Citations

e19545 Background: Cytogenetic abnormalities (CA) at diagnosis are important prognostic factors in multiple myeloma (MM), but there is limited information on how these abnormalities evolve at first relapse and their significance. Methods: This retrospective study included patients aged ≥18 years, with a confirmed diagnosis of MM who experienced at least one disease relapse and had fluorescence in situ hybridization analysis within six months of both diagnosis and relapse. Data on CA and clinical outcomes were collected. High-risk (HR) secondary CA were defined as the presence of deletion of chromosome 17p (del17p) or gain or amplification of chromosome 1q. The primary objective was to evaluate changes in HR secondary CA at first relapse, while the secondary objective was to assess the impact of the cytogenetic changes on overall survival (OS) from diagnosis. Based on the presence or absence of HR secondary CA, patients who were tested for HR secondary CA at both time points were classified into four groups: 1) persistent absence of HR secondary CA, 2) emergence of HR secondary CA at relapse, 3) persistent presence of HR secondary CA, and 4) loss of HR secondary CA at relapse. Results: A total of 233 patients diagnosed between 2004 and 2023 were included. HR secondary CA were tested in 98.7% (n= 230) of patients at diagnosis, with 24.8% (n=57) testing positive. At first relapse, testing for HR secondary CA was performed in 97.4% (n=227) of patients, of whom 23.8% (n=54) tested positive. Del17p was evaluated in 98.3% (n=229) of patients at baseline and 95.7% (n=223) at relapse, with positivity increasing from 10.9% (n=25) to 15.3% (n=34). Gain or amplification of chromosome 1q was evaluated in 49.4% (n=115) at baseline and 25.5% (n=60) at relapse, with positivity rate rising from 28.7% (n=33) to 38.3% (n=23). There were no differences in overall response rate or very-good-partial-response-or-better rates to the initial therapy at diagnosis between the groups. (Table) Emergence/persistence of HR CA were associated with lower OS from diagnosis. Conclusions: Emergence of HR secondary CA at first relapse in MM has prognostic significance. These findings highlight the importance of serial cytogenetic testing for risk stratification. Response rate to initial line of therapy and overall survival from diagnosis among patients tested for HR secondary CA both at diagnosis and first relapse (n=224). Outcome Persistent absence of HR secondary CA(n=142) Emergence of HR secondary CA at relapse (n=25) Persistent presence of HR secondary CA (n=27) Loss of HR secondary CA at relapse(n=30) p-value Overall response rate a 75% (106) 76% (19) 63% (17) 67% (20) 0.5 b Very-good-partial response or better response rate 43% (61) 36% (9) 44% (12) 40% (12) >0.9 b Median (95% CI) OS from diagnosis in years 11.3 (9.7-13.4) 7.5 (5.1-12.1) 6.1 (4.2-9.4) 10.1 (6.5-14.1) <0.0001 c a Partial response or better; b Chi-square test; c Log-rank test.

3520 Background: Recent analyses highlight nonhierarchical outcomes using the 8 th Edition AJCC staging system for CC. For instance, the 5-year survival rate for stages I and IIIa patients (pts) closely align. Additionally, tumor deposits (TDs) have been established as significant prognostic indicators. The AJCCCCEP commissioned this study to develop an updated pathological staging system for CC focused specifically on pts without distant metastasis (M0), while retaining the existing stage IV classification. Methods: Individual patient data (IPD) from pts diagnosed with cc (2010- 2017) in the NCDB were divided into training (70%) and internal validation (30%) datasets. External validation used IPD from clinical trials. The primary endpoint was overall survival (OS). Risk classification development for M0 pts incorporated ungrouped data on pathologic T categories, the number of involved regional lymph nodes (LN+), and TD counts. Recursive partitioning and regression tree analyses were applied to construct hierarchical staging levels. Pre-specified criteria required survival probabilities to be consecutive and show clear separations using Kaplan-Meier (KM) estimates with pairwise log-rank test P of < 0.005 for the training and < 0.05 for validation analyses. Results: Data from 281,997 pts (median age 67 years, 50% male, 81% white, 55% T3, 19% T4, 44% N+, 26% M+, and 11% with ≥1 TD) were analyzed, with a median follow-up of 7.3 years. The updated staging system (Table) met pre-specified criteria, with all observed pairwise P < 0.0001 in the development and internal validation sets. KM OS curves displayed a hierarchical separation across all sub-levels after the 1 st year of diagnosis. Consistent results were seen in pts treated with adjuvant chemotherapy in 4 trials (all pair-wise P < 0.0001). Conclusions: The proposed pathological staging system for M0 pts fulfills pre-specified criteria for hierarchical risk stratification, validated both internally and externally, and provides an evidence-based update. Pending review process, the AJCCCCEP will recommend that these changes be made to the Version 9 staging protocol for colon cancer to improve prognostication for CC pts. Stage T, # of LN+, # of TD M % of pts 1y OS (CI), % 3y OS (CI), % 5y OS (CI), % I T1, 0, 0 0 5 96 (95-97) 91 (90-92) 84 (83-86) IIa T2, 0, 0 0 10 95 (94-95) 88 (88-89) 80 (79-81) IIb T1, 0, 1+T1, 1+, 0T2, 0, 1+T2, 1-4, 0T3, 0, 0 0 27 93 (92-93) 84 (84-85) 75 (75-76) IIIa T1, 1+, 1+T2, 1-4, 1+T2, 5+, 0T3, 0, 1+T3, 1-4, 0 0 14 92 (91-92) 80 (80-81) 71 (70-72) IIIb T2, 5+, 1+T3, 1-4, 1+T3, 5+, 0T4a, 0-4, 0T4b, 0-2, 0 0 13 86 (86-87) 69 (68-70) 58 (57-59) IIIc T3, 5+, 1+T4a, 0-4, 1+T4a, 5+, anyT4b, 0-2, 1+T4b, 3+, any 0 5 78 (77-80) 53 (51-54) 40 (38-41) IVa Any 1a 19 59 (58-60) 28 (28-29) 17 (16-18) IVb Any 1b 7 43 (42-44) 14 (13-14) 6 (6-7) CI: 95% confidence internal; Peritoneum involvement data were not available before 2018 in NCDB. Thus, IVa/b were based on 7 th Edition.

TPS9607 Background: The majority of 100,000 annual new U.S. cases of mel consist of localized early-stage disease that undergo wide local excision (WLE) +/- SLN biopsy (SLNB). The tumor draining lymph node is the initial site of immune response including formation of tumor mediated immune suppression and pre-metastatic niches. SLN positivity is a key prognostic factor in early stage mel. Thus, the SLN is a target for local immune intervention to boost the antitumor response. Vusolimogene oderparepvec (RP1) is an intratumorally administered oncolytic immunotherapy with unique potential for neo-adjuvant therapeutic application. RP1 is constructed from a high potency HSV1 strain (RH018A) modified to replicate selectively in tumors (deletion of neurovirulence factors ICP34.5 and ICP47). RP1 encodes GM-CSF and a fusogenic GALV-GP R- protein to maximize oncolytic potency and induce immunogenic cell death. Preclinical and clinical data demonstrate robust antitumor efficacy (including non-injected lesions) of RP1 alone and in combination with checkpoint inhibitors in advanced mel. This trial addresses a crucial gap in understanding the impact of RP1 on SLN dynamics and preventing disease recurrence in high-risk patients (pts). We hypothesize that in pts with high risk, clinically node negative mel (pT3b-T4b), RP1 will reduce rates of SLN positivity as compared to a historic control by favorably reshaping the immune landscape of the primary tumor, SLN, and the peripheral blood. Methods: This is an investigator-initiated, single arm phase 1/2 trial (NCT06216938) designed to assess efficacy and safety of neo-adjuvant RP1 in high-risk, clinically node-negative, non-uveal mel. Eligibility criteria: pT3b, T4a, or T4b non-uveal mel with visible residual tumor or positive biopsy margins, ECOG ≤1, and no prior oncolytic virus therapy. Pts receive 3 doses of neo-adjuvant RP1 (10e6 PFU day 1, 10e7 PFU on days 15 and 21), injected at the primary tumor site followed by standard WLE and SLNB within 35 days of dose 1. Biopsy of residual tumor or archival tumor tissue is obtained pre-RP1 and archival tissue from WLE and SLNB is obtained post-RP1. Blood samples are obtained with each RP1 dose and 3 months post-therapy. Pts are followed for 3 years. Primary endpoint: rate of SLN positivity in the overall cohort. Secondary endpoints: treatment related adverse events (per CTCAE), recurrence free survival, and overall survival. Exploratory endpoints: immunophenotype and microenvironment of the primary tumor, SLN and peripheral blood pre- and post- RP1 (via IHC, IF, and flow cytometry). The observed rate of SLN positivity will be compared to the predicted rate (Melanoma Institute of Australia Prediction Tool for SLN metastatic risk) with a one-sided, one-sample proportion test. Kaplan-Meier estimates will be provided for survival endpoints. The trial is active with 13 of 25 pts enrolled in January 2025. Clinical trial information: NCT06216938 .

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.

3569 Background: Immune checkpoint inhibitors (ICIs) are a standard treatment for gastrointestinal (GI) cancers with mismatch repair deficiency (dMMR) or microsatellite instability (MSI). However, around 50% of patients develop resistance to ICIs, during treatment or after discontinuation. In these patients, the efficacy of reuse an ICI in patients progressing during a previous ICI (rechallenge), or in patients who progressed after discontinuation (reintroduction), remains unknown. The INFLATE study evaluates the efficacy of ICI reuse in patients who progressed on or after discontinuing ICI. Methods: This is a multicenter international retrospective study from the IMMUNODIG cohort, including patients from 34 centers in France, the United States, Italy, Belgium and Spain. All patients received ICI for dMMR/MSI GI cancer. We analyzed patients who had progressed following initial ICI (ICI-1) and subsequently received a rechallenge or a reintroduction with ICI (ICI-2), either monotherapy (mono-ICI) or biotherapy (bi-ICI). Results: A total of 77 patients were included, receiving bi-ICI (N = 34) or mono-ICI (N = 43) during ICI-2. The majority (76%) had a metastatic colorectal cancer. The reason for discontinuing ICI-1 was disease progression in 53% of cases, end of treatment in 15%, toxicity in 5% and other reasons in 26%. Patients who discontinued ICI-1 due to progression received MONO-ICI-2 in 29% of cases and BI-ICI-2 in 71%, whereas those who stopped for other reasons received MONO-ICI-2 in 86% and BI-ICI-2 in 14% of cases. Efficacy results are shown in Table 1. The ORR and DCR were 26% and 79% with MONO-ICI-2, and 16% and 71% with BI-ICI-2. Among patients who discontinued ICI-1 due to progression, BI-ICI-2 (N = 29) achieved an ORR and DCR of 8% and 65%, with a median PFS of 5.5 months (95%CI 4.07-10.4). These outcomes were 17%, 67%, and 3.7 months (95%CI 2.37-NA), respectively, with MONO-ICI-2 (N = 12). For patients who discontinued ICI-1 for reasons other than progression, BI-ICI-2 (N = 5) achieved an ORR and DCR of 60% and 100%, with a median PFS not reached (95%CI 11.5-NR), while MONO-ICI-2 (N = 31) achieved 29%, 82%, and 14.2 months (95%CI 11.2–NR), respectively. Conclusions: This is the first multicenter real-world study evaluating ICI reuse in dMMR/MSI GI cancers. In patients who discontinued ICI for reasons other than progression, reintroduction of ICI therapy upon progression achieves tumor control in 85% of cases. In cases of progression on mono-ICI, Bi-ICI re-challenge achieve tumor control in two-thirds of cases and might be to consider in some patients. ORR % DCR % PFS median (95%CI) OS median (95%CI) Overall N=77 21 76 7.65 months(5.5–11.5) 27.6 months(22.2–55.7) Discontinued ICI-1 due to Progression N=41 11 68 5.03 months(3.7–8.05) 26.7 months(21.1–NR) Discontinued ICI-1 for Other Reasons N=36 33 85 14.22 months(11.24–NR) 27.6 months(22.2–NR)

3504 Background: Among patients with resected node-positive colon cancer, nearly 30% will relapse despite standard adjuvant chemotherapy. Analysis of molecular residual disease (MRD) using circulating tumor DNA (ctDNA) may enable risk stratification for tumor recurrence and inform adjuvant treatment decisions. Methods: Postsurgical ctDNA was analyzed in patients with stage III colon carcinoma who participated in a phase 3 trial of adjuvant FOLFOX alone or combined with cetuximab (n = 3084) [NCCTG N0147]. We utilized a tissue-free epigenomic assay for ctDNA detection (Guardant Reveal) with sampling prior to start of adjuvant therapy. Among ctDNA positives, epigenomic tumor fraction (TF) was estimated and ctDNA genotyping was done with Guardant360 (panel of 739 genes). Median follow-up was 6.1 years (yr). Study endpoints included time-to-recurrence (TTR), disease-free survival (DFS) and overall survival (OS) analyzed by Kaplan–Meier method. Multivariable Cox proportional hazards models were used to assess prognostic utility of ctDNA status adjusting for confounders. Interaction between ctDNA and clinicopathological features were assessed. Results: Among 2260 patients with evaluable ctDNA data, 461 (20.4%) were ctDNA positive.Tumors were significantly associated with higher T, N stage, BRAF V600E , high grade, obstruction/perforation, and worse performance status. Positive vs negative ctDNA was significantly associated with shorter TTR (hazard ratio [HR] 4.33, 95% confidence interval [CI] 3.65-5.13, P < 0.0001), poorer DFS (HR 3.74, CI 3.18-4.39, P < 0.0001] and OS (HR 3.17, CI 2.63-3.83, P < 0.0001), adjusting for covariates and tissue MMR, KRAS and BRAF V600E . ctDNA positive vs negative patients had 3y DFS of 36.4% (95%CI 32.2-41.2%) vs 82.5% (95% CI 80.0-84.4%), respectively. Adverse prognosis was consistent across subgroups (all P < 0.05), with stronger detrimental effects for positive ctDNA in N1 (vs. N2), T1/2 (vs T3 or 4), and mismatch repair deficient tumors [interaction P = 0.0002 to 0.041). Among patients with positive ctDNA, TF in those who recurred/died within 3 yr was double of those who remained recurrence-free ( P = 0.0001). High vs. low ctDNA TF ( > vs ≤ median) further stratified TTR (HR 1.48, CI 1.17-1.88, P = 0.0011), DFS (HR 1.52, CI 1.21-1.92, P = 0.0004) and OS (HR 1.58, CI 1.21-2.07, P = 0.0009), adjusting for confounders. ctDNA positive cases, . Analyses of ctDNA detection by site of recurrence, ctDNA clearance, and genomic variant detection are ongoing. Conclusions: In the largest study evaluating tissue-free epigenomic-based MRD detection, we demonstrate a robust prognostic utility of postsurgical ctDNA. Tumor fraction provided further patient stratification and analysis is ongoing to identify a subgroup based on TF that may be unlikely to clear ctDNA despite adjuvant chemotherapy.

e24020 Background: Transcatheter aortic valve replacement (TAVR) is a widely adopted treatment for severe aortic stenosis, but outcomes in cancer survivors with prior chest radiation therapy (C-XRT) remain uncertain. This study compares the clinical outcomes of TAVR between patients with a history of C-XRT and those without prior radiation exposure (control group). Methods: Patients with prior chest radiation therapy (C-XRT) were compared to a control group without radiation exposure to evaluate key clinical endpoints. For each endpoint, odds ratios (OR) and 95% confidence intervals (CI) were determined, and heterogeneity was analyzed using the I² statistic. A p-value of <0.05 was considered statistically significant. Results: Nine studies were included in the meta-analysis, encompassing 3083 C-XRT and 8891 control patients. Patients with prior C-XRT showed significantly higher long-term mortality (OR 1.84, 95% CI [1.08, 3.13], p=0.02) compared to controls. Other outcomes, including access-related vascular complications, Acute Kidney Injury, Congestive heart failure, major bleeding, need for pacemaker, short-term mortality, and stroke, did not demonstrate significant differences between the groups. Conclusions: Cancer survivors with prior chest radiation therapy undergoing TAVR may experience higher long-term mortality compared to patients without radiation exposure. However, no significant differences were observed in other major outcomes. These findings suggest that while TAVR is a viable treatment for C-XRT patients, long-term risks require further investigation to optimize patient selection and management strategies. Outcomes. Outcome OR 95% Confidence Interval P value Access related vascular complications 1.12 [0.85, 1.48] 0.43 Acute kidney injury 0.54 [0.20, 1.50] 0.24 Congestive heart failure 1.38 [0.88, 2.17] 0.16 Long term mortality 1.84 [1.08, 3.13] 0.02 Major bleeding 0.96 [0.78, 1.17] 0.67 Need for pacemaker 1.05 [0.88, 1.26] 0.57 Short term mortality 1.66 [0.97, 2.84] 0.06 Stroke 1.25 [0.74, 2.11] 0.39

e24015 Background: Anthracyclines are effective cancer therapeutics but can cause cardiotoxicity. Recent studies suggest a connection between efficacy and toxicity in that the effects of anthracyclines on cancer cells leads to the release of interleukin 1-alpha (IL-1⍺), which negatively impacts cardiomyocyte metabolism and thereby cardiac function. This observation was made in in vivo and in vitro models of acute myeloid leukemia (AML); whether this holds true for other cancer cell lines remains unclear. Methods: Herein we characterized the cytokine profile of 9 cancer cell lines exposed to doxorubicin (1 µM for 24 hours) and then tested the effects of interleukin 1-alpha (IL-1⍺, 50-150 ng/mL) on the viability and metabolism of neonatal cardiomyocyte. We used Seahorse to assess cardiomyocyte glycolysis via extracellular acidification rate (ECAR) and mitochondrial oxidative phosphorylation based on the oxygen consumption rate (OCR). Results: As outlined in Table 1, different hematological and breast cancer cell lines showed a range of cytokine profile in response to doxorubicin exposure. Of the cytokines with putative action on cardiomyocyte metabolism IL-1⍺was one of the most induced in 3 out of 5 murine breast cancer, murine B- and T-cell lymphoma, as well as murine and human AML human and murine cell lines. Doxorubicin did not induce IL-1⍺ expression in macrophage cell lines (RAW) or directly in cardiomyocytes. Exposing neonatal cardiomyocytes to different concentrations of IL-1⍺ did not decrease but rather increased OCR and especially ECAR. Conclusions: These data confirm the release of IL-1⍺ from AML as well as several, but not all breast cancer cell lines. Furthermore, purified IL-1⍺ increased oxidative phosphorylation and glycolysis in murine neonatal cardiomyocytes. These data point out heterogeneity in the cytokine release pattern from anthracycline-treated cancer cell lines and their impact on cardiomyocyte metabolism. Further studies are required to define the nuances of crosstalk between cancer and the heart and its contribution to the variation in cardiotoxicity risk. Cytokine profile of cancer cell lines. Cytokines RAW Neonatal MC38HuPD-L1 EMT6 JC E0771 4T1 B Lymphoma: A20 T Lymphoma: E.G7-OVA AML Human: THP-1 AML mouse: C1498 ICAM-1, CD54 ++ ++ ++ ++ ++ ++ IL-1α IL-1F1 + + + + + + + IL-10 + + IL-16 ++ ++ ++ CXCL10/CRG-2 ++ + ++ ++ ++ ++ ++ ++ ++ M-CSF ++ ++ ++ + ++ ++ ++ ++ + RANTES CCL5 + ++ ++ ++ ++ TNF-α +++ + ++ + + + + +

e24010 Background: Cancer increases the risk of atrial fibrillation (AF), particularly in patients over 65 or those with pre-existing cardiovascular disease. Patients with active cancer are at a higher risk of arterial and venous thrombosis. Oral anticoagulation (OAC) is recommended in most patients with comorbidities, based on the CHA2DS2-VASc score. However, because OAC raises the risk of bleeding, it might not be appropriate for patients who have significant or frequent bleeding episodes, vascular malformations, or other contraindications. Anticoagulation in cancer patients is challenging due to thrombocytopenia, bleeding risks, and interactions with chemotherapy. Left atrial appendage Closure (LAAC) offers an alternative to anticoagulation for mitigating stroke risk in nonvalvular AF patients. However, this procedure has been offered less frequently as concerns regarding its prognosis among cancer patients remain unclear. This article aims to find the prognosis of cancer patients with LAAC. Methods: A systematic search was conducted in electronic databases from inception until June 2024 using appropriate Mesh terms. Pooled risk ratios (RR) with their corresponding 95% confidence intervals (CI) were calculated using random effects models. A p-value of <0.05 was considered statistically significant. Results: A total of 5 studies with a population of 1,20,502 (Cancer Patients: 3803 and Non- Cancer patients: 116699) were included which met all the inclusion criteria. An increased risk of in-hospital mortality among cancer patients with LAAC (RR=1.90; 95% CI=1.05–3.45, P=0.03) with statistically significant was observed. However, other parameters were comparable including, 30 days readmission (RR=1.12; 95% CI=0.95–1.032), all-cause mortality (RR=1.33; 95% CI=0.72–1.95), any bleeding complication (RR=1.04; 95% CI=0.37–1.70), Cardiovascular complication (RR=1.44; 95% CI=0.51–4.06), thromboembolism (RR= 2.28; 95% CI=0.57–9.06), and neurological complication (RR=0.81; 95% CI=0.17–1.46). Conclusions: There were increased chances of in-hospital mortality among cancer patients than in non-cancer patients with LAAC procedures. However, other parameters like cardiovascular complications, any bleeding complications, thromboembolism, and neurological complications were not significantly associated. Further studies are warranted to validate these findings.

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.