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The recent approval of encorafenib, cetuximab, and FOLFOX based on the phase III BREAKWATER trial has introduced a new standard of care for the first-line treatment of BRAF V600E–mutated metastatic colorectal cancer (mCRC). However, its safety and efficacy in patients with significant liver dysfunction remains unclear and, as such, patients are often excluded from pivotal clinical trials. This report presents a case of BRAF V600E–mutated mCRC presenting with extensive hepatic involvement and liver dysfunction. Despite the absence of guidelines, the patient was initiated on full-dose encorafenib, cetuximab, and FOLFOX. He experienced a rapid clinical and biochemical response, with near-normalization of liver enzymes after cycle 1, and complete functional recovery by cycle 3. Treatment was well tolerated, with no significant adverse events throughout 9 cycles. He subsequently transitioned to maintenance 5-FU, cetuximab, and encorafenib. Posttreatment blood-based next-generation sequencing revealed no residual actionable mutations. The patient then successfully underwent complete surgical resection of his primary tumor and metastatic disease with negative margins. This case highlights the importance of considering encorafenib-based therapy in select patients with BRAF V600E–mutated mCRC in the setting of compromised liver function.

Background: There is growing support for high-efficacy disease-modifying therapy (DMT) in multiple sclerosis (MS), but escalation (ESC) approaches remain common. Objective: To describe decision-making in a pragmatic trial of early high-efficacy treatment (EHT) versus ESC. Methods: DELIVER-MS is a multi-center, pragmatic, randomized controlled trial (RCT) with a parallel observational study (OBS), which enrolled treatment-naïve people with RRMS in 31 UK/US sites. Primary outcome was as follows: 36-month brain volume loss according to initial treatment approach (EHT vs. ESC). Stepwise multivariable logistic regression was used to predict participation in RCT versus OBS and choice of EHT versus ESC within the OBS cohort. Results: In total, 816 people with MS were enrolled. Participants declined randomization due to preference for a particular DMT (85%), efficacy concerns (20%), and safety concerns (9%). RCT versus OBS participation was associated with lower relapse rate ( p = 0.043) and greater brain parenchymal fraction ( p = 0.002). Among 374 in the OBS cohort, 125 (33%) chose ESC and 249 (67%) chose EHT. People commencing EHT had higher education attainment ( p < 0.001) and relapse rate ( p = 0.025). Conclusion: Baseline DELIVER-MS data demonstrate that participants with milder disease are more likely to participate in RCT. The choice of EHT versus ESC was associated with demographic factors and disease activity. Clinical trial registration: NCT03535298

BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have expanded from metabolic therapeutics to agents with broad effects on inflammation, tissue repair, cutaneous and adipose biology, and aging-related pathways. Clinicians increasingly encounter cutaneous manifestations and aesthetic sequelae with important implications for dermatologic counseling and multidisciplinary care. OBJECTIVE To review current evidence regarding GLP-1RA effects on skin biology, inflammatory dermatoses, wound healing, cutaneous adverse events, and aesthetic aging. MATERIALS AND METHODS A narrative review of clinical, translational, and mechanistic literature was performed, emphasizing psoriasis, hidradenitis suppurativa, wound repair, skin hypersensitivity reactions, autoimmune blistering disease, and facial volume loss associated with pharmacologic weight reduction. RESULTS GLP-1RAs are hypothesized to improve inflammatory skin conditions and wound repair through anti-inflammatory, immunometabolic, and proreparative pathways. Yet, their use may also be associated with injection-site reactions, hypersensitivity eruptions, rare autoimmune blistering disorders, and clinically significant facial deflation and skin laxity. Current evidence is strongest for mechanistic plausibility and observational clinical signals, whereas dermatology-specific randomized trials remain limited. CONCLUSION GLP-1RAs exert bidirectional effects on cutaneous biology. Recognition of both therapeutic opportunities and potential aesthetic or adverse sequelae is important, with patient counseling ideally occurring within a multidisciplinary framework that integrates metabolic benefits with skin health and appearance.

TPS1679 Background: Cancer care in the United States remains highly centralized, imposing substantial time, caregiver, and financial burdens on patients, particularly those residing in rural and medically underserved regions. While international experience supports the feasibility of home-based cancer therapy delivery, prospective U.S. clinical trial data are limited. The Cancer CARE Beyond Walls (CCBW) program was developed to address these gaps through a decentralized cancer care model integrating virtual oversight, remote monitoring, mobile clinical services, and community-based nursing partners. The study evaluates the feasibility, safety, and patient-centered impact of delivering cancer-directed therapy in patients’ homes or near-home mobile units in the Florida Panhandle, a region characterized by long travel distances to tertiary centers and limited oncology infrastructure. Methods: This is a phase 2, single-arm clinical trial evaluating the delivery of standard-of-care cancer-directed therapy outside of traditional infusion centers. Eligible adult patients (ECOG 0–3) with histologically confirmed malignancies receiving guideline-supported or FDA-approved systemic cancer therapy must demonstrate tolerability of at least one prior in-clinic treatment cycle. Following registration, patients transition to home-based or near-home mobile unit administration for a minimum of 12 weeks, with an option to continue up to 24 weeks. Care delivery is coordinated through a virtual command center providing real-time virtual oversight, remote monitoring, and escalation pathways. Treatment administration is performed by trained local home health nurses, medication shipping, and digital interaction with the electronic health record. A fully equipped mobile unit extends access to rural areas not covered by home health agencies. The primary endpoint is patient preference for treatment location at week 12. Secondary endpoints include safety, avoidable acute care utilization, patient-reported function and global health/quality of life, patient-reported symptoms, and satisfaction with care. Exploratory endpoints assess travel burden, patient perceptions of caregiver experience, and patient perceptions of home versus mobile unit care. Enrollment of 27 patients will provide 80% power to reject a 50% null rate (2-sided exact test, α=0.10), assuming 75% prefer decentralized care or express no preference. This investigator-initiated trial is open to accrual and is supported by a grant from the Florida Cancer Innovation Fund. Clinical trial information: NCT07285044 .

TPS10628 Background: Despite advances in cancer treatment, a lack of established population-level cancer screening strategies for early detection across cancer types contributes to cancer-related mortality. Emerging MCED liquid biopsy tests represent a screening approach with potential to enable detection of multiple malignancies at earlier stages in the disease process. We previously showed that an initial classifier based on a genome-wide methylome enrichment platform detected 12 cancer types, including early-stage, low-shedding tumors (Park et al. AACR 2023. Abs 1030). However, clinical performance of the platform has not been evaluated prospectively. Thus, the CAMPERR study (NCT05366881) was designed to train and validate a cell-free methylated DNA immunoprecipitation and high throughput sequencing (cfMeDIP-seq)-based test for detection and differentiation of 20 pre-selected cancer types, representing 93% of annual cancer incidence and 88% of annual cancer deaths. Longitudinal follow-up for a subset of participants with lung cancer will enable training and validation for MRD-based recurrence prognostication. Methods: This case-control study is enrolling participants with 20 different pre-specified cancer types (n=2400) and those without known cancer (n=3900). Eligible participants are ≥40 years of age and not receiving treatment for cancer at the time of enrollment or taking any demethylating/hypomethylating agents. Cases include individuals with newly diagnosed (≤120 days), untreated cancer or recurrence of a cancer originally diagnosed >5 years ago. Cancers of interest are stage I-IV bladder, brain, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatobiliary, leukemia, lung, lymphoma, multiple myeloma, ovarian, pancreatic, prostate, renal, sarcoma, and thyroid. Participants with stage I-III lung cancer will have clinical follow-up and blood draws after completion of first-line treatment, every 3 mo for the first year thereafter, and every 6 mo for an additional 2 years. Eligible control participants have not been diagnosed with invasive cancer in the last 5 years and will have clinical follow-up ≥12 mo from enrollment to evaluate cancer status. Liquid biopsy results will not be returned to clinicians or participants. The primary objective is cancer detection. Secondary objectives include detection of specific cancer types, identification of the tissue of origin, and prognostication of clinical outcomes (eg, recurrence-free survival, overall survival). CAMPERR is currently enrolling at 15 sites. As of December 3, 2025, 2108 of 2400 cancer cases have been enrolled, including prostate (n=225), lung (n=216), colorectal (n=211), breast (n=193), and pancreatic (n=192); controls are fully enrolled. Clinical trial information: NCT05366881 .

TPS10057 Background: Ewing sarcoma (EWS) is an aggressive tumor of the bone and soft tissue primarily affecting adolescents and young adults. For patients with recurrent disease, outcomes remain poor with 5-year survival rates of 10%–15%, highlighting the need for novel approaches. STEAP1 is highly expressed in EWS cell lines, xenograft models, and patient tumor samples 1 and is transcriptionally regulated by EWSR1::FLI1 , the main oncogenic driver in EWS. Xaluritamig, a humanized bispecific XmAb 2+1 T-cell engager targeting STEAP1 and CD3, has demonstrated potent, antigen-dependent T-cell–mediated lysis of STEAP1-expressing EWS cell lines 1 and induced robust in vivo antitumor activity in EWS xenograft models with concomitant CD8+ T-cell activation. In metastatic castration-resistant prostate cancer, another STEAP1-expressing solid malignancy, xaluritamig has shown meaningful antitumor activity and a manageable safety profile 2 supporting its clinical evaluation in R/R EWS. Methods: This ongoing, phase 1b, single-arm, open-label, two-part, multicenter study (NCT07297979) is evaluating xaluritamig in pediatric, adolescent, and adult patients with a histologic diagnosis of EWS and an EWSR1 :: ETS fusion gene locally confirmed by next-generation sequencing. Patients must have R/R EWS following ≥1 line of systemic therapy and Karnofsky or Lansky performance status ≥70. Part 1 (dose confirmation) consists of cohort 1 (age ≥12 years) and cohort 2 (age ≥2 to <12 years), and part 2 (dose expansion) includes patients aged ≥2 years with no upper age limit at enrollment. This study includes a 21-day screening period, a treatment period, a safety follow-up period, and a long-term follow-up period. Patients receive xaluritamig every 2 weeks once reaching the target dose until radiographic disease progression per RECIST v1.1, clinical disease progression, unacceptable toxicity, initiation of other anticancer therapy not permitted per protocol, withdrawal of consent, death, or end of study as determined by the sponsor, whichever is earlier. Primary endpoints are safety, tolerability, and determination of recommended dose(s) for expansion. Secondary endpoints are pharmacokinetics, preliminary antitumor activity, and immunogenicity. Biomarker evaluation as an exploratory endpoint includes assessment of serum cytokines, other pro-inflammatory markers, immune-cell subsets, circulating tumor DNA, STEAP1 protein expression, and tumor genomic profile and their association with safety and efficacy. CRS mitigation plan includes step-up dosing, steroid premedication, and administration of interleukin-6 inhibitors as needed. Site activation commenced in January 2026 and enrollment is ongoing. 1. Nolan-Stevaux O. Cancer Res. 2020;80(16_Suppl):DDT02–03. 2. Kelly WK, Danila DC, Lin CC, et al. Cancer Discov . 2024;14(1):76-89. Clinical trial information: NCT07297979 .

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.