Dimou, Anastasios

Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03–21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06–0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5–60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1–10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance.

9557 Background: High-dose interleukin-2 (IL-2) is administered following tumor-infiltrating lymphocyte (TIL) therapy, yet cardiotoxicity frequently limits dose delivery. The clinical significance of peri-dose troponin elevations during IL-2 remains poorly defined. We evaluated troponin kinetics during IL-2 dosing and their association with significant cardiac events and IL-2 interruption. Methods: We retrospectively analyzed patients with metastatic melanoma treated with TIL therapy followed by inpatient high-dose IL-2 at Mayo Clinic Rochester (N = 24; 87 IL-2 doses). High-sensitivity troponin and ECGs were obtained before and after each IL-2 dose. Clinically significant cardiac events were defined as QTc prolongation > 480 ms, arrhythmias (excluding isolated sinus tachycardia), new ECG abnormalities, vasopressor requirement, or cardiology consultation. Dose-level outcomes included cardiac events and subsequent IL-2 dose interruption. Paired troponin changes were assessed using Wilcoxon signed-rank testing. Dose-level associations were evaluated using clustered logistic regression to account for repeated IL-2 doses within patients. Results: 24 patients received 87 IL-2 doses (median 3 [IQR 2 - 5]). Median age was 63 years (IQR 54 - 70), and 58% were male. Baseline troponin median was 11 ng/L (IQR 6 - 21); 38% had baseline troponin > 14 ng/L. Post-dose troponin exceeded 14 ng/L in 16/24 patients (67%) and 48/87 doses (52%). Median delta troponin was 0 ng/L (IQR −1 to 6; range −24 to 133), with post-dose levels higher than pre-dose values ( p = 0.02). Clinically significant cardiac events occurred in 33% of patients; no post-IL-2 reductions in left ventricular ejection fraction were observed. At the dose level, cardiac events occurred only when post-dose troponin exceeded 14 ng/L (15/48 [31%] vs 0/39 doses; p < 0.001). In clustered logistic regression, post-dose troponin ≥15 ng/L was independently associated with cardiac events (OR 9.6, 95% CI 1.5 - 60.6; p = 0.02) and subsequent IL-2 dose interruption (OR 3.4, 95% CI 1.1 - 10.7; p = 0.04). When modeled continuously, each 1-unit increase in log-transformed post-dose troponin was associated with higher odds of cardiac events (OR 3.3, 95% CI 1.6 - 6.7; p = 0.001) and IL-2 interruption (OR 2.8, 95% CI 1.6 - 4.9; p < 0.001). Baseline troponin correlated with peak post-dose troponin (ρ = 0.44, p = 0.04). Conclusions: Peri-dose troponin elevations are common during post-TIL high-dose IL-2; however, higher post-dose troponin independently identifies clinically significant cardiac toxicity and predicts IL-2 interruption after accounting for repeated dosing within patients. Baseline troponin modestly predicts peak elevations, supporting standardized, risk-stratified troponin monitoring and prospective evaluation of toxicity-adaptive IL-2 delivery strategies in TIL therapy.

8519 Background: Non-classical mutations (NCM) of epidermal growth factor receptor (EGFR) represent a broad group of oncogenic mutations in non-small cell lung cancer (NSCLC), often associated with resistance to osimertinib (e.g., P-loop and αC-helix compressing [PACC] mutations). Patients (pts) with NCM have inferior clinical outcomes with a high incidence of CNS metastases (CNSm). Silevertinib (BDTX-1535) is a fourth-generation, covalent EGFR TKI with high CNS penetrance targeting both EGFR classical mutations and NCM. The antitumor activity and safety of silevertinib in pts with advanced NSCLC were evaluated in a Phase 2 trial (NCT05256290). Methods: Pts with advanced EGFR NCM NSCLC who received no prior systemic therapy were enrolled (Cohort 3) based on a local molecular test. Silevertinib 200 mg was administered orally once daily. The primary endpoint of objective response rate (ORR) was assessed using RECIST v1.1. CNS ORR was assessed using Response Assessment in Neuro-Oncology for Brain Metastases (RANO-BM) in pts with no prior CNS therapy. Secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (DCR), and safety. Results: From February 2024 to July 2025, 43 pts with 35 unique NCMs (including 25 pts with PACC mutations) were enrolled in Cohort 3: median age 70.0 years, 72% female, 74% white, and 42% never smoked cigarettes. As of November 3, 2025, median follow-up was 7.2 months. ORR by RECIST v1.1 is shown in the table. Sixteen pts (37%) had CNSm, including 7 pts (16%) with measurable CNS disease. RANO-BM CNS response was 86% (n=6/7). Complete clearance of EGFR VAF ctDNA was observed in 21/26 (81%) evaluable pts. Serious treatment-related adverse events (TRAEs) were reported in 5 pts (12%), and 4 pts (9%) discontinued treatment due to TRAEs. The most common TRAEs included rash (19%, grade 3), diarrhea (19%, grade 3), stomatitis (9%, grade 3), and paronychia (5%, grade 3). While 77% of pts had a dose reduction, 19/22 (86%) patients with a radiographic response maintained or deepened their response after dose reduction, including all patients with CNS response. Conclusions: Silevertinib demonstrated robust antitumor activity in treatment-naïve pts with a broad spectrum of NCM EGFR driver mutations with high intracranial activity in pts with brain metastases. The safety profile was consistent with the known AEs of the EGFR TKI class. Clinical trial information: NCT05256290 . Data as of November 3, 2025 N ORR n (%) 95% CI DCR n (%) 95% CI ITT Population * 43 26 (60) (44.4, 75.0) 39 (91) (77.9, 97.4) PACC mutations 25 14 (56) (34.9, 75.6) 22 (88) (68.8, 97.5) Compound mutations † 16 11 (69) (41.3, 89.0) 15 (94) (69.8, 99.8) *No pts with classical (E746_A750del or L858R) mutations were enrolled. † Presence of ≥ 2 NCMs. As of December 27, 2025, the 6-month PFS rate was 86% overall and 80% in pts with CNSm; available PFS and DOR data will be presented.

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: Melanoma brain metastases (MBM) represent a biologically distinct and clinically aggressive subset of melanoma. Comprehensive molecular characterization focused on intracranial disease remains limited. We aimed to define the genomic landscape of MBM and compare these findings with public melanoma datasets. Methods: We retrospectively identified 166 patients with histologically confirmed MBM across Mayo Clinic tri-sites (2011-2025). Molecular testing was performed in 123 patients (74.1%). Comprehensive next-generation sequencing (NGS; ≥300-gene platforms including Tempus, FoundationOne, Caris, NeoGenomics, and MayoComplete Solid Tumor Panel) was available in 41 patients (24.7%). Intermediate-depth profiling using the MayoComplete Melanoma Panel (17 genes) was performed in 21 patients (12.7%), and a targeted 5-gene melanoma driver panel (BRAF, NRAS, KIT, GNAQ, GNA11) in 52 patients (31.3%). cfDNA-based NGS was available in 12 patients (7.2%). Genomic alterations were summarized and benchmarked against TCGA-SKCM and MSK-IMPACT datasets via cBioPortal. We considered assay heterogeneity, as Mayo panels varied in sequencing depth and CNV coverage, and hybrid-capture platforms often under-detect TERT promoter hotspots. Results: Patients had a median age of 67 years, and 63% were male. BRAF mutations occurred in 48.8% (BRAF V600E/K 41.6%; non-V600 7.2%). Additional MAPK alterations included NRAS (17.5%), KIT (5.4%), GNAQ (1.2%), and GNA11 (0.6%). In the comprehensive NGS subset, tumor-suppressor alterations included CDKN2A (17.5%), PTEN (7.8%), NF1 (9.0%), TP53 (8.4%), and TERT promoter mutations (22.9%). Median TMB was 11.55 mut/Mb (IQR 5.0-25.5). Co-alterations included BRAF+CDKN2A (7.2%), BRAF+PTEN (4.2%), NRAS+CDKN2A (4.2%), NRAS+PTEN (1.2%), and CDKN2A+PTEN (3.6%); overall, 18.1% harbored MAPK driver + tumor-suppressor co-alterations. Compared with TCGA and MSK cohorts, MBM showed similar MAPK driver frequencies but fewer MAPK + tumor-suppressor co-alterations and lower CDKN2A, PTEN, and TP53 disruption, alongside a more prevalent of TERT promoter mutations (22.9% vs 7% and 2.1%), which may partly reflect coverage differences. Conclusion: MBM exhibit a distinct genomic profile characterized by reduced tumor-suppressor loss, fewer MAPK-tumor-suppressor co-alterations, and higher prevalence of TERT promoter mutations. While assay heterogeneity limits direct cross-cohort comparisons, these patterns suggest potentially distinct biological features of intracranial melanoma and underscore the need for harmonized, MBM-specific molecular studies to guide therapeutic development. Citation Format: Dina Elantably, Joseph B. Parker, Jakob Hamilton, Ahmed Abdelhakeem, Oluwatayo Adeoye, Saivaishnavi Kamatham, Winston Tan, Arkadiusz Z. Dudek, Anastasios Dimou, Matthew S. Block, Robert McWilliams, Svetomir Markovic, Mahesh Seetharam, Roxana Dronca, Ruqin Chen. Genomic landscape of melanoma brain metastases: Real-world analysis and comparison with public melanoma cohorts [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 2107.

1652 Background: Tarlatamab is a bispecific T-cell engager targeting DLL3 that has shown promise as a therapy in small cell lung cancer. Administering tarlatamab requires careful consideration of immune-related adverse events (AE), including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Prescribing information recommends patients to be monitored for 22-24 hours in an appropriate healthcare setting for cycle 1 (C1), days 1 and 8. At Mayo Clinic in Rochester MN (MCR), tarlatamab is initially administered in a hospital-based outpatient (HBO) setting utilizing an innovative remote patient monitoring system (RPM). In this study, we describe our RPM process and patient outcomes thus far. Methods: We retrospectively reviewed records of patients treated with tarlatamab from August through December 2024. All patients received tarlatamab in the HBO setting and were enrolled into RPM for C1, days 1–10. Patients attended daily HBO visits on days 1–3 and 8–10 of C1 and were required to stay within 30 minutes of the hospital with a 24-hour caregiver for 48 hours following infusion days in C1-2. Data on patient characteristics, frequency of RPM alerts, escalations, rate of CRS & ICANS, and need for hospitalizations were reported using descriptive metrics. Results: As part of RPM, patients are provided with a kit containing preconnected Bluetooth-enabled devices to measure vital signs (VS), including blood pressure (BP), heart rate (HR), temperature (T), and pulse oximetry (SpO2). The kit also includes a cellular-enabled tablet for electronic ICANS questionnaires, which upload directly into our electronic medical record system. Patients are required to log VS four times daily, monitored in real-time by a centralized virtual RPM nursing (RN) team. Embedded decision trees trigger alerts, prompting the RN team to contact patients and follow care pathways for escalations as needed. Among the 16 patients treated, the median age was 68 years, and the median ECOG PS was 1. During the 10-day RPM period, a total of 2,233 VS entries were recorded. Of these, 88% (14/16) of patients had alerts triggered, with a median of 2 alerts per patient. Alerts were mostly for out-of-range systolic BP (56%), HR (56%), and T (25%), with none for SpO2. The RN team escalated alerts in 50% (8/16) of the patients. Overall, 38% (6/16) of patients were managed entirely in the HBO setting. Among the 63% hospitalized, 56% had CRS limited to grade (G) 2, and 31% had ICANS limited to G3. Two patients were hospitalized for other indications. The mean length of stay was 2.6 days, with no ICU admissions. Conclusions: Our experience shows that frequent monitoring required with tarlatamab can be safely and effectively executed in an outpatient setting with the utilization of an RPM system. It can potentially minimize the burden of hospitalizations for patients and the healthcare system.

9503 Background: Neoadjuvant ± adjuvant immunotherapy improves event-free survival relative to adjuvant immunotherapy alone for patients with high-risk resectable stage III melanoma. However, the optimal regimen balancing efficacy and tolerability is not known. T-cell immunoglobulin and ITIM domain (TIGIT) is a promising immune checkpoint but its therapeutic potential in stage III melanoma is underexplored. Methods: In this phase II trial, patients with resectable, macroscopic stage III melanoma received four 21-day neoadjuvant cycles of 1200mg IV atezolizumab (atezo, anti-PD-L1) + 600mg IV tiragolumab (tira, anti-TIGIT), followed by therapeutic lymph node dissection (TLND) and eight 21-day adjuvant cycles of 1200mg IV atezo. Primary endpoints were pathologic response (of all patients initiating neoadjuvant therapy) and recurrence-free survival (RFS) from the time of TLND in patients who were operated on per protocol and received adjuvant therapy. Secondary endpoint was adverse events (AEs); exploratory endpoints included event-free survival (EFS) and distant metastasis-free survival (DMFS). Results: Thirty-four patients, median age 59 years, were accrued and initiated neoadjuvant atezo/tira. 76.5% had >1 metastatic lymph node involved at baseline and 73.5% presented with Stage IIIC disease. All 34 patients were evaluable for AEs, pathologic response and EFS. Four patients were diagnosed with metastatic disease during neoadjuvant treatment, while 30 had TLND per protocol and 28 received adjuvant treatment and were evaluable for RFS and DMFS. Major pathologic responses (MPR, ≤10% viable tumor) were observed in 16/34 patients (47.1%, Table). With 19.9 months median follow-up from registration, 12-month EFS was 72.0% (95% CI 57.9 to 89.5%). With 16 months median follow-up from operation, 12-month RFS was 73.3% (n=28, 95% CI 56.9 to 94.5%), while 12-month DMFS was 86.0% (n=28, 95% CI 72.2 to 100%). In the 16 patients with an MPR, 2 did not receive adjuvant treatment and were followed for 33.3 and 10.8 months without recurrence/death. In the remaining 14 patients, 12-month RFS and 12-month DMFS were both 91.7% (95% CI 77.3 to 100%). 5 patients (14.7%) experienced any grade 3+ AE with 2 (5.9%) at least possibly related to the neoadjuvant regimen. Conclusions: Among patients with high-risk resectable stage III melanoma, neoadjuvant atezo/tira was a promising regimen with a favorable safety profile and warrants further study. Identification of predictive biomarkers will allow for optimization of neoadjuvant therapy for individual patients. Clinical trial information: NCT03554083 . Pathologic response. N=34 Major Pathologic Response 16 (47.1%) Pathologic complete response (no viable tumor) 13 (38.2%) Near-pathologic complete response (0.1−10% viable tumor) 3 (8.8%) Pathologic partial response (>10.0−50% viable tumor) 2 (5.9%) Pathologic non-response (>50% viable tumor) 12 (35.3%) No per protocol operation 4 (11.8%)

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)