates initially declined from 1999 to 2010 but increased significantly from 2010 onward, with notable demographic, racial, and geographic disparities. These findings highlight the urgent need for targeted interventions and resource allocation to address these rising trends and reduce inequities across vulnerable populations.

e20551 Background: Lung cancer is leading cause of cancer related mortality globally, with non-small cell lung cancer (NSCLC) comprising approximately 80% of all cases. The combination of immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1), specifically Durvalumab, and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors, such as Tremelimumab has demonstrated clinical efficacy in both adjuvant and neoadjuvant settings. However, a comprehensive systematic review of the available data is currently lacking. This study aims to assess the therapeutic efficacy of Durvalumab combined with Tremelimumab in NSCLC focusing on key end points including progression-free survival, overall survival, overall response rate, and safety, with particular attention to any adverse events and mortality. Methods: A comprehensive literature search was performed to identify relevant studies published until March 2024 across PubMed, Google Scholar, and Embase databases. Outcomes were pooled using the random effects DerSimonian-Laird model and reported as hazard ratio (HR) with a 95% confidence interval. A p-value of less than 0.05 was considered statistically significant. Results: A total of 1600 patients with NSCLC were included in the analysis, with 825 patients receiving Durvalumab plus Tremelimumab, and 775 patient receiving Standard chemotherapy across four studies. For Efficacy, following parameters were statistically significant: Progression Free Survival HR 0.75, 95%CI: 0.59, 0.92; Overall Survival HR 0.8, 95%CI: 0.58, 0.99; Overall Response Rate HR: 0.68, 95%CI: 0.47, 0.88, Mean Duration of Response was 12.23 month. Safety outcomes revealed that Durvalumab plus Tremelimumab versus Standard chemotherapy were comparable in mean percentage in terms of following parameters: Any Adverse Event (85.1% vs 92.8%), Any Serious Adverse Event (28.9% vs 17.75%), any mortality (6.35% vs 3.4%), Adverse Event leading to discontinuation (11.6% vs 10.13%), Any treatment related adverse event (69.96% vs 85.6%) and Any Treatment Related Death (0.9% vs 0.3%). Conclusions: Efficacy outcomes in patients treated with Durvalumab plus Tremelimumab demonstrated clinically meaningful improvements while the safety profile was comparable to that of Standard chemotherapy. Given the increasing use of this combination therapy as adjuvant and neoadjuvant treatment for NSCLC, further clinical trials are warranted to confirm and validate these findings.

e20593 Background: Tislelizumab, an anti-PD-1 antibody, is emerging as a promising immunotherapy agent and has demonstrated clinical benefit and acceptable tolerability in recent lung cancer trials. This study aims to assess the safety and efficacy of Tislelizumab, as monotherapy or combined with chemotherapy (Group 1), as a superior treatment alternative for lung cancer compared to standard chemotherapy (Group 2) in improving patient outcomes. Methods: Following PRISMA guidelines, a systematic search was conducted through MEDLINE, Embase, Scopus, Science Direct, Cochrane (CENTRAL), and ClinicalTrials.gov from inception to December 2024 to identify Randomized Control Trials (RCTs). Hazards ratio (HRs) and risk ratios (RRs) were generated, by employing a Random-effects model with a 95% confidence interval (CI). Statistical analysis was performed using RevMan 5.4, with statistical significance set at p<0.05. Our outcomes of interest were Progression Free Survival (PFS), Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of response (DOR), and treatment-related adverse Events. Results: A total of 6 RCTs involving 2107 patients were included for analysis. Pooled analysis demonstrated that Group 1 significantly improved PFS, OS, and DOR with HRs of 1.85 (95% CI: 1.71-1.99; p <0.00001, I² = 0%), 2.01 (95% CI: 1.75-2.29; p <0.00001, I² = 0%) and 2.14 (95% CI: 1.52-3.03; p <0.0001, I² = 39%), respectively. Group 1 has better DCR and ORR compared to Group 2 with RRs of 1.52 (95% CI: 1.12-2.07; p= 0.007, I² = 97%) and 1.50 (95% CI: 1.20-1.86; p= 0.0003, I² = 83%), respectively. The high heterogeneity observed in the pooled analysis of DCR (I² = 97%) and ORR (I² = 83%) likely reflects variability in study populations, treatment protocols, and response assessment criteria across the included RCTs. Subgroup or sensitivity analyses could help identify contributing factors. Despite the heterogeneity, the pooled effect sizes indicate a statistically significant improvement in DCR and ORR with Tislelizumab, with caution warranted when generalizing these findings. Group 1 significantly reduced all-cause mortality compared to Group 2 (RR = 0.89; 95% CI: 0.83–0.95; p = 0.0003), with no heterogeneity (I² = 0%). No significant differences were found in adverse events, except for ALT elevations. (RR = 1.36; 95% CI: 1.14–1.61; p = 0.0006, I² = 25%). Conclusions: Tislelizumab, with or without chemotherapy, demonstrates greater PFS and OS benefits compared to chemotherapy alone in patients with lung cancer. There was a significantly reduced all-cause mortality in the intervention group; however, the observed increase in the risk of ALT elevation underscores the need for vigilant liver function monitoring. When combined with chemotherapy, Tislelizumab presents a promising treatment option for lung cancer.

8545 Background: Brain metastases (BM) correlate with poor prognosis, occurring in 10% of non-small cell lung cancer (NSCLC) patients (pts) at diagnosis and up to 40% over the disease course. Immunotherapy (IO) with or without chemotherapy has become the new standard of care for stage IV NSCLC. However, the survival benefit of IO in pts with BM remains unclear as most studies are limited to small sample sizes or highly selected pts with asymptomatic or treated BMs. This study represents the largest real-world data analysis evaluating the survival benefits of IO in stage IV NSCLC pts with BM. Methods: Demographics, clinical features, and survival were analyzed in stage IV NSCLC pts with BM from the National Cancer Database (NCDB) from 2014-2020. A multivariate Cox proportional hazards modeling assessed factors impacting mortality. Results: Of 204,249 pts with stage IV NSCLC, 30% had BM. The mean age was 68 years, with 54% male. Most pts were White (82%), followed by Black (12%) and Asian (3.1%). Government insurance covered 70% of pts, and 26% had private insurance. Adenocarcinoma was the predominant histology (62%), followed by squamous cell carcinoma (SCC) (20%). Liver and bone metastases were observed in 19% and 42% of pts, respectively. Among pts with BM, 18% received immunotherapy, 53% received chemotherapy, 66% received whole-brain radiation, and 18% received limited-brain radiation. Multivariate Cox analysis showed that pts receiving IO had a 46% lower mortality risk compared to not receiving IO (HR: 0.54, 95% CI: 0.51–0.56, p < 0.001), demonstrating the independent benefit of IO in pts with BM, regardless of brain radiation or chemotherapy. Females had a lower mortality risk than males (HR: 0.88, 95% CI: 0.85–0.91, p < 0.001). Asian (HR: 0.71, 95% CI: 0.64–0.79), Hispanic (HR: 0.76, 95% CI: 0.65–0.89), and Black pts (HR: 0.88, 95% CI: 0.84–0.93) had improved survival as compared to White. Pts with private insurance have lower mortality risk (HR: 0.94, 95% CI: 0.90–0.98), compared to lack of insurance (HR: 1.19, 95% CI: 1.08–1.31). SCC was linked to worse survival (HR: 1.28, 95% CI: 1.22–1.35). Conclusions: IO significantly improves survival in pts with NSCLC with BM, regardless of brain radiation therapy or chemotherapy. However, survival disparities based on histology, insurance status, and demographic factors persist, highlighting the need for more equitable treatment strategies.

8501 Background: TROPION-Lung02 (NCT04526691) evaluated the TROP2-directed antibody-drug conjugate (ADC) Dato-DXd plus pembro combination with or without Pt-CT in aNSCLC. Here we report primary analyses of pts receiving combination therapy in the 1L setting. Methods: Pts across 6 cohorts were dosed with Dato-DXd (4 or 6 mg/kg) plus pembro 200 mg alone (doublet) or with pembro plus Pt-CT (triplet; cisplatin 75 mg/m 2 or carboplatin AUC 5) Q3W. PD-L1 expression (tumor proportion score) was assessed locally by immunohistochemistry (22C3 assay). Primary objectives were safety and tolerability; efficacy was a secondary objective. Results: As of Apr 29, 2024, 96 pts received either the doublet (n=42) or triplet (n=54) combination as 1L therapy; 29% and 15% of pts were ongoing, respectively. Median ages were 65 (doublet) and 64 years (triplet). Median treatment durations were 9.7 and 5.8 months, respectively. Stomatitis (doublet, 57%; triplet, 33%) and nausea (doublet, 42%; triplet, 48%), primarily Gr 1–2, were the most common adverse events (AEs) across both regimens. Treatment related serious AEs occurred in 5 (12%) and 12 (22%) pts in each cohort and no deaths related to study drug were seen. Efficacy outcomes, including by histology, are summarized in the Table. Biomarker analyses, including efficacy by PD-L1 status, will be presented. Conclusions: In this largest data set to date evaluating an ADC combined with an anti-PD-1/L1 agent in the 1L setting, the combination of Dato-DXd plus pembro treatment both with and without Pt-CT elicited durable antitumor activity in pts with aNSCLC. Tolerability of the combinations was as expected, based on known profiles of the individual agents. Clinical trial information: NCT04526691 . All 1L (n=96) 1L, Nonsquamous (n=75) 1L, Squamous (n=21) Response, n (%) Doublet (n=42) Triplet (n=54) Doublet (n=33) Triplet (n=42) Doublet (n=9) Triplet (n=12) Confirmed objective response rate 23 (55) 30 (56) 17 (52) 24 (57) 6 (67) 6 (50) Complete response 1 (2) 2 (4) 1 (3) 2 (5) 0 0 Partial response 22 (52) 28 (52) 16 (49) 22 (52) 6 (67) 6 (50) Stable disease 14 (33) 18 (33) 12 (36) 14 (33) 2 (22) 4 (33) Progressive disease 3 (7) 2 (4) 3 (9) 1 (2) 0 1 (8) Disease control rate a 37 (88) 48 (89) 29 (88) 38 (91) 8 (89) 10 (83) Median duration of response, mo (95% CI) 20.1 (9.7–NE) 13.7 (5.7–NE) 24.9 (9.7–NE) 18.0 (8.0–NE) 12.0 (5.5–NE) 5.5 (4.1–NE) Median PFS, mo (95% CI) 11.2 b (8.2–21.3) 6.8 c (5.5–11.1) 11.2 (6.1–21.3) 10.8 (5.5–17.3) 10.2 (0.4–NE) 6.7 (1.0–8.2) a Proportion of pts with confirmed CR + PR + SD at 12 wks. b.c Median (95% CI) PFS follow-up, mo: b 17.3 (11.3−26.8); c 23.5 (17.3−27.9). mo, months; NE, not evaluable.

1649 Background: Findings from our prior large-scale comparative effectiveness trial showed the equivalent effect of delivering early palliative care via video versus in-person on quality of life among patients with advanced non-small cell lung cancer (NSCLC). We now report on whether the two care delivery modalities were equivalent with respect to patient-reported communication with clinicians about their end-of-life (EOL) care preferences and hospice utilization. Methods: Between 6/14/2018 and 5/4/2023, we enrolled 1250 patients with newly diagnosed advanced NSCLC in a randomized trial of early palliative care across 22 US cancer centers. Patients were randomly assigned to meet with a palliative care clinician every 4 weeks from enrollment through the course of the disease, either via video or in the outpatient clinic. Participants completed self-report surveys at baseline and weeks 12, 24, 36, and 48, including an item asking if they had discussed with their clinicians the care they would want to receive if dying (yes/no); patients’ final assessments prior to death or last follow up were analyzed. We reviewed patients’ health records to collect data on hospice referral and length of stay. To test the equivalence in these outcomes, we used a binomial generalized linear model with the identity link function (pre-specified equivalence margin of ±8% for patient-reported communication about EOL care) and linear regression (pre-specified equivalence margin of ±6 days for mean length of stay in hospice). P-values were adjusted for multiplicity using a Bonferroni correction. Results: Of the 1250 enrolled participants, 888 (71.0%) completed at least one survey post baseline regarding whether they communicated with clinicians about EOL care preferences. Among those, 29.1% of the video group and 26.0% of the in-person group reported “yes,” indicating that they recalled such EOL care discussions (difference = 3.1%, 95% CI: -1.8%, 8.1%; p = 0.26 for equivalence). During the course of the trial, 733/1250 (58.6%) patients died, of whom 537/733 (73.3%) were referred to hospice. Mean lengths of hospice stay were 25.3 days for the video group versus 25.1 days for the in-person group (difference = 0.2, 95% CI: -7.0, 7.4; p = 0.46 for equivalence). When excluding outlying patients receiving hospice services > 180 days (n = 13), the mean lengths of hospice stay were 19.1 (video group) versus 19.7 (in-person group) days (difference = -0.6, 95% CI: -4.6, 3.3; p = 0.06 for equivalence). Conclusions: Although thresholds were not met to confirm equivalence statistically, the two modalities for delivering early palliative care demonstrate very similar outcomes with respect to patient-clinician communication about EOL care and hospice utilization. These findings provide further evidence of the utility of video visits for providing high quality palliative and EOL care. Clinical trial information: ClinicalTrials.gov Identifier ( NCT03375489 ) .

3069 Background: Molecular targeted agents have revolutionized cancer diagnosis and treatment. Intraoperative molecular imaging (IMI) is a novel technique that entails performing real-time, in vivo optical imaging during surgery to ensure cancer clearance. A multicenter clinical trial was conducted using abenacianine, a cathepsin targeted near-infrared (NIR) IMI agent to visualize pulmonary nodules during surgery. The primary objective was to assess the efficacy of abenacianine in localizing pulmonary lesions, evaluating surgical margin, and identifying unsuspected disease. Methods: Participants scheduled to undergo surgery for known or suspected cancer in the lung received abenacianine (0.32 mg/kg intravenous) preoperatively 12 to 36 hours before surgery. During a standard-of-care surgery, the lung underwent IMI and additional disease not identified by conventional methods were identified and analyzed. Efficacy was measured by frequency of clinically significant events (CSEs) defined as localization of lesions not found by standard surgical techniques, identification of additional cancers, identification of positive surgical margins confirmed by histology, and detection of cancerous lymph nodes. Results: 89 participants were included in the study. The mean age was 67 years and 57 (64%) were female. Of 89 participants administered abenacianine who underwent standard of care surgical resection for known or suspected cancer in the lung, 40 (45%) had at least one CSE. Abenacianine with NIR imaging identified lesions that were not found by standard surgical methods in 34 (38%) participants, synchronous and occult cancers that were not found by pre-operative imaging in 2 (2%), margins within 10 mm of the closest staple line in 8 (9%), and lymph nodes determined to be cancerous in 1 (1%) participant. Tumors visualized by IMI with abenacianine included non-small cell lung cancers (adenocarcinoma, squamous cell carcinoma, neuroendocrine tumor) and cancers that metastasized to the lung (breast, colorectal, prostate, thymoma, renal cell, sarcoma). Abenacianine was safe and well tolerated in this study; there were no drug-related serious adverse events. Conclusions: This Phase 2 multicenter study demonstrated that using IMI with abenacianine during standard-of-care lung cancer surgery markedly improved clinical outcomes. Abenacianine localized tumors intraoperatively, identified synchronous and occult lesions, helped assess negative margin status, and identified cancerous lymph nodes enabling a more complete oncologic resection. Clinical trial information: NCT06145048 .