Citations

LBA514 Background: Preclinical and clinical data show that antibody-drug conjugates (ADCs) such as T-DXd may synergize with immunotherapy. Rilvegostomig (R) is a monovalent, Fc-reduced, dual checkpoint bispecific IgG1 monoclonal antibody against PD-1 and TIGIT receptors. R + T-DXd was evaluated as neoadjuvant therapy for up to 4 cycles. Methods: I-SPY2.2 is a phase II neoadjuvant trial with three neoadjuvant sequences (Blocks A/B/C). All HER2-negative subtypes were eligible for R + T-DXd in Block A. Predicted responders at the end of Block A or B could undergo surgery; otherwise, they continued to Block B +/- C. Block B pts received paclitaxel +/- carboplatin +/- pembrolizumab and Block C pts doxorubicin + cyclophosphamide (AC) +/- pembrolizumab, HR+ immune+ received IO in Blocks B/C. Results are analyzed by receptor and response predictive subtypes (RPS), that include expression-based immune, and luminal signatures with hormone receptor (HR) and HER2 status. Some pts were randomized to a control regimen (skipping R + T-DXd in block A and starting in block B). To minimize risk of interstitial lung disease (ILD) that could lead to treatment discontinuation, pts underwent pulmonary function tests and high-resolution chest CTs every 6 weeks. Abnormalities were reviewed in real time. The primary endpoint was pathologic complete response (pCR), within each RPS and HR/HER2 signature, with estimated pCR (EpCR) rates compared to subtype-specific block A goal rates and control pts in those groups. Other endpoints included safety and treatment discontinuation. Results: 105 pts were treated with R + T-DXd in block A, while 31 pts were randomized to the control regimen. Block A EpCR rate was 57% in the 12 HR+Immune+ pts vs a pre-specified goal of 15% (posterior probability, PP > .99). In 35 HR-Immune+ pts EpCR was 52% vs a pre-specified goal of 40% (PP = .87). No other groups (Immune-) had a PP > .85 for their respective pCR goal rate. HER2-IHC was 0 (27.6%), 1+ (49.5%) and 2+ (22.9%) in the treatment arm vs. 37.7%, 37.7%, and 24.7% in the control arm, with no difference in distribution between arms in immune subtypes. The most common adverse events in Block A were fatigue (84.8%), nausea (81.0%) and alopecia (58.1%). ILD was the most common adverse event of special interest in Block A and overall, occurring in 12 pts (11.4%; 7G1, 4G2, 1G3) during Block A and in 3 pts (G1, 2.9%) in other Blocks. 8 pts discontinued T-DXd + R due to ILD and proceeded to the next Block. Conclusions: When considering the full treatment strategy including block B and C regimens, experimental strategies had similar EpCR rates vs. controls in immune+ subtypes but block A rates exceeded pre-defined goal thresholds. This infers that treatment beginning with R + T-DXd has equivalent efficacy to standard of care for immune+ pts, but 64% pts with pCR skip chemotherapy (Block B) and 97% avoid AC (Block C). R + T-DXd participants avoided persistent ILD. Clinical trial information: NCT01042379 .

LBA5012 Background: There is a critical evidence gap on the relative benefits and harms of proton therapy (PT) compared with photon-based intensity-modulated radiation therapy (IMRT) in prostate cancer. Herein we report early results from COMPPARE, a non-randomized comparative study of outcomes with PT and IMRT in prostate cancer. Methods: Between 2018-2022, 2524 patients from 51 facilities (28 PT and 23 IMRT) enrolled in COMPPARE, including 1501 treated with PT and 1023 treated with IMRT, and were followed prospectively. Treatment naïve patients with localized prostate cancer except those with very high-risk disease were eligible. Treatment was pragmatic with daily standard fractionation (1.8-2.1 Gy) and moderate hypofractionation (2.4-3.1 Gy) permitted. Use of rectal spacers and androgen deprivation were at physician discretion. Patient-reported quality of life data and treatment team-reported toxicity and disease control outcomes were collected at baseline and pre-specified time intervals via VisionTreeOptimalCare; treatment planning and delivery data were collected via the Advanced Treatment Consortium. We analyzed 1404 PT patients and 939 IMRT patients. We report the early primary endpoint of the study, a comparison of patient reported bowel urgency and bowel frequency at 2-years using the EPIC tool, and the secondary endpoints of 2-year CTCAE v5 ≥ grade 2 gastrointestinal toxicity outcomes and 3-year freedom from biochemical progression (FFBP) results reported by the study teams. Results: Study sample size was targeted at 1,500 PT patients and 1,000 IMRT patients, and median follow-up time was 4.0 years. The primary endpoint and secondary toxicity 2-year endpoints focused on the alternative hypothesis of PT superiority. All results include inverse probability of treatment weighting. Using generalized linear mixed effects models, we found there to be no significant difference in EPIC bowel urgency scores (p = 0.324) or bowel frequency scores (p = 0.514) between PT and IMRT cohorts over time up to the 2-year endpoint. For grade 2 gastrointestinal toxicity, the 2-year cumulative incidence was 5.2% for PT and 5.6% for IMRT. Gray’s Test for competing risks showed a hazard ratio (HR) of 0.91 [95% confidence interval (CI): 0.65-1.28, p = 0.6] for PT versus IMRT. The exploratory non-inferiority endpoint of 3-year FFBP was 98.0% for PT and 97.9% for IMRT, and Gray’s Test showed a HR of 0.95 (95% CI: 0.52-1.71, p = 0.90). Conclusions: Analysis of early results of COMPPARE show no significant differences between PT and IMRT in patient reported bowel frequency and urgency, grade ≥2 gastrointestinal toxicity, or FFBP. Assessment of long-term disease control, late toxicity and secondary malignancy will require longer follow-up. Clinical trial information: NCT03561220 .

LBA10509 Background: The MCED test (Galleri) detects a shared cancer signal from cell-free DNA in blood and predicts a cancer signal origin (CSO) to guide diagnostic (dx) workup. PF2 (NCT05155605) is a large, prospective, multicenter, interventional study of the MCED test’s performance and safety in a diverse US intended-use population. Methods: PF2 enrolled participants aged ≥50y without clinical suspicion of cancer or cancer diagnosis/treatment within 3y of enrollment. Primary objectives were MCED performance and safety in terms of dx testing triggered by a positive (cancer signal detected) MCED test result. Participants with a positive MCED test underwent targeted dx workup guided by the predicted CSO(s). Participant-reported anxiety was assessed with the State Trait Anxiety Inventory. Results: PF2 enrolled 35,878 participants; 32,007 with a 12m cancer assessment were analyzable for performance. Of 287 (0.9%) with a positive MCED test, 173 were diagnosed with cancer within 12m, for a cancer detection rate of 0.5% (95% CI 0.5-0.6%) and positive predictive value of 60.3% (54.5-65.8%). Specificity was 99.6% (99.6-99.7%). 12m episode sensitivity was 69.8% (62.8-76.0%) in a prespecified subgroup of 12 cancers responsible for ⅔ of US cancer deaths, 66.2% (55.1-75.8%) in a subgroup of 6 aggressive cancers with low 5y survival, and 39.3% (34.9-44.0%) across all cancers. Overall CSO prediction accuracy was 91.3% (86.2-94.7%) across all cancers. The MCED test detected 151 new primary and 22 recurrent cancers; additional cancers detected by screening were those with USPSTF A/B (n=31) and C (n=60) recommended screening. Of 151 MCED-detected new primaries, 80 (53.0%) were clinical stage I-II; 107 (70.9%) were stage I-III. Of 80 MCED-detected stage I-II cancers, 71.2% had no USPSTF A/B screening recommendation. Of 35,335 participants analyzable for safety, 213 (0.6%) had invasive procedure(s) to evaluate a positive MCED test result, of which 90% were nonsurgical and 1.8x more likely for participants with vs without cancer diagnosis. Most (87.6%) had a CSO-guided dx evaluation. There were 5 study-related adverse events during the time of dx workup; none were serious. Anxiety temporarily increased for participants with a positive MCED test and cancer diagnosed, and returned to baseline by 12m. Of participants with a positive MCED test, median time from test result to dx resolution was 48d (95% CI 43-56). Few participants (7/63 [11.1%]) had cancer found by dx PET/CT after a targeted dx workup that did not reveal cancer. Conclusion: The MCED test demonstrated robust performance with a favorable safety profile. When MCED testing was added to USPSTF A/B screening, 6.5x more cancers were detected by screening, most at early stages. The diverse, representative PF2 participant population supports the generalizability of these findings to the US intended-use population. Clinical trial information: NCT05155605 .

Abstract Background Wide-spread mast cell (MC)-associated symptoms and MC activation syndrome (MCAS) are often reported in patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD). The goal of this study was to develop a novel MC score based on 11 self-reported MC-related conditions with clinical and research utility to better understand MC symptoms in hEDS and HSD patients. Methods From November 1, 2019, to June 13, 2025, patients ( n =2,141) filled out an Intake Questionnaire at the Mayo Clinic Florida EDS Clinic that included 11 self-reported questions related to categories of MC-related conditions for a MC score ranging from 0/11 to 11/11. Based on the MC score distribution in hEDS and HSD patients, a MC score of 0-1 was considered a low MC score and ≥5 was considered a high MC score. Symptoms/comorbidities were compared between patients with high vs. low MC scores. Results From the 2,141 hEDS/HSD patients, 535 (25.0%) had a MC score ≥5 (Hi MC). MCAS-specific symptoms such as nausea and vomiting were reported more often in hEDS/HSD patients with a high vs. low MC score ( p <0.0001). Random clinical blood tryptase and urinary MC markers were not elevated in patients with high MC scores ( n =50/group), although high MC scores were found to significantly reduce urinary creatinine levels indicating that the protein used to normalize data was affected by MC activity. In contrast, random blood IgE, tryptase and major basic protein (MBP) by ELISA were increased in patients with high MC scores (e.g., IgE hEDS p =0.0004, HSD p =0.003). Of note, the percentage of patients reporting abuse or post-traumatic stress disorder was nearly doubled in patients with high vs. low MC scores (Abuse and PTSD: hEDS p < 0.0001; HSD p < 0.0001). Overall, 109/135 (80.7%) in hEDS and 129/135 (95.6%) in HSD reported more symptoms/comorbidities if they had a high MC score. Conclusions We found that hEDS/HSD patients with high MC scores self-reported more widespread symptoms/comorbidities and higher MC-related blood markers than patients with low MC scores indicating the utility of this tool to evaluate the level of widespread MC activity in hEDS, HSD and other patients.

PURPOSE Cholangiocarcinoma is a rare cancer associated with poor prognosis. Pemigatinib was the first FGFR1-3 inhibitor approved for second-line therapy and beyond, on the basis of the phase II FIGHT-202 trial. Here, we assess efficacy and safety of first-line pemigatinib. METHODS FIGHT-302 is a phase III, randomized, global trial evaluating pemigatinib as first-line therapy (ClinicalTrials.gov identifier: NCT03656536 ). Adults with advanced cholangiocarcinoma with FGFR2 rearrangement were randomized 1:1 to receive pemigatinib (13.5 mg once daily) or chemotherapy (1,000 mg/m 2 gemcitabine plus 25 mg/m 2 cisplatin once per day on days 1 and 8 of every 3-week cycle for ≤8 cycles) and were stratified by prior receipt of chemotherapy, geographic region, and tumor burden. Pemigatinib crossover was allowed for patients progressing on chemotherapy. The primary end point was progression-free survival (PFS). Secondary efficacy, safety, and exploratory end points were also analyzed. RESULTS Overall, 4,563 patients were prescreened, 196 were screened, and 167 randomly assigned to receive pemigatinib (n = 83) or chemotherapy (n = 84) before early closure of the study because of a change in standard of care. The median PFS was 8.3 months in the pemigatinib group versus 6.8 months in the chemotherapy group (hazard ratio, 0.58 [95% CI, 0.39 to 0.87]; nominal P = .0078); objective response rate was 47% versus 15%, and the median duration of response was 14.2 versus 6.3 months. Median overall survival was similar (24.4 v 25.0 months, respectively). In the crossover group (n = 42, second-line pemigatinib), the median PFS was 8.1 months. Safety was consistent with the known profile of pemigatinib. CONCLUSION To our knowledge, this was the largest, first-line, randomized, phase III trial of a targeted therapy for advanced FGFR2- rearranged cholangiocarcinoma. Pemigatinib demonstrated prolonged median PFS compared with chemotherapy, with no new safety findings.

Abstract Introduction Despite progress in understanding placebo effects in clinical trials of inflammatory bowel disease (IBD), there is a limited understanding of how socioeconomic factors of recruiting countries impact placebo rates. We investigated the association of socioeconomic factors across recruitment sites on placebo rates in IBD randomized controlled trials. Methods We examined the association of clinical and endoscopic remission and response to the weighted Gross National Index (GNI) per capita, Human Development Index (HDI), and out-of-pocket health expenditures as a percentage of current health expenditures (OOP_CHE) of identified trials using mixed effects linear regression. Results Across 76 trials (Crohn’s disease [CD]: n = 32; ulcerative colitis [UC]: n = 44), placebo response rates over time were largely stable, with a small increase across time in clinical remission for CD trials (β = 0.4% per increase in study year, 95% CI: 0.3%-0.84%, P = .04) and a small decrease across time in endoscopic response for UC trials (β = −1.39% per increase in study year, 95% CI: −1.79, −0.99, P &lt; .001). Clinical response was most susceptible to changes in socioeconomic factors in IBD trials (β = −2.96% per 10 000 USD increase in study GNI, 95% CI: −4.98, −0.95%, P = .004; P &lt; .05 for HDI and OOP_CHE). Across both conditions, decreases in clinical response were associated with increases in HDI and OOP_CHE (CD HDI: β = −1.15% per 0.01 increase in study HDI, 95% CI: −2.24, −0.06%, P = .04; UC HDI: β = −0.66% per 0.01 increase in study HDI, 95% CI: −1.19, −0.12%, P = .02). Discussion We found that placebo clinical response was most susceptible to influences of site-level socioeconomic wellbeing. These findings highlight that estimation of placebo rates in trial planning should account for geographic location of recruiting sites.

ABSTRACT Incomplete aneurysm occlusion after flow disruption treatment strongly depends on the persistence of strong flow into the aneurysm, which in turn depends on the aneurysm and parent artery geometry as well as the device placement. However, at the time of treatment it remains challenging to predict future outcomes (complete or incomplete occlusion). This paper describes a strategy to evaluate the local hemodynamic environment created immediately after flow‐modifying device deployment to treat cerebral aneurysms and connect it to the subsequent long‐term outcomes. The approach is based on the concept of angiographic signatures that can be extracted from DSA sequences or computational models and represented as images that can be used to compare different aneurysmal environments. The methodology is demonstrated on two small series of four experimental rabbit aneurysms each, treated with either intrasaccular flow disruptors or endoluminal flow diverters. Noticeable differences in the angiographic signatures of completely and incompletely occluded aneurysms at follow‐up were observed. Specifically, larger values of mean transit times and longer time‐to‐peaks were observed deeper into the aneurysms that remained incompletely occluded in both series. The findings suggest that angiographic signatures can be used to assess the underlying hemodynamic environment immediately after device implantation and prognosticate the likelihood of future complete or incomplete occlusion.

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

Abstract Severe neuropathies with predominant involvement of motor fibres can resemble lower motor neuron disease (LMND) phenotypes. Given the fatal prognosis of LMND, identifying underlying autoimmune syndromes is crucial to provide treatment options to patients. We investigated a novel autoantibody binding pattern observed on murine teased sciatic nerve fibres. Target antigens were identified using immunoprecipitation combined with mass spectrometry. Target specificity of these autoantibodies was validated in cell-based assays, neutralization assays and knock-out models. A retrospective study cohort consisting of different neuropathies (chronic inflammatory demyelinating polyradiculopathy n = 86, Guillain–Barré syndrome n = 37, multifocal motor neuropathy n = 18, diabetic neuropathy n = 30, other inflammatory neuropathies n = 10), amyotrophic lateral sclerosis (n = 50), multiple sclerosis (n = 50) and healthy controls (n = 50) was negative for septin multimer autoantibodies. Histopathological analysis of skin and the sural nerve including electron microscopy was performed in one seropositive patient, and autoantibody binding was characterized in vitro. Extensive immunotherapy was initiated in one patient, with clinical and serological follow-up over 4 years. Among 3543 total samples tested, three patients (two male, one female)—diagnosed with the LMND variant of amyotrophic lateral sclerosis (aged 65, 72 and 79 years, respectively)—showed a novel and distinct autoantibody binding pattern of indirect immunofluorescence staining on peripheral nerves, targeting Schmidt–Lanterman incisures (SLIs), paranodes and the abaxonal myelin. Target identification and validation revealed septin multimers as autoantibody epitopes. Despite the primarily intracellular location of septins, autoantibody binding was evident in living myelinated dorsal root ganglia, primarily at SLIs (‘incisuropathy’). Septin multimer autoantibodies further initiated complement deposition on fixed and permeabilized cell-based assays. Sural nerve and skin biopsies showed inflammation, myelin and axonal pathology. Extensive immunotherapy in one patient was followed by disease stabilization over 3 years. The other two patients died of rapid disease progression: one of them received no immunotherapy while the other had ineffective treatments with single administrations of intravenous immunoglobulin and rituximab. Our data suggest that septin multimer autoimmunity occurs in severe motor-predominant neuropathies which can clinically resemble a neurodegenerative LMND. Screening for septin multimer autoantibodies should be considered in patients presenting with this phenotype. Follow-up studies need to determine the direct pathogenicity of septin multimer autoantibodies, their potential as a biomarker of an autoimmune syndrome and responses to immunotherapy in larger cohorts.

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 .