Hamilton, Jakob Skyler

e21607 Background: The association between timing of palliative care referral and survival outcomes in patients with melanoma brain metastases (MBM) treated with immune checkpoint inhibitors remains poorly characterized. Methods: We conducted a retrospective cohort study of patients with MBM treated with combination ipilimumab and nivolumab at Mayo 3 sites from 2016 to 2024. Palliative care referral timing relative to MBM diagnosis was categorized as early (≤56 days), late ( > 56 days), or none. Patients without referral documentation were excluded from referral-based analyses. Overall survival (OS) was estimated using Kaplan–Meier methods and compared with log-rank tests. Multivariable Cox proportional hazards models were used to identify factors independently associated with OS, with stepwise selection (entry p < 0.25; stay p < 0.15). Results: Among 147 patients, 139 had referral information: 33 (23.7%) early, 56 (40.3%) late, and 50 (36.0%) no referral. Median OS differed significantly by referral timing (log-rank p < 0.0001): 2.8 months (early), 7.9 months (late), and 47.8 months (no referral). Among patients with ECOG 2–3, a higher proportion had early or late referral (each 42.9%) compared with no referral (14.3%), whereas patients with ECOG 0–1 were more evenly distributed across referral groups (early 21.6%, late 40.0%, none 38.4%). In multivariable analysis of 88 patients with complete covariate data, both early (HR 4.54; p = 0.0016) and late referral (HR 2.86; p = 0.011) were independently associated with worse OS compared with no referral. Progressive disease versus objective response (HR 4.45; p = 0.0002), hemorrhagic metastases (HR 2.79; p = 0.0015), male sex (HR 2.07; p = 0.044), and increasing age (HR 1.02 per year; p = 0.032) were also associated with inferior OS. Treatment with ipilimumab 1 mg/kg plus nivolumab 3 mg/kg showed a trend toward improved OS compared with ipilimumab 3 mg/kg plus nivolumab 1 mg/kg (HR 0.48; p = 0.055). Conclusions: Timing of palliative care referral was strongly associated with overall survival in patients with MBM treated with ipilimumab and nivolumab. Although patients with ECOG 2–3 were more frequently referred early or late, ECOG category overall did not clearly differentiate referral timing groups, suggesting referral may reflect unmeasured clinical factors beyond baseline performance status. Prospective studies incorporating more granular functional and symptom measures are needed to better define the role of palliative care integration in this population. Multivariable cox model for overall survival. Variable Comparison HR P value Referral timing Early vs None 4.54 0.0016 Late vs None 2.86 0.011 Best overall response PD vs ORR 4.45 0.0002 SD vs ORR 2.16 0.098 Hemorrhagic metastases Yes vs No 2.79 0.0015 Sex Male vs Female 2.07 0.044 Age Per year increase 1.02 0.032 Regimen Ipi1+Nivo3 vs Ipi3+Nivo1 0.48 0.055

e17027 Background: Guidelines recommend active surveillance for low-risk prostate cancer and definitive therapy for high-risk disease. We evaluated national patterns of risk-misaligned care and the survival consequences of undertreatment. Methods: National Cancer Database prostate cancer cases diagnosed from 2010–2022 were analyzed. Low-risk disease was defined as clinical T1–T2, Grade Group 1, and PSA < 10; overtreatment was definitive treatment vs active surveillance or no treatment. High-risk disease was defined as Grade Group ≥4, PSA ≥20, or clinical T3–T4; undertreatment was no definitive local therapy or incomplete definitive therapy. Multivariable logistic regression evaluated factors associated with misalignment. Overall survival (OS) among high-risk patients was assessed using multivariable Cox regression. Results: Among low-risk patients (N = 124,562), overtreatment occurred in 40% of cases. Overtreatment was more common among young men (adjusted odds ratio [aOR] 0.982; p < 0.001) and less common at academic centers (aOR 0.414; p = 0.015). Compared with White men, odds of overtreatment were lower among Black men (aOR 0.946; p = 0.002) and Asian men (aOR 0.827; p < 0.001), with additional variation by education and region (all p < 0.001). Among high-risk patients (N = 318,532), undertreatment affected 27.3% of patients and was more common among older men (aOR 1.061; p < 0.001). Compared with White men, undertreatment was higher among Black men (aOR 1.479; p < 0.001) and lower among Asian patients (aOR 0.863; p < 0.001) (overall race p < 0.001). Compared with private insurance, undertreatment was higher in Medicaid (aOR 2.038; p < 0.001) and uninsured patients (aOR 2.649; p < 0.001), and slightly lower with Medicare (aOR 0.931; p < 0.001) (overall insurance p < 0.001). Multiple comorbidities were associated with higher undertreatment (≥2 vs 0: aOR 1.252; p < 0.001). Facility type was not independently associated (p = 0.490), while region remained significant (overall p < 0.001). In the survival cohort (high risk) (N = 338,919), undertreatment was associated with substantially worse OS (HR 2.745, 95% CI 2.706–2.784; p < 0.001), adjusted for age (HR 1.056; p < 0.001), race (p = 0.001), insurance (p < 0.001), comorbidity (p < 0.001), income (overall p < 0.001), education (overall p < 0.001), and facility region (overall p < 0.001). Conclusions: Low-risk overtreatment remains common nationwide and varies across patient and health-system factors. In high-risk disease, undertreatment affects over one-quarter of patients and disproportionately impacts Black men and those with Medicaid or no insurance. Undertreatment confers a nearly threefold mortality hazard (adjusted HR 2.75; p < 0.001), highlighting a major national quality gap and the urgent need for system-level interventions to ensure equitable, guideline-concordant delivery of definitive therapy.

e16435 Background: Peritoneal metastasis in pancreatic ductal adenocarcinoma (PDAC) is historically associated with a dismal prognosis and limited response to systemic therapy alone. The role of locoregional therapy remains controversial. This study evaluated the survival impact and safety of HIPEC, with or without cytoreductive surgery (CRS), compared to standard-of-care systemic therapy in patients with peritoneal metastatic PDAC. Methods: We conducted a comparative analysis of 130 patients with peritoneal metastatic PDAC, comprising a study cohort treated with HIPEC (n = 33) and a control group treated with systemic chemotherapy alone (Non-HIPEC, n = 97). HIPEC patients received induction chemotherapy (predominantly FOLFIRINOX) followed by HIPEC ± CRS. Co-primary endpoints included 12 months survival, and 6 months progression free survival (PFS). Secondary endpoints evaluated Overall Survival (OS ), safety of CRS, and impact of germline mutation status on survival. Study was approved under IRB protocol 25-008762. Results: The 12-month OS rate was significantly higher in the HIPEC group compared to the chemotherapy-only control group (100% vs. 52.6%, P < 0.001). The 6-month PFS rate in the HIPEC group was 63.0% vs. 47.94 in-only control group (P < 0.001). For secondary endpoints, the HIPEC group demonstrated a significantly longer median OS of 33.0 months vs. 17.0 months for controls (P < 0.001). Within the HIPEC cohort, the addition of CRS (n = 25) significantly improved outcomes compared to HIPEC alone (n = 8): median OS improved from 21.5 to 36.0 months (P = 0.03). Germline testing was performed in 61% of HIPEC patients and 48% of controls, identifying pathogenic mutations in 25% and 17%, respectively. Identified pathogenic mutations in both groups included ATM (n = 4), MUTYH (n = 2), BRCA2 (n = 1), CHEK2 (n = 1), PALB2 (n = 1), and KIT (n = 1). In the control group, specific mutations drove divergent outcomes; ATM median OS: 23.5 months vs. MUTYH : 8.0 months (P = 0.04). Conversely, in the HIPEC+CRS cohort, survival was excellent regardless of genetic profile: mutation carriers achieved a median OS of 33.0 months compared to 31.0 months in wild-type patients (P = 0.85). Despite a 34.8% postoperative complication rate in the HIPEC group, there was no perioperative mortality. Conclusions: In selected patients with peritoneal metastatic PDAC, HIPEC provides a substantial survival advantage over systemic therapy alone, achieving a 100% 12-month survival rate and more than doubling the median overall survival. Importantly, germline mutation status did not preclude survival benefit, with mutation carriers deriving equal efficacy from the multimodal approach. These findings support HIPEC+CRS as a highly effective strategy that may overcome adverse biologic drivers.

e15501 Background: CP is the backbone of first-line therapy for recurrent or metastatic ASCC. In practice, Q3-week CP has been explored as a potential alternative to the standard (d1,8,15 Q28-day cycle) dosing, though its efficacy is not known. This study evaluated CP scheduling and clinical survival associations in metastatic ASCC. Methods: This multicenter retrospective cohort study included patients with metastatic ASCC treated with first-line CP, identified using the Mayo Data Explorer database. Electronic health records were reviewed to collect baseline clinical characteristics, treatment regimens, responses, progression-free survival (PFS), and overall survival (OS). Descriptive statistics were used to summarize patient demographics. Survival was estimated using Kaplan–Meier methods. Multivariable Cox proportional hazards models were used to compare survival by dosing schedule, adjusting for age, ECOG performance status, HPV (p16) status, liver metastasis, and prior chemoradiation. Results: 54 patients treated between 2020-2025 with first-line CP for metastatic ASCC were included. Baseline patient demographics were balanced between dosing groups (Table 1). Median follow-up time was 26.2 months. For Q3-week CP (n = 21), median PFS and OS were 9.8 (95% CI 8.1, NR) and 27.0 (95% CI 15.7, NR) months, respectively, while median PFS was 6.5 (95% CI 4.5,15.3) months with standard CP (n = 33) and median OS was not reached (95% CI 11.2, NR). Response rate was 76% with Q3-week and 60.6% with standard CP (p = 0.23) dosing. Survival outcomes were similar when comparing Q3-week CP relative to standard CP dosing using multivariable analysis (PFS HR 0.68, 95% CI 0.33–1.41; OS HR 1.67, 95% CI 0.67–4.14). Higher ECOG and liver metastasis were independently associated with inferior outcomes, while HPV was associated with improved survival. Subsequent therapy patterns were similar between CP schedule groups. Ten patients (16.9%) received local therapy, and 24 of 28 patients with progression received further systemic therapy, including 21 (87.5%) treated with immunotherapy. Conclusions: Survival outcomes were similar across dosing schedules, suggesting Q3-week CP may be a reasonable alternative to standard CP, with potential to reduce treatment-related burden in metastatic ASCC. Future analysis will compare toxicity profiles between CP dosing schedules, including in combination with PD1 inhibitors given the results of the POD1UM-303 trial. Patient demographics (n=54). Variable Q3-week CP (n=21) Standard CP (n=33) p-value Sex Female 16 (76.2%) 24 (72.7%) 0.77 Male 5 (23.8%) 9 (27.3%) Age Median (Q1, Q3) 62 (50.5, 69) 64 (55.5, 70) 0.57 BMI Median (Q1, Q3) 27.1 (21.9, 34.4) 27.4 (22.5, 31.7) 0.72 ECOG 0 9 (42.9%) 11 (34.4%) 0.53 ≥ 1 12 (57.1%) 21 (65.6%) Confirmed HPV (p16) Positive 16 (76.2%) 24 (72.7%) 0.77 Prior chemoradiation Yes 17 (81.0%) 21 (63.6%) 0.17

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%