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Phase II randomised controlled trial on postoperative radiotherapy, in high-risk, resected, non-medullary, non-anaplastic thyroid cancers (THYRO-RT).
6082 Background: Locally advanced thyroid cancers have high rates of locoregional recurrence after standard treatment with surgery and radioactive iodine (RAI). Repeated surgery and RAI in recurrent disease contributes to significant morbidity. Retrospective studies have shown that the addition of adjuvant external beam radiotherapy (EBRT) may improve locoregional control in selected high-risk patients. This randomized phase II trial evaluated the role of adjuvant EBRT in reducing locoregional recurrence (LRR) in high-risk resected thyroid cancer. Methods: This was a phase II randomized controlled trial comparing surgery with RAI versus surgery with RAI plus EBRT in high-risk resected thyroid cancers. Patients with resected non-medullary, non-anaplastic thyroid cancer and predefined high-risk features were randomized (1:1) between July 2013 and April 2021. Patients randomized to EBRT received 6-MV IMRT with daily IGRT to a dose of 60 Gy in 30 fractions over six weeks. The primary endpoint was locoregional recurrence. Secondary endpoints included acute and late toxicity (LENT-SOMA scale) and quality of life. Results: Seventy-two patients were randomized, with 36 assigned to each arm; five patients withdrew consent. Overall, 86.6% had pathological T4a disease and 89.6% had pathological N1a/b disease. Further, 71.6% demonstrated extracapsular nodal extension and R1/R2 resection was seen in 49.3% of the patients. With a median follow-up of 102 months, on an intention to treat analysis, LRR occurred in 19.4% of patients in the surgery + RAI arm (OR 1.376, 95% CI 0.852-2.222), and 9.7% in the Surgery+RAI+EBRT arm (OR 0.611, 95% CI 0.299-1.632). This difference was not statistically significant (p = 0.263). Logistic regression analysis did not identify any factor significantly associated with LRR. There was no significant difference in 10 year-locoregional recurrence free survival between the two arms. Grade 3 acute radiation induced toxicity was observed in two patients. At last follow up, there was one death in the entire cohort, which was non-cancer related. Conclusions: In this very high-risk, resected thyroid cancer cohort, the addition of adjuvant EBRT to surgery and RAI did not significantly decrease locoregional recurrence. The overall acute toxicity was low and if adjuvant EBRT is indicated, it can be delivered with acceptable toxicity. Clinical trial information: NCT03669432 .
Biomarker study of BND-22 in combination with cemiplimab in solid tumors.
TPS2676 Background: Immune checkpoint inhibitors benefit only a subset of patients, indicating a need to identify other therapeutic targets and understand the role of tumor microenvironment in shaping immune response. Immunoglobulin-like transcript-2 (ILT2) is an inhibitory receptor expressed on monocytes, dendritic cells, NK cells, and subset of T cells. ILT2 binds multiple MHC class-I molecules, with highest affinity for HLA-G, which is frequently overexpressed in solid tumors. Engagement of HLA-G/ILT2 pathway inhibits key immune functions, including cytotoxicity, cytokine production, antigen presentation, phagocytosis and proliferation. ILT2 expression can be upregulated following anti PD-1 therapy, suggesting a mechanism of resistance to checkpoint blockade. Inhibition of this pathway could potentially promote antitumor immune responses. BND-22, a first-in-class humanized IgG4 mAb, selectively binds to ILT2 on NK/T cells/macrophages, blocking its interaction with HLA-G. In preclinical studies and in a phase I trial, BND-22 alone and in combination with a PD-1 inhibitor demonstrated enhanced anti-tumor activity. The study revealed a dose-dependent activation in immune markers. Building on this finding, we initiated a phase II biomarker study (NCT06651593) of BND-22 in combination with cemiplimab, a recombinant human IgG4/kappa anti–PD-1 mAb, to further understand immune biology and explore the tumor microenvironment. Methods: The study has 2 patient cohorts: Cohort 1: patients with cholangiocarcinoma, who have had prior immunotherapy and Cohort 2: patients with microsatellite stable colorectal cancer and ovarian cancer who are anti–PD-1/PD-L1 naïve. Approximately 40 patients will be enrolled (10 per indication and an additional 10 to the best performing indication). The dose of BND-22 is 10 mg/kg IV on Day 1 every 3 weeks (Q3W), based on the dose escalation trial (NCT04717375). The dose of cemiplimab is the FDA-approved dose of 350 mg IV on Day 1 Q3W, starting at C2D1. Each cycle = 21 days. The combination will be administered for a max of 24 months in the absence of progression or until progression, unacceptable toxicity, death, withdrawal of consent, or discontinuation. Biopsy tissues and peripheral blood samples for biomarker analyses will be collected at baseline, on treatment, and at progression (for patients with CR, PR, or SD≥6 months). The primary objective is 1) to identify biomarkers related to mechanism of action and predictors of response, resistance, and survival 2) evaluate the association between the biomarkers and outcomes. The secondary objective is to evaluate efficacy, safety, and tolerability of this combination; identify imaging characteristics predictive of response and toxicity; and, evaluate TCR beta variable polymorphism and its relationship with immune-related adverse events. Enrollment is ongoing; 2 patients in Cohort 1 and 10 patients in Cohort 2 have been treated. Clinical trial information: NCT06651593 .
Immune checkpoint inhibitor–induced autoimmune type 1 diabetes: Clinical characteristics and management outcomes from a multicenter retrospective study.
e23330 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 pathways have significantly improved survival in multiple cancers but may trigger immune-related adverse events (irAEs). Autoimmune type 1 diabetes mellitus (T1DM) is a rare endocrine irAE with permanent insulin dependence. This study aimed to characterize the clinical profile, onset, and outcomes of ICI-induced T1DM across multiple oncology centers. Methods: We retrospectively reviewed adult patients who developed new-onset insulin-dependent diabetes following ICI therapy between January 2018 and August 2025 across three tertiary cancer centers. Diagnosis of ICI-induced T1DM required hyperglycemia with low or absent C-peptide and/or positive pancreatic autoantibodies. Data on demographics, cancer type, ICI class, time to onset, presentation, and outcomes were analyzed descriptively. Results: Among 3,254 patients treated with ICIs, 27 (0.83%) developed autoimmune T1DM. Median age was 62 years (range, 38–79), and 56% were male. Most cases followed PD-1 inhibitor therapy (78%). Median onset time was 9 weeks (range, 3–40) after treatment initiation. Diabetic ketoacidosis occurred in 70% of cases at presentation. Anti-GAD antibodies were positive in 46%, and mean C-peptide level was 0.10 ng/mL. All patients required lifelong insulin. ICI therapy was resumed in 41% after stabilization. No diabetes-related deaths occurred. Oncologic outcomes were comparable to the overall treated cohort. Conclusions: ICI-induced autoimmune T1DM is an uncommon but irreversible immune-related adverse event. Early glucose monitoring and patient education are essential for timely detection and prevention of ketoacidosis. Multidisciplinary coordination between oncology and endocrinology teams facilitates safe ICI continuation without compromising cancer outcomes.
Adebrelimab in combination with anlotinib and chemotherapy as neoadjuvant therapy for resectable stage II-III non–small cell lung cancer (NSCLC): A prospective, single-arm, phase II trial.
e20073 Background: Immunotherapy combined with chemotherapy as neoadjuvant treatment for NSCLC has demonstrated significant clinical benefits, yet various treatment regimens continue to be explored during neoadjuvant therapy for resectable NSCLC. We report here the efficacy and safety of adebrelimab combined with anlotinib and chemotherapy in neoadjuvant treatment for stage II-III NSCLC. Methods: Eligible patients (pts) were resectable stage II and III (IIIA and T3N2M0 IIIB) NSCLCs without EGFR/ALK/ROS1 alterations. Patients received neoadjuvant treatment with adebrelimab＋anlotinib , 4 cycles and chemotherapy 3-4 cycles, followed by surgical resection.The primary endpoint was major pathological response (MPR), secondary endpoints inluding pathological complete response rate (pCR), objective response rate (ORR), event free survival (EFS), overall survival (OS), and safety (NCI-CTCAE v5.0). Results: From March 2025 to January 2026, 44 pts was screened and 37 eligible pts enrolled. 81.1% were male, 62.2% had squamous cell carcinoma, 78.4% of pts had a history of smoking, and 75.7% were stage III pts. As of January 24, 2026, all 37 pts received at least one cycle of neoadjuvant therapy, with 28 pts completed the full four-cycle regimen. Surgery was performed in 25 pts (1 pts refused surgery, 1 pts withdrew informed consent, and1 pts died unexpectedly), 100% achieved R0 resection. Pathological assessment was completed in 25 patients, demonstrating pCR in 14 (56.0%) and MPR in 18 (72.0%). 34 pts had an objective response per RECIST v1.1, including 6 with complete response and 17 with partial response. The ORR was 67.6% and DCR was 97.1%. 35 pts were included in the safety analysis. Grade ≥3 treatment-related adverse events included thrombocytopenia (11.4%), lymphopenia (8.6%) and leukopenia (5.7%). One patient died due to an accidental fall. No surgical delays occurred due to adverse events. No deaths related to tumor treatment were identified. Conclusions: Adebrelimab in combination with anlotinib and chemotherapy as neoadjuvant therapy showed a high proportion of MPR and pCR for resectable stage II-III NSCLC, and the safety profile was well tolerated. Future clinical studies with larger sample sizes are needed to be validated. Clinical trial information: ChiCTR2500100571.
Longitudinal analysis of PD-1 receptor occupancy in spleen and tumor-infiltrating lymphocytes in a murine model.
e14580 Background: Anti-PD-1 antibodies restore T-cell-mediated anti-tumor immune responses by blocking the interaction between PD-1 and programmed cell death ligand 1 (PD-L1). Following anti-PD-1 administration, PD-1 receptor occupancy (RO) on circulating T cells has been shown to vary widely in a dose-independent manner. We have previously demonstrated that subset-specific PD-1 RO on circulating T cells is associated with clinical outcomes. Given that tumor-infiltrating lymphocytes (TILs) are more directly involved in anti-tumor immunity than peripheral T cells, RO on TILs is expected to be more precisely correlated with anti-tumor activity. However, research to date has focused almost exclusively on peripheral T cells, and an analysis of PD-1 RO on TILs has not yet been reported. This study aimed to clarify the distinct kinetics of PD-1 RO on TILs and systemic T cells. Methods: BALB/c mice bearing CT-26 colon tumors were treated with a single dose (150 μg) of rat anti-PD-1 antibody on day 10 post-tumor inoculation. Spleen and TILs were harvested at 24 hours, 1 week, and 2 weeks post-injection. PD-1 RO was assessed via flow cytometry using anti-rat IgG to detect in vivo-bound antibody and anti-mouse PD-1 to assess total receptor expression. Based on the antibody binding status, T-cell subsets (CD8+, CD4+, and Foxp3+ Tregs) were classified into three functional states: saturated (PD-1−IgG+), representing complete receptor blockade where in vivo antibody prevents subsequent PD-1 detection; unsaturated (PD-1+IgG+), representing partial binding; and unbound (PD-1+IgG−). Matched-pair analysis was performed between splenic and intratumoral T cells within each individual mouse. Results: At 24 hours post-administration, PD-1 receptor saturation was approximately 40% in both the spleen and tumor-infiltrating lymphocytes (TILs) across total CD3+ T cells. RO on splenic T cells remained relatively stable at 40% after 1 week, and then decreased to 10% by 2 weeks. In contrast, RO on TILs exhibited a much more rapid decline, with RO dropping sharply to approximately 4% at 1 week and then to 2% by 2 weeks. Matched-pair analysis of individual mice confirmed that RO was significantly lower in TILs than in splenic T cells as early as 1 week post-injection. Despite this overall trend, inter-individual and subset-specific variability was also noted. Conclusions: Our results demonstrate that the kinetics of PD-1 blockade within the tumor environment are distinct from those in systemic circulation. This discrepancy suggests that systemic monitoring may not fully reflect the actual state of PD-1 blockade within the tumor microenvironment. We are currently investigating the correlation between these intratumoral RO dynamics and anti-tumor responses to identify more precise parameters for therapeutic success.
Comparative real-world survival outcomes of ribociclib and abemaciclib in breast cancer.
11167 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), including ribociclib and abemaciclib, are widely used in hormone receptor–positive, HER2-negative high-risk early-stage breast cancer in combination with endocrine therapy. While randomized trials have demonstrated survival benefits, comparative real-world outcomes between these agents remain limited. This study evaluates all-cause mortality among patients treated with ribociclib versus abemaciclib using a large real-world database. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network, a global federated health research network, including adult patients with breast cancer treated with ribociclib (n = 7,697) or abemaciclib (n = 12,626) within the past 20 years. Two cohorts were constructed and balanced using 1:1 propensity score matching (PSM) based on age at diagnosis, sex, and race. The primary outcome was all-cause mortality at 1, 3, and 5 years. Kaplan–Meier survival curves and Cox proportional hazards models were used to estimate survival probabilities and hazard ratios. Results: After PSM, a total of 15,374 patients were included (7,687 per cohort). Mean age was 60.2±13.5 years in the ribociclib cohort and 60.2±13.4 years in the abemaciclib cohort. Most patients were female (99%) and White (72%). At 1 year, survival probability for ribociclib was 91.5% compared with 89.0% for abemaciclib (hazard ratio 0.74, 95% CI 0.66–0.84; log-rank p < 0.001). There was no significant difference in survival probabilities at 3 years (70.1% vs 72.1%) or 5 years (56.6% vs 55.1%), with hazard ratios not significantly different from 1.0. Conclusions: In this real-world analysis, ribociclib use was associated with lower all-cause mortality at 1 year compared with abemaciclib; however, this difference did not persist at longer follow-up. These findings should be interpreted cautiously given potential residual confounding and differences in clinical indications between agents. Further studies accounting for disease stage and treatment context are warranted.
Tumor recurrence or treatment effect? Large multi-institutional evaluation of an AI risk assessment model in glioma and brain metastases.
2080 Background: Distinguishing true tumor recurrence (TuR) from radiation necrosis (RN) on post-treatment MRI scans remains a major neuro-oncology challenge. We hypothesized that an integrated Spatial, Morphologic, and Textural radiomics risk (SMART-risk) model that comprehensively captures local and spatial organization of lesion heterogeneity, can unravel distinct biology across TuR and RN, on clinical MRI; and improve distinction over a data-driven ResNet50 deep learning model. Methods: We retrospectively collected multi-institutional post-treatment MRI cohorts: brain metastases (233 studies; from Cleveland Clinic (CCF), University Hospitals Cleveland (UH), University of Wisconsin (UW); and glioma (340 studies from Indiana University (IU), Dana-Farber Cancer Center, Thomas Jefferson University (TJU), and CCF). Over 80% of the studies were pathologically confirmed as TuR or RN. Institution-held-out external testing was performed (metastases: train CCF+UH, test UW; glioma: train IU+TJU+Dana-Farber Cancer Center, test CCF). Following segmentation, 944 radiomic features/lesion were extracted including graph-based spatial organization of tumor heterogeneity (GrRAiL), local gradient texture heterogeneity (COLLAGE), Haralick, and morphology. LASSO-selected features were integrated in a Random Forest classifier. Performance metrics included cross validation accuracy (CV), test accuracy, F1 score, and AUC; interpretability used SHAP. Comparison was performed with a ResNet50 baseline model. Results: SMART-Risk demonstrated consistent discrimination on the institution-held-out external test set (Table 1) with ~80% accuracy; ~10-15% improvement over a ResNet50 model. SHAP analysis indicated that features corresponding to spatial organization and local heterogeneity, i.e. average path length, node count and entropy measures, were dominant contributors (Mann–Whitney U test, p ≤ 0.001). Recurrent tumors showed higher spatial complexity and greater heterogeneity than RN. Conclusions: SMART-Risk may provide a noninvasive approach to distinguish TuR from RN on routine post-contrast T1-weighted MRI. By integrating spatial-organization (GrRAiL), texture (COLLAGE/Haralick), and morphology features, SMART-Risk captures complementary signatures and may improve discrimination compared with any single feature family. An AI-based SMART-Risk approach may reduce diagnostic ambiguity, support earlier treatment decisions, and avoid unnecessary invasive procedures. Test set performance of SMART-Risk vs ResNet50 for TuR vs RN classification. Cohort (external test site) Model CV accuracy Test accuracy F1 score AUC Metastatic cohort (UW) SMART-Risk 0.78 ± 0.08 0.79 0.78 0.86 Metastatic cohort (UW) ResNet50 0.70 ± 0.09 0.60 0.67 0.63 Glioma (CCF) SMART-Risk 0.83 ± 0.06 0.80 0.84 0.87 Glioma (CCF) ResNet50 0.69± 0.10 0.65 0.77 0.70
First-line GemCis ± immunotherapy vs FGFR inhibition in ctDNA-detected <i>FGFR2</i> fusion–positive advanced cholangiocarcinoma: A real-world analysis.
4159 Background: Advanced cholangiocarcinoma (aCCA) carries a poor prognosis. Approximately 40% of aCCA harbor targetable biomarkers; however, standard first-line (1L) therapy is gemcitabine-cisplatin (GemCis) ± immune checkpoint inhibitors (ICI), regardless of genomic status. Emerging data suggest that oncogene-driven molecular subsets of aCCA may exhibit reduced sensitivity to ICI, raising questions about the benefit of adding ICI to chemotherapy in genomically defined populations. Therefore, we compared outcomes for aCCA pts with ctDNA-detected FGFR2 fusions ( FGFR2 +) treated with targeted therapy vs. GemCis ± ICI. Methods: Real-world data was sourced from InfinityAI Data Library, a database combining de-identified genomic information from Guardant360 (Guardant Health, Palo Alto, CA) and clinical data from administrative claims. aCCA pts with an FGFR2 fusion detected prior to 1L therapy between Sept. 2018 and June 2025 were analyzed. Outcomes were assessed via real-world time to treatment discontinuation (rwTTD), real-world time to next treatment (rwTTNT) and real-world overall survival (rwOS) in months with 95% confidence intervals. Log-rank tests were used to compare Kaplan-Meier survival curves. Results: 149 FGFR2 + aCCA pts with treatment and outcomes data were identified. 18.1% (27) were treated with GemCis, 45.6% with GemCis + ICI (68), and 19.5% (29) with FGFRi. FGFR2 + pts treated with 1L FGFRi had improved rwTTD, rwTTNT, and rwOS compared to GemCis and GemCis + ICI, with significantly improved rwTTD in those treated with FGFRi vs GemCis + ICI (Table 1). Based on these data, the addition of ICI to GemCis was not associated with improved outcomes in FGFR2+ pts. Conclusions: Real-world outcomes in ctDNA-detected FGFR2+ aCCA did not improve with addition of ICI to 1L GemCis. In contrast, 1L FGFRi was associated with longer treatment duration and delayed need for subsequent therapy. These findings suggest standard chemo-immunotherapy may not be optimal for all biomarker-defined aCCA subgroups and support the use of ctDNA testing to inform biomarker-drive 1L treatment selection abd sequncing strategies, warranting prospective validation. Outcomes in FGFR2+ pts by 1L therapy. rrwTTD rrwTTNT rrwOS FGFRi vs GemCis 9.1 (4.9-11.5) vs 4.2 (2.3-6.2) HR=0.68, p=0.22 20.8 (8.3-20.8) vs 13.8 (5.6-30.3) HR=0.64, p=0.33 NR (16.9-NR) vs 17.5 (10.3-28.4)HR=0.48, p=0.16 FGFRi vs GemCis + ICI 9.1 (4.9-11.5) vs 5.2 (3.9-7.8)HR=0.62, p=0.03 20.8 (8.3-20.8) vs 8.9 (7.9-NR) HR=0.51, p=0.06 NR (16.2-NR) vs 20.9 (10.7-NR)HR=0.43, p=0.11 GemCis vs GemCis + ICI 4.2 (2.3-6.2) vs 5.2 (3.9-7.8) HR=0.91, p=0.91 13.8 (5.6-30.3) vs 8.9 (7.9-NR) HR=0.8, p=0.61 17.5 (10.3-28.4) vs 20.9 (10.7-NR) HR=0.89, p=0.69
AI-driven TILs spatial analysis to identify high-density hot spots as a superior prognostic marker in triple-negative breast cancer.
e12562 Background: Tumor-infiltrating lymphocytes (TILs) are a robust prognostic biomarker in triple-negative breast cancer (TNBC). However, conventional whole-slide mean density overlooks spatial heterogeneity and potential signals from localized hot spots. We systematically analyzed TIL distribution across multiple spatial scales to identify the optimal evaluation method for prognostication. Methods: We analyzed 61 node-positive TNBC patients who underwent primary surgery without neoadjuvant therapy, selected from 3,902 breast cancer resection cases (2002-2016). Our AI-based pathological image analysis tool, DeepPathFinder, segmented epithelium and lymphocytes, with stroma defined as non-epithelial regions. Pathologist-annotated tumor bed regions were divided into square tiles of 250, 500, and 1000 μm for multi-scale analysis. For each patient and scale, we calculated stromal lymphocyte density per tile and derived patient-level distribution quantiles (Q25, Q50, Q75, and Q90). The conventional TILs score was defined as the ratio of lymphocyte area to stromal area across the entire WSI. Patients were dichotomized into high and low groups based on the cohort median. Survival curves were compared using the log-rank test, and hazard ratios (HR) were estimated via Cox regression. Results: With 23 DFS and 21 OS events, higher quantiles (Q75, Q90) consistently showed superior stratification across all scales. For DFS, 1000-μm hot spot density (Q90) provided the most robust stratification (HR 0.25, 95% CI 0.10-0.63, p = 0.002), significantly outperforming the conventional TILs score (HR 0.40, p = 0.032). For OS, both methods showed similar value (Q90: HR 0.28, p = 0.006; TILs score: HR 0.29, p = 0.006). Conclusions: Optimizing spatial resolution to capture 1000-μm high-density hot spots provides stronger prognostic signals than whole-slide averages, highlighting spatial immune architecture as a critical survival determinant in TNBC. Multi-scale prognostic analysis of stromal TILs density metrics. Metric 250μm DFS 250μm OS 500μm DFS 500μm OS 1000μm DFS 1000μm OS Q25 -** -** 0.68 (0.30-1.55) 0.3584 0.62 (0.26-1.48) 0.2775 0.41 (0.17-0.96) 0.0345* 0.35 (0.14-0.88) 0.0201* Q50 0.41 (0.17-0.96) 0.0345* 0.35 (0.14-0.88) 0.0201* 0.41 (0.17-0.96) 0.0345* 0.35 (0.14-0.88) 0.0201* 0.43 (0.18-1.01) 0.0462* 0.37 (0.15-0.93) 0.0276* Q75 0.35 (0.14-0.84) 0.0146* 0.37 (0.15-0.93) 0.0276* 0.26 (0.10-0.66) 0.0023* 0.27 (0.10-0.71) 0.0046* 0.33 (0.14-0.81) 0.0104* 0.36 (0.14-0.90) 0.0221* Q90 0.26 (0.10-0.66) 0.0023* 0.28 (0.11-0.73) 0.0054* 0.33 (0.14-0.81) 0.0104* 0.37 (0.15-0.92) 0.0252* 0.25 (0.10-0.63) 0.0015* 0.28 (0.11-0.73) 0.0057* Note: Values shown as HR (95% CI) p-value. *p<0.05. **Excluded due to predominance of zero values (>70%), preventing stratification.
Phase 1/2 study of CLIO-8221, a HER2-targeted, dual-payload exatecan and ATR inhibitor antibody-drug conjugate (ADC) in patients with advanced HER2-expressing solid tumors.
TPS3162 Background: CLIO-8221 is a novel anti-HER2 ADC designed to overcome topoisomerase 1 inhibitor (Topo1i) resistance by incorporating both Topo1i (exatecan) and ataxia telangiectasia and rad3-related protein inhibitor (ATRi; berzosertib) payloads. Enabled by proprietary dual-payload ADC linker technology, CLIO-8221 uses an Fc-engineered trastuzumab, site-specifically conjugated with a stable protease-cleavable linker designed for optimal efficacy and tolerability. Trastuzumab deruxtecan (T-DXd) has redefined the treatment paradigm for HER2-expressing breast cancer and is emerging as a frontline treatment option. However, most patients develop resistance and disease progression. Topo1i-induced replication stress triggers activation of the DNA damage response pathway, which is an important driver of Topo1i resistance. Studies show that ATRi synergizes with Topo1i to enhance DNA damage and increase antitumor activity. In preclinical studies, CLIO-8221 binds with high affinity and specificity to HER2-expressing tumor cells and is rapidly internalized to release the Topo1i and ATRi payloads to drive direct tumor cell killing with a strong bystander effect. CLIO-8221 shows superior in vivo efficacy across tumor models with a range of T-DXd sensitivity, inducing tumor regression after a single dose in T-DXd resistant and refractory xenograft models. Additionally, CLIO-8221 is designed to minimize off-target uptake through Fc engineering for abrogated FcγR binding, and a proprietary hydrophilic linker for reduced macropinocytosis. CLIO-8221 is well tolerated in nonclinical toxicity studies in non-human primates. Methods: CLIO-8221-001 is a Phase 1/2, first in human dose-escalation and -expansion study. Eligible patients are adults with metastatic or unresectable HER2-expressing solid tumors, including those who previously received T-DXd. Patients must have measurable disease per RECISTv1.1 and have previously received therapies known to confer clinical benefit unless ineligible, refused by the patient, or not available in the region. CLIO-8221 will initially be given by intravenous infusion on Day 1 of a 21-day cycle; treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to assess the safety and tolerability of CLIO-8221 and to identify the maximum tolerated dose, if reached, and recommended Phase 2 dose. Phase 1 of the study utilizes a BOIN dose-escalation design with an expansion phase, while Phase 2 comprises tumor-specific expansion cohorts treated at the doses recommended from Phase 1. Antitumor activity, PK, immunogenicity, and biomarkers including HER2 status and ctDNA dynamics will also be evaluated. Enrollment is planned at sites in Australia, US, and China (NCT07300943). Clinical trial information: NCT07300943 .
Clinical significance of the preoperative cachexia index as a prognostic predictor in patients with extrahepatic cholangiocarcinoma undergoing radical surgery.
e16336 Background: The cachexia index (CXI) has been proven to have prognostic value in various tumors. Extrahepatic cholangiocarcinoma (ECC) is an aggressive malignancy with poor postoperative outcomes. Aim of this study was to evaluate the prognostic significance of CXI in ECC patients undergoing radical surgical resection. Methods: A total of 244 patients diagnosed with ECC who underwent radical surgical resection from January 2016 to December 2021 were retrospectively involved. CXI was calculated using the formula: CXI = (skeletal muscle index × serum albumin level) / neutrophil-to-lymphocyte ratio (NLR). Clinicopathological characteristics and survival outcomes were compared between the low-CXI and high-CXI groups. Results: A total of 244 ECC patients were divided into low-CXI group (n = 122) and high-CXI group (n = 122) according to the median value. Patients in the low-CXI group had a lower skeletal muscle area(SMA), hemoglobin, lymphocyte, serum sodium, serum calcium, serum phosphorus, and a higher total bilirubin, conjugated bilirubin, alkaline phosphatase. The median overall survival(OS) and disease-free survival(DFS) times of the low-CXI group were significantly worse than those of the high-CXI group(OS, 38 vs 53 months, p = 0.0288; DFS, 34 vs 53 months, p = 0.0398). Multivariate Cox regression analysis revealed that age(HR = 1.032, 95%CI = 1.007-1.057, p = 0.010), a preoperative CXI(HR = 0.996, 95%CI = 0.991-1.000, p = 0.047), TNM stage(p < 0.001), and perineural invasion(HR = 0.483, 95%CI = 0.290-0.805, p = 0.005) were prognostic factors for ECC patients undergoing radical surgery. No significant prognostic correlation was observed between CXI levels and outcomes in the high CA19-9 group(p = 0.1431) and hilar cholangiocarcinoma group(p = 0.1649). Conversely, in the CA199-normal group(p = 0.0324), jaundiced group(p = 0.0353), non-jaundiced group(p = 0.0138), and distal cholangiocarcinoma group(p = 0.0324), the low-CXI group consistently demonstrated poorer prognosis. Conclusions: Preoperative CXI can serve as a useful prognostic biomarker for postoperative outcomes in ECC patients.
Oral mucin expression in the early diagnosis of esophagogastric cancer.
e16099 Background: Challenges in early diagnosis of esophagogastric carcinoma (EGC) may partly explain its poor long-term survival and why only 37.5% of patients are eligible for potentially curative treatment with perioperative chemo(radio)therapy and surgical resection. A non-invasive risk stratification test that could identify patients with early EGC is urgently needed. Mucins MUC2 and MUC5AC are abundant in the oral cavity and the upper gastrointestinal (GI) tract. They may be implicated in EG tumorigenesis via pro-inflammatory pathways and interaction with the microbiome. This study examines whether salivary mucin expression could yield potential markers of early EGC. Methods: A multi-center observational cohort study was conducted at two specialist cancer centers in the UK following obtainment of ethical approval (Ref 23/PR/0816). Subjects with benign upper GI diseases including gastro-esophageal reflux, Barrett’s metaplasia or EGC were recruited. Whole saliva was collected immediately prior to upper GI endoscopy or surgery, and tissue biopsies during endoscopy or esophagogastrectomy. Clinical data including medications, oral health and smoking history were collected from all subjects. Expression of MUC2 and MUC5AC , and pro-inflammatory cytokines IL1β and IL6 were evaluated by RT-qPCR. The ability of salivary mucin expression to distinguish subjects with cancer from other recruited subjects was evaluated by receiver operating characteristic (ROC) analysis yielding area under the curve (AUC) values, and logistic regression in GraphPad Prism version 10.1.2. Statistical significance was confirmed when p< 0.05. Results: A total of n= 217 subjects were recruited: n= 47 with upper GI symptoms, n= 42 with Barrett’s metaplasia and n= 128 with EGC. Expression of salivary MUC2 mRNA was lower in Barrett’s metaplasia (p< 0.05) and treatment- naïve EG adenocarcinoma tissue (p< 0.05) compared to subjects with benign upper GI diseases. In comparison, MUC2 mRNA expression was higher in EG tumor tissue than in benign upper GI disease. Expression of IL1β and IL6 mRNA expression in tumor correlated positively with MUC2 mRNA in tumor (p< 0.05) suggesting an association between mucins and pro-inflammatory pathways in tumorigenesis. ROC curve analysis demonstrated that salivary MUC2 expression was able to distinguish subjects with esophageal and type 1-2 gastro- esophageal junction (GEJ) adenocarcinoma, and type 3 GEJ and gastric adenocarcinoma from benign upper GI diseases with an AUC of 0.912 and 0.968 (p< 0.0001). Univariate logistic regression showed that male gender (p= 0.00439) and smoking (p= 0.0208) were significantly associated with EGC. Conclusions: Salivary mucin expression can potentially distinguish subjects with EGC from those with benign upper GI diseases. This research forms the basis for further studies investigating the use of oral mucin expression in early diagnosis of EGC.
Primary analysis of pembrolizumab combined with chemotherapy in platinum-sensitive recurrent low-grade serous ovarian cancer: The NOGGO PERCEPTION phase II study.
5595 Background: Low-grade serous ovarian cancer (LGSOC), a rare ovarian malignancy, exhibits a very limited responsiveness to chemotherapy. There is a pressing need for new therapeutic combinations with modern agents to enhance response rates and prognosis in this patient subgroup. Immune checkpoint inhibitors offer a promising pathway, having shown effectiveness in various malignant diseases, including selected cases of ovarian cancer. If our trial should show pembrolizumab effectivity in LGSOC, it would be a signal and impulse for future clinical studies in this rare disease. Methods: This multi-center, single-arm phase II study evaluates pembrolizumab in combination with platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin [PLD] or carboplatin plus gemcitabine) and as maintenance therapy in recurrent LGSOC. Eligible patients include those with disease progression or recurrence ≥6 months post prior platinum-based therapy and ECOG performance status 0-1. The primary endpoint is the 12-month progression-free survival (PFS) rate. Secondary endpoints include response rate (RR), PFS and ORR based on Ki67 expression. Using Simon’s two-stage design, 33 patients were enrolled. Success is defined as ≥11 patients achieving 12-month PFS. Assuming a true PFS rate of 40%, the study has 5% type I error and 80% power. Results: Data from 33 patients were evaluated. At data cut-off, 12 patients were progression free at 12-months (median PFS 15.5 months) while 19 patients progressed or died within 12 months (median PFS 5.6 months). Overall PFS median was 8.4 months. Comparing the subgroups of pre-treatment Ki67 expression <3.6% vs. ≥ 3.6%, the median PFS was 5.1 vs. 8.8 months. Four patients remain on pembrolizumab treatment; two of these have not yet reached the 12-month PFS endpoint. Median patient age was 52 years (range: 37-81), with ECOG performance status 0 in 30 patients (90.9%). Most patients had one prior chemotherapy line (61.1%; range: 1-5). Chemotherapy regimens included carboplatin + PLD (75.8%) and carboplatin + gemcitabine (24.2%). SAEs were reported in 22 patients (66.7%), with 11 (33.3%) considered treatment-related. Conclusions: The study achieved its primary objective in terms of the 12-months PFS and thus suggests efficacy of pembrolizumab in patients with platinum-sensitive recurrent LGSOC. Clinical trial information: 2023-508155-40-00.
A phase 2 trial of cetuximab for patients with locally advanced/metastatic chordoma.
11527 Background: Unresectable/metastatic chordoma is a rare notochordal malignancy with no approved systemic treatments. EGFR is widely expressed on chordomas. Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that inhibits EGFR signaling. In vivo testing of cetuximab has demonstrated growth inhibition and regression of chordoma. An investigator-initiated, single center, phase II study (NCT05041127) was developed to evaluate the efficacy of cetuximab for patients (pts) with advanced/metastatic chordoma. Methods: Eligible pts were ≥18 years of age, had adequate organ function, and had an ECOG performance status (PS) of ≤2. Any prior line of therapy was allowed except EGFR inhibitors. A minimum of 10 pts and maximum of 29 pts were to be enrolled onto the trial based on Simon's two-stage optimal design (H 0 RR 5% vs H 1 RR 20%; one-sided α=0.05; power=80%). Pts received cetuximab 500 mg/m 2 IV Q2 weeks until disease progression or unacceptable toxicity. The primary end point was response rate (RR) according to RECIST 1.1. Secondary objectives included safety/tolerability and survival metrics. Efficacy was assessed in the modified intention-to-treat (mITT) population (≥1 dose; ≥1 post-baseline scan). Exploratory objectives included analysis of the EGFR pathway at 2 time points from research-related biopsies. Pt reported outcomes (PROs) were assessed with MDASI (general and spine) questionnaires at several time points on study. Results: From May 2022 to Dec 2025, 29 pts enrolled. 4 were excluded from the efficacy analysis (2 withdrawal, 1 cetuximab allergy, 1 has not completed the 1 st imaging assessment). Median age was 58 years (range 21-76), 15 (58%) were men, and 24 (92%) had ECOG PS of 0 or 1. The most common primary site was skull base (46%). Tumor was classified as locally recurrent in 8 pts (31%) and metastatic in 18 pts (69%). One median line of prior systemic therapy was noted (range, 0-6). At a median follow up of 28.7 months, 12 pts (48%) had radiographic cytoreduction (any tumor reduction [ATR]), but only 2 pts (8%) had a partial response (PR). Neither PR was associated with an EGFR gene alteration. Stable disease (SD) was noted in 23 pts (92%). Preliminary median PFS and median OS was 9.9 months (95% CI, 6.3 to 13.4) and 38.8 months (95% CI, 18.6 to NR), respectively. Significantly longer PFS was observed in SD-ATR (log-rank p=0.038), with median of 14.2 months in SD-ATR versus 9.6 months in SD without tumor reduction. 7/26 pts (27%) experienced a grade 3 cetuximab-related adverse event (AE), the most common being rash in 4 pts (15%). No grade 5 AE related to cetuximab was reported. Dose reduction occurred in 2 pts (8%). 4 pts (15%) discontinued the study due to toxicity. 4 pts remain on study. Conclusions: Although the primary end point has not been reached, 2 PRs are noted, and pts with SD-ATR have a longer PFS. Translational and PRO analysis are ongoing to better define biological predictors of cetuximab activity in chordoma. Clinical trial information: NCT05041127 .
Epidemiological trends and burden of retinoblastoma mortality in South Asia: A retrospective analysis from 1990 to 2023 with advanced machine learning forecasting to 2050.
e22610 Background: Retinoblastoma is a rare but highly curable pediatric malignancy, yet mortality remains substantial in low- and middle-income regions. Comprehensive evaluations of long-term mortality trends and future burden in South Asia are limited. We assessed temporal patterns of retinoblastoma mortality from 1990–2023 and projected trends through 2050. Methods: Age-standardized mortality rates (ASMRs) for retinoblastoma were obtained for South Asia and individual countries from 1990–2023 using IHME GBD 2023 data. Temporal trends were quantified using estimated annual percentage change (EAPC) with 95% confidence intervals (CIs), stratified by sex. Machine learning–based ARIMA time-series models were used to forecast ASMRs to 2050 with uncertainty intervals (UI). Results: Across South Asia, retinoblastoma mortality declined significantly from 1990–2023 (both sexes EAPC −3.38; 95% CI −3.63 to −3.13), with a steeper reduction among males (−3.69; −3.94 to −3.44) than females (−3.07; −3.34 to −2.80). Regional ASMRs decreased steadily over the study period, reflecting sustained improvements in survival. India demonstrated the most pronounced decline (both sexes EAPC −4.45; −4.68 to −4.22), with comparable reductions in males (−4.50; −4.76 to −4.25) and females (−4.40; −4.64 to −4.15). Bangladesh experienced substantial decreases in mortality (both sexes EAPC −1.81; −2.19 to −1.43), particularly among females (−2.57; −2.84 to −2.29). Nepal showed consistent declines across sexes, while Bhutan also demonstrated significant reductions. In contrast, Pakistan exhibited near-stable mortality trends (both sexes EAPC −0.23; −0.48 to 0.02), with a slight increase among females (0.08; −0.24 to 0.40). Forecasting analyses suggest continued declines in retinoblastoma mortality across most South Asian countries through 2050, although widening uncertainty intervals indicate persistent disparities. Conclusions: Retinoblastoma mortality has declined substantially across South Asia over the past three decades, with the most rapid improvements observed in India. However, heterogeneous trends highlight persistent inequities in early diagnosis and access to curative care. Location Sex EAPC Lower 95%CI Upper 95%CI Bangladesh Both -1.81 -2.19 -1.43 Bangladesh Female -2.57 -2.84 -2.29 Bangladesh Male -1.24 -1.71 -0.77 Bhutan Both -1.41 -1.79 -1.04 Bhutan Female -0.89 -1.29 -0.48 Bhutan Male -1.92 -2.28 -1.55 India Both -4.45 -4.68 -4.22 India Female -4.40 -4.64 -4.15 India Male -4.50 -4.76 -4.25 Nepal Both -2.34 -2.89 -1.78 Nepal Female -2.37 -2.93 -1.81 Nepal Male -2.31 -2.87 -1.75 Pakistan Both -0.23 -0.48 0.02 Pakistan Female 0.08 -0.24 0.40 Pakistan Male -0.77 -0.95 -0.58 South Asia Both -3.38 -3.63 -3.13 South Asia Female -3.07 -3.34 -2.80 South Asia Male -3.69 -3.94 -3.44
G8 geriatric score as a determinant of survival and treatment in metastatic breast cancer.
e24121 Background: Metastatic breast cancer in elderly women remains a major therapeutic challenge, with frequent undertreatment driven by concerns about frailty and toxicity. The G8 geriatric screening score has demonstrated prognostic value in older cancer populations, but its impact on treatment strategy and survival in metastatic breast cancer is poorly defined. This study aimed to evaluate the association between baseline G8 score, treatment patterns, and survival outcomes in a real-world cohort. Methods: We conducted a retrospective descriptive and analytic cohort study including 93 women aged ≥70 years with metastatic breast cancer treated between 2018 and 2024. All patients had baseline G8 assessment and were classified as impaired (≤14) or non-impaired ( > 14). Clinical, pathological, and therapeutic data were collected. Results: A total of 93 elderly women with metastatic breast cancer were included. The median age was 76.2 years (range 70–89). Fifty-eight patients (62.4%) had a G8 score ≤14. After a median follow-up of 26 months, median PFS was 14.6 months (95% CI: 12.8–16.4) in the G8 non-impaired group compared with 7.2 months (95% CI: 6.1–8.3) in the impaired group (HR 1.89; 95% CI: 1.21–2.95; p = 0.002). Median OS was 38.5 months (95% CI: 34.1–42.9) in patients with G8 > 14 versus 18.7 months (95% CI: 16.3–21.1) in those with G8 ≤14 (HR 2.31; 95% CI: 1.42–3.75; p < 0.001). In univariate analysis, G8 impairment, ECOG performance status ≥2, triple-negative subtype, presence of visceral metastases, and non-chemotherapy first-line treatment were significantly associated with worse OS. In multivariate Cox regression, G8 impairment remained independently associated with poorer OS (HR 2.08; 95% CI: 1.27–3.41; p = 0.004), after adjustment for performance status, tumor subtype, and treatment strategy. Conclusions: The G8 geriatric screening score is an independent prognostic factor for survival and treatment tolerance in elderly women with metastatic breast cancer. Its routine use could improve risk stratification and guide personalized therapeutic strategies in this vulnerable population.
Pyrotinib plus nab-paclitaxel as adjuvant therapy for patients with N0/N1mi, HER2-positive early-stage breast cancer: 3-year iDFS results of the phase II PHAEDRA trial.
533 Background: While dual anti-HER2 therapy is standard in the adjuvant setting for HER2-positive early breast cancer, treatment de-escalation is an attractive strategy for patients with low-risk disease. Previous studies (e.g., APT, ATEMPT) of adjuvant trastuzumab plus chemotherapy or T-DM1 monotherapy in this population reported 3-year invasive disease-free survival (iDFS) rates of 93.4%-98.7%. Pyrotinib, an irreversible pan-HER2 tyrosine kinase inhibitor, is effective in HER2-positive breast cancer; however, data supporting its use in the adjuvant setting for low-risk disease are limited. This study evaluated the efficacy and safety of adjuvant pyrotinib plus nab-paclitaxel in this population. Methods: This multicenter, single-arm, phase II trial enrolled women aged 18-75 with primary tumor size ≤3 cm and node-negative (N0) or micrometastases (N1mi), histologically confirmed HER2-positive early breast cancer. Patients received nab-paclitaxel (260 mg/m² IV, q3w) plus pyrotinib (400 mg PO, qd) for 12 weeks (4 cycles), followed by pyrotinib monotherapy (400 mg, qd) for one year. The primary endpoint was iDFS. Secondary endpoint was adverse events (AEs) graded by CTCAE v5.0. Results: From January 8, 2021, to September 21, 2023, 263 patients were enrolled and received treatment. Median age was 51 years; 60.8% (160/263) were hormone receptor-positive, and 97.7% (257/263) were node-negative. At the data cutoff (December 30, 2025), with a median follow-up of 36.2 months, 9 iDFS events were observed. The estimated 3-year iDFS rate was 96.8% (95% CI 93.4-98.5). One death occurred and overall survival data were immature. The most common grade ≥3 treatment-related AEs were diarrhea (50.6%), neutropenia (14.4%), and decreased white blood cell count (14.4%). No serious AEs were reported. Treatment interruption, dose reduction, and discontinuation due to AEs occurred in 12.2%, 3.4%, and 1.5% of patients, respectively. Conclusions: Adjuvant pyrotinib combined with nab-paclitaxel showed promising 3-year iDFS and a manageable safety profile in patients with low-risk, HER2-positive early breast cancer. This regimen represents a potential oral de-escalation strategy for this population. Clinical trial information: NCT 04659499 . Efficacy outcomes. Efficacy outcomes Pyrotinib + nab-Paclitaxel（n=263） Events, n(%) 9 (3.4) 24 months 36 months 48 months iDFS rate, (95% CI) 98.77(96.24, 99.60) 96.83(93.42, 98.49) 93.17(85.03, 96.96) DDFS rate, (95% CI) 99.18(96.76, 99.79) 98.77(96.23, 99.60) 95.03(86.00, 98.29) LRFS rate, (95% CI) 99.18(96.75, 99.79) 98.18(95.18, 99.32) 94.47(85.76, 97.92) iDFS: invasive disease-free survival; DDFS: distant disease-free survival; LRFS: locoregional recurrence-free survival.
Efficacy and safety of trifluridine–tipiracil with VEGF inhibitors and EGFR inhibitors in metastatic unresectable colorectal cancer: A network meta-analysis.
e15629 Background: Introduction:Metastatic unresectable colorectal cancer (mCRC) poses a particular challengewhen patients cannot receive standard first-line FOLFOX (5-fluorouracil, leucovorin, oxaliplatin)or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) because of age, comorbidities, or poorEastern Cooperative Oncology Group (ECOG) performance status. To guide treatment in thisunderstudied population, we conducted a network meta-analysis to indirectly compare theefficacy and safety of alternative regimens, including Trifluridine–tipiracil (TAS‐102), TAS‐102plus bevacizumab, TAS‐102 plus panitumumab, and capecitabine plus bevacizumab in mCRC. Methods: We manually searched major medical databases and identified 12 studies for directand indirect comparisons of alternative agents in mCRC. Forest plots were generated using Rsoftware using random effects model. Results: Progression‐free survival was significantly longer with capecitabine plus bevacizumab(MD 1.97 months; 95% CI 0.39–3.55) and TAS‐102 plus bevacizumab (MD 2.30 months; 95%CI 1.59–3.04) than with TAS‐102 alone, with no meaningful difference between the twocombinations (MD −0.35 months; 95% CI −1.75–1.06). Overall survival improved significantlyonly with TAS‐102 plus bevacizumab versus TAS‐102 monotherapy (MD 2.94 months; 95% CI1.45–4.44), while capecitabine plus bevacizumab and TAS‐102 plus panitumumab did notsignificantly prolong OS (MD 1.54 months; 95% CI −2.02–5.10 and MD 1.50 months; 95% CI−5.22–8.22, respectively). Grade ≥3 neutropenia was much less frequent with capecitabine plusbevacizumab than with TAS‐102 plus bevacizumab (OR 0.02; 95% CI 0.01–0.05) and TAS‐102alone (OR 0.04; 95% CI 0.02–0.10), and occurred less often with TAS‐102 alone than withTAS‐102 plus bevacizumab (OR 0.54; 95% CI 0.40–0.73). TAS‐102 plus bevacizumab achieveda significantly higher disease control rate than TAS‐102 alone (OR 2.55; 95% CI 1.72–3.78),whereas capecitabine plus bevacizumab showed a numerically but not significantly higher DCR(OR 1.99; 95% CI 0.99–4.02), with similar DCR between the two bevacizumab‐based regimens. Conclusions: Capecitabine plus bevacizumab and TAS‐102 plus bevacizumab both improve PFSversus TAS‐102 alone, but only TAS‐102 plus bevacizumab significantly prolongs OS.Capecitabine plus bevacizumab is associated with substantially less grade ≥3 neutropenia,while TAS‐102 plus bevacizumab provides the greatest improvement in disease control.
Effect of perioperative esketamine on postoperative recovery in breast cancer patients undergoing modified radical mastectomy: A systematic review and meta-analysis.
e24074 Background: Modified radical mastectomy (MRM) is associated with significant acute postoperative and potential chronic pain. Esketamine offers potent analgesia with a theoretically more favorable side-effect profile than racemic ketamine, though its impact on recovery appears dependent on dosing strategies. This NMDA receptor antagonist may mitigate central sensitization, which is critical for preventing persistent post-surgical pain. This study evaluated the effect of esketamine on pain intensity, quality of recovery, and clinical efficiency in the context of MRM. Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted, comparing perioperative esketamine to placebo or active control in patients undergoing MRM. Databases searched included PubMed, EMBASE, and Cochrane Library. Risk of bias was assessed using the Cochrane tool. Primary outcomes included 24-hour Visual Analogue Scale (VAS) pain scores and Day-1 Quality of Recovery-15 (QoR-15) scores. Secondary outcomes were the requirement for rescue analgesia, time to extubation, and duration of PACU stay. Random-effects models and subgroup analyses (bolus vs. infusion; dose levels) were utilized to investigate heterogeneity and clinical variables. Results: Nine RCTs (n = 749) met the inclusion criteria. Esketamine reduced 24-hour VAS scores (WMD -0.85; 95% CI -1.03 to -0.66). Subgroup stratification revealed this effect was associated with continuous infusion (WMD -1.07; 95% CI -1.20 to -0.94; I2 = 0%), whereas single-bolus administration showed no significant effect (WMD 0.01). Quality of recovery (QoR-15) scores improved (WMD 8.01; 95% CI 5.95 to 10.08), with greater improvements observed in low-dose protocols (WMD 11.50). Furthermore, low-dose esketamine did not increase the incidence of adverse psychotropic effects or postoperative nausea and vomiting. Esketamine was associated with a 69% reduction in the risk of requiring rescue analgesia (RR 0.31; 95% CI 0.16 to 0.60). Regarding efficiency, esketamine did not delay extubation (WMD -0.16 min). PACU stay duration exhibited a dose-dependent divergence: low-dose regimens shortened stays (WMD -2.85 min; P = 0.02), while high-dose combinations prolonged them (WMD 6.78 min; P < 0.00001). Conclusions: The data suggests that continuous intraoperative esketamine infusion, rather than single-bolus dosing, is associated with improved analgesic outcomes and quality of recovery in breast cancer surgery. Low-dose regimens appear to improve recovery metrics without delaying extubation or PACU discharge. These results emphasize the opioid-sparing potential of esketamine and advocate for standardized, weight-based infusion protocols. These findings support the consideration of low-dose esketamine infusions as a component of multimodal analgesia for mastectomy.
Accessibility of mandated coverage: Insurer and care team perspectives on barriers for cancer patients to receive insurance coverage for fertility preservation despite state-mandated coverage.
e23038 Background: Several states require select insurers to cover fertility preservation for enrollees at risk of iatrogenic infertility; however, variability in mandate implementation remains. Massachusetts (MA) has mandated coverage by commercial insurers since July 2024 (Bill S.598). We sought to identify barriers for cancer patients to receive insurance coverage for fertility preservation despite state-mandated coverage in MA. Methods: We recruited pediatric and adult multidisciplinary cancer care team members at a MA academic cancer center and MA insurance industry employees for a qualitative interview guided by the Consolidated Framework for Implementation Research (CFIR). Transcripts were thematically analyzed using Atlas.ti. Results: Of 20 participants (65% female, 85% White), 14 were from the clinical setting (6 clinicians, 3 in operations, 2 administrative clinicians, 2 administrators, 1 in payor relations) and 6 were from the insurance setting (3 insurers, 2 clinicians employed by insurers, 1 regulator). Policy-level barriers included “ambiguity in terms of what is and isn’t covered...opaqueness in terms of how you get reimbursed” [operations], mandated coverage for the retrieval cycle but not for associated medications [administrator], state Medicaid policies (“the law excludes and strictly forbids Medicaid from covering [fertility preservation]” [insurance clinician]), and lack of clarity about whether mandates apply to insured dependents (“there is a lot of unknown information...even if they have fertility benefits, how would they affect a dependent?” [clinician]). Payor-level barriers included having a “general utilization management group that reviews requests” rather than a “specific infertility review department” [administrator]. Clinician/care setting-level barriers included clinicians lacking time to “look into nitty gritty details [of insurance mandates].” Patient-level barriers included limited “knowledge and appreciation of benefits” [insurer], limited awareness of mandates [clinician], switching to a health plan that no longer provides coverage [regulator], and urgency of treatment limiting time to appeal coverage denials [administrative clinician]. Conclusions: Despite a state mandate, multi-level barriers to accessing insurance coverage for fertility preservation were reported. Structural limitations at the policy level may shape the context in which the fertility preservation mandate is implemented across payors, clinicians/care settings, and patients. Alleviating the onus on patients by strengthening clinician/care setting capacity to help patients access their benefits may improve mandate implementation. Efforts to operationalize the mandate across levels are needed to reduce ongoing barriers despite formal requirements for coverage.