Youssef, Amal

e16323 Background: Advanced EP-NEC are typically treated with the combination of platinum plus etoposide. Despite therapy, outcomes remain poor, with reported median overall survival (OS) of 12-13 months. Early initiation of systemic therapy is commonly practiced given the aggressiveness; however, recent data from small cell lung carcinoma (SCLC) suggest that shorter TTI does not necessarily improve OS. The impact of TTI on outcomes in EP-NEC has not been well studied. Methods: We conducted a multicenter retrospective cohort study across three Mayo Clinic sites including adults with biopsy-confirmed stage IV EP-NEC diagnosed between 2005 and 2025. TTI was defined as days from pathologic diagnosis to initiation of first-line systemic therapy. A binary cutoff (≤14 vs > 14 days) was determined using receiver operating characteristic (ROC) analysis, and TTI was also analyzed as a continuous variable. OS and progression-free survival (PFS) were estimated using the Kaplan–Meier method and evaluated using Cox proportional hazards models. Multivariable analyses adjusted for age, sex, ECOG performance status, presence of liver metastases, and first-line treatment strategy (chemotherapy alone vs chemotherapy plus immunotherapy). Results: Among 248 pts, median age was 61 years. Median OS for the cohort was 13.9 months (95% CI, 11.7–16.7), and median PFS was 5.7 months (95% CI, 5.3–6.3). Pts with TTI > 14 days had longer median OS compared with those treated within ≤14 days (16.4 vs 10.1 months), with improved OS on unadjusted analysis (HR 0.69, 95% CI 0.50–0.96; p = 0.028), though this association was not statistically significant after multivariable adjustment (HR 0.74, 95% CI 0.53–1.05; p = 0.097). Pts with TTI > 14 days also had longer median PFS compared with ≤14 days (6.5 vs 4.8 months), with improved PFS on unadjusted analysis (HR 0.67, 95% CI 0.51–0.88; p = 0.0038). On multivariable analysis, TTI > 14 days remained independently associated with improved PFS (HR 0.75, 95% CI 0.56–1.00; p = 0.047). However, when analyzed as a continuous variable, TTI was not independently associated with OS (HR 0.99, 95% CI 0.98–1.00; p = 0.173) or PFS (HR 0.99, 95% CI 0.98–1.00; p = 0.089). Conclusions: In this multicenter cohort of pts with metastatic EP-NEC, earlier initiation of systemic therapy (≤14 days) was not associated with improved overall survival, and longer time-to-treatment was independently associated with improved PFS. However, when TTI was analyzed as a continuous variable, no statistically significant associations were observed, suggesting that the observed benefit with delayed treatment may reflect pt selection or clinical context rather than a direct biological effect. These findings may provide reassurance in scenarios where short delays are necessary—for biomarker testing or clinical trial enrollment—and highlight the need for further investigation in the era of precision oncology.

1557 Background: Immunotherapy is now a standard-of-care treatment for lung cancer across most stages. Access to immunotherapy and molecular diagnostic tests in conflict-affected countries such as Syria remains poorly described. As the principal cancer center in Syria, Al-Bairouni University Hospital (ABUH) provides care for nearly three-quarters of all cancer cases nationally. We conducted this study to evaluate access to immunotherapy and molecular diagnostic services at ABUH. Methods: A mixed-methods study was performed between 2022 and 2024 at ABUH. This study included a retrospective cohort of all patients diagnosed with lung adenocarcinoma. Quantitative data included disease stage at diagnosis, molecular testing rates, and immunotherapy utilization. In addition, a qualitative patient survey was thematically analyzed to explore barriers to treatment access in a separate cohort of patients with mixed tumor types. Results: Among 2,920 patients diagnosed with lung cancer, 1,393 (47.7%) had lung adenocarcinoma. The median age at diagnosis was 61 years; 79.7% of patients were male. Smoking history was as follows: Current 792 (56.9%), Former 268 (19.2%), never smoked 318 (22.8%) At presentation, 3 patients (0.2%) had stage I disease, 40 (2.9%) stage II, 174 (12.5%) stage III, and 778 (55.8%) stage IV disease, staging was unknown for the rest of the patients. EGFR mutation testing was performed by ABUH for 226/1393 patients (16.2%) only, with positive results identified in 124 cases (8.9%). PD-L1 testing was conducted by ABUH in only 32/1393 patients (2.3%) and was positive in 23 (1.65%). Of all patients with lung adenocarcinoma, only 5 patients (0.6%) with stage IV disease received immunotherapy. All were treated with nivolumab. Thematic analysis of qualitative data (35 patients) revealed that high treatment costs and limited drug availability are the primary barriers to accessing immunotherapy. Conclusions: This study represents the first evaluation of access to immunotherapy for patients with lung cancer in Syria. Even at ABUH, the country's main cancer center, access to immunotherapy and molecular testing remains markedly limited. International collaboration is necessary to expand diagnostic infrastructure, standardize data reporting, and enhance financial protection mechanisms. These are critical steps toward achieving better cancer care in Syria.

619 Background: Well-differentiated G3 GEP-NETs are rare and heterogeneous diseases, limiting phase III trials and definition of clear standards of care. Building upon our preliminary cohort of 76 patients (pts), we present an updated and expanded retrospective analysis across three Mayo Clinic tertiary centers. Methods: We included pts with histologically confirmed well-differentiated G3 GEP-NETs diagnosed since 2017 (new WHO classification) from the three Mayo Clinic sites (Rochester, Phoenix, Jacksonville). Endpoints were ORR, DCR, PFS, and OS across treatment lines. PFS/OS were estimated by Kaplan-Meier. OS was defined from treatment start. Multivariate Cox regression was used to evaluate the association of clinic-pathologic features (age, sex, tumor functionality, Ki-67, primary tumor site, stage at diagnosis, presence of liver metastasis, number of metastatic sites at diagnosis) with OS (p<0.05). Results: 111 pts (median age 62 y, range 22–83). Primary sites were pancreas (58%), small bowel (19%), unknown (9%), and rectum (5%). Most tumors were G3 at diagnosis (88%); the remainder evolved from prior G1/G2. Ki-67 was 20–55% in 83% of cases. Most were nonfunctional (70%); functional subtypes included carcinoid (13%) and gastrinoma (8%). Median plasma 5-HIAA was 38.5 ng/ml (5–1394). Advanced disease was present in 85%. Common metastatic sites included liver (85%), lymph nodes (32%), bone (26%), peritoneum (10%), and lung (9%). Median number of metastatic sites was 1 (range 0–5). Median number of systemic treatment lines was 2 (range 0–8). The most frequent regimens and outcomes are shown in the Table. Insulin-secreting tumors (HR 2.16, 95% CI 1.33–25.73, p=0.019) and ≥2 metastatic sites (HR 2.13, 95% CI 1.05–4.31, p=0.035) were associated with inferior OS. Conclusions: This represents one of the largest real-world datasets of well-differentiated G3 GEP-NETs and provides a deeper evaluation of treatment strategies and prognostic factors. CAPTEM, SSAs, and PRRT with Lu-177 emerged as the most commonly used therapies, with PRRT showing the most favorable outcomes. Insulin secretion and higher metastatic burden were confirmed as adverse prognostic factors. CAPTEM SSAs PRRT Lu-177 Carboplatin plus etoposide FOLFOX Everolimus Sunitinib N of pts (%) 64 (58) 44 (40) 37 (33) 24 (19) 18 (13) 11 (10) 8 (7) Line of therapy (%) First 36 (56.3) 27 (61.4) 5 (13.5) 13 (59.2) 5 (7.2) 1 (9.0) 1 (12.5) Second 15 (23.4) 13 (29.5) 13 (35.2) 3 (13.6) 5 (35.7) 3 (27.3) 2 (37.5) Third or higher 13 (20.3) 4 (9.1) 19 (51.3) 6 (27.2) 8 (57.1) 7 (63.7) 5 (62.5) DCR (%) 60.9 56.8 75.0 52.2 71.4 45.5 37.5 ORR (%) 34.4 13.6 44.4 30.4 35.7 18.2 12.5 mPFS (95% CI) 8.0 (5.3-10.6) 6.2 (2.8-9.5) 11.2 (9.1-13.3) 7.3 (2.8-11.8) 4.4 (2.4-6.4) 3.9 (2.2-5.6) 3.9 (1.54-6.26) mOS (95% CI) 40.1 (23.0-57.2) 50 (22.6-77.4) 76.1 (16.3-135.8) 33.0 (21.0-45.0) 21.1 (15.0-27.2) NE NE