Behl, Deepti

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.

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.

e21521 Background: Outcomes following tumor-infiltrating lymphocyte (TIL) therapy vary in real-world practice, and accessible predictors are needed to inform patient selection and timing of referral. We evaluated whether baseline disease burden, metastatic distribution, and treatment delivery factors are associated with outcomes following TIL therapy. Methods: We retrospectively analyzed patients with metastatic melanoma treated with TIL therapy across Mayo Clinic sites (N = 27 infused). Baseline disease burden was characterized using AJCC metastatic stage and organ-specific involvement. A composite high visceral burden variable was defined as the presence of M1d disease and/or liver metastases. Bridging therapy use prior to infusion was recorded. Post-infusion IL-2 exposure was categorized as low (0-2 doses) vs. high (3-6 doses). Best overall response (BOR) was summarized using RECIST-based standard criteria. Overall survival (OS) and progression-free survival (PFS) were measured from TIL infusion and estimated using Kaplan–Meier methods with univariable Cox regression. Results: Median age at infusion was 62.0 years; 59.3% were male. Melanoma subtypes included cutaneous (81.5%) and mucosal (18.5%). Bridging therapy was used in 48.1%. Baseline metastatic stage was M1a/M1b in 18.5%, M1c in 63.0%, and M1d in 18.5%. Median follow up was 8.3 months. BOR included complete response (18.5%), partial response (37.0%), stable disease (22.2%), and progressive disease (22.2%), yielding an objective response rate of 55.6% and disease control rate of 77.8%. Patients with high visceral disease burden experienced inferior OS vs. those without high visceral burden (median 5.2 vs 13.4 months; HR 4.77, 95% CI 1.22–18.63; p = 0.014). Bridging therapy was not associated with OS or PFS. Higher post-infusion IL-2 exposure (seen in 77.8% of patients) was associated with improved OS (median 9.0 vs 3.7 months; HR 0.16, 95% CI 0.04–0.67, p = 0.005), likely reflecting early post-infusion clinical tolerance rather than a causal treatment effect. Median PFS for the cohort was 3.6 months and did not differ by IL-2 exposure ( p = 0.3), metastatic stage ( p = 0.8), bridging therapy ( p = 0.7), liver metastases ( p = 0.2), or LDH above upper limit of normal ( p = 0.1). Conclusions: The above findings are hypothesis generating and will support evaluation in larger cohort. In this real-world cohort of patients treated with TIL therapy, baseline visceral disease burden was strongly associated with survival outcomes, while bridging therapy did not compromise post-infusion efficacy among patients proceeding to infusion. Post-infusion IL-2 exposure correlated with OS and likely reflects early treatment tolerance. These readily available clinical features may inform patient counseling, referral timing, and sequencing decisions as TIL therapy enters broader clinical use.

e20648 Background: Immune checkpoint inhibitors have become a mainstay of treatment for lung cancer. However, their effectiveness varies, and is strongly influenced by patient characteristics. Smoking is the most important etiologic factor for lung cancer, and is expected to be associated with a high tumor mutational burden, which may in turn influence immunotherapy response. However, the extent to which smoking status modifies the benefit of immunotherapy in real-world populations is not well established. Methods: We identified 43,437 cases of invasive lung cancer with documentation of smoking status from the California Cancer Registry 2010-2021. Immunotherapy was documented as given or not given. Smoking status was defined as never, current or former. Cox regression was used to assess the unadjusted risk of mortality associated with immunotherapy and after adjusting for age, sex, race/ethnicity, stage, socio-economic status (SES), Charlson Comorbidity Index and insurance status. Analyses were conducted separately for current and former and never smokers. Results: Smoking status was documented for 43,347 cases (never = 15.887, current = 27,056, and former = 404). There were 4,014 cases treated with immunotherapy. The unadjusted risk of mortality for patients treated with immunotherapy was increased in non-smokers whereas immunotherapy reduced the risk of mortality in current and former smokers. After adjustment, all patients had a reduced risk of mortality, but current and former smokers had a higher risk reduction than non-smokers. Conclusions: Smoking modifies the effect of immunotherapy in patients with lung cancer, and our data suggests patients who currently or formerly smoked may derive a greater benefit from immunotherapy. This will need careful patient messaging as we continue public efforts towards smoking cessation. Unadjusted and adjusted* hazard ratios and 95% confidence intervals for immunotherapy. Unadjusted Adjusted* HR (95%CI) HR (95%CI) Never smokers 1.35 (1.26, 1.45) 0.76 (0.70, 0.82) Current or former smoker 0.86 (0.82, 0.91) 0.52 (0.49, 0.55) *Adjusting for age, sex, race/ethnicity, stage, SES, Charlson Comorbidity Index and insurance status.

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.

9523 Background: Primary Central Nervous System (CNS) Melanoma is a rare and aggressive malignancy, comprising 1% of melanoma cases and 0.07% of brain tumors. Due to its rarity, its natural history, molecular features and optimal management remain poorly defined. Methods: We retrospectively reviewed patients at our institution between January 1998 and October 2025 with primary CNS melanoma or melanocytoma with melanoma transformation. Clinical characteristics, molecular profiling, treatments and survival outcomes were collected. Overall survival (OS) and progression free survival (PFS) were estimated using Kaplan-Meier curves. Results: Nineteen patients were identified, including eight (42%) with melanocytoma to melanoma transformation. Median time of transformation was 34.4 months. Thirteen (68%) patients were female with a median age at diagnosis of 59.3 years. Common presenting symptoms were sensory disturbances (58%), pain (53%), motor deficits (37%) and nausea or vomiting (32%). At diagnosis, location of disease was spinal (n=12), intracranial (n=6) and multifocal (n=1). Thirteen patients had leptomeningeal involvement. Molecular profiling was performed in 15 patients, revealing mutations in GNAQ (n=7), GNA11 (n=3), CKIT (n=2), BAP1 (n=1), EIF1AX (n=1), and BRAF v600 (n=1). Thirteen (68%) patients underwent subtotal resection (STR), five (26%) gross total resection (GTR) and one radiation only. Median resected tumor size was 1.7 cm. Seventeen (94%) patients had recurrence at a median of 9.1 months, and four patients underwent repeat surgery. Fourteen (74%) patients received adjuvant radiation and 14 (74%) received immunotherapy, most commonly ipilimumab with nivolumab (71%). Nine patients received chemotherapy: temozolomide (n=5), bevacizumab (n=2) and one each of intrathecal IL-2, tebentafusp, imatinib and encorafenib with binimetininb. Four patients received chemotherapy before immunotherapy. Median OS from diagnosis of CNS melanocytoma or melanoma was 50.9 months (13.4 – 80). Median OS from time of transformation to melanoma or CNS melanoma diagnosis was 24.0 months (11.9 – NA). One-, three- and five-year OS rates were 73%, 53% and 40% respectively. GTR was associated with increased median OS compared to STR (80.0 vs 19.7 months, p= 0.02). Age at diagnosis, immunotherapy, chemotherapy, adjuvant radiation, STR with or without radiation, disease location, leptomeningeal involvement, tumor size >3cm and presence of GNAQ mutation were not associated with survival. Median PFS was 3 months with chemotherapy and 5.7 months with immunotherapy. Conclusions: To our knowledge, this is the largest single center study of primary CNS melanoma. Outcomes remain poor, with survival primarily associated with GTR. The predominance of GNAQ and GNA11 alterations with rare BRAF v600 mutations highlight the distinct biology of primary CNS melanoma and need for novel targeted therapies.

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: High-dose interleukin-2 (IL-2) is administered after tumor-infiltrating lymphocyte (TIL) infusion to promote in-vivo expansion and persistence, yet optimal dosing and the clinical significance of out-of-specification (OOS) TIL products remain unclear. We investigated the impact of number of infused IL-2 doses and manufacturing OOS status on outcomes in metastatic melanoma treated with commercial TIL therapy. Methods: We retrospectively analyzed 31 patients treated across three Mayo Clinic sites. Planned IL-2 was 600,000 IU/kg every 12 hours for ≤6 doses; actual dosing varied based on clinical tolerance. Patients were grouped as low (0-2) vs high (≥3) IL-2 doses. TIL products were classified as within-specification or OOS per commercial release criteria. Survival associations were evaluated using Kaplan-Meier and multivariable Cox regression. Results: In our 31-patient cohort, the median age was 59 years (range 17-77), 58% were male, and 84% had ECOG 0. At TIL infusion, M-stage distribution was M1a 6%, M1b 10%, M1c 61%, and M1d 23%. LDH was elevated above the upper limit of normal in 42%. The median number of IL-2 infusions was 4 (range 0-6); 58% of patients received ≥3 doses, while 2 patients (6%) received none. Out-of-specification (OOS) TIL products occurred in 6 patients (19%). Best responses included complete response (26%) and partial response (23%), for an overall response rate of 48% and a disease-control rate of 61% (CR + PR + SD). Among responders, the median duration of response was 84 days (95% CI 73-95). At data cutoff, the median follow-up was 253 days (95% CI 137-370). The most common grade 3/4 toxicities occurring &gt;14 days after TIL infusion were lymphopenia (39%), anemia (16%), and thrombocytopenia (10%). Median progression-free survival (PFS) was 99 days (95% CI 73-125) with 20 progression events, and median overall survival (OS) was 193 days (95% CI 32-354) with 13 deaths. Number of infused IL-2 doses was dependent on patients tolerability. Receiving ≥3 IL-2 doses was associated with improved overall survival (394 vs 101 days; p &lt; 0.001) and a trend toward longer progression-free survival (110 vs 59 days; p = 0.055). OOS products predicted inferior PFS (30 vs 110 days; p = 0.003) and showed a trend toward worse OS (120 vs 394 days; p = 0.079). In multivariate analysis, ≥3 IL-2 doses independently improved PFS (HR 0.20, 95% CI 0.06-0.69; p = 0.011) and OS (HR 0.09, 0.02-0.36; p = 0.001), while OOS status increased risk of progression (HR 8.10, 2.24-29.25; p = 0.001) and death (HR 6.16, 1.35-28.20; p = 0.019). Conclusions: Higher number of infused doses IL-2 and meeting commercial TIL release criteria were independently associated with improved outcomes. Citation Format: Mohamed A. Aboelatta, Jeffrey E. Johnson, Jabra G. Zarka, Matyáš Benada, James W. Jakub, Roxana S. Dronca, Ruqin Chen, Mahesh Seetharam, Deepti Behl, Svetomir N. Markovic, Lisa A. Kottschade, Heather N. Montane, Matthew S. Block, Anastasios Dimou, Robert R. McWilliams, Paula Gill, Yi Lin, Arkadiusz Z. Dudek. Impact of number of IL-2 infusions and product out of specification status on outcomes of tumor infiltrating lymphocyte therapy for melanoma [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 3706.