BACKGROUND:Small cell lung cancer (SCLC) is an aggressive malignancy in which radiotherapy remains integral across both limited and extensive stages (ES-SCLC). Tarlatamab has shown improved survival versus chemotherapy and is the preferred second-line therapy. Early tarlatamab studies restricted radiotherapy use limiting knowledge of concurrent use. We evaluated the safety and efficacy of real-world concurrent radiotherapy with tarlatamab in ES-SCLC using the DLL3 PanTUMOR database. METHODS:We performed a multicenter retrospective analysis of adults treated with tarlatamab for ES-SCLC between May 2024 and July 2025. Patients receiving radiotherapy after tarlatamab initiation were assigned to the concurrent radiation arm; others formed the nonradiotherapy (non-RT) arm. The primary endpoint was the rate of grade ≥ 3 adverse events attributed to radiotherapy. Secondary endpoints included overall survival (OS), progression-free survival (PFS), tumor regression at irradiated sites, discontinuation due to adverse events, and maximum CRS or ICANS grade. RESULTS:Among 109 patients (23 concurrent RT, 86 non-RT), baseline characteristics were balanced. Stereotactic radiotherapy was most common (56.5%), predominantly to the brain. Only 1 patient (4.3%) experienced grade ≥ 3 radiotherapy-related toxicity after whole-brain radiotherapy. Median OS was not reached in the concurrent RT arm versus 7.5 months in non-RT (P = .155); median PFS was 4.6 versus 3.1 months (P = .606). Tumor regression occurred in 5 of 6 evaluable patients (83.3%). No delayed CRS or ICANS were observed after the tarlatamab step-up phase. CONCLUSIONS:Concurrent radiotherapy with tarlatamab is safe, with low severe toxicity, frequent local tumor response, and a trend toward improved OS, supporting further study in ES-SCLC.

Purpose Recurrence in early-stage laryngeal carcinoma after radiation therapy often necessitates a total salvage laryngectomy (TSL). Understanding the genetic landscape that influences cancer progression after radiation therapy may help future treatments. We investigated early-stage laryngeal carcinoma patients treated with radiotherapy to identify mutation patterns that predispose to disease recurrence. Methods The patient cohort had 35 early-stage laryngeal head and neck squamous cell carcinoma (HNSCC) patients (T1=15, T2=20,) treated with radiotherapy (RT). We stratified patients: Responders (no recurrence, N=14), non-responders (recurrence within 12 months, N=21), and non-responders undergoing TSL (N=18). We employed whole exome sequencing to characterize gene mutations using the Genome Analysis Toolkit (GATK) for variant detection and impact on critical biological pathways and post-radiotherapy patient outcomes. Pathway analysis Ingenuity and Reactome Pathway Analysis tools were used to explore the mutated gene pathways. Results – Differential mutation analysis was performed in the respective groups to find driver genes. In the pre-treatment samples, KCNT2 and AGAP6 mutations were exclusively found in non-responders (OR=0, P=0.005 and OR=0, P=0.027, respectively), while ADAMTS7 mutations were solely present in responders (OR=inf, P=0.019). PLEC mutations were more prevalent in responders (OR=11.6, P=0.006). Pathway analysis revealed that significant genes were involved in the RND2 GTPase cycle, protein O-glycosylation-related diseases, and apoptotic pathways. Post-treatment analysis in patients undergoing TSL had enrichment of mutations in apoptosis regulation pathways. Conclusions – The study reveals that mutations in apoptosis controlling genes were predominantly represented in the larynx non-responder patients both in the pre-radiotherapy and post-TSL populations.

Background Tarlatamab is the preferred second-line therapy for extensive stage small cell lung cancer (ES-SCLC). However, strict eligibility criteria from trials limit the understanding of safety and efficacy in broader patient populations. Methods Patients with ES-SCLC treated with tarlatamab after platinum-based chemotherapy at nine cancer centers were included. Predefined univariate subgroup analyses for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) included age, performance status, disease burden (>3 metastatic tissue types involved), CNS disease, hepatic disease, and oxygen use among others. Efficacy endpoints were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results A total of 109 patients were analyzed across several high-risk features. Any grade CRS was significantly associated with high disease burden (p=0.002), hepatic disease (p=0.002), and baseline oxygen use (p=0.034). Any grade ICANS was significantly associated with high disease burden (p=0.022) and a history of treated or untreated CNS disease (p=0.015). Within the subgroup of patients with CNS disease unstable brain metastasis was associated with higher any grade ICANS (p=0.021). The ORR was 33.7%, PFS of 3.58 months, and median OS of 8.48 months. CNS-specific ORR was 33.3%, including four complete responses without radiation. Conclusion High disease burden, hepatic disease, and baseline oxygen use may increase CRS risk with high disease burden and CNS disease driving ICANS risk. Tarlatamab demonstrated manageable toxicity with clinically relevant efficacy across high-risk patient populations supporting broad access to this therapy.

PURPOSE:STAT3 is important in promoting a pro-oncogenic tumor microenvironment. This first randomized trial of a STAT3-targeting ASO with pembrolizumab assessed whether this first-line combination would improve outcomes compared with pembrolizumab alone in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS:This multicenter, randomized, open-label, controlled study (NCT05814666) enrolled patients with previously untreated R/M-HNSCC with positive PD-L1 expression (combined positive score [CPS] ≥1). Patients were stratified by CPS (1-19; ≥20) and randomized 2:1 to danvatirsen 3mg/kg IV weekly (with 2 loading doses in week 1) plus pembrolizumab 200mg IV every 3 weeks or pembrolizumab alone. Patients received 21-day treatment cycles until progressive disease, unacceptable toxicity, or voluntary withdrawal. Primary endpoint was overall response rate (ORR: partial + complete response per RECIST-v1.1). RESULTS:69 patients were randomized and 66 treated (51 [77.3%] male), 45 with danvatirsen + pembrolizumab, 21 with pembrolizumab alone. Enrolment was stopped due to lack of response in the CPS 1-19 cohort after ≥1 scan (~6 weeks of treatment) and in the CPS ≥20 cohort after ≥2 scans (~12 weeks). In the final analysis, ORRs were 15.6% and 14.3%, respectively (risk difference 1.3, P=1.0). The treatment-emergent adverse-event rate was increased in the combination arm (97.8% vs 85.7%), and the combination side effect profile was similar to previous danvatirsen studies. CONCLUSIONS:Combination danvatirsen + pembrolizumab did not improve ORR compared to pembrolizumab alone in first-line treatment of R/M-HNSCC. Further exploration of STAT3-targeted approaches is needed within the context of immunotherapy.

Abstract PD-1/PD-L1-targeting antibodies have revolutionized cancer treatment but most pts fail to respond (primary resistance) or lose response (secondary resistance). Anti-PD-1 therapy resistance mechanisms are poorly understood; other checkpoint inhibitor pathways are important investigational targets based on animal model studies. Co-expression of PD-1, LAG3, and TIM3 is associated with functional T-cell exhaustion and may contribute to resistance. Antibodies targeting LAG3 and TIM3 are potential candidates for overcoming anti-PD-1 resistance; LAG3 is also clinically supported as a target for resistance in pts with melanoma. INCAGN2385-203 is a randomized, phase 2 study to evaluate the efficacy and safety of retifanlimab (anti-PD-1) + INCAGN02385 (anti-LAG3) and retifanlimab + INCAGN02385 + INCAGN02390 (anti-TIM3) combinations vs retifanlimab alone in immunotherapy naïve PD-L1-positive (CPS ≥1) recurrent/metastatic SCCHN. Objective response rate was numerically higher in anti-LAG3-containing arms (∼30%) vs the retifanlimab monotherapy arm (20%). Median progression-free survival was similar in all 3 arms. To evaluate pharmacodynamic biomarkers associated with LAG3 and/or TIM3 blockade in the context of PD-1 inhibition, flow cytometry was used to evaluate frequency changes of CD4 and CD8 T cells, regulatory T cells, and memory T cells, as well as activation and proliferation markers in whole blood samples. T-cell proliferation and activation were observed in all 3 arms. T-cell proliferation (CD4 and CD8) measured by frequency change of Ki67-positive T cells and HLA-DR expression was more pronounced in both anti-LAG3-containing arms vs the retifanlimab alone arm. No significant difference in regulatory T cells was observed between the 3 arms. Naïve CD4 and CD8 T cells decreased at similar levels at cycle 1, day 8 across all arms. A steady decrease of central memory CD4 and CD8 T cells up to cycle 4, day 1 was observed with retifanlimab alone, whereas retifanlimab + anti-LAG3 showed elevation of central memory T-cell frequencies in both CD4 and CD8 T cells up to cycle 1, day 15, before decreasing steadily up to cycle 4, day 1; there was no obvious change from baseline to cycle 4, day 1 in the triplet arm. Opposite trends were observed in effector memory CD4 and CD8 T cells. Retifanlimab alone produced a steady increase, whereas retifanlimab + anti-LAG3 showed decreases in CD4 (up to cycle 1, day 15) and CD8 (up to cycle 2, day 1) effector memory T cells before increasing steadily. These preliminary results suggest that LAG3 and/or TIM3 blockade may have unique effects on T-cell function. LAG3 with PD-1 blockade may overstimulate T cells and lead to T-cell elimination, highlighting the need for dose optimization. Further evaluation of T-cell responses of PD-1/PD-L1 blockade with other checkpoint inhibitors, including those targeting LAG3 and TIM3, is warranted. Citation Format: Robert I. Haddad, Denis Soulières, Prakash Neupane, Amaury Daste, Zhiwan Dong, Jin Lu, Michelle Kinder, Jeff Jackson, Richard Schaub, Nawel Bourayou, John Janik, Christophe Le Tourneau. Comparison of T-cell activation status in patients treated with retifanlimab in combination with anti-LAG3/Anti-TIM3 vs retifanlimab alone [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 7747.

BACKGROUND:Pembrolizumab monotherapy and pembrolizumab-chemotherapy demonstrated superior overall survival (OS) versus cetuximab-chemotherapy (EXTREME) in the primary analysis of the phase III KEYNOTE-048 study of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) in the first-line setting. We report updated data with 5 years of follow-up. METHODS:Adults with previously untreated R/M HNSCC incurable by local therapy were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab plus chemotherapy, or EXTREME. The primary endpoints were OS and progression-free survival (PFS). RESULTS:Overall, 882 participants were assigned to pembrolizumab, pembrolizumab-chemotherapy, or EXTREME. Median study follow-up was 69.2 months (pembrolizumab) and 68.6 months (pembrolizumab-chemotherapy). Median OS remained longer for pembrolizumab versus EXTREME in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20 (HR, 0.61; 95 % CI, 0.46-0.81) and CPS ≥ 1 populations (HR, 0.74; 95 % CI, 0.61-0.89), and similar in the total population (HR, 0.82; 95 % CI, 0.69-0.97). Pembrolizumab-chemotherapy prolonged median OS in the PD-L1 CPS ≥ 20 (HR, 0.63; 95 % CI, 0.47-0.84), CPS ≥ 1 (HR, 0.65; 95 % CI, 0.53-0.79), and total (HR, 0.72; 95 % CI, 0.60-0.86) populations. The 5-year OS rate in the total population was 14.4 % for pembrolizumab versus 6.5 % for EXTREME and 16.0 % for pembrolizumab-chemotherapy versus 5.2 % for EXTREME. There was no clinically meaningful difference in PFS among pembrolizumab, pembrolizumab-chemotherapy, or EXTREME groups in any populations. CONCLUSIONS:These 5-year follow-up results support the use of pembrolizumab and pembrolizumab-chemotherapy as first-line standards of care for R/M HNSCC. CLINICAL TRIAL INFORMATION:NCT02358031. PRIOR PRESENTATION:Presented at the European Society for Medical Oncology Congress, September 9-13, 2022.

e20127 Background: Small cell lung cancer (SCLC) remains the most aggressive lung cancer with poor prognosis. Tarlatamab (T), a bi-specific T-cell engager, is approved for use in extensive stage SCLC after progression on a platinum-based chemotherapy based on the DeLLphi-301 trial. Due to the restrictive inclusion criteria of this trial, significant gaps remain in understanding treatment outcomes for many patients (pts). Methods: This is a single-center, IRB-approved, retrospective study in pts who were treated with T from 05/2024 to 12/2024 for SCLC (cohort 1) or extrapulmonary small cell carcinoma (cohort 2). Pts were eligible if they received at least 1 dose of T. The primary objective was to evaluate the safety of T and secondary objectives include response rate (RR), progression-free survival (PFS) and overall survival (OS). Results: A total of 21 pts were included in cohort 1 and 3 pts were included in cohort 2. Baseline characteristics can be found in the Table. In cohort 1,13 pts (61.9%) developed cytokine release syndrome (CRS) (Grade ≥ 3: 2 pts,15.3%). 10 pts (47.6%) developed immune effector cell associated neurotoxicity syndrome (ICANS) (Grade ≥ 3: 3 pts,14.2%). In cohort 2, any grade CRS occurred in 2 pts (66.7%) and grade 1 ICANS occurred in 1 pt (33.3%). All CRS and ICANS events occurred after cycle 1 day 1(C1D1), except for 1 pt who experienced transient grade 1 CRS on cycle 1 day 8. 17 pts were evaluated for response in cohort 1 (PR=35.2%, SD=17.6%). Notably, the RR in pts with T use in the 2nd line and with liver metastasis (mets) was 40% and 38.5%, respectively. Median PFS was 2.2 months and median OS was 4.1 months. 1 pt noticed a CR in the CNS without any radiation. Conclusions: Our study showed the safety and ORR of T are consistent with findings from the DeLLphi-301 trial. However, median PFS and OS were notably shorter, likely due to the small sample size and the inclusion of pts with poor prognostic factors like oxygen use, poor ECOG status, and untreated CNS mets. The higher incidence of CRS and ICANS following C1D1 highlights the need for vigilant monitoring during initial cycles. Future studies with larger pt population and longer follow-up are warranted to evaluate T in the real-world settings. Cohort 1 (21 pts) Cohort 2 (3 pts) Median age, yr 67 74 Sex, no. (%) M/F 11(52.3)/10(47.6) 2(66.7)/1(33.3) Ethnicity, no. (%) W/AA/A 19(90.4)/1(4.8)/1(4.8) 2(66.7)/1(33.3)/0(0) ECOG, no. (%) 0-1/2+ 16(76.1)/5(23.8) 2(66.7)/1(33.3) Brain mets, no. (%) 14(66.6) 2(66.7) Liver mets, no. (%) 16(76.1) 2(66.7) Baseline Oxygen Use, no. (%) 5(23.8) 0(0) Metastatic sites <5/>5 11(52.4)/10(47.6) 2(66.7)/1(33.3) CR/PR/SD/PD, no. (%) 0(0)/6(35.2)/3(17.6)/8(47) Unevaluable CRS C1D1 Any Grade/3+ 13(61.9)/2(9.5) 2(66.7)/0(0) ICANS C1D1 Any Grade/3+ 10(47.6)/3(14.3) 1(33.3)/0(0) Best Response by Baseline characteristic, no. (%)Liver mets2 nd line tarlatamabPlatinum resistant 5/13 (38.5)2/5 (40)1/8 (12.5)

TP53 wild-type and mutant patients received similar definitive treatment.

Introduction: SCLC remains the most aggressive lung cancer with a poor prognosis. Tarlatamab, a bispecific T-cell engager, is approved for use in extensive-stage SCLC after progression on a platinum-based chemotherapy on the basis of the DeLLphi-301 trial. Because of the restrictive inclusion criteria of this trial, substantial gaps remain in our understanding of treatment for many patients. Methods: We performed a retrospective chart review of patients who were treated with tarlatamab at the University of Kansas Cancer Center from May 2024 through December 2024 for SCLC (cohort 1) or extrapulmonary small cell carcinoma (EPSCC) (cohort 2). Patients were included if they received at least one dose of tarlatamab regardless of baseline characteristics. Results: A total of 21 patients were included in cohort 1, and three patients were included in cohort 2. In the SCLC cohort, 14 patients (66.6%) had central nervous system (CNS) involvement, five patients (23.8%) required baseline oxygen, and five patients (23.8%) had an Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or greater. There were 13 patients (61.9%) who developed cytokine release syndrome (CRS), with grade 3 or higher CRS noted in two patients (15.3%). There were 10 patients (47.6%) who developed immune effector cell–associated neurotoxicity syndrome (ICANS), with three patients (14.2%) developing grade 3 or higher ICANS. In the three patients with extrapulmonary small cell carcinoma, any-grade CRS occurred in two patients (66.7%), and grade 1 ICANS occurred in one patient (33.3%). Characteristics such as ECOG of 2 or higher, baseline oxygen use, and untreated CNS metastases are associated with high rates of CRS and ICANS. In 17 patients evaluable for best response in cohort 1, partial response was seen in six (35.2%) patients. No patients in cohort 2 had disease assessment performed at the time of data cutoff. Alternative CNS disease control using tarlatamab alone or with concurrent radiation provided clinical benefit to three patients. Conclusions: Baseline risk factors such as oxygen dependence, poor ECOG performance status, bulky disease, and untreated CNS involvement may increase CRS and ICANS rates after tarlatamab. However, subsequent doses exhibited a more favorable safety profile, supporting outpatient administration and reduced observation time. CNS management strategies, including concurrent radiation or monotherapy with tarlatamab, exhibited promising efficacy. These findings highlight the need for further research into CRS and ICANS risk stratification, optimal CNS management, and efficacy in extrapulmonary small cell carcinoma through larger studies.

e21020 Background: Cancer accounts for huge non-communicable disease burden in Nepal with majority of patients presenting at an advanced stage accounting for 9% of total annual deaths. Diagnosis of cancer at advanced stages can result in missed treatment opportunities, worse outcomes, and higher health care costs which needs to be addressed. Many factors contribute to the delay in diagnosis and management of cancers but gap in physician knowledge attributing to lack of hematology-oncology training appears to be one of the major causes. Adequate hematology-oncology education for trainees therefore is essential for early diagnosis and improvement in outcome of the patients with problems related to cancer or its treatment. Herein we evaluated the current status of hematology-oncology education in post graduate Internal Medicine programs in Nepal. Methods: A prospective survey was conducted across 23 medical colleges offering Internal Medicine programs in Nepal from June 2024 to November 2024. Head of departments or faculty members from these Internal Medicine programs were invited to participate by completing the survey sent through emails online. A structured, self-administered questionnaire focusing on the current status of hematology-oncology education like rotations during training, availability of hematologist/ oncologist as faculty in the department for teaching-learning and availability of multidisciplinary team involved with diagnosis and treatment related to cancer was used. The curriculum of the internal medicine program was also evaluated for hematology oncology education framework used for the program. Results: Among the 23 medical colleges surveyed, only 9 (40.9%) included a mandatory hematology rotation, while 10 (45.5%) offered a mandatory oncology rotation. Most of the colleges offered rotation of 15 days to only a month during the 3 years residency training. Hematologist was available as faculty in only 7 (31.8 %) medical colleges while oncologists (medical oncologist and/or radiation oncologist) in 14 sites. Multidisciplinary team for cancer care exposure was available at 8 centers. The curriculums were non-uniform across various universities. None of the programs offered their residents an organized oncology curriculum or suggested a reference book or other oncology-related resource. Conclusions: The need of hematology oncology education during residency training with standardized curriculum in order to prepare next generation of physician in improving cancer care in Nepal seems to be a high priority in light of increasing cancer morbidity and mortality in the country.

Purpose:The purpose of this study was to compare the efficacy of oral morphine (MOR) with oral tramadol (TRM) in control of pain as well as physical well-being in patients (pts) with moderate cancer pain (MCP) using the Edmonton Symptom Assessment Scale (ESAS). Methods:An Institutional Review Board (IRB) approved randomised phase II trial was performed in opioid-naive pts with MCP as defined by pain score in numerical rating score (NRS) of 4-6. Patients were randomised to receive MOR syrup 5 mg 4 hourly or TRM 50 mg four times a day. Titration of dose was done in both groups for 3 days in case of inadequate pain control as per standard recommendation for MOR or until the maximum recommended daily dose for TRM. MOR was changed to prolonged release form on Day 4. The primary endpoint was the number of early responders, defined as pts with at least 20% reduction in pain intensity on NRS on Day 3. The secondary outcome was the number of patients with highly meaningful pain reduction, defined as a decrease in pain intensity on NRS by ≥5 and improvement in physical well-being with ESAS at Day 7. Results:Sixty-eight pts consented and were randomised, 34 in each arm. The primary endpoint occurred in 94.1% pts in MOR and 55.9% in TRM (p < 0.001). The number of patients with highly meaningful pain reduction was significantly higher in MOR than in TRM (76.5% versus 32.35%; p < 0.001). Improvement in general physical well-being as assessed by ESAS was better in the MOR group. No difference in adverse effects was noted between the treatment arms. Conclusion:In this study, MOR was superior to TRM in the control of pain with statistically significant differences in the primary and secondary endpoints. Therefore, early use of MOR skipping the World Health Organization sequential analgesic ladder for MCP may be a higher value option in resource-scarce country with limited access to healthcare.

e15577 Background: HER2-overexpressing cancers represent a distinct group of malignancies. Based on the DESTINY-PanTumor02 trial, the FDA recently approved T-DXd for HER2-positive previously treated solid tumors. However, the trial excluded patients (pts) with an ECOG > 1 and those with brain metastases, leaving a gap in real-world data on the use of T-DXd in these frail populations. Methods: This single-center, IRB-approved, retrospective study included all pts with non-breast cancer who received at least one dose of T-DXd. The objective was to assess the real-world experience, particularly in pts who did not meet the clinical trial inclusion criteria. The primary objective was to assess safety, while secondary objectives included disease control rate (DCR, defined as partial response (PR) or stable disease (SD)), progression free survival (PFS), and overall survival (OS). Results: A total of 37 pts were included. Baseline characteristics are summarized in the table. Notably, 8 pts (22%) had ECOG > 1 and 9 (24%) had brain metastases. Adverse events (AEs) occurred in 30 pts (81%), leading to dose reductions (DR) in 15 pts (41%). Common AEs resulting in DR included fatigue (14%), cytopenia (8%), and anemia (5%). Nine pts (24%) had grade 3 or 4 AEs and 3 pts (8%) had grade 3 or 4 pneumonitis. The median final dose of T-DXd was 5.4 mg/kg (range: 3.2-6.4). Treatment discontinuation due to AEs was observed in 5 pts (13%), including pneumonitis (3 pts, 8%) and fatigue (2 pts, 5%). The median duration of treatment was 3.8 months (range: 0.5-21). The DCR was 69%, with 18 pts (49%) achieving PR and 7 (19%) achieving SD. Additionally, 7 pts (78%) with brain metastases achieved PR. In pts with HER2 3+ tumors, the DCR was 82%, with 5 pts (36%) achieving PR. Twelve pts (32%) received subsequent treatments, including chemotherapy (58%) and anti-HER2 therapies (42%), with a DCR of 50%. At the time of data cutoff, 16 pts (43%) remained on treatment. The median PFS was 7.3 months and the median OS was 10.2 months. Conclusions: T-DXd demonstrates a favorable safety profile and durable clinical benefit in a real-world, frailer pt population. The safety and efficacy data align with the results from the DESTINY-PanTumor02 trial, with pneumonitis observed in 8% of pts and a DCR of 69%. Further analysis of clinical and genomic risk factors will be presented. Baseline clinical characteristics. Median Age (range), yr 62 (29-82) Gender (male), n(%) 21(57) Race (white), n(%) 28(76) ECOG (>1), n(%) 8(22) Smoking history, n(%) 17(46) Primary cancer, n(%) Esophageal, 9(24); Colorectal, 7(19); Biliary tract, 5(14); Lung, 11(30); Gynecologic, 4(11) HER2 expression, n(%) Total, 20(54); HER2 2+, 6(16); HER2 3+, 14(38) ERBB2/HER2 amplification on FISH or NGS, n(%) 22(59) Comorbidity (COPD), n(%) 2(5) DCR by primary cancer type, n(%) Esophageal, 6(67); Colorectal, 4(57); Biliary tract, 4(80); Lung, 9(82); Gynecologic, 1(25)

e24106 Background: Food and Drug Administration (FDA) approved Tarlatamab, a bispecific T-cell engager (TCE) demonstrating promising survival outcomes in patients with Extensive-stage small cell lung cancer (ES-SCLC). However, it is associated with significant adverse events (AEs), including cytokine release syndrome (CRS) in 50-60% of patients, and immune effector-associated neurotoxicity syndrome (ICANS) in 8%-28%, but with 0% mortality as observed in the landmark DeLLphi-301 trial. We aimed to review the real-world (RW) data on immune-related adverse events like CRS, ICANS, and non-ICANS neurotoxicity using the FDA Adverse Event Reporting System (FAERS) database. Methods: We queried FAERS using a search-by-product strategy using the terms “Tarlatamab” and “Tarlatamab Dlle” on 22nd January 2025 and retrieved 2 results showing 185 adverse events (AEs). Descriptive statistics were carried out, and disproportionality analysis was done by calculating the reportable odds ratio (ROR) with 95% confidence intervals (CI). ROR was considered significant when the lower limit of the 95% CI was > 1. Results: A total of 185 AEs were reported with Tarlatamab, with immune system disorders (n=73,39.4%) and Nervous system disorders (n=69,37.2%) representing the largest systems of AEs. CRS is the single most common AE reported (n=73,39.4%) followed by ICANS (n=48, 25.9%). 28% (n=21) of CRS patients were hospitalized and 25% (n=7) of them died. Similarly, 35.4% (n=17) required hospitalization for ICANS, and 23.5% (n=4) of them died. Overall CRS is associated with 8% mortality and ICANS is associated with 9% mortality. ROR with Tarlatamab for CRS was 1628.6 (1212.0, 2188.7), ICANS was 2321.5 (1689.9, 3194.8) and non-ICANS neurotoxicity was 3.29 (2.11, 5.11). (Table) Conclusions: Our study revealed CRS and ICANS as the most common AEs, associated with high mortality rates compared to the pivotal trial. (8% in thevs 0% in the clinical trial). This may reflect a broader selection of patients in real-world settings. Better patient selection and preemptive management strategies for high-risk patients must be explored. Baseline demographics and adverse events profile. Baseline characteristic feature Total events (n=185) CRS (n= 73) ICANS (48) Non-ICANS Neurotoxicity (n=22) Total number of adverse events 185(100%) 73 (39.4%) 48 (25.9%) 22 (11.8%) Age groups18-6465-85 15 (8.1%)18 (9.7%) 3 (4.1%)8 (10.9%) 3 (6.30%)7 (14.5%) 3 (13.6%)3 (13.6%) GenderMaleFemale 49 (26.4%)63 (34.0%) 20 (27.3%)24 (32.8%) 12 (25.0%)20 (41.6%) 3 (13.6%)14 (63.6%) OutcomesDiedHospitalized 22 (11.8%)48 (25.9%) 7 (9.5%)21 (28.7%) 4 (8.3%)17 (35.4%) 1 (4.6%)7 (31.8%) ROR (95% CI) - 1628.6 (1212.0, 2188.2) 2321.5 (1686.9,3194.8) 3.29 (2.11,5.11) CRS: Cytokine release syndrome; ICANS: Immune effector cell associated neurotoxicity syndrome; ROR: Reportable Odds ratio.

List of all observed somatic mutations in TP53.

Adverse events at least possibly related to study drug by NIH-NCI Common Terminology Criteria for Adverse Events (CTCAE), version. 4.0.