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Background In the C-144-01 phase II trial of lifileucel – a first-in-class autologous tumor-infiltrating lymphocyte (TIL) therapy recently approved for advanced/metastatic melanoma – and up to six interleukin-2 (IL-2) doses, 1 2 ‘rash’ was a treatment-emergent adverse event in 37.2% of individuals 3 TIL/IL-2-associated eruptions have not yet been described or associated with tumor response.Methods The MGB/DFCI Research Patient Data Registry was queried for patients who received ‘lifileucel,’ ‘Amtagvi,’ or ‘LN-144.’ The lifileucel admission and oncology follow-up encounters were reviewed for demographics, eruption features, dermatopathology, and oncologist assessments of tumor response on 30-day post-TIL restaging scans. 4 A pre-specified crude sensitivity analysis tested for independent association between IL-2 dosing (‘high IL-2’ as 4-6 doses; ‘low IL-2’ as 1-3 doses), rash, and 30-day response. Binomial family linear regressions modeled tumor response as a binary outcome, with development of lifileucel/IL-2 skin toxicity as a binary predictor. Adjustments were made for age, sex, IL-2 dose number, and TIL delivery-to-discharge days.Results Among 44 individuals (34.1% female; median age 57 years), 22 (50.0%) developed a lifileucel-associated cutaneous eruption ( table 1). Eruptions were asymptomatic or mildly pruritic central-predominant morbilliform eruptions with occasional purpuric features (figure 1A-F). Dermatopathology from a representative case demonstrated a lymphocyte-predominant interface infiltrate with rare eosinophils and dermal mucin (figure 1G-J).Individuals with cutaneous eruptions had a significantly higher 30-day ORR than those who did not develop cutaneous eruptions (68.2% vs 27.3%, p=0.01). Female sex also was descriptively associated with an increased ORR (80.0% vs 31.0%, Fisher’s p=0.004). Individuals who developed skin toxicity received more mean IL-2 doses (4.77 vs 3.64, p=0.02); however, ‘high IL-2’ recipients did not more frequently demonstrate response (high IL-2: 50.0% vs low IL-2: 43.8%, p=0.76).In the unadjusted logistic regression, lifileucel/IL-2 skin toxicity was associated with tumor response (OR 5.71, 95%CI 1.63–22.47, p=0.009). This association was durable when adjusted for IL-2 dose number (aOR 7.21, 95%CI 1.81–36.28, p=0.008), and when adjusted for age, sex, TIL delivery-to-discharge days, and IL-2 dose number (a’OR 11.59, 95%CI 2.06–100.59, p=0.011).Conclusions This study demonstrates a positive prognostic association between lifileucel-associated morbilliform eruptions and 30-day ORR. While IL-2 monotherapy can cause similar morbilliform eruptions, 5 6 this IL-2-dose-adjusted analysis suggests that lifileucel-associated skin toxicity may represent a non-IL-2-mediated marker of underlying anti-tumor efficacy, assessable during the lifileucel-associated hospital admission 3-4 weeks prior to 30-day restaging. Limitations include sample size, retrospective data, and selection bias favoring more pronounced cutaneous eruptions; we recommend future analyses investigating further-out response endpoints.References Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022;10(12):e005755. doi:10.1136/jitc-2022-005755Thomas SS, Gogas H, Hong YK, et al. Efficacy and safety of lifileucel, an autologous tumor-infiltrating lymphocyte cell therapy, and pembrolizumab in patients with immune checkpoint inhibitor-naive unresectable or metastatic melanoma: Updated results from IOV-COM-202 cohort 1A. J Clin Oncol. 2024;42(16_suppl):9505-9505. doi:10.1200/JCO.2024.42.16_suppl.9505Food and Drug Administration. AMTAGVI (lifileucel) suspension for intravenous infusion: package insert. Published online 2024. https://www.fda.gov/media/176417/download?attachmentSchwartz LH, Litière S, de Vries E, et al. RECIST 1.1-Update and clarification: from the RECIST committee. Eur J Cancer Oxf Engl. 1990. 2016;62:132-137. doi:10.1016/j.ejca.2016.03.081Wolkenstein P, Chosidow O, Wechsler J, et al. Cutaneous side effects associated with interleukin 2 administration for metastatic melanoma. J Am Acad Dermatol. 1993;28(1):66-70. doi:10.1016/0190-9622(93)70011-hLudwig C, Goh V, Rajkumar J, Au J, Tsoukas M. Drug eruptions associated with tumor therapy: Great imitators. Clin Dermatol. 2020;38(2):208-215. doi:10.1016/j.clindermatol.2019.10.006Ethics Approval This study was approved by the Mass General Brigham IRB, under Protocol #: 2020P002307.Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.Abstract 380 Table 1Patient characteristics a Pembrolizumab (2); b Encorafenib/binemetenib (1); Dabrafenib/trametinib (1); Ripretinib (1); All p-values are calculated from Fisher’s exact test, except for two-tailed t-tests where indicated (*) to compare independent means, with alpha set at 0.05Abstract 380 Figure 1Clinical photography and dermatopathology of lifileucel/interleukin-2-associated morbilliform eruption. A) Face. B) Chest. C) Back. D, E) Bilateral arms; left arm biopsy site. F) Bilateral legs. G-H) Interface dermatitis (H&E stain, 200x and 400x). I) Rare eosinophils (circled) (H&E stain, 600x). J) Colloidal iron stain with dermal mucin (400x)