Citations

2558 Background: Clinical validation studies have shown that early dynamic changes in circulating tumor DNA (ctDNA) tumor fraction (TF) can predict clinical outcomes. Yet few studies have evaluated the clinical value of longitudinal monitoring throughout the course of treatment. Here we evaluate longitudinal changes in ctDNA TF and clinical outcomes in an advanced real-world pan-cancer cohort of patients (pts) treated with immune checkpoint inhibitors (ICIs). Methods: The cohort included deidentified pts from the Tempus clinicogenomic database with stage IIIB or IV solid tumors who underwent ctDNA NGS and were treated with an FDA-approved ICI +/- chemotherapy (CT). Pts had a pre-treatment baseline liquid biopsy (T0) and ≥1 on-treatment sample Ti within 21-180 days of ICI. xM for treatment response monitoring estimates TF via an ensemble algorithm that incorporates variant and copy number information. Response status was determined at each on-treatment timepoint Ti relative to T0. Pts were classified as a Molecular Responder (MR) if TF < 1% at T0 and Ti or if TF decreased by ≥ 50% from T0 to Ti; otherwise, they were classified as a Molecular Non-Responder (nMR). Pts with TF < 0.09% at T0 and Ti were classified as ctDNA not detected. The longitudinal cohort included pts with ≥2 on-treatment timepoints, further classified based on the most frequent classification across each Ti as longitudinal MR, longitudinal nMR and longitudinal ctDNA not detected. If no classification was dominant, the most recent classification was used. Real-world overall survival (rwOS) was defined from T1 to death and assessed by log-rank test. Results: The full cohort of 84 pts with > 10 solid tumors included 34.5% (n = 29) NSCLC and 16.7% (n = 14) SCLC. The majority of pts (59.5%, n = 50) received ICI+CT, (64.0% first-line [1L]), and 40.5% (n = 34) ICI-only (35.3% 1L). rwOS was longer for 53 MRs vs. 18 nMRs (median not reached vs. 7.0 months, P < 0.005); 13 pts had no ctDNA detected. The longitudinal subcohort of 35 pts was 31.4% (n = 11) NSCLC, 20.0% (n = 7) prostate cancer, and 14.3% (n = 5) SCLC; 45.7% (n = 16) ICI+CT (56.3% 1L), 54.3% (n = 19) ICI-only (31.6% 1L). On average, pts had 3 on-treatment liquid biopsies, with a median time between on-treatment samples of 91 days. Twelve pts were longitudinal nMRs (10 MR or ctDNA not detected at T1), 18 longitudinal MRs, and 5 longitudinal no ctDNA detected. There were 6 death events in the longitudinal nMRs, 3 in the longitudinal MRs (all > 18 months after T1), and no death events in the longitudinal no ctDNA detected group. Longitudinal MRs had longer rwOS than longitudinal nMRs (median 37.4 months vs 8.7 months, P < 0.005). Conclusions: Longitudinal nMR was associated with worse survival compared to longitudinal MR. Longitudinal, molecular biomarker dynamics may be a useful clinical treatment decision tool for monitoring treatment response to ICI therapy.

10035 Background: Ewing sarcoma (EwS) is a rare malignancy of children, adolescents and young adults for which outcomes have progressively improved through intensification of conventional chemotherapy, including interval compression of cycles. Prior cooperative group reports of relapsed EwS included patients treated less intensively and with fewer treatment options at relapse. Here, we report overall survival (OS) and prognostic factors post-first recurrence in patients with EwS treated with frontline interval-compressed chemotherapy. Methods: We included patients treated on the last three phase 3 COG EwS studies treated with interval compressed chemotherapy, which accrued from 2001-2019. Patients with initially localized disease (L-EwS) were treated on AEWS0031 arm B and AEWS1031. Patients with initially metastatic disease (M-EwS) were treated on AEWS1221. The primary outcome was OS from first relapse. Demographic and clinical data from original diagnosis and from relapse were analyzed as potential prognostic factors. Kaplan-Meier survival curves were constructed and groups compared with log-rank tests. Results: 366 patients experienced disease recurrence as first event and were included in this analysis (AEWS0031 arm B, n = 69, AEWS1031, n = 115, for a total of 184 with L-EwS; AEWS1221, n = 182, all with M-EwS). Median age at relapse was 16 years. Median time from initial enrollment to first relapse was 1.52 years and was shorter for patients with M-EwS (Kruskall-Wallis, p < 0.001). First relapses were isolated local, isolated distant, and combined in 24%, 70%, and 6.4% of patients, respectively. Metastatic stage at initial diagnosis was associated with increased risk of post-first recurrence OS event (p < 0.0001). Two-year OS post-first recurrence (OS 2y ) was 25.6% for patients with M-EwS and 48.5% for patients with L-EwS. Time to first recurrence was also a predictor of post-recurrence survival (p < 0.0001): patients with initial L-EwS and relapse < 2 years from diagnosis had OS 2y of 31.4% vs. 70.8% for later relapses. Patients with initial M-EwS and relapse < 2 years from diagnosis had OS 2y of 18.9% vs. 71.2%. Patients with combined relapses had higher risk of post-relapse death compared to other patterns of failure (p = 0.003), an effect that was largely driven by the one seen in patients with initial L-EwS. Conclusions: Overall survival of patients with first recurrent EwS after having received modern era therapy with interval compressed chemotherapy on recent COG trials remains poor, particularly for M-EwS, early relapse and combined relapses. These data will inform the design of trials for this relapsed population and provide critical data to help counsel patients about goals of care at first relapse.

10032 Background: Identifying clinical and biological factors associated with outcomes in localized Ewing sarcoma (ES) will enable risk-stratified clinical trials with the goal of improved outcomes for high-risk patients and decreased treatment toxicity for low-risk patients. The specific aims of this analysis in localized ES patients were 1) to classify extraosseous (EO) primary tumors with subdivisions into deep (viscera, glands, body cavities, muscle, nerves) and superficial (cutaneous and subcutaneous) sites, and 2) to understand the relationship between baseline clinical factors (age, sex, primary tumor site, size (maximum dimension and volume)) and event-free survival (EFS). Methods: The analytic cohort included ES patients treated with ICC on AEWS0031 and AEWS1031. Primary tumor sites were defined as pelvic, non-pelvic, and EO (deep vs. superficial). Post-enrollment EFS was the primary endpoint. Univariate analyses used the Kaplan–Meier method (logrank test). Multivariable analyses used Cox proportional hazards models. To assess the impact of tumor volume as a continuous variable, a subgroup analysis was conducted using AEWS1031 only, as tumor volumes were collected prospectively on this study. Visual exploration of effects of continuous variables on EFS event hazard used restricted cubic splines with 3 knots. Tests were performed at the 5% level. Results: AEWS0031 (n = 628) and AEWS1031 Regimen B (n = 283) yielded 911 patients. In univariate analyses, difference in risk of EFS event was observed between tumor sites ( P = 0.03). EO tumors had the highest estimated EFS compared to pelvic and non-pelvic (5 year EFS 84.7% vs. 72.4% and 75.9%). Superficial EO appeared to be a very low-risk group, albeit interpretations are limited by the small group size and singular event (one second malignant neoplasm among 15 patients). In multivariable analysis of the combined cohort, sex, race, and ethnicity were not prognostic. EO tumors may be associated with decreased hazard compared with non-pelvic bone primaries (HR 0.58, P = 0.07), and tumors ≥200 mL with increased hazard (HR 1.56, P < 0.01). In the subgroup analysis, tumor volume and age were prognostic and in visualizations age was non-linearly related to the hazard of EFS event, increasing until approximately 15 years. Tumor volume was non-linearly related to the hazard of EFS event and increased until approximately 400 mL. Conclusions: Patients with ES and primary tumors ≥200 mL continue to be at higher risk of an EFS event when treated with ICC, and EO tumors may be lower risk compared with other sites. Risk of an event appears to remain constant in ES patients ≥15 years or with primary tumors ≥400 mL. These findings should be validated in prospective trials and tumor biology integrated with clinical factors to improve risk stratification for localized ES.

10019 Background: The reported incidence of second malignant neoplasms (SMN) in long-term survivors of Hodgkin lymphoma (HL) is derived from patients treated with outdated radiation therapy (RT) techniques. We modeled the risk of SMN in pediatric patients with high-risk classic HL treated with modern mediastinal RT. Methods: In patients who received mediastinal RT on the Children’s Oncology Group study AHOD1331, we modeled the lifetime attributable risk (LAR) at 70 years of age of thyroid, lung, and breast carcinoma. This value indicates the absolute increased risk of SMN at 70 years of age due to RT, above the baseline population risk (mean baseline rates at 70 years of age are 0.7%, 3.3%, and 8.9% for thyroid, lung, and breast carcinoma, respectively, https://seer.cancer.gov/data/ ). Results: In 296 patients who received protocol-directed mediastinal RT, median age at diagnosis was 15.1 years, 55% were female, and 98% had large mediastinal adenopathy. Following 5 cycles of chemotherapy, patients received RT targeting the mediastinum based on criteria of this study; in addition, some patients received RT to other supradiaphragmatic sites that contained slowly responding lesions, including the axilla (n = 3, 1%), lung (n = 7, 2.4%), upper neck (n = 4, 1.3%), and lower neck (n = 8, 2.7%). The RT modality was proton therapy in 25.3%, photon intensity modulated RT (IMRT) in 45.6%, and photon 3-dimensional conformal RT (3D-CRT) in 27.7%. The RT prescription dose was 21 Gy in 83% and 30 Gy in 16% who had a partial metabolic response at the completion of chemotherapy. The mean (range) doses to the thyroid, lungs, and breasts were 12.8 Gy (0-30.3), 8.0 Gy (0.1-15.2), and 4.2 Gy (0.2-14.5), respectively. For the complete cohort, the mean LAR at 70 years of age of thyroid carcinoma was 0.063% and of lung carcinoma was 5.34%. For females, the mean LAR at 70 years of age of breast carcinoma was 2.92%. The Table summarizes the LAR for each SMN, stratified by RT modality. Conclusions: In patients treated with mediastinal RT on a recent multi-institutional study of pediatric HL, the predicted long-term risk of SMN is substantially lower than in historical cohorts. Clinicians should consider the toxicity associated with a current RT approach when selecting therapies and counseling patients. Clinical trial information: NCT02166463 , this is a post hoc modeling study that includes patients enrolled on this study. Mean [range] lifetime attributable risk (%) at an attained age of 70 years for thyroid, lung, and breast carcinoma. Thyroid Lung Breast (females) 3D-CRT 0.046 [0.002-0.332]N=81 5.07 [0.12-10.82]N=82 1.82 [0.67-5.98]N=46 IMRT 0.064 [0.001-0.386]N=135 6.24 [2.22-11.79]N=135 4.36 [0.66-8.43]N=76 Proton 0.086 [0-1.160]N=74 4.15 [0.94-7.77]N=75 1.45 [0.17-7.23]N=40

11549 Background: Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm with a subset associated with unicentric Castleman disease (UCD). However, the impact of CD association on clinicopathologic features and survival outcomes remains unclear. This study aims to elucidate differences in disease characteristics and outcomes in FDCS with and without CD to guide future research and clinical practice. Methods: We retrospectively analyzed 41 FDCS patients seen at Mayo Clinic between January 2000 and December 2024. Patients were categorized into CD-related (n = 9) and FDCS-only (n = 32) groups. Demographic, clinical, pathological, and survival data were compared. Kaplan-Meier survival analyses were used to evaluate overall survival (OS) and progression-free survival (PFS). Epstein-Barr virus-associated inflammatory FDCS were excluded. Results: The CD-related group was younger at diagnosis (46.0 vs. 58.0 years, p = 0.041). Among those with CD-related FDCS, FDCS was diagnosed concurrently as CD in 6/9 (66.7%) and after the diagnosis of CD in 3/9 (33.3%). The FDCS-only patients were more likely to have extranodal disease (71.9% vs. 22.2%) and to have metastasis (62.5% vs 22.2%). One CD-related FDCS patient had paraneoplastic pemphigus. Among 11 patients with next-generation sequencing (NGS) results, 9 had pathogenic mutations. The most common pathogenic mutations included CDKN2A, CDKN2B, and TRAF3 copy number losses. Surgery was the preferred first-line intervention in FDCS-only and CD-related FDCS groups (19/32, 59.4% vs. 6/9, 66.7%). Eight out of 32 (25.0%) of the FDCS-only group received chemotherapy at first-line, most commonly Gemcitabine/Docetaxel or Adriamycin/Ifosphamide. While Gemcitabine/Docetaxel was the most preferred in the second line, different regimens were pursued in the third and later lines of therapy, including Pembrolizumab, Pazopanib, and stem cell transplant. Five out of 6 patients in the CD-related FDCS group received either adjuvant radiation or chemotherapy, which led to complete remission during the follow-up periods. The median follow-up was 22.4 months for the whole population. There was a trend for better OS and PFS among CD-related FDCS patients. The respective 2-year OS rates were 100% and 66.7%, and 2-year PFS rates were 57.1% and 43.1% for CD-related FDCS and FDCS-only patients, respectively. Conclusions: This study provides novel insights into clinicopathologic differences and survival trends for FDCS. Our data would suggest a less aggressive disease course among CD-related FDCS, which implies the need for different treatment strategies for CD and non-CD-related FDCS. Further research is warranted to elucidate these mechanisms, such as multi-omic analysis on benign FDC proliferation in the microdissected UCD areas and the adjacent FDCS cells to determine factors associated with progression to sarcoma.

TPS11585 Background: Soft tissue sarcomas (STS) with genomic complexity are often aggressive but may be sensitive to further genotoxic stress. Leiomyosarcoma (LMS), a common STS, frequently harbors genomic complexity and DNA damage response (DDR) dysregulation. Preclinical data showed hyper-dependency on DNA-PK-mediated non-homologous end joining (NHEJ) DDR, and low-dose liposomal doxorubicin (LD-LPD) synergized with the DNA-PK inhibitor peposertib to inhibit tumor growth in LMS models. We hypothesize that a low, sensitizing dose of LPD enhances DNA damage and safely synergizes with peposertib in LMS and other genomically complex STS. Methods: This phase 1, open label, multicenter dose escalation and dose expansion study (NCT05711615) evaluates LD-LPD given intravenously (IV) on day 1 of 28-day cycles with peposertib given orally (PO) twice daily (BID) continuously (Table). Up to 18 patients (pts) over 18 years-old with advanced or unresectable LMS, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, dedifferentiated liposarcoma, and synovial sarcoma, ECOG performance status ≤2, who received ≥1 prior line of systemic therapy (including anthracycline ≤300 mg/m 2 ) are eligible for dose escalation. Dose expansion will include 12 pts with LMS. The primary objective is to determine the recommended phase 2 dose of LPD+peposertib based on the dose limiting toxicity rate. The Bayesian Optimal Interval (BOIN) design will inform dose escalation decisions. Secondary endpoints for the expansion cohort include adverse event rate, progression-free survival, and objective response rate per RECIST v1.1. Potential predictive biomarkers and changes in DDR biomarkers will be evaluated on biopsies during screening and at cycle 1 day 7. Circulating tumor DNA (ctDNA) collected at baseline (dose escalation and dose expansion), on treatment and at progression (dose expansion) will be correlated with disease activity and response. This trial activated on 8-May-2023 through the Experimental Therapeutics Clinical Trials Network (ETCTN) and is enrolling at select sites in the United States. Dose escalation is ongoing as of January 2025. Clinical trial information: NCT05711615 . Planned dose levels for dose escalation. Dose Escalation Schedule Dose Level Dose Liposomal doxorubicin Peposertib (tablet) -1 10 mg/m 2 IV 50 mg PO BID 0* 10 mg/m 2 IV 100 mg PO BID +1 10 mg/m 2 IV 150 mg PO BID +2 10 mg/m 2 IV 200 mg PO BID +3 15 mg/m 2 IV 200 mg PO BID +4 20 mg/m 2 IV 200 mg PO BID *Starting dose.

TPS11580 Background: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract. KIT and platelet-derived growth factor receptor α ( PDGFRA ) mutations remain the key oncogenic drivers in the majority of patients with advanced GIST, with acquired secondary drug-resistant mutations contributing to the heterogeneity and complexity of the disease. The diversity of these resistance mutations allows escape from standard-of-care tyrosine kinase inhibitor (TKI) therapy, creating an unmet need for novel therapies that inhibit all clinically relevant GIST-driving mutations. DCC-3009 is an investigational, highly potent, and selective switch-control KIT and PDGFRA inhibitor designed to act against known clinically relevant primary and secondary GIST-driving mutations while limiting off-target effects. Preclinical data showed that DCC-3009 has strong antitumor effects in xenograft models driven by resistant KIT mutations, optimized solubility and oral bioavailability, and low risk of cytochrome P450 inhibition. Here, we describe an ongoing phase 1/2 study evaluating DCC-3009 as a monotherapy in patients with advanced GIST. Methods: This study is a multicohort, open-label, phase 1/2 trial evaluating the safety, tolerability, and efficacy of DCC-3009 in patients with advanced GIST (NCT06630234). This trial uses a modular approach, with each module defined according to the therapy (DCC-3009 alone or in combination with other anticancer agents) and divided into 2 parts (dose escalation and dose expansion). For inclusion in the DCC-3009 monotherapy dose escalation, adult patients (≥18 years) must have histologically or cytologically confirmed advanced GIST with documented KIT or PDGFRA mutation and progression on or intolerance to at least 1 approved TKI regimen in the advanced setting (imatinib if KIT -mutant). Patients must have at least 1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors version 1.1 (mRECIST v1.1) and an Eastern Cooperative Oncology Group Performance Status of 0 or 1 at screening. Exclusion criteria include receiving systemic anticancer therapy (encompassing investigational agents) within 14 days or less than 5 half-lives, radiotherapy within 14 days prior to first dose of study drug, prior or concurrent malignancy requiring treatment or expected to need treatment for active cancer, known allergy or hypersensitivity to the study drug components or any of its excipients, and impaired oral absorption or malabsorption syndrome. Enrolled patients across monotherapy dose escalation will receive DCC-3009 orally in 28-day cycles. The primary outcome measures for monotherapy dose escalation include safety assessment. Secondary outcome measures include objective response rate, duration of response, and progression-free survival by mRECIST v1.1, as well as overall survival and pharmacokinetics. Clinical trial information: NCT06630234 .

TPS11579 Background: Gastrointestinal stromal tumors (GIST) are commonly driven by mutations in the receptor tyrosine kinase KIT . Resistance to approved tyrosine kinase inhibitors (TKIs) arises from additional KIT mutations in the ATP-binding pocket (AP) and activation loop (AL). No single approved TKI broadly suppresses all resistant clones, and overlapping VEGFR inhibition and toxicity limits TKI combinations. The type I TKI bezuclastinib (“BEZ,” CGT9486) inhibits KIT AL resistance mutations, does not inhibit VEGFR, and has complimentary activity with sunitinib (“SUN,” inhibitor of KIT AP resistance mutations). The first-in-human study (PLX121-01) and ongoing Peak trial (NCT05208047) evaluated BEZ+SUN showing promising safety and efficacy in GIST. SARC044 investigates BEZ+SUN in patients (pts) with SUN-resistant, KIT-mutant GIST, and correlatives aim to determine mechanisms of response and resistance (NCT06208748). Methods: SARC044 is a multi-center, open label, single-arm phase II trial enrolling up to 40 adult pts with KIT exon 9 or 11-mutant GIST resistant to imatinib and SUN. After TKI washout (baseline, “b/l”), pts initiate BEZ 600 mg daily for 2 weeks, then add SUN 37.5 mg daily, taking both drugs continuously (28-day cycles) until mRECISTv1.1 progression or unmanageable toxicity. Response evaluations (RE) are performed every 8 weeks (wk) through 15 months (mo) on study, then every 12 wk. Circulating tumor DNA (ctDNA) is collected at b/l, cycle 1 day 15 (C1D15), C2D1, C3D1, and progression. Targeted exome sequencing (TES) of ctDNA will track primary/resistant KIT mutation dynamics across therapy. 18 FDG PET/CTs are performed in 20 pts at b/l, C1D15, and C2D1, which guide a biopsy of a resistant tumor. TES, allele-specific and long-read PCR (to detect AP+AL mutation phasing), and immunoblotting (evaluating KIT pathway activation) will be performed on tissue. EORTC QLQ-C30 surveys collect pt-reported outcomes (PRO) at b/l, on treatment, and at progression. The primary endpoint is median progression-free survival (mPFS) and secondary endpoints include overall survival at 1 and 2 years, clinical benefit rate at 16 wk, adverse event rate, PRO, and KIT mutation profile in ctDNA and tissue. 35 evaluable pts achieves 83% power (p<0.05, one-sided) in a one-sample log-rank test to detect a mPFS of 6.5 mo vs 4 mo (historic control). Expected accrual is 12 mo across 4 sites in the United States with ~36 mo to study completion. Clinical trial information: NCT06208748 .

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.

e20615 Background: Patients with Stage IV NSCLC have a poor prognosis, with approximately 25-30% succumbing to the disease within the first three months. However, survival outcomes can vary significantly depending on individual factors and advancements in treatment options. Therefore, it is crucial to identify patients at high risk of poor survival outcomes to tailor personalized treatment strategies and optimize clinical management. An international study has been conducted to generate prognostic scores for patients with Stage IV NSCLC. Methods: A retrospective observational study was conducted using real-world data (RWD) from South Korea (ROOT-HEALTH database from Samsung Medical Center), the USA (COTA NSCLC dataset) and France (CIAN lung cohort from Centre Léon Bérard). Patients with stage IV NSCLC between January 2008 and December 2023 were included. The study's primary objective was to learn from patients ‘baseline characteristics affecting overall survival (OS) and progression-free survival (PFS) to derive a prognostic score reflecting relative risk of death for given patient. A partition strategy was used, with 70% of the cohort for training and 30% for validation. Data-driven feature elimination has been applied to avoid overfitting of the models. Nested cross-validation reduced selection bias in hyperparameter tuning and model selection. Results: A total of 7,805 patients with NSCLC were included in the final analysis (USA: n=610, France: n=271, Korea: n=6,924). In the Korean dataset, the model achieved a C-index of 0.872 for OS using 35 selected variables. For the USA dataset, the model, based on 15 selected variables, demonstrated a C-index of 0.707 for OS. For PFS, the Korean dataset demonstrated a C-index of 0.823, the USA dataset achieved a C-index of 0.664, and the French dataset reported a C-index of 0.64, using 15 selected variables. The important predictors for OS included albumin, neutrophil/lymphocyte ratio, bilirubin, and druggable mutations. For PFS, important predictors included LDH, albumin, hemoglobin, MET mutation, bilirubin, and BMI. The prognostic scores derived from these models allowed to identify patients with higher risk of death, than average, in each country. Conclusions: This study generates prognostic scores for OS and PFS in stage IV NSCLC using longitudinal international data from the USA, France, and South Korea throughout the cancer journey. It has the potential to support better treatment strategy for severe patients in clinical practice and early decision-making in clinical studies. Further research utilizing diverse international cohorts is essential to refine prognostic scores and enhance personalized treatment strategies for stage IV NSCLC patients.