Shanshal, Mohamed

e23223 Background: Early-stage lung cancer is potentially curable with surgery, yet emergency or nonelective presentation represents a care-delivery phenotype reflecting failures in early diagnosis or access to care rather than tumor biology alone. The national impact of emergency presentation among surgically treated, presumed early-stage lung cancer patients is poorly defined. This study evaluates emergency versus elective presentation as a care-delivery phenotype and its association with perioperative morbidity, failure-to-rescue, and inpatient outcomes. Methods: A survey-weighted analysis of the National Inpatient Sample (2016–2023) was conducted. Adult lung cancer hospitalizations were identified using ICD-10-CM C34* in any diagnosis position. A presumed early-stage surgical cohort was defined by curative-intent lung resection without metastatic disease, malignant pleural effusion, or palliative care coding. The primary exposure was nonelective versus elective admission. Outcomes included in-hospital mortality; ICU-level care, defined by invasive mechanical ventilation, shock, or respiratory failure; major complications; failure-to-rescue; length of stay; and hospitalization cost and charges. Multivariable survey-weighted models adjusted for patient demographics, payer, neighborhood income, hospital characteristics, and year. Results: In the weighted cohort of 422,925 hospitalizations, nonelective admission occurred in 27.3%. After multivariable adjustment, nonelective admission was independently associated with higher odds of in-hospital mortality (adjusted odds ratio [aOR] 2.59, 95% CI 2.22–3.03), ICU-level care (aOR 4.53, 95% CI 4.32–4.76), and major complications (aOR 5.00, 95% CI 4.78–5.23), as well as longer length of stay (+2.42 days). Notably, failure-to-rescue among patients with major complications did not differ by admission type (aOR 0.90, 95% CI 0.77–1.05), indicating that excess mortality associated with nonelective presentation is driven by presentation severity and care pathway rather than differences in rescue quality. In unadjusted analyses, nonelective presentation was associated with higher mortality (2.21% vs 0.68%), greater ICU-level care use (33.8% vs 8.9%), more frequent major complications (45.0% vs 12.4%), and longer length of stay (7.84 vs 4.99 days) compared with elective admissions. Conclusions: In a procedure-defined, presumed early-stage lung cancer surgical cohort, nonelective admission identifies a common care-delivery failure phenotype associated with higher perioperative morbidity, ICU-level care, in-hospital mortality, and longer hospitalization. Emergency presentation represents a systems-level vulnerability in curative-intent lung cancer care and serves as a scalable and actionable marker for quality improvement and disparity-focused analyses.

e23193 Background: Small cell lung cancer (SCLC) is typically treated with outpatient systemic therapy; inpatient chemotherapy during acute hospitalization represents a high-risk care-delivery phenotype driven by delayed diagnosis, access barriers, or acute clinical decompensation rather than tumor biology alone. National data describing this care pathway and its inpatient outcomes remain limited. Methods: The U.S. National Inpatient Sample (2016–2023) was analyzed using survey weights. Adult hospitalizations meeting an ICD-10–based proxy definition for small cell lung cancer, defined by lung cancer diagnoses combined with neuroendocrine malignancy codes and excluding palliative care admissions, were identified. Inpatient chemotherapy was defined using ICD-10-PCS administration codes with prespecified sensitivity definitions. Outcomes included in-hospital mortality (primary), ICU-level care, sepsis, acute kidney injury, length of stay, hospitalization costs, and routine discharge. Multivariable survey-weighted logistic regression adjusted for patient demographics, payer, admission characteristics, and hospital factors. Results: The analytic cohort included 2,507 unweighted hospitalizations, representing 12,535 nationally weighted admissions. In multivariable analyses adjusting for demographics, payer, admission characteristics, and hospital factors, inpatient chemotherapy was independently associated with higher in-hospital mortality (adjusted odds ratio [aOR] 2.31, 95% CI 1.48–3.60) and greater ICU-level care (aOR 2.80, 95% CI 1.86–4.23). These associations were consistent across prespecified sensitivity analyses. In unadjusted analyses, inpatient chemotherapy occurred in 12.3%–19.3% of admissions annually from 2016–2023 and was associated with higher mortality (8.7% vs 5.2%), greater ICU-level care (11.8% vs 4.9%), longer length of stay (11.6 vs 7.0 days), higher costs ($38,446 vs $23,746), and lower routine discharge rates (42.8% vs 48.4%). Among 400 admissions with procedure-day data, chemotherapy was administered a mean of 3–5 days after admission. Late inpatient chemotherapy (day ≥2) was associated with higher mortality (10.6% vs 5.6%), greater ICU-level care (14.8% vs 9.2%), longer hospitalization (14.1 vs 8.0 days), and higher costs ($46,203 vs $28,025) compared with early chemotherapy (day 0–1), supporting inpatient chemotherapy as a marker of late care escalation rather than planned inpatient treatment. Conclusions: Inpatient chemotherapy identifies a high-risk care-delivery phenotype in hospitalized small cell lung cancer, with higher mortality, greater ICU-level care, and increased resource use, supporting its role as a marker of late care escalation or system-level barriers and a scalable quality indicator.

e20700 Background: Leptomeningeal metastases (LM) are a particularly challenging complication of EGFR-mutant non–small cell lung cancer (NSCLC) and are often associated with rapid neurologic decline. Intrathecal (IT) chemotherapy is frequently used in this setting, but its efficacy and safety have not been well defined. We conducted a systematic review and meta-analysis to assess neurologic response and treatment-related toxicity associated with IT chemotherapy in EGFR-mutant NSCLC with LM. Methods: We performed a PRISMA-guided search of MEDLINE, EMBASE, Cochrane CENTRAL, and targeted grey literature to identify prospective and retrospective studies reporting outcomes of IT chemotherapy in EGFR-mutant NSCLC with LM. Quantitative analyses were restricted to studies with extractable endpoints. Neurologic response and grade ≥3 toxicity were pooled using random-effects generalized linear mixed models with logit transformation. Heterogeneity was assessed using I² and τ². Prespecified sensitivity analyses examined neurologic response by route of administration (lumbar puncture vs Ommaya reservoir), concomitant EGFR-TKI use, and study design or era. Results: Four studies comprising 76 patients reported extractable neurologic response data. The pooled neurologic response rate was 81.9% (95% CI, 64.0%–92.0%), with moderate heterogeneity (I² = 63.4%, p = 0.04). Grade ≥3 toxicity was reported in three studies (n = 59), with a pooled incidence of 11.8% (95% CI, 3.2%–34.9%) and substantial heterogeneity (I² = 71.3%, p = 0.03). Myelosuppression was the most frequently reported severe adverse event, and no consistent signal of severe neurologic toxicity was identified. Exploratory sensitivity analysis suggested higher neurologic response in LP-treated cohorts compared with mixed LP/Ommaya cohorts; however, this finding was driven by a single small study and is likely influenced by limited sample size and selection bias and should be considered hypothesis-generating only. Neurologic response was otherwise consistent across study designs and eras. Stratification by concomitant EGFR-TKI use was limited by incomplete reporting. Median overall survival was variably reported and ranged from approximately 7 to 12 months. Conclusions: In EGFR-mutant NSCLC with leptomeningeal metastases, IT chemotherapy is associated with a high pooled neurologic response and relatively uncommon severe toxicity, although heterogeneity across studies remains substantial. The observed neurologic benefit appears consistent across study designs and is more likely related to underlying EGFR-sensitive disease biology than to a definitive effect of route of administration. These findings support further prospective evaluation of IT chemotherapy as part of multimodal treatment strategies in this high-risk population.

8077 Background: Small cell lung cancer (SCLC) is an aggressive malignancy with poor prognosis. This study evaluates national trends in surgical management of early-stage SCLC using the National Cancer Database (NCDB), aiming to identify factors associated with improved outcomes and assess the survival benefit of surgical resection. Methods: Patients diagnosed with clinical stage T1–T3 N0 M0 SCLC between 2004 and 2022 were identified from the NCDB. Exclusions included non-SCLC histologies, advanced or missing staging, non-lobectomy surgeries, and incomplete survival data. Propensity score matching (1:1) was used to balance surgical and non-surgical cohorts based on demographic, clinical, and socioeconomic variables. Kaplan-Meier and Cox regression analyses were used to evaluate overall survival, stratified by T stage. Results: Among 17,762 patients with early-stage SCLC, 3,234 (18.2%) underwent lobectomy with mediastinal lymph node dissection. Surgical rates increased from 5% in 2004, 17% in 2013 to 24% in 2021. Surgery was more common in T1 (26.5%) than T2 (11.4%) or T3 (4.6%) disease. After matching, surgery was associated with improved survival across all T stages, with no significant interaction between T stage and surgical benefit (p=0.43). Older age, male sex, and higher comorbidity scores predicted worse outcomes. Among surgical patients, 2.3% received neoadjuvant therapy and 71.6% received adjuvant treatment. Systemic therapy-both neoadjuvant (HR 0.63) and adjuvant (HR 0.69)-was significantly associated with improved survival. Conclusions: Lobectomy remains underutilized in early-stage SCLC but is linked to significantly improved survival. Albeit small patient's number, neoadjuvant systemic therapy further enhanced survival, supporting broader use of surgery and multimodal treatment in appropriately selected patients Univariable results 1 Multivariable results 2 Characteristic No. deaths Person-months HR (95% CI) p-value HR (95% CI) p-value Charlson score <0.001 <0.001 0 761 77727 1.00 (ref) 1.00 (ref) 1 623 60483 1.06 (0.95,1.18) 1.07 (0.96,1.20) 2 or more 350 27025 1.30 (1.15,1.48) 1.30 (1.13,1.48) Clinical T-stage 0.011 0.014 cT1N0M0 1266 124916 1.00 (ref) 1.00 (ref) cT2N0M0 406 33924 1.18 (1.06,1.32) 1.20 (1.06,1.35) cT3N0M0 62 6393 0.96 (0.75,1.24) 1.00 (0.76,1.31) Residual disease <0.001 <0.001 No residual tumor 1626 158838 1.00 (ref) 1.00 (ref) Residual tumor 92 4699 1.91 (1.55,2.36) 1.91 (1.52,2.40) Neoadjuvant systemic treatment 0.253 0.034 No 1629 154116 1.00 (ref) 1.00 (ref) Yes 30 3495 0.81 (0.56,1.16) 0.63 (0.41,0.97) Adjuvant radiation 0.067 <0.001 No 1209 118925 1.00 (ref) 1.00 (ref) Yes 452 40471 1.11 (0.99,1.23) 1.33 (1.18,1.51) Adjuvant systemic treatment <0.001 <0.001 No 563 44045 1.00 (ref) 1.00 (ref) Yes 1096 113566 0.75 (0.68,0.83) 0.69 (0.62,0.78)

8094 Background: Patients with extensive-stage small cell lung cancer (ES-SCLC) who progress after platinum-based chemotherapy plus immunotherapy have limited options. Whether adding lurbinectedin while continuing immune checkpoint blockade at relapse improves outcomes is unknown. We report results for the platinum-resistant cohort (progression ≤3 months from last chemotherapy) of MC1923. Methods: MC1923 is a phase II trial using a Simon optimal two-stage design. Patients were assigned to a starting dose of durvalumab 1500 mg IV plus lurbinectedin 3.2 mg/m 2 IV on Day 1 of 21-day cycle. The primary endpoint was the 6-month progression-free survival rate (PFS6). Accrual continued to 22 eligible patients if ≥2/9 achieved PFS6; the regimen would be considered promising if ≥7/22 (32%) were alive and progression-free at 6 months. Secondary endpoints included adverse events (AEs), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-two patients enrolled (02/04/2022–05/21/2025); all were eligible and treated. Median age was 66 years; 32% were male; ECOG performance status was 0 in 9% and 1 in 91%; 96% had prior atezolizumab. Median cycles delivered were 4 (range 1–13). PFS6 was 4/22 (18.2%; 95% CI, 7.5–44.1%), below the prespecified threshold. Median PFS was 3.1 months (95% CI, 1.6–5.3). ORR was 13.6% (3/22; all partial responses; 95% CI, 2.9–34.9%). At data cutoff (12/18/2025), 4 patients were alive; median follow-up was 16.8 months (range 5.5–39.6). Median OS was 7.4 months (95% CI, 4.3–18.6) and 1-year OS was 33.1% (95% CI, 17.6–61.9%). One (1) patient discontinued treatment with durvalumab due to AE. No treatment-related Grade 5 AEs occurred; Grade 3–4 AEs at least possibly related to treatment occurred in 32% (7/22); Grade 4 AEs occurred in 5% (1/22), all hematologic. Most common Grade 3 AEs were decreased neutrophils and white blood cells (each 9%). Conclusions: Durvalumab plus lurbinectedin demonstrated manageable toxicity in platinum-resistant ES-SCLC after chemoimmunotherapy but did not meet the prespecified PFS6 efficacy threshold, supporting the need for alternative strategies in this high-risk population. Clinical trial information: NCT04607954 .

Abstract Background: Small cell lung cancer (SCLC) remains an aggressive malignancy with limited treatment options and a 5-year survival rate under 10%. Delta-like ligand 3 (DLL3), expressed in &gt;85% of SCLC but absent from normal tissue, represents an attractive therapeutic target. Existing DLL3-directed antibody-drug conjugates suffer from poor payload stability and limited tumor penetration. To overcome these limitations, we engineered a DLL3-targeted nano-immunoconjugate (NIC) of SN38, the active metabolite of irinotecan, using an albumin-based nanoscaffold. Methods: SN38 was encapsulated in a human serum albumin (HSA) matrix and non-covalently coated with a recombinant anti-DLL3 monoclonal antibody to yield DLL3-SN38-NIC. Stable conjugation was confirmed by HSA-IgG interactions and zeta-potential shift. Binding kinetics were evaluated using Biacore surface plasmon resonance (SPR) and Octet bio-layer interferometry (BLI) employing AHC biosensors to determine DLL3-antibody affinity and specificity. Cytotoxicity was assessed using IncuCyte live-cell imaging across five SCLC cell lines (DMS454, SHP77, NCI-H82, NCI-H889, and NCI-H211) with varying DLL3 expression. Results: DLL3-SN38-NIC retained high-affinity DLL3 binding (KD ≈ 3 × 10-10 M) and demonstrated potent cytotoxicity in SCLC cell lines. NIC formation did not reduce cytotoxic activity compared with free SN38, confirming preserved potency. Cytotoxicity trends were consistent across lines with variable DLL3 expression, and DLL3 antibody alone exhibited negligible cytotoxicity. These findings confirm that nano-immunoconjugate formation maintains drug activity and DLL3 binding; additional in-vivo studies are underway to evaluate pharmacokinetics and tumor selectivity. Conclusions: Albumin-based DLL3-SN38-NICs represent a novel nano-oncologic platform that preserves SN38 potency and achieves high-affinity DLL3 engagement. Ongoing studies will assess in-vivo selectivity, biodistribution, and therapeutic potential in DLL3-positive SCLC and other neuroendocrine malignancies. Citation Format: Mohamed Shanshal, Lin Yang, Liyi Geng, Wendy Nevala, Aaron S. Mansfield, Bharath Wootla, Konstantinos Leventakos, Kyle Korshavn, Svetomir N. Markovic. Albumin-based DLL3-targeted nano-immunoconjugates of SN38 preserve potency and demonstrate high-affinity DLL3 binding in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 449.

e20120 Background: In May 2024, the FDA approved tarlatamab, a Delta-like ligand (DLL3)/CD3-targeted bispecific T-cell engager, for patients with extensive-stage small cell lung cancer (SCLC) with disease progression following platinum-based chemotherapy and at least one other prior line of therapy. We aim to evaluate the real-world outcomes of agent. Methods: We conducted a retrospective multi-site single center analysis of adult patients who received tarlatamab at Mayo clinic sites including Arizona, Florida, Iowa, Minnesota, and Wisconsin. Data analysis was performed with Blue Sky statistics version 10.4. Results: Twenty patients with a median age 67 years (range 43-76) were included. Patients were predominantly women (55%) and all had a history of tobacco use. Metastatic disease commonly involved liver (55%) and CNS (60%). Majority (90%) had received prior PDL-1 therapy. 25% (5/20) of patients received prior gamma knife and in addition 10% (2/20) received whole brain radiation treatment in our cohort. Median time from CNS radiation and tarlatamab initiation was 4 months (range 3-28). Other characteristics, outcomes, and toxicity are presented in Table 1. Cytokine release syndrome (CRS) Grade (G) 1 was observed in 45% patients. G 2, 3 and 4 CRS were observed in 5% patients respectively. G 1 CRS was managed with acetaminophen initially followed dexamethasone 10mg or methylprednisone 1g if no improvement in 24 hours. Tocilizumab was used 20% patients for G 1,2,3 and 4 CRS depending on clinical course. Immune effector cell-associated neurotoxicity (ICANS) G 1 occurred in 10% patients, followed by G 2 in 15% and G 3 in 5% patients. ICANS was managed in a multidisciplinary fashion. All patients had resolution of CRS and ICANS. Conclusions: In this study investigating the real-world outcomes and toxicity of tarlatamab, a higher incidence of ICANS was observed than that reported in the DeLLphi-301 trial. The association between presence of CNS metastatic disease, prior CNS radiation and incidence of ICANS needs to be explored further. Mayo Clinic report of tarlatamab real world outcomes and toxicity. Patient Characteristics, Tarlatamab Outcomes and Toxicity Mayo Clinic Report DeLLphi-301 trial- Part 1 & 2 DeLLphi-301 trial- Part 3 ECOG no. (%) 2-4 4 (20) 0 (0) 0 (0) Metastatic Disease no.(%) 19 (95) 98 (98) 32 (94) Median no. of previous lines of therapy (range) 3 (2-4) 2 (1-6) 2 (2-6) Objective Response (%) 30% 40% CRS no (%) 12 (60) 49 (49) 19 (56) ICANS no (%) 6 (30) 7 (7) 4 (12) Neutropenia Grade 3 no (%) 2 (10) 6 (6) 2 (6) Fatal CRS, ICANS or Neutropenia 0 (0) 0 (0) 0 (0)

Abstract Recent studies have described the tumor microenvironment and the key transcription factors in untreated small cell lung cancer (SCLC), but less is known about the salient features in recurrent SCLC (rSCLC). This information could provide valuable insight about the effectiveness of second and later line therapies. In this study, we compared transcriptome profiles (by RNA-seq) of rSCLC against untreated primaries (pSCLC). rSCLC samples (n=23) were obtained from frozen biopsies in patients enrolled in our MC1923 (NCT04607954) phase 2 clinical trial whose disease progressed after chemoimmunotherapy. The pSCLC group (n=73) included publicly available data from fresh frozen primary tumors after surgical resections. Normalized expression data were used in immune deconvolution and gene set enrichment analysis (GSEA) in molecular signature database. Additional GSEA included gene sets describing ASCL1 (A), NEUROD1 (N), ASCL1 and NEUROD1 (AN), and POU2F3 (P) transcription factor activities which are used for subtyping of SCLC. Immune deconvolutions by multiple software algorithms suggested depletion of immune infiltrates in rSCLC compared with pSCLC including dendritic cells, B cells, CD8+ T cells, and M1 macrophages. Furthermore, we found decreased chemotaxis and increased apoptosis of dendritic cells, reduced TNF signaling, and reduced lymphocyte co-stimulation in rSCLC by GSEA. Additionally, in comparisons with pSCLC, rSCLC tumors had significantly lower enrichment scores for POU2F3 activity, representing the SCLC-P subtype (p &lt; 0.007). Importantly, the SCLC-P was recently reported to be more immune inflamed than the other A, N, and AN subtypes. Altogether, our analyses provide strong evidence that the tumor microenvironment of rSCLC is significantly more immunosuppressed and with reduced immune cell infiltrates compared to pSCLC. Developing therapeutic strategies aimed at “warming” the tumor microenvironment and enhancing anti-tumor immune activity in ongoing multimodal therapies of recurrent SCLC will likely provide significant benefits to patients. Citation Format: Farhad Kosari, Mohamed Ali, Sarah H. Johnson, Alex Adjei, Julian R. Molina, Aaron S. Mansfield, Anastasios Dimou, Kaushal Parikh, Mohamed Shanshal, Katherine E. Smith, Ailsa G. Luce, Anna J. Schwecke, Janet Lensing, Ying-Chun Lo, John C. Cheville, George Vasmatzis, Konstantinos Leventakos. Small cell lung cancer (SCLC) at recurrence has a “colder” tumor microenvironment than primary SCLC according to gene expression profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6614.