Citations

TPS7101 Background: Patients with high-risk CLL/SLL not achieving a complete response (CR) after ≥ 12 months of BTK inhibitor (BTKi) monotherapy remain at risk for early progression due to residual disease and BTKi resistance. A BCL-2 inhibitor (BCL-2i) introduces a complementary, BCR-independent apoptotic mechanism that may deepen responses and prolong progression-free survival (PFS). Lisaftoclax, a selective oral BCL-2i with a short half-life (4-6 h), enables once-daily dosing and is approved in China as second-line CLL therapy. Lisaftoclax monotherapy has demonstrated overall response rates (ORRs) of 67% in relapsed/refractory CLL and 62.5% in BTKi-refractory disease, including del(17p)/ TP53 -mutated cases. Lisaftoclax combined with acalabrutinib achieved ORRs >97% with favorable tolerability. This study evaluates whether lisaftoclax plus BTKi (acalabrutinib, zanubrutinib, or ibrutinib) improves PFS and/or overall survival (OS) (vs continued BTKi monotherapy) in patients with CLL/SLL and residual disease after prolonged BTKi treatment. Methods: This study will enroll approximately 440 patients randomly allocated to receive lisaftoclax plus BTKi or BTKi alone. Eligible patients have CLL/SLL and, after ≥12 months of BTKi monotherapy (lines 1-3), have achieved neither CR nor progressive disease (PD). Randomization is stratified by del(17p)/ TP53 status. Key inclusion criteria include age ≥18 years, ECOG PS 0-2, and residual disease with either high-risk features (del(17p)/ TP53 mutation, unmutated IGHV , or complex karyotype [≥5 abnormalities]), or measurable residual disease with lymph nodes ≥2.5 cm in the absence of high-risk features. Exclusion criteria include prior BCL-2i therapy or Richter transformation. Patients in the investigational arm will undergo a 5-day oral lisaftoclax ramp-up to 400 mg once daily plus physician's choice of BTKi in 28-day cycles until progression or toxicity. Control patients continue their current BTKi monotherapy. Safety and disease assessments (CT/MRI) will occur regularly. The primary endpoint is PFS by independent review committee (iwCLL 2018); key secondary endpoint OS; and other secondary endpoints, PFS by investigator, ORR, duration of response, MRD negativity, and safety. Enrollment is ongoing across 126 sites in 18 countries (ClinicalTrials.gov ID: NCT06104566). Clinical trial information: NCT06104566 .

TPS655 Background: Early (14-28 day) on-treatment suppression of tumor proliferation during neoadjuvant endocrine therapy (NET) is strongly associated with favorable long-term outcomes in estrogen receptor–positive (ER+) HER2– breast cancer. In premenopausal women, tamoxifen with or without ovarian function suppression (OFS) results in suboptimal Ki-67 suppression compared with aromatase inhibitor + OFS. (Z)-endoxifen (ENDX), the active metabolite of tamoxifen, dually inhibits ER signaling and PKCβ1-mediated AKT activation, supporting its evaluation as an alternative NET strategy in this population. Methods: EVANGELINE (NCT05607004) is an ongoing, multicenter, open-label Phase 2 study evaluating daily 40 mg ENDX plus goserelin administered every 28 days as neoadjuvant therapy in premenopausal women with ER+/HER2–, cT2–3, cN0–1 breast cancer. The primary objective is to determine the proportion of patients with baseline Ki-67 >10% who achieve Ki-67 ≤10% after 4 weeks of therapy. A Simon two-stage design is used to test whether the Week 4 Ki-67 ≤10% rate is at least 65%, with 20 patients enrolled into the first stage and, if promising, another 25 patients enrolled into the second stage (cohort A). A parallel cohort of 20 patients with baseline Ki-67 ≤10% (cohort B) is enrolled to assess objective response rate (ORR) at 24 weeks per RECIST v1.1. Secondary objectives include examining safety and tolerability, residual cancer burden, and PEPI score. Correlative analyses include examining effect of treatment on select tumor and plasma biomarkers. Clinical trial information: NCT05607004 .

TPS649 Background: While advancements in early-stage breast cancer (ESBC) treatment have improved survival, disease recurrence and therapeutic resistance remain significant challenges. Current biomarkers guide initial treatment, yet novel diagnostics are required to improve risk stratification and recurrence prediction. Circulating tumor DNA (ctDNA) offers a non-invasive method for detecting minimal residual disease (MRD), potentially enabling the identification of molecular relapse before radiographic progression. However, deeper validation of ctDNA kinetics across the treatment continuum is needed to inform precision oncology strategies in ESBC. Additionally, the logistical complexity of tissue-dependent assays presents a barrier to scalability. In order to address these gaps, the purpose of the GEMINI-BREAST study is to evaluate a methylation-based, tissue-free ctDNA assay (Tempus xM) and integrate this with comprehensive clinical and multi-omic data to determine prognostic utility for invasive disease-free survival (iDFS) and long term outcomes in patients with ESBC. Methods: GEMINI-BREAST (NCT07211178) is a prospective, non-interventional, multi-center study enrolling up to 900 participants with ESBC treated with curative intent. Eligible patients enroll into one of three analytical cohorts (n ~ 300 each): Cohort 1 enrolls pre-neoadjuvant therapy (high-risk HR+/HER2- [Stage II-III], HER2+ [Stage II-III], or TNBC [Stage I-III]); Cohort 2 enrolls post-surgery/pre-adjuvant therapy (same subtypes, no evidence of disease); and Cohort 3 enrolls long-term survivors (high-risk HR+/HER2- [Stage II-III], ≥ 5 years since diagnosis). Longitudinal blood samples for ctDNA analysis and archival tissue for NGS are collected at standard-of-care intervals, including, as applicable: pre-neoadjuvant, neoadjuvant on-treatment (weeks 3, 6, 12) and post-treatment, post-surgical/pre-adjuvant, adjuvant on-treatment (every 3 months), end of definitive therapy, surveillance for up to 5 years (every 3-6 months for Cohorts 1/2; every 6-12 months for Cohort 3), and at progression/recurrence. The primary objective is to evaluate the association between ctDNA dynamics (Cohort 1) or MRD status (Cohort 2/3) and iDFS, with secondary endpoints assessing overall survival, lead time to recurrence, and the predictive value of ctDNA clearance for pathological complete response. Recruitment is currently ongoing at U.S. sites. Clinical trial information: NCT07211178 .

TPS4642 Background: Although first-line (1L) EV + pembrolizumab has improved outcomes for patients with la/mUC, most experience disease progression, highlighting an unmet need for novel therapies. TROP2 is a glycoprotein highly expressed in several epithelial tumors, including UC. Dato-DXd is a TROP2-directed antibody–drug conjugate comprising an anti-TROP2 monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload (DXd), designed to induce selective tumor-cell death and reduce systemic exposure to the payload. Dato-DXd has demonstrated durable efficacy and a manageable safety profile in patients with la/mUC both as monotherapy (TROPION-PanTumor01 [NCT03401385]) and in combination with immunotherapy (TROPION-PanTumor03 [NCT05489211]). We describe a Phase 2/3 trial comparing the efficacy and safety of Dato-DXd + platinum CT (carboplatin or cisplatin) vs gemcitabine + platinum CT in participants with la/mUC with disease progression on or after EV + pembrolizumab. Methods: TROPION-Urothelial03 (NCT07129993) is a global, multicenter, randomized, open-label, Phase 2/3 trial. In Part A (Phase 2), ~60 participants will be randomized 1:1 to receive Dato-DXd 4 or 6 mg/kg + platinum CT. In Part B (Phase 3), ~570 participants will be randomized 1:1 to receive Dato-DXd at the recommended Phase 3 dose (determined using Part A data) + platinum CT vs gemcitabine + platinum CT. Randomization in Part A is stratified by assignment of platinum CT (carboplatin vs cisplatin), and in Part B, by assignment of platinum CT, presence vs absence of liver metastasis at screening, and time to progression on 1L EV + pembrolizumab (<6 vs ≥6 months). Study treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, death, loss to follow-up, or other reasons per protocol. Radiographic tumor assessments occur every 6 weeks for 54 weeks, then every 12 weeks. The primary endpoint of Part A is objective response rate (ORR) by investigator per Response Evaluation Criteria in Solid Tumours, version 1.1 (RECIST 1.1). The dual primary endpoints of Part B are progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints include duration of response by investigator per RECIST 1.1 (Part A), and PFS by investigator per RECIST 1.1 and ORR by BICR and investigator per RECIST 1.1 (Part B). In Part A, ORR will be summarized with 2-sided 95% exact confidence intervals using the Clopper–Pearson method by trial group. In Part B, PFS and OS will be compared between trial groups using a log-rank test stratified by randomization stratification factors, with hazard ratios from the stratified Cox regression model. Clinical trial information: NCT07129993 .

TPS2673 Background: The main challenge for developing CAR T therapies for solid tumors is the lack of targets that distinguish tumor from normal cells, resulting in on-target, off-tumor toxicity. Tmod logic-gated CAR T therapy addresses this challenge by incorporating 2 CARs on the same T cell: an activator targeting a marker on both tumor and normal cells, and a blocker targeting HLA-A*02 that inhibits CAR T activity against normal cells while allowing activation against tumor cells (with HLA-A*02 LOH), improving tumor selectivity and decreasing toxicity. Early safety results from 3 ongoing phase 1/2 clinical trials of logic-gated, Tmod CAR T therapy (EVEREST-1, EVEREST-2, and DENALI-1) have demonstrated manageable safety and tolerability in patients with advanced solid tumors (Grierson et al, SITC , 2024; Ward et al, SITC 2025; Specht et al, SABCS , 2025). Early efficacy results include the first ever reported complete response in a patient with non-small cell lung cancer following treatment with a CAR T-cell therapy (A2B694). A2B543 is an autologous Tmod CAR T therapy that contains the same Tmod construct as A2B694 with an added membrane-tethered IL-12 (memIL12) booster. Specifically, A2B543 is comprised of autologous Tmod cells transduced with 2 lentiviral vectors: one expressing both the HLA-A*02-targeted blocker and the mesothelin-targeted CAR activator; and a second expressing the memIL12 booster. Interleukin 12 (IL-12) is a potent, pro-inflammatory cytokine that plays a crucial role in inducing antitumor immune responses; however, systemic IL-12 can be prohibitively toxic (Jia et al, Front Immunol , 2022). In A2B543, expression of the memIL12 cassette is under the control of an NFAT promoter and is induced during antigen engagement or T cell activation. This inducible memIL12 is designed to reduce the toxicity associated with systemic IL-12 while enhancing the long-term potency and persistence of Tmod (Zhang et al, J Immunother Cancer , 2025). Methods: EVEREST-2 (NCT06051695) is a phase 1/2, open-label, nonrandomized study evaluating the safety and efficacy of A2B543 in adults with recurrent/metastatic mesothelin-expressing cancers with tumor-associated HLA-A*02 LOH, including mesothelioma, colorectal, non-small cell lung, pancreatic, or ovarian cancer. Patients are enrolled through BASECAMP-1 (NCT04981119), a master prescreening study that identifies patients with HLA LOH via next-generation sequencing and cryopreserves leukapheresis product. Upon progression, A2B543 is manufactured and then administered after lymphodepletion. The phase 1 primary objective is to evaluate the safety and tolerability of A2B543 and identify a recommended phase 2 dose (RP2D). The phase 2 primary objective is to assess overall response rate. Clinical trial information: NCT06051695 .

e23510 Background: There is minimal data comparing the prognostic models (PM) developed to predict recurrence of Gastrointestinal stromal tumors (GIST). Current PM include tumor size, location, and mitotic index (MI) but lack genotypic data. This analysis compares the performance of the National Institute of Health, Armed Forces Institute of Pathology, and Memorial Sloan Kettering Cancer Center models for predicting tumor recurrence with and without adjustment for c-kit Exon 11 mutation status (MS). Methods: This is an IRB-approved single-institution retrospective analysis. Adults with GIST mentioned in their medical records from 2014 – 2025 at the authors’ institution were identified. 330 patients with documented biopsy-proven GIST were included. Data was collected by manual review. PM were evaluated using multivariate analysis, adjusting for surgical resection, systemic therapy, and c-Kit exon 11 MS. Predictive performance was measured by area under the curve (AUC) and receiver operating characteristics (ROC) analysis. Results: Mean age at diagnosis was 64.6 years (SD =13.1 years). 46.7 % of patients were male. Primary GIST was most common in the stomach (63.9%) and small bowel (23.6%). Primary tumors were an average of 6.5 cm (SD 5.6 cm) with a MI of 6.6/50 HFU (SD = 13.4 50/HFU). Patients received resection (80.9%) and first-line systemic therapy with imatinib (43.3%). Recurrence occurred in 17.9% of patients. 19.4% of patients completed genetic testing, of which 51.6% were c-Kit exon 11 mutation positive. The predictive performance of all PM was not statistically different with (p value = 0.16) or without (p value = 0.18) adjustment for c-Kit exon 11 MS (Table 1). However, adjusting for c-Kit exon 11 MS improved AUC for all PM. Conclusions: Adjusting PM for c-KIT exon 11 status improved the predictive performance of all PM, although the results were not significant. This study found no significant difference in the performance of PM that predict GIST recurrence, which aligns with the one other study on this topic. Lack of significance may be due to a small sample size, which also limited the multivariate analysis. Including genotypes in PM that predict GIST recurrence should be further explored with larger multi-center datasets that can adjust for multiple mutations. Multivariate analysis comparing prognostic models for gastrointestinal stromal tumors at predicting recurrence with and without adjustment for c-KIT exon 11 genotypes using receiver operating characteristic. Without c-Kit exon 11 AUC (95% Confidence Interval) P value NIH 0.86 (0.81,0.90) 0.18 AFIP 0.87 (0.82,0.91) MSKCC 0.89 (0.84,0.94) With c-Kit exon 11 genotype NIH 0.80 (0.67,0.93) 0.16 AFIP 0.84 (0.73,0.95) MSKCC 0.90 (0.80,0.99) NIH: National Institute of Health, AFIP: Armed Forces Institute of Pathology, MSKCC: Memorial Sloan Kettering Cancer Centre. AUC: Area under the curve.

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.

e16377 Background: 1L systemic treatment of mPDAC can lead to severe adverse events (AEs). To contextualize the safety profile of irinotecan-based regimens, real-world data were used to characterize AEs and their management in patients receiving 1L mPDAC treatment with FOLFIRINOX (FFX) or gemcitabine+Nab-paclitaxel (Gem+NabP). Methods: De-identified data from Mayo Clinic electronic health records (all sites; records collected 2010–2023) were used. Natural language processing was leveraged to confirm staging and metastatic classification and to extract treatment data. Adults with mPDAC with stage IV and/or TNM staging of M1 who received ≥ 1 dose of FFX or Gem+NabP were included. Primary endpoint: proportion of patients with AEs of interest (diarrhea, nausea, vomiting, neuropathy, and neutropenia) following initiation of 1L treatment. Secondary endpoints: proportion of patients who received treatment for each AE of interest, median time to resolution and treatment of each AE of interest, and proportion of patients who switched mPDAC treatment or had dose reductions due to AEs. Results: In total, 405 patients (FFX, 197; Gem+NabP, 208) were identified. The proportions of patients who experienced and were treated for any-grade AEs of interest are reported in the Table. Of the AEs of interest, neutropenia resolved most quickly (median time from onset to resolution, FFX: 9.5 days; Gem+NabP: 12.5 days); neuropathy took the longest time to resolve (FFX: 44.0 days; Gem+NabP: 74.0 days). Median time to AE treatment was shortest for nausea and vomiting (both 0.0 days for FFX and for Gem+NabP). Time to treatment was longest for neuropathy (FFX: 158.5 days; Gem+NabP: 70.0 days). Only 5.1% of patients on FFX and 13.4% on Gem+NabP received treatment for neuropathy. Of patients in the FFX group who switched/reduced treatment (n=140), 58.6% received a dose reduction and 7.1% switched to Gem+NabP due to AEs. Conclusions: At the Mayo Clinic sites, incidence of any-grade AEs associated with 1L mPDAC treatment were similar or higher than rates of any-grade or ≥ 2/3–4 grade AEs reported in the literature. Nausea, vomiting and diarrhea were the most commonly treated AEs for both irinotecan-based (FFX) and non-irinotecan-based (Gem+NabP) 1L regimens; neutropenia and neuropathy were less commonly treated. FFX dose reductions were commonly attempted before switching regimens. Proportion experiencing any-grade AE (AE incidence in the literature) Proportion experiencing AE treated for an AE FFX Gem+NabP FFX Gem+NabP Diarrhea 74.6% (50–80%, any grade) 43.8% (< 5%, any grade) 92.5% 56.0% Nausea 81.7% (45%, any grade) 72.1% (20%, grade ≥ 2) 98.8% 96.7% Vomiting 54.8% (10%, any grade) 42.8% (20%, grade ≥ 2) 98.1% 98.9% Neutropenia 58.9% (45%, grade 3–4) 48.1% (12–21%, grade 3–4) 62.1% 46.0% Neuropathy 59.9% (25%, grade 3–4) 32.2% (30%, grade 3–4) 5.1% 13.4%

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.

9573 Background: Clinical Stage III (cSIII) melanoma patients are at high risk of recurrence following therapeutic lymph node dissection (TLND) and adjuvant therapy. Neoadjuvant immunotherapy based regimens have shown promising results in this setting, with pathological response being the best predictor of recurrence free survival (RFS) and distant metastases free survival (DMFS). T-cell Receptor (TCR) abundance and clonality are being explored as biomarkers. Methods: In the phase II NeoACTIVATE (NCT03554083) trial, patients were treated based on BRAF status with 12 weeks of neoadjuvant atezolizumab, vemurafenib and cobimetinib (Arm A, BRAF-mutated) or atezolizumab and cobimetinib (Arm B, BRAF wildtype), followed by TLND and 6 months adjuvant atezolizumab. TCR sequencing (n=23) was performed on the pretreatment involved lymph node (iLN) and on the same node, along with an adjacent uninvolved node (uiLN) after TLND. The fraction productive of T cells (fpTC) was defined as the percentage of in-frame TCR sequences (capable of encoding a functional expressed receptor protein) of all TCR sequences identified. Simpson Clonality Index (SCI) was used to measure relative abundance of specific clones, with a higher score indicating a more monoclonal repertoire. Comparisons were made using the Wilcoxon Rank Sum test. Results: 30 patients were enrolled, 15 in each arm. 2 patients were not operated on, and one did not receive adjuvant treatment, leaving 27 patients for outcome analysis. 3-year RFS was 55.6% (95% CI 9.5%-77.8%), median of 62.2 months (95% CI 19-NR); DMFS was 64.3% (95% CI 48%-86.3%), median 62.2 months (95% CI 33.9-NR). The fpTC was higher in the pretreatment iLN for those without an RFS event (p=0.04) with a trend in the uiLN as well (p=0.06). Patients without a DMFS event had a higher fpTC in the uiLN (p=0.03) but not in the iLN. The SCI was significantly higher only in the post treatment iLN for patients without an RFS event (p=0.03) and was not significantly different when compared based on DMFS status. When performing pairwise comparisons of nodes based on recurrence status, we found that patients who did not suffer an RFS event had a significantly higher SCI in the post treatment iLN compared to the uiLN (p=0.02). Conclusions: Neoadjuvant immunotherapy and targeted therapy for cSIII melanoma can lead to durable RFS. Higher pretreatment fpTC as well as higher post-treatment iLN TCR clonality were both associated with improved RFS. These data indicate that TCR repertoire characteristics within iLN and uiLN may reflect differential immune responses to neoadjuvant therapy and could inform future studies evaluating biomarkers to stratify risk of recurrence and allow personalization of therapy. Clinical trial information: NCT03554083 . fpTC Simpson Clonality Index RFS event DMFS event RFS event DMFS event Pretreatment iLN 0.04 0.12 0.43 0.11 Posttreatment iLN 0.09 0.09 0.03 0.12 uiLN 0.06 0.03 0.79 0.48 Δ iLN (post-pre) 0.79 0.37 0.07 0.41 Δ posttreatment iLN – uiLN 0.21 0.21 0.02 0.08