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9558 Background: Ipilimumab 3 mg/kg plus nivolumab 1 mg/kg (Ipi3+Nivo1) is the standard immunotherapy regimen for metastatic melanoma with brain metastases (MBM) but is associated with significant immune-related toxicity, particularly neurologic toxicity. Ipilimumab 1 mg/kg plus nivolumab 3 mg/kg (Ipi1+Nivo3) has demonstrated improved tolerability in extracranial melanoma, though comparative data in MBM are limited. We compared efficacy and toxicity of these dosing strategies in a multisite real-world cohort. Methods: We retrospectively identified patients with MBM treated with ipilimumab plus nivolumab across three Mayo Clinic sites between 2016 and 2024. Patients were classified by induction dosing as Ipi1+Nivo3 or Ipi3+Nivo1. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method and compared using log-rank tests. Best overall response (BOR) and toxicity outcomes were summarized descriptively. Results: Among 147 patients (Ipi1+Nivo3 n=32; Ipi3+Nivo1 n=115), 144 were evaluable for survival. Median age was higher in the Ipi1+Nivo3 group (69.5 vs 66.0 years); males predominated in both groups (71.9% vs 61.7%), and the cohort was predominantly White (>96%). Most patients had ECOG 0–1 in both groups (84.4% in Ipi1+ Nivo3 and 90.4% in Ipi3+Nivo1). BRAF mutation status was balanced between regimens, with approximately half of patients harboring BRAF-mutant disease (51.6% vs 53.2%). Median OS was 18.5 months (95% CI, 5.7–54.7) with Ipi1+Nivo3 versus 10.6 months (95% CI, 6.5–19.1) with Ipi3+Nivo1 (log-rank p=0.25). Two-year OS was 45.9% and 35.0%, and five-year OS was 24.5% and 19.2%, respectively. Median PFS was 7.3 months (95% CI, 1.8–10.9) versus 2.8 months (95% CI, 2.1–4.4) (log-rank p=0.16). BOR was available for 138 patients; objective response rates were 35.5% and 31.8%, respectively. 3–5 adverse events occurred in 24.1% of Ipi1+Nivo3 versus 30.5% of Ipi3+Nivo1 patients. Hospitalizations were less frequent (16.7% vs 36.1%), and neurologic adverse events occurred only with Ipi3+Nivo1 (11.9% vs 0%). Conclusions: In this multisite real-world MBM cohort, Ipi1+Nivo3 demonstrated comparable efficacy, numerically longer survival, and a more favorable toxicity profile compared with standard Ipi3+Nivo1. Notably, no neurologic toxicity was observed with the Ipi1+Nivo3 regimen. These findings support further prospective evaluation of lower dose ipilimumab strategies. Response and survival outcomes. Outcome Ipi1 + Nivo3 Ipi3 + Nivo1 Complete response (CR) 2 / 31 (6.5%) 8 / 107 (7.5%) Partial response (PR) 9 / 31 (29.0%) 26 / 107 (24.3%) Objective response rate (ORR = CR+PR) 11 / 31 (35.5%) 34 / 107 (31.8%) Disease control rate (DCR = CR+PR+SD) 18 / 31 (58.1%) 51 / 107 (47.7%) Median PFS, months (95% CI) 7.3 (1.8–10.9) 2.8 (2.1–4.4) 2-year PFS 27.6% 22.3% Median OS, months (95% CI) 18.5 (5.7–54.7) 10.6 (6.5–19.1) 2-year OS 45.9% 35.0% 5-year OS 24.5% 19.2%

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.

9510 Background: Although acute toxicities associated with adoptive cellular therapy using lifileucel are well described and largely occur within the first 2 weeks of treatment, adverse events beyond this early window remain incompletely characterized. We sought to characterize treatment-related adverse events (AEs) with emphasis on those starting or persisting ≥2 weeks after lifileucel infusion. Methods: We conducted a retrospective multicenter study across three centers (Moffitt Cancer Center, Massachusetts General Hospital, and Mayo Clinic). Patients with advanced melanoma treated with lifileucel were included. The primary endpoint was incidence and characterization of AEs occurring or persisting ≥2 weeks after standard of care lifileucel infusion. Results: Among 79 patients (median follow-up 11 months [95% CI, 9.6–15]), median age was 63 years (range 30–79), 59% were male (n = 47), 41% were female (n = 32), and ECOG PS was 0–1 in 98%. Patients received a median of 5 IL-2 doses (range 0–6). Of 79 patients, 78 experienced treatment-related adverse events that either persisted or occurred >2 weeks after cell infusion. A total of 308 delayed treatment-related adverse events were identified; 96 were new events (31%) and 212 (69%) were continued toxicities that started < 2 weeks after cell infusion. Lymphopenia was the most common delayed or persistent toxicity, occurring in a majority of patients (n = 68/79, 86%). Treatment-associated anemia (n = 59/79, 75%), fatigue (n = 56/79, 71%) and thrombocytopenia (n = 24/79, 30%) were also common. Viral infections occurred in 9.0% (n = 7), including CMV/EBV viremia (n = 1) and respiratory or gastrointestinal viral infections (metapneumovirus, parainfluenza, SARS-CoV-2, and norovirus). Hemophagocytic lymphohistiocytosis (HLH) occurred in 2 patients (n = 2/79, 3%) and was fatal in both cases. No other toxicity related deaths were noted. Autoimmune toxicities directly attributable to TIL included vitiligo in 9% (n = 7; median onset 41 days), uveitis in 5% (n = 4; median onset 26 days), and sensorineural hearing loss in 1% (n = 1; onset 28 days). All patients underwent TIL infusion in the inpatient setting; a total of 14 of 79 patients (18%) were re-admitted after discharge due to treatment-related toxicity (median time from infusion 19 days). Conclusions: In this multicenter real-world cohort, toxicities persisting beyond two weeks were largely driven by lymphodepleting chemotherapy–associated immunosuppression and cytopenias. These findings highlight the importance of structured post-discharge monitoring and support ongoing efforts to de-intensify lymphodepleting chemotherapy to improve safety while maintaining clinical benefit.

9525 Background: Melanocortin-1 receptor (MC1R) is a novel target for radiopharmaceutical therapy and is highly expressed on melanoma tumor cells. VMT01 is an MC1R-targeted peptide. 203 Pb is used for patient selection via SPECT imaging. Peptide radiolabeling with 212 Pb delivers alpha-particle therapy. Here, we present data on the treatment of adult patients with MC1R-positive metastatic melanoma receiving [ 212 Pb]VMT01 either as a monotherapy or in combination with the programmed death-1 (PD-1) checkpoint inhibitor, nivolumab. Methods: This is an ongoing phase I/IIa, first-in-human, prospective, multicenter, open-label, radioactive dose-finding and dose-expansion trial. The objectives are to investigate safety, pharmacokinetics, dosimetry, and efficacy. Participants receive up to 3 treatment cycles with either [ 212 Pb]VMT01 3 mCi, 5 mCi, or 1.5 mCi monotherapy, or combination therapy with [ 212 Pb]VMT01 (1.5 mCi) + nivolumab (480 mg, Q4W) or [ 212 Pb]VMT01 (3 mCi) + nivolumab. Participants are evaluated for any DLTs for the first 6 weeks after cycle 1. Efficacy is assessed by RECIST v1.1 criteria by the investigator. Results: As of 24 December 2025, 26 participants (53.8% male; median age: 68 years [range: 27-81]) with MC1R-positive metastatic melanoma were enrolled. The median prior systemic therapies was 4. All 26 enrolled participants received ≥1 dose of [²¹²Pb]VMT01. No DLTs were reported. All SAEs (including one grade 5 SAE) were attributed to disease progression. Most TEAEs were grade 1 (19.2%) and grade 2 (34.6%). Grade 3 TEAEs occurred in 8 participants (30.8%), 5 on monotherapy and 3 on combination therapy (3 mCi + nivolumab). Of the 22 evaluable participants, 1 PR, 9 SD, and 12 PD were reported. Four participants had progression-free survival of ≥6 months. Conclusions: [ 212 Pb]VMT01 as a monotherapy and in combination with nivolumab was generally safe and well-tolerated in 26 enrolled participants, with antitumor activity observed at the 3 mCi dose level. These data may be supplemented with a more complete follow-up at the time of the meeting. Clinical trial information: NCT05655312 .

9535 Background: MUM carries a poor prognosis with few effective treatments, especially for HLA-A*02:01-negative pts. While a subset of MUM pts responds to immune checkpoint inhibitors, the comparative efficacy of IPI+PD1 versus PD1 monotherapy is unclear. This study compares objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety between these regimens in MUM. Methods: MUM pts treated with PD1 or IPI+PD1 at 15 major melanoma centres (from Australia, Europe, United States and Israel) were included. Demographics, patient and disease characteristics, and clinical outcomes were examined. Univariate and multivariate (MVA) analyses were performed to identify clinical predictors of response and survival. Results: Of 412 MUM pts treated, 150 (36%) had PD1 and 262 (64%) received PD1+IPI. Compared to the PD1 group, PD1+IPI-treated pts were younger (64 vs. 70 years; p<0.001), had higher rate of elevated LDH (44% vs. 31%; p=0.037), and more frequently had prior treatment with tebentafusp (6.5% vs. 1.3%; p=0.031). Median follow-up from commencement of PD1+/-IPI was 4.9 years (95% CI 4.7 – 6.1). ORR was higher in IPI+PD1 group (18%) vs. PD1 (9%) (p=0.008), particularly in males (p=0.009), patients with liver metastases (p=0.018) and with lung metastases (p=0.011), with elevated LDH (p=0.047) and with no prior treatment with tebentafusp (p=0.007). PFS and OS at 1 and 2 years were numerically higher with IPI+PD1 (1- and 2-year PFS: 23% and 15%; 1- and 2-year OS: 63% and 39%) vs. PD1 (1- and 2-year PFS: 17% and 11%; 1- and 2-year OS: 54% and 36%), but these differences were not statistically significant (p>0.05). On MVA, adjusting for predefined variables (age, gender, ECOG PS, LDH, presence/absence of liver/lung metastases, prior treatment with tebentafusp), IPI+PD1 was associated with higher ORR (OR 2.71, 1.30 – 6.05; p=0.01) but not with PFS or OS compared to PD1. Presence of liver metastases (ORR [OR 0.28; 95% CI 0.13 - 0.64], PFS [HR 1.61; 95% CI 1.11 - 2.34], OS [HR 2.02; 95% CI 1.32 - 3.10]), ECOG PS≥2 (PFS [HR 1.82; 95% CI 1.07 - 3.10], OS [HR 2.24; 95% CI 1.25-4.01]), elevated LDH (PFS [HR 1.66; 95% CI 1.30 - 2.11], OS [HR 2.39; 95% CI 1.84-3.10]) and prior tebentafusp treatment (OS [HR 2.36; 95% CI 1.21-4.59]) were also independent predictors of response and/or survival. A higher percentage of pts experienced grade ≥3 immune-related adverse events (irAEs) in the IPI+PD1 group compared to the PD1 group (34% vs 13%, p<0.0001). Most pts ceased treatment due to progression (234, 57%), and more pts stopped due to toxicity in the IPI+PD1 vs. PD1 group (25% vs. 9%, p<0.0001). Conclusions: In pts with MUM, IPI+PD1 demonstrated a higher ORR but did not improve survival compared with PD1 alone. IPI+PD1 was more toxic, leading to early treatment discontinuation in one-quarter of pts. These findings may help guide treatment selection in MUM.

9551 Background: Lymphodepleting (LD) chemotherapy is required prior to tumor-infiltrating lymphocyte (TIL) therapy, yet the depth, kinetics, and completeness of peripheral T-cell recovery in practice remain poorly defined. Using a pooled, multi-institution cohort, we characterized longitudinal CD4 and CD8 T-cell reconstitution and the prevalence of CD4 lymphopenia following TIL therapy. Methods: We conducted a retrospective multicenter study across Mayo Clinic, Moffitt Cancer Center, and Massachusetts General Hospital of patients with metastatic melanoma treated with TIL (N = 41, median follow-up 7.6 months). Absolute CD4 and CD8 T-cell counts and CD4:CD8 ratios were assessed at baseline (pre-LD), week 4, month 3, and month 6 post-TIL. Clinically significant CD4 lymphopenia was defined as CD4 < 200 cells/µL. All patients received Pneumocystis jirovecii and antiviral prophylaxis, with antibacterial and antifungal prophylaxis administered per institutional protocols. Post-TIL infections were recorded. Paired changes from baseline were evaluated using Wilcoxon signed-rank testing. Results: Median age was 65 years (range 35-79), and 68% were male. At baseline, 16 patients (39%) had CD4 counts below the institutional lower limit of normal prior to LD. Eighteen patients (44%) received bridging therapy prior to TIL and had lower baseline CD4 and CD8 counts compared with those who did not ( p < 0.05 for both); however, post-TIL CD4 and CD8 recovery trajectories did not differ between groups. CD4 counts declined sharply following LD and demonstrated incomplete and heterogeneous recovery. Median CD4 decreased from 490 cells/µL at baseline to 250 at week 4, 290 at month 3, and 220 at month 6, remaining significantly below baseline at all post-TIL timepoints ( p < 0.05). Clinically significant CD4 lymphopenia was observed in 45% (10/22) of evaluable patients at month 3 and in 50% (44%, 7/16) at month 6. In contrast, CD8 counts increased early after TIL (median 240 to 590 cells/µL at week 4; p = 0.004) and remained higher than baseline at month 6. The CD4:CD8 ratio inverted from a median of 2.02 at baseline to 0.46 at week 4 and remained below 1.0 through month 6, reflecting sustained CD4 suppression despite CD8 recovery. Post-TIL infections occurred despite widespread prophylaxis, including bacterial (13%), viral (10%), and fungal (4.9%) infections. Conclusions: In a multi-institution cohort, LD chemotherapy preceding TIL is associated with profound and prolonged CD4 T-cell suppression, persistent CD4:CD8 inversion, and a high prevalence of CD4 < 200 cells/µL through 6 months. These findings identify delayed immune reconstitution as a common and clinically relevant consequence of TIL therapy and support prospective optimization of antimicrobial prophylaxis duration, vaccination timing, and immune monitoring strategies.

8045 Background: Surgical resection is the primary therapy for stage I-II NSCLC but not performed in a subset of patients due to comorbidities or self-election, who instead undergo radiation with or without systemic therapy (RT±ST). Little is known about the demographic, tumoral, therapeutic, and quality-of-life (QOL) characteristics of this non-surgical group. Understanding their differences from the surgical group is essential for developing precision treatment strategies and tailored survivorship guidelines. Methods: In a prospectively enrolled (1997-2016) and followed (through 2025) cohort of 20,951 primary lung cancer patients, 6,486 (31%) had stage I-II NSCLC, including 5,359 (83%) treated surgically (Surgical) and 1,113 (17%) otherwise (Non-surgical). Preexisting diseases were grouped into cancer, lung, and other comorbidities. QOL data were available for 40% of all patients. Descriptive analysis of demographics, tumor features, treatment patterns, and QOL metrics, as well as survival analysis (median years and overall survival [OS] rates) were conducted. QOL measures, on overall and 15 symptom and functional domains, were scored 0 (worst) to 10 (best), with 1-unit difference considered clinically and statistically meaningful. Results: At time of diagnosis, compared to the Surgical, the Non-surgical patients were older (median 73 v 68 years), more likely to have smoked cigarettes (91% v 83%), squamous cell and unspecified NSCLC (53% v 28%), stage IIB (19% v 12%), and preexisting lung comorbidities (71% v 58%). Non-surgical patients more frequently received RT±ST than the Surgical (70% v 21%) and had shorter median survival (2.5 v 7.8) years. Within the Non-surgical, 28% had no cancer treatment (No-Tx), 44% RT-only, 7% ST-only, and 19% both (RT+ST); their respective median diagnosis ages were 74, 76, 68, 70 years; median survival were 1.7, 2.7, 2.2, 3.2 years; 5-year OS (95%CI) at 25% (21-31), 25% (21-29), 26% (17-38), 30% (25-37); and 10-year OS at 9% (7-14), 7% (5-10), 10% (5-21), 9% (6-14), respectively. RT-only group had highest rates of comorbidities (37-84%) and the No-Tx the lowest (31-66%). Although the overall QOL scored the same for all groups, RT-only patients reported the worst scores on multiple symptoms burden, and the No-Tx reported the least pain and lung cancer symptoms but the worst on mental well-being and social activities. Conclusions: Non-surgically managed stage I-II NSCLC cases present clinically distinct patients with the shortest median survival in No-Tx group and highest 5-year survival in RT+ST. RT-only patients were oldest, had the most comorbidities, and reported the worst symptom burdens. These differences highlight the need for more in-depth analyses and studies (considering age, histology, comorbidity, QOL, etc.) to support tailored therapeutic strategies and survivorship care for patients who decline or are not suitable for surgery.

7028 Background: Axi-cel, autologous anti-CD19 CAR T-cell therapy, showed long-term survival and curative potential in R/R LBCL (ZUMA-1; Neelapu et al. Blood . 2023). Few studies have examined long-term outcomes beyond clinical trials. Here we report long-term real-world outcomes of axi-cel in R/R LBCL using large-sample CIBMTR data. Methods: A total of 1500 adults from 79 US centers receiving commercial axi-cel after ≥2 LOT for LBCL from Oct 2017-Aug 2020 were enrolled in a post-marketing requirement study. A protocol was developed prior to the study’s implementation, reviewed by Kite and CIBMTR. This is a secondary analysis of said study. Key outcomes were progression-free survival (PFS), overall survival (OS), time to next therapy (TTNT), disease-specific mortality (competing risks were non-relapse deaths), subsequent malignancies, and non-relapse mortality (NRM). Outcomes were analyzed descriptively. Cases with missing data were excluded separately for each endpoint. Results: As of Aug 2025, 1446 patients (pts) were included in the analysis. Median age at infusion was 62.2 y (range, 19.6-90.8: 38% of pts ≥65 y); 65% were male. Five percent of pts had ECOG PS ≥2 and 16% had high-grade lymphoma. Pts had a median of 3 (range, 2-4) prior LOT, 28% had prior autologous hematopoietic cell transplantation, and 50% received bridging therapy. At 59.7 mo median follow-up, median PFS (95% CI) was 7.9 mo (6.3-10.9) and 5-y PFS was 30% (27-32). The median OS was 25.7 mo (21.6-30.2); 5-y OS was 38% (35-41). The 5-y cumulative incidence of disease-specific mortality was 51%. Among pts who were progression-free at 2, 3, 4, or 5 y post-infusion, the OS at 6 y (95% CI) was 73% (68-78), 81% (76-86), 90% (84-94), and 94% (89-97), respectively. The median duration of response (DOR) was 25.3 mo (95% CI, 20.7-32.8) and 5-y DOR was 38% (35-41). The median TTNT was 12.2 mo and 30% did not need additional LOT at 5 y. Of pts who received subsequent salvage therapy, 12 (2%) received cell therapy, 39 (7%) received hematopoietic cell transplant, and 475 (90%) received other therapy. The 1, 2, 3, 4, and 5-y cumulative incidence of relapse (95% CI) was 49% (46-51), 52% (50-55), 54% (52-57), 55% (53-58), and 56% (53-59), respectively. No new safety signals were observed. The primary causes of death (n=864; 60%) were primary disease (540; 63%), infection (111; 13%), and organ failure (57; 7%). The 5-y cumulative incidence of NRM was 16% (95% CI, 14-18). At 5 y, 11% (95% CI, 10-13) had subsequent malignancies, mostly therapy-related myeloid neoplasms (6%) and non-melanoma skin cancer (3%); none were directly attributed to axi-cel. Conclusions: This real-world study showed sustained survival at 5 y among pts with R/R LBCL treated with axi-cel after ≥2 LOT, consistent with ZUMA-1. Infection and organ failure were common causes of NRM. These results continue to support the use of axi-cel with curative intent in R/R LBCL.

566 Background: Endocrine therapy (ET) resistance (ETR) remains a primary challenge in ER+ breast cancer. Analyzing pretreatment tumor transcriptomes across trials with early response endpoints can reveal shared and specific ETR signatures. This study utilizes baseline RNA data from the Phase III ALTERNATE trial (Alliance A011106, NCT01953588; Anastrozole [A], Fulvestrant [F], or AF) and the ACOSOG Z1031B trial (NCT00824941) to identify predictors of early Ki67 response in postmenopausal ER+/HER2– patients. Methods: ETR was defined as week-4 on-treatment Ki67 >10%. Baseline gene expression from ALTERNATE was analyzed to identify differentially expressed (DE) genes (Wilcoxon test, P<0.05) and Hallmark pathways associated with ETR, both across and within individual treatment arms. Feature selection was performed using mixOmics. A Pan-Endocrine Therapy Signature (PETS) was developed by uniting DE genes identified across all three ALTERNATE arms and Z1031B. All statistical analyses were conducted in R (P<0.05). Results: Overall ETR rate in the ALTERNATE RNA-seq cohort (n=733) was 26%. ETR was associated with high Risk of Recurrence (ROR), Oncotype RS, and Mammaprint scores (calculated from RNA-seq data in research setting). In luminal tumors (n=649), ETR was linked to chr 3q13.33, 8q24.13, and 20q13.12 cytoband upregulation and 17q21, 18q23, 3p21.1, and 10q24.32 cytoband downregulation. ETR tumors showed T-cell, E2F target, and interferon-γ enrichment; sensitive tumors favored early estrogen response and muscle differentiation. At individual gene level, high MYBL2 , PIF1 , TROAP and with low HJURP predicted ETR across all samples (AUC>0.70). A deep learning model using all protein-coding genes achieved AUC 0.82 (training) and 0.79 (test) in predicting ETR. Cross-trial integration identified ETR-associated PETS, enriched for genomic instability. PETS performed comparably to established signatures and strongly correlated with MYBL2 signature (r=0.93). Top ETR predictors were MYBL2 , AURKB , and EME1 for Arm A and IL4I1 , TNFAIP6 , and ANLN for Arm AF. AF-resistant tumors were enriched for systemic lupus and RIG-I–like receptor signaling; sensitive tumors favored PI3K–AKT, EGFR TKI resistance, AMPK, and insulin signaling. Conclusions: Baseline transcriptomics identify shared and therapy-specific ETR markers. The 15-gene PETS defines a convergent resistance signature, performing similar to established signatures in predicting ETR and correlating with MYBL2. Enrichment of cell-cycle and immune pathways in resistant tumors may suggest patient stratification approach for alternative or combinatorial strategies to overcome early ETR in ER+ breast cancer. Acknowledgement: https://acknowledgments.alliancefound.org. Support: U10CA180821, U10CA180882, U24CA1. Clinical trial information: NCT01953588 .

6028 Background: RET alterations are targetable oncogenic drivers in multiple solid tumors and TCs. Pralsetinib is an oral, potent, selective RET inhibitor granted accelerated approval by the FDA for adults and children aged ≥12 y with advanced/metastatic RET fusion-positive TC who require systemic therapy and are radioactive iodine-refractory, based on ARROW trial (NCT03037385) results. Accelerated approval for medullary TC (MTC) was withdrawn by the sponsor in 2023 due to recruitment challenges in the confirmatory trial. We report final efficacy and safety in ARROW patients with RET -altered TC and MTC. Methods: Phase 2 ARROW patients were enrolled from 84 sites in 13 countries. Primary end points were overall response rate (ORR; per RECIST v1.1) and safety. Progression-free survival (PFS), overall survival (OS), and safety were assessed in patients with advanced/metastatic TC and MTC who received ≥1 dose of pralsetinib (Efficacy Population [EP]). ORR and duration of response (DOR) were assessed in the Measurable Disease Population (MDP). Results: At the May 20, 2024, data lock, 28 patients with RET -altered TC and prior systemic treatment and 145 patients with RET -altered MTC received pralsetinib 400 mg/d (median treatment duration: 24.7 mo [TC]; and 35.4 mo [MTC]). In the TC and MTC groups, median age was 58 and 57 y; 39% and 64% were male; median (range) prior lines of treatment was 2 (1, 9) and 1 (1, 6). 53.8% of MTC patients had prior systemic treatment. In TC and MTC patients, ORRs (95% CI) were 91.7% (73.0, 99.0) and 68.2% (59.5, 76.0) (Table). Treatment-related adverse events (TRAEs) occurred in 27 (96%) TC and 142 (98%) MTC patients; 68% and 67% had grade ≥3. TRAEs in ≥35% of TC and MTC patients were increased AST (50% and 38%) and ALT (43% and 30%), decreased white blood cell count (39% and 30%), and anemia (39% each). Death due to a TRAE occurred in 1 TC patient (liver injury) and 1 MTC patient (pneumonia). Safety was consistent with prior reports. Conclusions: The final analysis of ARROW confirms that pralsetinib yields clinically meaningful and durable responses in patients with RET -altered TC and MTC with a manageable safety profile consistent with prior reports. Clinical trial information: NCT03037385 . Efficacy summary. All MTC MTCPrior Cabozantinib/Vandetanib MTC Treatment-Naïve TCPrior Systemic Treatment MDP, n 132 60 62 24 ORR, % (95% CI) 68.2(59.5, 76.0) 56.7(43.2, 69.4) 79.0(66.8, 88.3) 91.7(73.0, 99.0) Complete response, n (%) 12 (9.1) 2 (3.3) 7 (11.3) 4 (16.7) Partial response, n (%) 78 (59.1) 32 (53.3) 42 (67.7) 18 (75.0) DOR, median, mo (95% CI) 39.6(29.4, NE) 21.7(15.1, 34.8) NR(36.8, NE) NR(16.0, NE) DOR follow-up, median, mo (95% CI) 45.7(41.0, 48.4) 48.9(36.9, 58.7) 45.1(40.4, 47.8) 35.4(26.9, 40.0) EP, n 145 67 67 28 OS, median, mo (95% CI) NR(54.6, NE) 42.2(31.2, NE) NR(NE, NE) NR(25.4, NE) PFS, median, mo (95% CI) 37.2(27.5, 55.5) 24.9(19.9, 35.0) 55.3(36.8, NE) NR(14.7, NE) NE, not evaluable; NR, not reached.