Citations

3510 Background: Patients with RAS-mutated mCRC have limited treatment options. Chemotherapy in combination with bevacizumab (Bev) has been the standard first-line treatment for the past two decades, yet the prognosis for these patients remains poor. Onvansertib (Onv), a selective PLK1 inhibitor, has previously demonstrated synergy with chemotherapy in the second line setting. The Phase 2 randomized CRDF-004 trial evaluated onvansertib plus standard-of-care (SoC; FOLFIRI or FOLFOX with Bev) in as first-line RAS-mutated mCRC. Methods: Patients with first-line KRAS or NRAS mutant mCRC were randomized to SoC alone or SoC plus onvansertib (20 mg or 30 mg). The primary endpoint was objective response rate (ORR) as determined by a blinded-independent central review (BICR) using RECIST v1.1. Key secondary endpoints included progression-free survival (PFS), duration of response, and safety. PFS was assessed by BICR and investigator assessments combined. Results are presented in the intent-to-treat population (ITT). Results: At the data cutoff of 22 Jan 2026,110 patients were randomized with a median follow up of approximately 10 months. Baseline characteristics were relatively balanced across arms. Onv 30 mg + FOLFIRI + Bev demonstrated numerically higher ORR (n = 13/18, 72.2%, 95% CI: 46.5, 90.3) compared with the FOLFIRI + Bev control arm (n = 8/19, 42.1%, 95% CI: 20.3, 66.5), the FOLFOX + Bev control arm (n = 8/18, 44.4%, 95% CI: 21.5, 69.2) and the combined control arms (SoC: n = 16/37, 43.2%, 95% CI: 27.1-60.5). Onv 30mg + FOLFIRI + Bev demonstrated a p-value of 0.051 for confirmed ORR vs. SoC; and a p-value of 0.045 for the 6-month ORR compared to FOLFIRI + Bev (n = 10/18, 55.6%, 95% CI: 30.8-78.5 vs. n = 4/19, 21.1%, 95% CI: 6.1-45.6, respectively). The median PFS for the control arms was 10.97 months (95% CI: 7.52, NR) for FOLFIRI + Bev, 9.89 months (95% CI: 9.43, NR) for FOLFOX + Bev and 10.97 months (95% CI: 9.43-15.44) for the combined SoC arms. The median PFS in the Onv 30mg+ FOLFIRI + Bev arm was not reached (95% CI: 9.72-NR). The PFS HR of 30mg + Onv +FOLFIRI + Bev vs FOLFIRI + Bev was 0.38 (95% CI: 0.12-1.17) and vs SoC was 0.37 (95% CI: 0.13-1.02, p = 0.048). The clinical benefit from Onv treatment was further evidenced by the 12-month PFS rates, 61.9% (95% CI: 40.1, 95.8) in the Onv 30 mg + FOLFIRI + Bev arm vs. 28.4% (95% CI: 9.3, 86.9) in the FOLFIRI + Bev arm, and 30.1% (95% CI: 13.8-65.7) in the SoC. Onvansertib was well tolerated, with no unexpected toxicities observed; the most common grade ≥3 adverse event was neutropenia. PK data support moving forward with the onvansertib 30mg dose with FOLFIRI + Bev. Conclusions: Onvansertib plus FOLFIRI and bevacizumab demonstrated improved antitumor activity and manageable safety in first-line RAS-mutated mCRC. These results support further clinical and support planned confirmatory Phase 3 evaluation. Clinical trial information: NCT06106308 .

3109 Background: Poly(ADP-ribose) glycohydrolase (PARG) is an enzyme that catalyzes the removal of poly-ADP-ribose (PAR) chains from proteins during DNA damage repair. PARG inhibition leads to selective cell death in tumors with underlying replication fork defects, including BRCAm tumors, through a mechanism distinct from PARP inhibition. ETX-19477 is an oral, potent, and selective PARG inhibitor that shows robust preclinical activity in mouse models of ovarian, breast, and gastric cancers. Methods: ERADIC8 is an open-label, multicenter, Phase 1/2 study, consisting of two parts, dose escalation and dose expansion. A Bayesian Optimal Interval Design was used to enroll patients (pts) into dose escalation cohorts, with enrichment for pts with BRCAm high grade serous ovarian (HGSOC) and breast cancers. The primary objective is to assess safety/tolerability of ETX-19477 and define the maximum tolerated dose (MTD) and recommended Phase 2 dose(s). Secondary and exploratory objectives include pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity per RECIST v1.1. ETX-19477 is given orally once or twice daily in 21-day cycles. Results: As of Jan 6 2026, 45 pts were enrolled into the study across 11 dose levels (range: 80-750 mg QD, 190-350 mg BID). Tumor types included ovarian (n=24, BRCAm: 18), breast (n=8, BRCAm: 7), endometrial (n=6, BRCAm: 0), colorectal (CRC, n=3, BRCAm: 1), and other (n=4, BRCAm: 0) cancers. Treatment-related AEs (TRAEs; any grade) occurring in >20% of pts were nausea (53%), vomiting (38%), and fatigue (24%). The only Gr3 TRAE occurring in >5% of pts was neutropenia (16%). There was one Gr4 TRAE of neutropenia in 1 pt (2%) and no Gr5 TRAEs. ETX-19477 exposure is dose proportional, and the BID regimen achieves >85% PARG inhibition throughout the dosing interval in a blood-based PAR accumulation pharmacodynamic assay. As of the data cutoff, dose escalation is ongoing at 350 mg BID (MTD has not been defined) and dose expansion is ongoing at 200-300 mg BID. Among BRCAm, HGSOC pts enrolled at BID dose levels, there were 7 evaluable pts with a median of 4 prior lines of therapy (range 2–11): 2 pts achieved a partial response (PR, 29%) and 3 pts achieved stable disease (SD, 43%). Both pts with PRs were platinum-resistant and received prior PARP inhibitor treatment. 1 pt with BRCAm CRC remains on active therapy (250 mg BID) with SD for 7 months. Conclusions: ETX-19477 was well tolerated and showed anti-tumor activity in heavily pretreated pts with BRCAm, platinum-resistant HGSOC during dose escalation. These findings provide the first clinical proof-of-concept of PARG inhibition in HGSOC. ETX-19477 is being further evaluated in the dose expansion phase of the study. Clinical trial information: NCT06395519 .

2652 Background: Circulating Tumor Cells (CTCs) are prognostic for poor outcomes in metastatic Breast Cancer (mBC), however CTCs are uncommon in mBC (<20%) and many pts without CTCs often progress. Cancer associated macrophage-like cells (CAML) are prognostic inflammatory pro-tumorigenic PD-L1 expressing macrophages common in mBC pt blood (>90%). In a previous randomized phase II trial, CTC & CAML decreases post Bria-IMT induction correlated with clinical benefit. Bria-IMT is an allogenic whole cell vaccine engineered to express tumor associated antigens & GM-CSF, promoting adaptive & innate immune responses. The ongoing Bria-ABC (NCT06072612) phase 3 study compares Bria-IMT to physician’s choice (TPC) in late stage mBC. We present interim results, without treatment arm comparison, for Progression Free Survival (PFS) by CTC & CAML changes as the exploratory part of the trial. Methods: This still blinded ongoing multicenter randomized open label Phase 3 trial evaluates Bria-IMT+ checkpoint inhibitor (CPI) vs TPC in mBC pts lacking approved therapies. Pts are randomized 1:1:1 to Bria-IMT+CPI, TPC, or Bria-IMT monotherapy (discontinued after 150 pts). The Bria-IMT consists of cyclophosphamide, irradiated SV-BR-1-GM cells, micro-dose pegylated α IFN at each inoculation site. CPI is administered day -3 to 3. TPC followed standard of care. Blinded anonymized blood was taken at baseline (BL), prior to therapy & 2nd (T1) taken at cycle 3 (~4 weeks post initiation). CTCs & CAMLs, and PD-L1 expressions, were quantified using LifeTracDx liquid biopsy with analysis of PFS by censored univariate analysis. Results: At time of analysis, >250 consented, >170 randomized, 119 had BL and 78 had T1. Median age 56 yrs [34–83], median 6 [2–13] prior lines of therapy, 31% TNBC, 62% ER+/PR+, & 15% HER2+. ≥1 CTCs were found in 25% (30/119) at BL & 22% (17/78) at T1. ≥1 CAMLs were found in 93% (111/119) at BL & 95% (74/78) at T1. At BL, ≥1 CTC was not significant for PFS (HR=1.7, CI95% 1.0-2.9, p=0.0513), but ≥2 CTCs was significant for worse PFS (HR=1.8 CI95% 1.1-3.1, p=0.0480). At T1, ≥1 CTCs nor ≥2 CTCs correlated with PFS (HR=0.9, p=0.8392) & (HR=1.6, p=0.1079), respectively. Further, a decrease in CTCs was seen in 11 pts but did not correlate with PFS (HR=0.7, p=0.6552). ≥1 CAML at BL nor T1 correlated with PFS (HR=1.2 CI95% 0.7-2.0, p=0.6811) or (HR=0.9 CI95% 0.7-2.5, p=0.5307), respectively. However, 51 pts (65%) had a decrease or stable CAML counts between BL & T1 which did significantly correlate with better PFS (HR=2.2 CI95% 1.2-3.9, p=0.0154). Conclusions: In an ongoing analysis of a heavily treated mBC pts, we observed that in the entire blinded population, 65% of pts had stability/drop in CAMLs significantly correlated with better PFS. Treatment arm specific comparisons will not be unblinded until completion of the designated milestone (144 mortalities). Clinical trial information: NCT06072612 .

2016 Background: Bevacizumab therapy (Bev) for recurrent glioblastoma (rGBM) has not demonstrated improved overall survival (OS) in randomized clinical trials. However, single-center and preliminary multi-center studies suggest that relative cerebral blood volume (rCBV) measured with dynamic susceptibility contrast MRI (DSC-MRI) at baseline or shortly after treatment initiation may predict response to Bev. The primary aim of ECOG-ACRIN EAF151 was to evaluate whether early binary change in rCBV, assessed 2–3 weeks after initiation of Bev-containing therapy, identifies patients with an OS benefit of ≥4 mos. Pre-specified secondary aims assessed baseline rCBV; post-hoc exploratory analyses examined early post-Rx rCBV. Methods: A prospective, phase II multi-center trial without randomization enrolled subjects with rGBM receiving their first Bev-containing therapy. Progression was determined by local sites (RANO criteria; MRI within 28 days of registration, ≥42 days since end of chemoradiation). Baseline (S0) and follow-up (S1) DSC-MRI were performed before the first Bev infusion (within 3 days), and 12-25 days post-infusion but before the second infusion. Anatomic MRI and DSC-MRI (double-dose Gadavist injection, full-dose preload) complied with recommended protocols. Mean normalized (nRCBV) and standardized (sRCBV) rCBV were extracted from contrast-enhancing tumor ROIs. A 2-sided logrank test (α=0.1) was used to test the primary aim (change in mean nRCBV from S0 to S1, ≥0 vs. <0). Cox regression with restricted cubic splines was used to assess the association between continuous rCBV markers and OS. Results: 146 subjects were accrued from 33 sites. 134 completed S0 and 118 completed both S0 and S1. After exclusion of uninterpretable scans, 107 were evaluable for change in rCBV, and 124 for baseline rCBV. There was no statistically significant difference in OS between subjects with binary increase (n=40; median OS 8.0 mos [90% CI 5.5–9.2]) vs. decrease (n=67; 7.9 mos [90% CI 6.3–10.3]) in mean nRCBV (p=0.67). Based on the spline fits, we observed a strong nonlinear association between OS and continuous nRCBV and sRCBV at both S0 and S1: low marker values are associated with lower risk, but beyond a threshold, higher values are not associated with greater risk. As an exploratory analysis, we estimated optimal cut points (nRCBV: S0=1.11, S1=1.16; sRCBV: S0=1.13, S1=0.99) and found that subjects whose S1 rCBV decreased below threshold had a median OS 2.7 mos (nRCBV, HR 0.61 [90% CI 0.41–0.88]) and 5.2 mos (sRCBV, HR 0.43 [90% CI 0.28–0.63]) longer than subjects whose rCBV either increased or did not decrease below threshold. Conclusions: EAF151 prospectively evaluated whether DSC-MRI markers predict OS in patients with rGBM treated with Bev. Although the change in these markers was not predictive, both baseline and early post-Rx markers were predictive of OS. Clinical trial information: NCT03115333 .

Estimates of fibromyalgia prevalence vary widely worldwide due to differences in diagnostic criteria, study methodology, and population characteristics. Accurate estimates are essential to inform population-level surveillance, guide resource allocation, and highlight disparities in disease recognition and access to care. The objective of this systematic review and meta-analysis was to determine the global prevalence of fibromyalgia in the general population, and secondarily to identify factors moderating prevalence variation and to assess prevalence in defined at-risk subpopulations. Pooled prevalence estimates with 95% confidence intervals (CIs) were calculated using the inverse variance heterogeneity model with Freeman–Tukey transformation. Subgroup analyses were performed by sex, diagnostic criteria, country, and other study characteristics, and meta-regression assessed moderators including publication year and Human Development Index (HDI). Of 21,645 records identified, 1,728 underwent full-text review and 882 studies were included in the final analysis. Across 38 countries and 30,070,032 individuals (188 studies), the pooled fibromyalgia prevalence in the general population was 1.40% (95% CI, 0.49–2.47), with substantial heterogeneity (I 2 = 100%) and very low certainty of evidence. Among at-risk subpopulations (9,771,123 participants; 768 studies), prevalence was markedly higher in autoimmune and inflammatory conditions, such as chronic urticaria (37.1%), interstitial cystitis (30.8%), systemic sclerosis (20.6%), celiac disease (20.5%), and inflammatory bowel disease (19.9%), and elevated in chronic pain, rheumatologic, and post-infection cohorts. Meta-regression identified publication year (β = 0.008, P < .001) and HDI (β = 0.725, P = .002) as significant moderators of prevalence. In conclusion, fibromyalgia affects 1% to 2% of the global population, with substantially higher rates in at-risk subpopulations. Temporal and socioeconomic trends emphasize diagnostic inconsistency and global disparities in care.

Isolated pulmonary valve endocarditis (PV-IE) is a rare condition. Its epidemiology, clinical profile, and management remain poorly characterized. A systematic review was conducted to provide a contemporary characterization (2020–2025) of adult cases with isolated PV-IE. Individuals with previous cardiac surgeries, cardiac implantable electronic devices (CIEDs), or long-term venous catheters were excluded. Of 1902 citations identified, 72 studies were selected with 79 eligible cases, mostly case reports. Patients were predominantly male (78.5%) with a median age of 43 years. Congenital heart disease (CHD) and injection drug use (IDU) were risk factors in 30.4% and 27.8% of cases, respectively, while 41.8% had neither (No-CHD/IDU group). Staphylococcus aureus was the leading pathogen (39%), followed by streptococci (16.5%) and Enterococcus faecalis (8.9%). Vegetations were large (median, 19.5 mm), and pulmonary septic emboli highly prevalent (~93% of cases). More than half (54.4%) of patients underwent surgery. Hospital mortality was low (7.6%). Differences across risk factor subgroups were observed, with higher median age in No-CHD/IDU patients and more staphylococcal etiology in patients with IDU, although treatment approaches and mortality did not differ. This review highlights distinct characteristics and the overall favorable short-term prognosis of isolated PV-IE, underscoring the need for larger, systematically collected datasets.

Background: Asymptomatic intracranial atherosclerotic arterial stenosis (ICAS) is an underrecognized entity for which vascular risk-factor optimization is the primary management strategy, with no current indication for routine antiplatelet therapy or endovascular intervention for primary stroke prevention. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events, including stroke, in high-risk cardiometabolic populations, but their association with outcomes in asymptomatic ICAS is yet to be evaluated. The present study aims to evaluate the association between GLP-1RA use and cerebrovascular outcomes in adults with asymptomatic ICAS. Materials and Methods: We used the TriNetX US Collaborative Network (71 healthcare organizations) to identify adults (≥18 years) with ICAS between 1 January 2016 and 31 December 2025, and excluded patients with prior cerebral infarction, intracranial hemorrhage, or cerebrovascular ischemic syndromes. Exposure was defined as initiation of any GLP-1 receptor agonist (lixisenatide, semaglutide, liraglutide, tirzepatide, dulaglutide) during the 6 months before or on the date of index ICAS diagnosis. Outcomes were assessed at 1 year, and included ischemic stroke, all-cause mortality, and a composite of ischemic stroke or mortality. Propensity-score matching (1:1) was performed, including demographics, vascular risk factors, comorbidities, antithrombotics, lipid/diabetes therapies, and cardiometabolic laboratory/physiologic measures. Results: Before matching, 1746 GLP-1RA users and 71,792 non-users met inclusion criteria; after matching, 1728 patients remained in each cohort. GLP-1RA use was associated with lower 1-year risk of ischemic stroke (4.40% vs. 6.10%; hazard ratio [HR] 0.70, 95% CI 0.52–0.95; p = 0.044), lower all-cause mortality (3.40% vs. 9.40%; HR 0.35, 95% CI 0.26–0.47; p < 0.001), and lower composite outcome risk (7.50% vs. 15.00%; HR 0.48, 95% CI 0.39–0.59; p < 0.001). Notably, these associations were observed despite matching for HbA1c, LDL cholesterol, BMI, and systolic blood pressure, suggesting potential effects beyond measured cardiometabolic risk profiles. Conclusions: In this large, propensity-matched cohort of adults with a-ICAS, GLP-1RA use was associated with lower ischemic stroke, all-cause mortality, and composite outcome at 1 year. These findings are hypothesis-generating and require further prospective studies to confirm this observation.

OBJECTIVE Historically, craniopharyngioma (CP) was divided into adamantinomatous CP (ACP) and papillary CP (PCP) subtypes based on histopathological features. However, each harbors a unique genetic profile and progressively differing treatment paradigms, leading to their reclassification by the WHO in 2016 as two distinct entities. Descriptive in nature, this large multi-institutional study aimed to establish current differences between the presentation, treatment patterns, and clinical course of these pathologies to serve as a baseline for future studies as new treatment paradigms emerge. METHODS The authors queried the Registry for Adenomas of the Pituitary and Related Disorders (RAPID) database, which encompassed patients from 14 participating institutions across the United States between 2000 and 2024. The database was screened for adult patients who underwent initial CP treatment with a confirmed histopathological diagnosis of ACP or PCP. Patient demographic characteristics, clinical course, tumor treatment, and outcomes data were collected and compared by CP type. RESULTS The final analysis included 273 ACP and 99 PCP adult patients who underwent initial surgical treatment. ACP patients presented younger on average (mean 48.3 vs 52.8 years, p = 0.034). PCP patients were more likely to present with hypothyroidism (33.3% vs 20.5%, p = 0.010), hyperlipidemia (25.3% vs 15.8%, p = 0.036), fatigue (28.3% vs 17.6%, p = 0.024), temperature intolerance (9.1% vs 1.5%, p < 0.001), and cardiac arrhythmia (6.1% vs 1.1%, p = 0.006). The groups demonstrated similar postsurgical and neuroendocrinological outcomes. Postoperative median (IQR) progression-free survival did not significantly differ between groups (19.0 [7.0–37.0] for ACP vs 5.0 [3.5–7.5] months for PCP, p = 0.972). ACP patients were more likely to receive radiation after surgery (27.8% vs 15.2%, p = 0.012). CONCLUSIONS This large multicenter descriptive study aimed to characterize similarities and differences between the clinical courses of molecularly distinct ACP and PCP, which has not previously been described. The findings should serve as a baseline to inform future studies, particularly with the recent introduction of targeted therapy for PCP.

OBJECTIVE Frailty is a known predictor of adverse outcomes in pituitary surgery, yet its impact regarding craniopharyngioma remains unclear. The authors assessed preoperative frailty, measured by the 11-factor modified frailty index (mFI-11), and its association with perioperative morbidity among adult patients undergoing craniopharyngioma surgery. METHODS Using the Registry for Adenomas of the Pituitary and Related Disorders (RAPID) database, the authors performed a retrospective cohort study of the records of patients ≥ 18 years of age who underwent craniopharyngioma surgery between June 2007 and November 2024. Patients were stratified into the following categories according to their numeric mFI-11 score: fit (scores 0 and 1), managing well (scores 2 and 3), and mildly frail (scores 4–6). Primary outcomes included hospital length of stay (LOS) and discharge disposition. Secondary outcomes included 90-day readmission, surgical outcomes, and complications. Multivariable analyses were performed to identify independent predictors of hospital LOS and non-home discharge, adjusting for age, surgeon experience, American Society of Anesthesiologists class, complications, and surgical approach. RESULTS Among 278 patients (221 fit, 43 managing well, 14 mildly frail), higher-frailty patients were older (mean age 47.8 ± 16.1 years in fit vs 60.1 ± 12.5 years in managing well vs 67.6 ± 8 years in mildly frail, p < 0.001) and more likely to present urgently (24.2% vs 36.4% vs 78.6%, p = 0.001). Gross-total resection was achieved less frequently in frail patients (44.8% vs 24.3% vs 23.1%, p = 0.030). Overall complication rates were similar; however, increasing frailty was associated with higher rates of postoperative mortality (0% vs 2.8% [1/36] vs 7.7% [1/13], p = 0.018), pneumonia (0.5% [1/195] vs 2.8% [1/36] vs 15.4% [2/13], p = 0.006), and reintubation (2.6% [5/195] vs 2.8% [1/36] vs 30.8% [4/13], p = 0.002). Higher frailty was associated with a stepwise rise in median [IQR] LOS (5 [3–8] days vs 7 [4–12] days vs 13 [6.5–21.8] days, p < 0.001) and remained an independent predictor of extended LOS on multivariable analysis (β = 1.729 per point, p = 0.006). Rates of non-home discharge showed a similar pattern (9.2% vs 30.0% vs 64.3%, p < 0.001), with frailty independently predicting non-home discharge (OR 2.352, 95% CI 1.527–3.822). Unplanned 90-day readmission rates were significantly higher in the mildly frail cohorts (22.5% vs 45.7% vs 53.8%, p = 0.002). CONCLUSIONS The mFI-11 scores independently predicted perioperative morbidity following craniopharyngioma resection. Incorporating frailty screening into preoperative screening may improve risk stratification, family and patient counseling, and discharge planning.