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Use of duration of response as an interpretable endpoint in non-small cell lung cancer drug approvals.
e23020 Background: Overall response rate (ORR) is used as an early endpoint indicative of efficacy in oncology clinical trials, especially in accelerated approvals. Trials reporting ORR often include duration of response (DoR) as a secondary endpoint contextualizing durability. However, as a time-to-event endpoint, interpreting DoR, including in single-arm trials (SATs), is challenging given the inability to separate treatment effect from disease natural history and dependent censoring. In randomized controlled trials (RCTs), as DoR is limited only to responders, randomization is lost and potential subgroup effects arise. We analyzed DoR use in trials supporting original approvals in non-small cell lung cancer (NSCLC). Methods: The study included original approvals indicated for the treatment of NSCLC from August 26, 2011 through July 2, 2025. Data from the labels and multi-disciplinary review were found using the Drugs@FDA database. Descriptive analyses assessed the use of DoR as an endpoint, its reporting on the label, definitions, and associations with approval pathway and trial design. Results: Thirty drugs were included, representing 20 accelerated and 11 traditional approvals based on 39 trials (9 RCTs and 30 SATs). 74.2% of approvals used ORR as the primary endpoint (20 accelerated, 3 traditional) and DoR was a secondary endpoint in 87.1% (27/31) of approvals, including all accelerated approvals. The majority of trials (80.7%) supporting approvals with DoR as a secondary endpoint were SATs for 20 accelerated and 1 traditional approval. All approved drugs using DoR as an endpoint reported DoR in the label, with heterogenous metrics reported: 1 (3.8%) only DoR range reported, 1 (3.8%) median (mDoR) and range, 7 (26.9%) mDoR and 95% confidence interval (CI), 15 (57.7%) mDoR, 95% CI, and landmark(s), and 2 (7.7%) DoR range and landmark(s). For the 17 labels reporting landmark DoRs, 15 reported at 6 months, 3 reported at 9 months, 9 reported at 12 months, and 1 reported at 18 months. Only 4/26 (15.4%) labels where DoR was reported also reported follow-up duration and 6/26 (23.1%) did not report follow-up time anywhere in the review documents, despite its direct impact on DoR interpretation. Lastly, 10/26 (38.5%) of drugs with a DoR endpoint did not define or had incomplete definitions of DoR; within those with detailed definitions, there were discrepancies in how the start and end date for DoR were defined. Conclusions: DoR is a secondary endpoint in the majority of NSCLC approvals, especially in accelerated approvals. Most trials assessing DoR are SATs, in which time-to-event endpoints are known to be less interpretable. There was also significant variation in the metrics reported and definitions used, which can greatly impede endpoint interpretation. While DoR provides valuable context for ORR, these irregularities impede clinical interpretation. Further alignment of its appropriate use is needed.
Kitchen radon exposure, ventilation behaviors, and awareness in non-smoking female lung adenocarcinoma patients.
e22554 Background: Radon is an established lung carcinogen, yet its exposure characteristics within household kitchen microenvironments and related behavioral factors remain poorly characterized. We investigated kitchen radon exposure, ventilation behaviors, and awareness among non-smoking female lung adenocarcinoma patients to inform targeted prevention strategies. Methods: A cross-sectional study was conducted in 90 lifelong non-smoking women with histologically confirmed lung adenocarcinoma. Continuous radon monitoring compliant with national standards was performed for 30 days in kitchens, bedrooms, and living rooms. Standardized questionnaires assessed cooking behaviors, exhaust fan usage, and motivations. Structured cognitive assessments evaluated awareness of radon and indoor pollutants. Associations between radon levels, behaviors, and housing characteristics were analyzed. Results: Kitchen radon concentrations were significantly higher than other living spaces. Without exhaust fan use, peak kitchen concentrations reached 752±124 Bq/m³, exceeding the WHO reference level by 7.5-fold; with fan use, levels decreased to 315±58 Bq/m³ but remained elevated. Continuous exhaust fan operation for ≥10 minutes reduced radon concentrations to < 200 Bq/m³, representing a ~55% post-cooking reduction. No patients initiated exhaust fans before cooking, and only 18% delayed shutdown after cooking, with < 8% delaying ≥10 minutes. Major barriers included noise disturbance (70%), electricity cost (22%), and habitual immediate shutdown (8%). Awareness of radon was extremely low: 99.1% had no prior knowledge, with a mean awareness score of 0.3±0.2 (5-point scale). Radon exposure correlated with building age, exhaust duct design, structural type, water use frequency, and natural stone materials. Conclusions: Home kitchens represent a significant yet underrecognized source of radon exposure in non-smoking female lung adenocarcinoma patients. Profound deficits in awareness and suboptimal ventilation behaviors, driven largely by noise concerns, contribute to elevated exposure. Incorporating kitchen radon monitoring, improving exhaust fan design, and promoting evidence-based ventilation practices may substantially reduce radon-related lung cancer risk.
A common gene expression signature across multiple myeloma disease stages to identify high-risk of disease progression.
7560 Background: An accurate and timely identification of high-risk (HR) disease is crucial to maximize therapeutic opportunities nowadays available for multiple myeloma patients. Methods: In this study, 105 consecutive patients with smoldering (SMM = 33), newly diagnosed (NDMM = 42) and relapse/refractory (RRMM = 30) myeloma were enrolled. Bone marrow samples were processed by SKY92 assay (Skyline Dx) to detect HR gene expression (GE) signature and cytogenetics according with manufacturer guidelines. Statistics were performed using GraphPad Prism 8 and R (v4.4.2). Two-sided statistical tests were used, with significance of P < 0.05 and Benjamini–Hochberg method for false discovery rate (FDR) correction. Results: Based on SKY92 quality requirements, this test was feasible in the 81.1% of SMM, 92.8% of NDMM and 80.0% of RRMM cases, showing an increased detection of HR SKY92 signature frequency from SMM (18%) toward NDMM (43.5%) and RRMM (67%, P = 0.0018). By comparing SKY92 virtual FISH with available standard FISH data we observed a high performance of t(4;14), t(14;16/20) and gain1q detection with an accuracy [95%(CI)] of 97.9 (93.9-100), 85.2 (71.8-98.6) and 87.2 (77.7-96.8) respectively, decreasing to 66.7 (49.8-83.5) for del17p suggesting that this chromosomal aberrancy can be less likely recapitulated by GE-based projections. NDMM HR SKY92 patients showed a worst overall survival compared to patients with SKY92 standard risk (SR, P = 0.0079), a trend maintained in RRMM with a nearly significant statistics due to the cohort sample size ( P = 0.093). These results suggested that HR patients could share a transcriptional trademark across disease stages. This hypothesis was tested by comparing SKY92 HR NDMM and RRMM versus SR GE data with the following observations: (i) relative risk-related clusterization by a principal component analysis (PCA) and (ii) modulation of canonical pathways frequently altered in cancer by a gene set enrichment analysis (GSEA). To test the predictivity of GE-based approaches in the asymptomatic phase of myeloma we projected GE data of SMM on the PCA bi-dimensional space previously generated with NDMM and RRMM data and we observed a partial overlap of samples based on SKY92 risk profiles across MM stages. Interestingly, a GSEA comparing SKY92 HR vs SR SMM outlined deregulated gene pathways associated with inflammation and aggressive disease. Consistently, available follow up data show a progression rate of 60% for HR SKY92 SMM compared with 0% of the SR group (P = 0.173). Conclusions: Our findings support the use of GE-based tools for MM patient’s risk profiling and HR-related cytogenetic detection if FISH is not available. Furthermore, it provides evidence that HR patients share transcriptional traits across asymptomatic and symptomatic phases consistent with recent findings underlying common genomic features shared by a portion of SMM with MM.
Real-world utilization and outcomes of lenalidomide in MDS with low blasts and isolated deletion 5q (MDS w 5q).
11198 Background: Lenalidomide is the preferred first-line agent for lower risk MDS w 5q. It is associated with higher rates of transfusion independence and cytogenetic remission and has demonstrated survival benefit in selected clinical trial populations. Large nationwide studies are lacking in this subgroup. Methods: We identified adults aged > 18 years with MDS w 5q diagnosed between 2006 and 2021 using the National Cancer Database (NCDB), corresponding to Lenalidomide approval. Demographic, socioeconomic characteristics, insurance status, Charlson-Deyo comorbidity index (CCI), and treatment variables were extracted. The primary outcome was receipt of lenalidomide therapy. Secondary outcomes included overall survival (OS). Patients were categorized into pre-Affordable Care Act (ACA) and post ACA periods. Multivariable logistic regression and relative risk models were used. OS was estimated using Kaplan-Meier methods and differences between groups were compared with log-rank tests. Multivariable Cox proportional hazards model was used to assess factors associated with survival. P < 0.05 was considered significant. Results: We identified 3,328 individuals with MDS w 5q, median age of 77 years; 56.1% were women. The majority were non-Hispanic white 87%, followed by 6% non-Hispanic blacks and 4% Hispanic patients. Predominant insurance type was Medicare (78.3%). CCI score of 2 and higher was present in 15%. Overall, 21% of patients received Lenalidomide. Utilization increased significantly in the post-ACA, compared with pre-ACA (32% vs 12%, p < 0.001). On multivariable analysis, post -ACA period was independently associated with higher odds of Lenalidomide receipt (OR 3.01-4.34, P < 0.001), while Medicaid was associated with lower likelihood of treatment compared with Medicare (OR 0.26-0.96, p = 0.04). Other demographic and socioeconomic variables were not independently associated with treatment receipt. Median OS for the overall cohort was 15.7 months. In multivariable Cox analysis, worse OS was associated with age > 80 (HR 1.0; ref = 61-70), receipt of chemotherapy (HR 1.35) and increasing commodity burden [CDS: HR 1.27; CDS:2 HR 1.45, CDS 3: HR 1.95; all p < 0.001). Female sex was associated with improved survival(HR 0.76; p < 0.001). Lenalidomide receipt was not independently associated with OS after adjustment (HR 1.05; p = 0.27). Conclusions: This is the largest study evaluating receipt of lenalidomide in MDS with 5q deletion. Lenalidomide utilization increased substantially following ACA implementation, leading to improved access to disease modifying therapy. However, Medicaid insurance was associated with lower treatment receipts. Survival outcomes were primarily driven by age, commodity burden and treatment intensity rather than Lenalidomide receipt, highlighting persistent disparities and limitations of registry-based analysis.
Association between physical disability status and up-to-date colorectal cancer screening: A cross-sectional study.
e13747 Background: Colon cancer is the second most common cause of cancer death in men and women combined, with an estimated 158,850 new cases in 2026. While mortality has decreased due to increases in screening and prevention, major disparities persist in access to these services. Although USPSTF guidelines strongly recommend routine screenings, patients with physical disabilities face disproportionate barriers to access. The objective of this study was to examine whether physical disability was associated with compliance with USPSTF-recommended colorectal cancer screenings in adults living in the US. Methods: An analytical, cross-sectional study was performed using the 2023 National Health Interview Survey (NHIS) dataset. Adults aged 18 years and older with available data on disability status and cancer screening measures were included. Exclusion criteria consisted of individuals with a prior colectomy or a history of ulcerative colitis or colorectal cancer. The primary exposure was physical disability status, and the main outcome was up-to-date colorectal cancer screening status. Covariates include age, race/ethnicity, education, income-to-poverty ratio, urban–rural classification, health insurance status, and selected comorbidities. Unadjusted and adjusted logistic regression analyses were conducted to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI). Results: Among 11,856 adults included in the analysis, 7.5% had a physical disability (n = 887). There was no statistically significant association between physical disability status and compliance with colorectal screenings (OR 0.95 CI, 0.81-1.11). Several covariates were independently associated with screening adherence. Conclusions: The absence of significant disparity in colorectal cancer suggests that current screening infrastructure and guidelines may be effectively mitigating disability-related disparities in colorectal cancer screening. Futurestudies should identify the factors that contribute to equitable colorectal cancer screening access and examine how these successful strategies can be applied to reduce disparities in other preventive cancer screenings. Adjusted associations between physical disability status and colorectal screening compliance status. Physical Disability Status Colorectal Cancer Screening Compliance Adjusted 1 OR 2 (95% CI 3 ) No Reference Yes 0.95 (0.81-1.11) 1 Odds ratio; 2 Confidence interval; 3 adjusted for age, race/ethnicity, education, income-to-poverty ratio, urban–rural classification, health insurance status, and selected comorbidities (hypertension, diabetes, immunocompromised, anxiety, and depression).
Prognostic value of androgen receptor (AR) in breast cancer: A systematic review.
e12762 Background: The androgen receptor (AR) is a potential therapeutic target for breast cancer (BC). Nonetheless, the utility of AR is being called into question due to inconsistent data about its prognostic value. This meta-analysis aimed to investigate AR expression and its impact on overall survival (OS) and disease-free survival (DFS). Methods: PubMed, Medline, Web of Science, Scopus, Cochrane Library, Embase, Google Scholar, and CINAHL databases were searched to identify relevant studies that assessed the relationship between AR expression and prognosis in patients diagnosed with BC. The hazard ratios (HR) and confidence intervals (CI) of OS and DFS were pooled and displayed as forest plots. Additionally, Cochran’s Q and I2 statistics were used to assess heterogeneity. Funnel plots and Egger’s tests were performed to evaluate potential publication bias. Finally, subgroup analysis was conducted to assess the influence of the AR cutoff on OS and DFS outcomes. Results: Of the 1465 articles identified, 28 met the inclusion criteria and were included in this meta-analysis. AR positivity defined by IHC was associated with improved OS (HR, 0.904; 95% CI, 0.848–0.964; P = 0.002) and DFS (HR = 0.810; 95% CI = 0.738–0.890; P = 0.000) in all BC patients. Furthermore, we noticed that the prognostic value of AR depends on the BC subtype. Indeed, neither the triple negative breast cancer (TNBC) subtype (HR = 0.919; 95% CI = 0.786-1.075; p = 0.290) nor the unrelated BC subtype (HR = 0.936; 95% CI = 0.845-1.037; p = 0.208) revealed AR-related benefits for OS, while only the ER-negative subtype did not reveal AR-related benefits for DFS (HR = 1.154; 95% CI = 0.867-1.536; p = 0.327). However, only the high cutoff improved OS in ER-negative (HR = 1.480; 95% CI = 1.024-2.139; P = 0.037) and TNBC (HR = 0.546; 95% CI = 0.335-0.891; = 0.016) subtypes. Interestingly, there was no statistical evidence of publication bias. Conclusions: Our research demonstrates that AR expression is a reliable predictor of good prognosis for patients with BC, but it depends on the BC subtype. The differential predictive significance of AR expression in various BC subtypes has been discussed in more detail, and additional research is required to corroborate these results. It is clear that androgens and AR affect the biology of BC in a variety of ways. As a therapeutic target, AR should be extensively investigated in BC.
A phase 2 randomized trial of radium-223 dichloride and cabozantinib in patients (pts) with renal cell carcinoma (RCC) with bone metastases (BM): RADICAL (Alliance A031801).
4500 Background: BM occur in ~30% of RCC pts and are associated with poor survival and symptomatic skeletal events (SSEs). Radium-223, an alpha-emitting bone-seeking radioisotope, prolongs survival in advanced prostate cancer. A pilot study of radium-223 with VEGF tyrosine kinase inhibitors (TKI) in RCC with BM showed safety and early efficacy (McKay, CCR, 2018). Cabozantinib is a TKI that showed efficacy in BM. RADICAL (NCT04071223) was designed to investigate cabozantinib ± radium-223 in RCC with BM. Methods: This open label multicenter study enrolled RCC pts with ≥1 symptomatic BM not previously irradiated and Karnofsky performance status ≥60%. Prior therapies were allowed; non-clear cell population was limited to 20%. Randomization was 1:1 to cabozantinib with (Arm A) or without (Arm B) radium-223, stratified by osteoclast-targeted therapy (OTT), prior therapy, baseline opioid use, and IMDC risk. In Arm A, cabozantinib was 40 mg daily cycle 1, 60 mg thereafter if tolerated; radium-223 was 1.49 microcurie/kg IV every 28 days for 6 doses. In Arm B, cabozantinib was 60 mg daily. The primary endpoint was SSE-free survival (SSE-FS). Secondary endpoints were safety, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). The study was designed with 85% power to detect improvement in 6-month SSE-FS from 65% to 78% (one-sided α=0.05), with planned interim futility analysis at 50% of expected events. Results: From 12/2019 to 9/2025, 90 pts were enrolled and evaluable for the interim analysis. Median age was 63 years; 74.4% male, 90.0% White, 83.3% clear cell histology. 11.1% were treatment naïve, 80.0% received OTT, 51.1% had baseline opioid use. IMDC risk was 16.7% favorable, 68.9% intermediate, 14.4% poor. Median cabozantinib dose was 31.4 mg (Arm A) and 40.0 mg (Arm B); median radium-223 cycles was 6. Median follow-up was 13.1 (range 0.1-49.4) months with 50 events, 17 SSEs (Arm A: 10; Arm B: 7) and 33 deaths (Arm A: 13; Arm B: 20). Outcomes are in Table. 71 pts were evaluable for response. ORR was 22.2% (Arm A), 22.9% (Arm B). Any grade treatment-related adverse events were 97.7% (Arm A), 93.2% (Arm B); grade ≥3 were 65.9% (Arm A), 56.8% (Arm B). The trial closed after interim analysis as SSE-FS did not meet the prespecified futility boundary (HR≤1). Conclusions: Radium-223 did not improve the primary endpoint of SSE-FS when added to cabozantinib but a numerical prolongation in OS was observed. Combination treatment was safe. Alternative radiotherapeutics warrant investigation in RCC. Clinical trial information: NCT04071223 . Interim efficacy analysis. Arm Median(95% CI) HR (95% CI) Stratified SSE-FS A 17.9 (15.0-NE) 1.24 (0.62-2.48) B 17.6 (10.9-NE) Unstratified SSE-FS A 17.9 (15.0-NE) 0.90 (0.51-1.59) B 17.6 (10.9-NE) OS A 32.2 (17.9-NE) 0.77 (0.42-1.41) B 21.3 (12.3-NE) Stratified PFS A 11.0 (5.8-17.4) 1.39 (0.72-2.66) B 11.2 (9.0-18.5)
Metastatic phenotype at diagnosis for prediction of survival in de novo stage IV neuroendocrine carcinoma of the breast: A SEER Research Plus analysis.
e13106 Background: Neuroendocrine carcinoma of the breast (NECB) is a rare malignancy, and population-level data describing metastatic patterns and outcomes in de novo stage IV disease remain limited. Identification of high-risk metastatic phenotypes at diagnosis may inform prognostication in this understudied population. Methods: We performed a retrospective population-based analysis using SEER Research Plus to identify patients diagnosed with de novo stage IV NECB between 2010 and 2021, defined as Combined Summary Stage (2004+) = distant. Metastatic sites at diagnosis (bone, liver, lung, brain) were summarized among cases with known status. Metastatic phenotypes were categorized as visceral (liver and/or lung and/or brain involvement) versus non-visceral, and bone-only versus any visceral involvement. Overall survival (OS) was estimated using Kaplan–Meier methods and compared using log-rank tests. Results: Fifty patients with de novo metastatic NECB were identified. Among cases with known metastatic site data, bone was the most frequent site of metastasis (59.2%), followed by liver (34.0%), lung (30.4%), and brain (16.7%). Among patients with complete metastatic site information (n = 45), 46.7% presented with single-site metastasis and 40.0% with ≥2 metastatic sites at diagnosis. Median OS for the overall cohort was 25.0 months, with estimated 1-, 3-, and 5-year OS rates of approximately 55%, 32%, and 25%, respectively. Visceral metastases at diagnosis were associated with significantly inferior survival compared with non-visceral disease (median OS ~7 vs ~38 months; p≈0.01). Liver involvement identified a particularly high-risk subgroup, with markedly shorter survival compared with absence of liver metastases (median OS ~3 vs ~32 months; p≈0.002). In contrast, patients with bone-only metastatic disease demonstrated more favorable survival compared with those with any visceral involvement (p < 0.05). Survival outcomes among patients with brain metastases were poor, though analyses were limited by small sample size. Conclusions: In this contemporary population-based analysis of de novo stage IV NECB, metastatic phenotype at diagnosis strongly influenced survival. Visceral involvement, particularly liver metastases, identified a high-risk subgroup with poor outcomes, while bone-only metastatic disease was associated with more favorable survival. These findings provide contemporary survival benchmarks for metastatic NECB and support risk stratification in this rare breast cancer subtype.
Urokinase gene knockout and melanoma mitochondria: Association with free radical oxidation processes.
e21535 Background: Mitochondria play a key role in carcinogenesis, and an imbalance in the oxidant-antioxidant system influences tumor development. The growth rate of malignant neoplasms varies, and knockout animals are used to model this process. Deficiency of the urokinase gene (uPA) allows for the reproduction of a slower tumor progression. The aim of the research was to study the intensity of free radical processes and antioxidant defense in the mitochondria of tumor and skin cells in female uPA-knockout mice during the growth stages of B16/F10 melanoma. Methods: The study was conducted on female mice (n=126): intact and experimental group (n=21+42) — genetically modified C57BL/6-Plau<tm1.1Bug> ThisPlau<GFDhu/GFDhu> mice (uPA–/–); intact and control group (n=21+42) — C57Bl/6 mice (uPA+/+). B16/F10 melanoma was transplanted subcutaneously, and animals were sacrificed at 1 and 3 weeks post-transplantation. Mitochondria were isolated from tumor and skin cells at the maximum distance from the melanoma focus by differential centrifugation. The concentrations of superoxide dismutase (SOD-2) (pg/mg), glutathione peroxidase-1 (GPX-1) (ng/mg), malondialdehyde (MDA) (μmol/g protein), and advanced oxidation protein products (AOPP) (μmol/g) were determined in the mitochondria by ELISA. Statistical analysis was performed using Statistica 10.0. Results: Tumor volume was smaller in uPA–/– animals compared to uPA+/+ mice. In tumor mitochondria of uPA–/– mice at 1 week, SOD-2 and AOPP levels were 2.5-fold and 11.3-fold higher, respectively, while GPX-1 and MDA levels were 4.7-fold and 9.6-fold lower than in uPA+/+ mice. At 3 weeks of B16/F10 growth, SOD-2 and AOPP levels in tumor mitochondria of uPA–/– females remained higher (1.9-fold, p<0.05 and 8.6-fold, respectively), and GPX-1 and MDA levels were lower (9.3-fold and 3.6-fold) compared to uPA+/+ females. In skin mitochondria of intact uPA–/– females, SOD-2 and GPX-1 levels were 1.8-fold (p<0.05) and 5.1-fold lower, respectively, while MDA and AOPP levels were 3.1-fold and 3.2-fold higher than in intact uPA+/+ mice. At 1 week of B16/F10 growth in uPA–/– mice, skin mitochondrial SOD-2 was 2.7-fold lower, GPX-1 was 15-fold lower, MDA was 5.8-fold lower, while AOPP was 2.6-fold higher. At 3 weeks, uPA–/– females showed increased skin mitochondrial SOD-2 (15.4-fold) and MDA (3-fold), and decreased AOPP (7.2-fold) and GPX-1 (6-fold). Conclusions: Slowed melanoma growth in uPA–/– mice is associated with a restructuring of mitochondrial oxidative balance. In the tumor: increased AOPP with decreased MDA suggests a shift in stress targets. The combination of elevated SOD-2 and reduced GPX-1 indicates activation of primary antioxidant defense against a possible depletion of the glutathione system. A similar but dynamic imbalance in skin mitochondria confirms the systemic influence of genotype and tumor on the redox homeostasis of the target organ.
In silico phase III clinical trial of avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma using a machine learning model transfer approach.
e16500 Background: Randomized clinical trials (RCTs) are the gold standard for establishing treatment benefit, but are resource-intensive. An in silico virtual trial that enables exploration of treatment effects from available data could complement this process. We aimed to demonstrate the feasibility of an in-silico clinical trial using a machine learning (ML) model transfer approach, leveraging RCT data to generate counterfactual outcomes and assess whether such a framework reproduces observed RCT behavior in real-world TCGA data. Methods: ML models were trained on the JAVELIN Renal 101 RCT using RNA-seq data and internally validated for overall-survival (OS) and progression-free survival (PFS) within each arm (Avelumab+Axitinib (AA) and Sunitinib). They were then applied to the opposite arm to generate counterfactual survival predictions under alternative therapy. Treatment effects were summarized using Kaplan-Meier analysis and restricted mean survival times (RMST; τ = 24 months) based on available follow-up data. Results: In the available JAVELIN Renal 101 RCT data, AA demonstrated a significant PFS benefit compared with Sunitinib (median PFS 13.6 vs 8.1 months; ΔRMST 2.68 months [95% CI: 1.24-4.03], p = 0.001), but no OS benefit (p = 0.11). In our counterfactual analysis, PFS preserved a robust treatment effect favoring AA (median PFS 12.4 vs 8.3 months; ΔRMST 2.29 [95% CI: 0.72-3.65] months, p = 0.003), while OS did not (p = 0.45) (Table 1). Application to the TCGA cohort revealed similar results. Conclusions: This work demonstrates how the model transfer approach can be used to estimate counterfactual treatment outcomes and support a more informed transition from single-arm phase II to randomized phase III development. By enabling pre-testing of new drugs against established standards within an in-silico setting, this approach provides a practical means to evaluate expected benefit and improve patient selection before launching RCTs. Moreover, this framework would allow for testing drugs in rare diseases where a randomized study is not feasible. Landmark survival probabilities. Outcome Time (months) AA Observed Sunitinib Observed AA Counterfactual Sunitinib Counterfactual PFS 6 68.7% (63.9-73.9) 55.8% (50.8-61.4) 68.4% (63-73.1) 57.6% (51.7-63.1) PFS 12 53.5% (48.3-59.2) 39.5% (34.4-45.3 52.0% (46-57) 40.3% (34.4-45.7) PFS 18 43.7% (38.3-49.9) 29.1% (23.9-35.3) 41.5% (35.4-46.4) 27.8% (21.6-33.3) PFS 24 33.4% (26.1-42.7) 29.1% (23.9-35.3) 29.8% (21.1-37.2) 27.8% (21.6-33.3) OS 6 95.7% (93.6-97.9) 92.4% (89.7-95.1) 95.7% (93.3-97.8) 93.6% (91.2-96) OS 12 87.3% (83.9-90.9) 83.5% (79.7-87.4) 86.9% (82.9-90.2) 84.4% (80.2-88.2) OS 18 78.9% (74.5-83.6) 74.8% (70.2-79.7) 77.3% (71.6-81.1) 75.1% (69.3-79.4) OS 24 70.0% (64-76.6) 65.9% (59.9-72.5) 67.5% (59.1-73) 65.7% (58.1-70.7) AA: Avelumab+Axitinib.
A prediction nomogram for perioperative deep vein thrombosis risk in breast cancer patients: A retrospective cohort study with prospective clinical application.
e13541 Background: Deep vein thrombosis (DVT) represents a prevalent postoperative complication among breast cancer perioperative patients. However, there remains a paucity of validated predictive models specifically designed for perioperative DVT risk assessment in this population. This study aims to analyze the risk factors and develop a nomogram model for predicting perioperative DVT in breast cancer patients, subsequently prospect validate its risk stratification utility, and assess the preventive effects of dextran 40. Methods: This retrospective study analyzed clinical data from 594 breast cancer surgery patients who underwent surgery and did not receive prophylactic anticoagulation between May and November 2024 as the modeling cohort, which was randomly divided into a training cohort (n=416) and a validation cohort (n=178) at a 7:3 ratio. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors, and a nomogram prediction model was constructed. Model performance was evaluated using receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and calibration curves. A clinical validation cohort was prospectively collected from April to August 2025, which was stratified into high-risk and low-risk groups based on the risk score derived from the nomogram model. DVT occurrence between the two groups was compared to evaluate the model's discrimination ability, and the preventive effect of dextran 40 on DVT was analyzed. Results: Multivariate regression analysis revealed that elevated D-dimer levels, age >50 years, BMI ≥28 kg/m², hypertension, and diabetes were independent risk factors for perioperative lower extremity DVT in breast cancer patients. The nomogram model demonstrated good predictive performance in both the training cohort (AUC=0.790) and internal validation cohort (AUC=0.819). In the clinical validation cohort, the model classified 281 patients (64.0%) into the high-risk group, which exhibited a significantly higher DVT incidence than the low-risk group (14.6% vs. 1.2%, P<0.001). Further analysis revealed that among the high-risk group (n=281), patients treated by dextran 40 had a DVT incidence of 10.0% (16/160), significantly lower than that of control group (21.5%, 26/121). But in the low-risk group (n=157), the DVT incidence rates were 1.2% (1/84) in the intervention group and 1.4% (1/73) in the control group, with no statistically significant difference (P=0.920). Conclusions: D-dimer, age >50 years, BMI ≥28 kg/m², hypertension, and diabetes are the risk factors for perioperative DVT in breast cancer patients and successfully established nomogram prediction model. In clinical practice, dextran 40, not affecting wound healing, provides a preventive benefit in DVT high-risk patients.
Risk evaluation and mitigation strategies for approved oncology drug and non-cellular biologic products from 2008 to 2025: An FDA analysis.
e23029 Background: The Food and Drug Administration Amendments Act of 2007 (FDAAA) granted FDA the authority to require Risk Evaluation and Mitigation Systems (REMS), when necessary, to help ensure that the benefits of an otherwise effective therapy outweigh serious risks. We sought to review and summarize FDA approved REMS for oncology drug and non-cellular biologic products. Methods: We examined FDA’s databases for REMS required for FDA oncology drug and non-cellular biologic products approved from January 1, 2008, to December 31, 2025. We characterized approved REMS for all products as well as for novel products (defined as new molecular entities and original biologics) approved in 3 successive 6-year periods: 2008-2013; 2014-2019; and 2020-2025. Results: Our analysis showed that 27 REMS were required for products under FDA Oncology’s purview. Of these, 56% were for products with hematologic malignancy indications; 56% required ≥ 1 element to assure safe use (ETASU); and 52% are still active. Of these 27 REMS, 20 were for novel products approved after FDAAA enactment, corresponding to 9% of all novel oncology products approved since 2008 (vs. 10% for novel non-oncology products). There were proportionally more REMS required for novel oncology products approved in 2008-2013 ( n = 8 [18%]) than in 2014-2019 ( n = 6 [8%]) or in 2020-2025 ( n = 6 [7%]). Conclusions: The majority of approved non-cellular oncologic (and related) products in the U.S have not required REMS to ensure that their respective benefits outweigh their risks, and most recent novel oncology drugs were approved without a REMS. However, when REMS were required, they often included ETASUs. Since REMS with ETASU have the potential to increase burden on the healthcare system and/or adversely impact patient access, REMS for oncology products are continuously being re-evaluated to ensure their ongoing relevance to, and adequacy for, the mitigation of product-specific risks to ensure that their potential benefit(s) outweigh serious risks to the American public. Characteristics of REMS for FDA-approved oncology drug and non-cellular biologic products since FDAAA enactment. REMS for all oncology products( N =27) * REMS for novel oncology products2008-2013( N =8) REMS for novel oncology products2014-2019( N =6) REMS for novel oncology products2020-2025( N =6) Accelerated Approval, n (%) 10 (40) ** 3 (38) 3 (50) 4 (67) REMS at Initial approval, n (%) 20 (95) *** 7 (88) 6 (100) 6 (100) Hematological malignancies, n (%) 15 (56) 2 (25) 4 (67) 6 (100) REMS with ≥ 1 ETASU, n (%) 15 (56) 4 (50) 2 (33) 6 (100) Currently active REMS, n (%) 14 (52) 1 (13) 3 (50) 6 (100) *Includes REMS for 6 products already approved prior to 2008 and 1 non-novel product approved in 2023; **Denominator excluded 2 products approved prior to accelerated approval legislation passed in 1991; ***Excludes REMS for 6 products already approved prior to 2008.
Biomarker testing patterns and patient outcomes for metastatic NSCLC, CRC, and metastatic/recurrent HNSCC at Texas Oncology.
e20661 Background: Biomarker testing is essential for selecting targeted and immunotherapy regimens in non–small cell lung cancer (NSCLC), colorectal cancer (CRC), and head and neck squamous cell carcinoma (HNSCC). Although clinical guidelines recommend comprehensive molecular profiling, real-world adoption and timing vary, particularly in community oncology settings. We evaluated biomarker testing patterns and their association with treatment initiation in routine practice. Methods: This retrospective observational study included adult patients with newly diagnosed metastatic NSCLC, CRC, or recurrent/metastatic HNSCC treated at Texas Oncology between January 2022 and May 2025. Consult-only patients and those enrolled in clinical trials were excluded. Biomarker testing included genomic and protein-based markers with established clinical relevance and was classified as early if results were available prior to first-line (1L) therapy initiation and late if results were received after treatment start. Outcomes included testing rates, biomarkers assessed, multiple testing modalities, specimen types, timing, patient and clinical characteristics, and treatment patterns across lines of therapy. Results: Among eligible patients (NSCLC n=3,465; CRC n=2,600; HNSCC n=190), overall biomarker testing rates exceeded 95% across tumor types, with individual biomarker testing ranging from 64–96%. Biomarker prevalence was consistent with known disease-specific epidemiology. Next-generation sequencing (NGS) was the most frequently used modality (87% in NSCLC/CRC; 72% in HNSCC), followed by immunohistochemistry (IHC). Tissue biopsy was the most common specimen source (≈45–58%); liquid biopsy alone accounted for <11%, and combined tissue and liquid testing for <4%. Broad NGS panels (≥15 genes) comprised most tests (≈83% NSCLC/CRC; 69% HNSCC). Early testing occurred in ≈65–85% of patients. There were no observed differences in timing of testing by demographic variables, whereas poorer performance status was associated with delayed testing in NSCLC and HNSCC. Patients with early testing more frequently initiated biomarker-informed 1L therapies, including targeted agents and/or immunotherapy with or without chemotherapy, compared with late testing (90% vs 49% in NSCLC; 84% vs 53% in CRC; 91% vs 49% in HNSCC). In contrast, patients tested late more often initiated chemotherapy-based regimens, with increased use of biomarker-directed therapies in subsequent lines. Conclusions: In this large U.S. community oncology cohort, biomarker testing rates were consistently high across tumor types and encompassed a broad range of biomarkers and testing technologies. Early testing was associated with greater use of biomarker-informed 1L therapies, underscoring the importance of timely testing to improve precision-guided treatment decisions in real-world practice.
Real-world outcomes of first-line lenvatinib versus sorafenib in advanced HCC.
e16228 Background: Lenvatinib and sorafenib are approved first-line tyrosine kinase inhibitors for patients with unresectable or metastatic hepatocellular carcinoma (HCC). Although randomized trials demonstrated non-inferior survival, differences in toxicity and tolerability may influence real-world outcomes. While immune-checkpoint inhibitor combinations are now preferred first-line therapy, TKIs remain essential for patients with contraindications to immunotherapy. Methods: We conducted a retrospective cohort study using the TriNetX Research Network. Adults (≥18 years) with advanced HCC initiating first-line lenvatinib or sorafenib were identified. The index date was treatment initiation. The primary outcome was overall survival (OS). Secondary outcomes included hospitalization, emergency department (ED) visits, ascites/paracentesis, hepatic encephalopathy, and hypertension. One-to-one propensity score matching was performed adjusting for age, sex, and baseline comorbidities. Cox proportional hazards models were used. Results: A total of 16,588 patients were identified (5,292 lenvatinib; 11,296 sorafenib). After propensity score matching, 2,514 patients were included in each cohort. Baseline characteristics were well-balanced, including age (65.8 vs 66.0 years), sex (78% male), hypertension (51.8% both), ascites (19.4% vs 18.7%), and hepatic encephalopathy (3.7% vs 3.6%). No significant difference in overall survival was observed between lenvatinib and sorafenib (median 519 vs 501 days; HR 1.03, [0.95-1.11]; p = 0.51), suggesting time-varying treatment effects (proportional hazards p = 0.007), with survival probability at end of follow-up favoring sorafenib (20.57% vs 4.15%). Mortality risk was slightly higher with lenvatinib (51.0% vs 48.0%; risk difference 3.1% [CI 0.3-5.8%]; p = 0.031). No significant differences were observed in hospitalization (34.6% vs 36.9%; p = 0.37), ED visits (31.3% vs 32.9%; p = 0.37), ascites/paracentesis (24.4% vs 22.1%; p = 0.086), GI bleeding (14.7% vs 14.4%; p = 0.82), variceal bleeding (4.2% vs 3.8%; p = 0.56), or hepatorenal syndrome (5.5% vs 5.0%; p = 0.44). Lenvatinib was associated with significantly higher rates of hepatic encephalopathy (7.4% vs 5.7%; RR 1.30, 95% CI 1.05-1.61; p = 0.018), acute kidney injury (22.2% vs 19.7%; RR 1.12, 95% CI 1.00-1.26; p = 0.046), and new-onset or worsening hypertension (25.8% vs 18.4%; RR 1.4, 95% CI 1.20-1.64; p < 0.001). Conclusions: In this propensity score-matched analysis, lenvatinib and sorafenib demonstrated equivalent median overall survival in advanced HCC. However, lenvatinib was associated with significantly higher rates of hepatic encephalopathy, acute kidney injury, and new-onset hypertension, which may inform treatment selection. Limitations include the retrospective design, potential residual confounding, and limited availability of detailed tumor staging and performance status.
Burnout (BO) among oncology professionals in the Middle East and North Africa (MENA): Meta-analysis of pre–post COVID trends, contributors, and predictive value of single-item screening tool.
9010 Background: BO among oncology professionals is prevalent and may have changed following the COVID-19 pandemic. We conducted a meta-analysis of MENA studies to evaluate temporal trends in overall burnout and subdomains, identify contributing predictors, and assess the screening performance of thought of quitting oncology (TQ). Methods: Ten cross-sectional studies (N = 2,486) reporting Maslach Burnout Inventory (MBI) outcomes were included: six pre-COVID and four post-COVID. Pooled prevalence estimates were generated for emotional exhaustion (EE), depersonalization (DP), personal accomplishment (PA), and overall BO. Study-level meta-regression evaluated the effects of time period (pre- vs post-COVID), demographics, specialty, and their interaction on observed trends. Performance of TQ was assessed as a screening tool with pooled sensitivity, specificity, and predictive values. Results: The pooled prevalence of BO was 57.1% (95% CI, 40.6–72.8), increased from 48.2% in the pre-COVID period to 77.2% post-COVID (Δ +29.0 percentage points). High EE increased from 41.3% pre-COVID to 70.9% post-COVID (Δ +29.6 percentage points). DP increased from 36.8% to 55.8% (Δ +19.0 percentage points). Low PA showed minimal change (35.4% pre-COVID vs 35.1% post-COVID; Δ −0.3 percentage points). The heterogeneity estimate was high due to inter-study differences related to time period, setting, and baseline burnout prevalence, which were statistically adjusted for. TQ screening demonstrated reasonable sensitivity (82.4%) and PPV (79.9%), but low specificity (46.5%) and NPV (50.5%). Table 1 shows study-level factors contributing to BO prevalence trends. Conclusions: BO among oncology professionals increased post-COVID in the MENA region. The rise was driven by age-dependent effects plus time period. EE increased uniformly, while DP and low PA showed more complex patterns. A single-item question assessing TQ demonstrated strong rule-in screening utility for identifying clinicians at risk. Meta-regression analysis of study-level moderators of BO prevalence. Outcome Best Predictor(s) R² Pattern EE Period + Age + Med Onc. % 86.2% Additive effects: Post-COVID, younger, more Med Onc. independently increase EE DP None significant 0.0% PA Period × Age 50.4% Moderation: Age moderates pandemic effect on PA Overall Burnout Period × Age 55.3% Moderation: Age moderates pandemic effect on BO
Assessing the clinical utility of MRI for preoperative staging of early-stage cervical cancer in a limited-resource setting: A retrospective study from Botswana.
e17502 Background: Cervical cancer is the number one cause of cancer-related mortality for women in Botswana, the care of which is complicated by the country’s severe shortage of gynecologic oncologists. A recent noninferiority trial suggests that some stage I cervical cancers can successfully be treated with simple hysterectomy (SH) instead of radical hysterectomy (RH), potentially easing the burden on specialists, reducing recovery time, and avoiding excess morbidity associated with RH. However, accurate risk assessment of invasion is crucial when choosing between SH and RH to ensure optimal patient outcomes. This study investigates the feasibility of using magnetic resonance imaging (MRI) to stage early cervical cancer and guide surgical decision-making in a low-resource setting in Botswana. Methods: Data were retrospectively collected for patients who underwent preoperative MRI and curative surgery for cervical cancer at Princess Marina Hospital (PMH) in Gaborone from September 2022 to December 2024. All patients were FIGO stage IA1-IB2 and had not received chemotherapy or radiation prior to surgery. Descriptive analysis comparing staging and tumor sizes across clinical diagnosis, MRI results, and final pathology was completed. Results: Thirty-two patients with early-stage cervical cancer were included in this study, 15 (47%) of whom underwent RH and 17 (53%) underwent SH. Distribution of clinical, post-imaging, and post-surgical staging is shown in table 1. Staging between MRI and final surgical pathology was concordant in 16 (50%) patients. Four patients had the same stage across clinical, MRI, and surgical staging. Conclusions: The use of MRI for staging early-stage cervical cancer in Botswana may not accurately capture the extent of tumor invasion, highlighting the challenges of translating evidence for less invasive surgical strategies to resource-limited settings. Distribution of clinical, post-imaging, and post-surgical stage changes. Number (n = 32) Percent Clinical stage vs. MRI stage Upstaged 6 19% Downstaged 1 3% None 15 47% NVT on MRI 10 31% MRI stage vs. pathology stage Upstaged 6 19% Downstaged 10 31% None 16 50% MRI, magnetic resonance imaging; NVT, no visible tumor.
Nivolumab + ipilimumab (NIVO + IPI) vs NIVO in microsatellite instability high/mismatch repair-deficient metastatic colorectal cancer (MSI-H/dMMR mCRC): CheckMate 8HW subgroup analyses including treatment-free status and outcomes in long-term survivors.
3532 Background: In the phase 3 CheckMate 8HW trial, both dual primary endpoints of progression-free survival (PFS) were met for first-line (1L) NIVO + IPI vs chemotherapy (HR 0.21; P < 0.0001) and NIVO + IPI vs NIVO in all lines (HR 0.62; P = 0.0003) in patients (pts) with centrally confirmed (CC) MSI-H/dMMR mCRC. We report explorative subgroup analyses of NIVO + IPI vs NIVO. Methods: The study design was described previously (Andre NEJM 2024). Pts with MSI-H/dMMR mCRC per local testing were enrolled. After randomization, IHC and PCR based tests were used for central confirmation. Results: In all randomized pts, 84% (296/354) in the NIVO + IPI and 81% (286/353) in the NIVO arm had CC MSI-H/dMMR; in 1L pts, 85% (171/202) and 85% (170/201) had CC MSI-H/dMMR, respectively. Median follow-up in all randomized pts was 55.1 (range 24.7–68.5) mo. Pts receiving NIVO + IPI had improved disease control rates vs NIVO in 1L (85% vs 81%, respectively) and all lines (84% vs 76%, respectively). Pts with complete or partial response (CR/PR) or stable disease (SD) on 1L NIVO + IPI had improved PFS vs NIVO. In all lines, pts with CR/PR or SD receiving NIVO + IPI had improved overall survival (OS) vs those on NIVO (Table). Pts receiving NIVO + IPI had improved disease-specific OS vs NIVO (HR 0.47; 95% CI 0.32–0.68). In all lines, pts on NIVO + IPI had improved PFS and OS vs NIVO regardless of the number of sites of metastasis (Table). After treatment, 82% (185/226) of pts on NIVO + IPI were alive and treatment free vs 67% (125/186) on NIVO; 90% (198/220) and 79% (141/178) of pts were alive and systemic treatment free, respectively. In pts surviving ≥4 years, baseline characteristics and incidence of treatment-related adverse events were consistent with the all randomized CC population. Further analyses will be presented. Conclusions: NIVO + IPI demonstrated clinical benefit vs NIVO across subgroups, as shown by numerically increased PFS and OS in pts with CR/PR or SD, and improved PFS and OS regardless of number of metastatic sites. No defining characteristic was identified in long-term survivors vs all randomized CC pts. These results further support NIVO + IPI as a standard of care treatment for MSI-H/dMMR mCRC. Clinical trial information: NCT04008030 . 1L NIVO + IPI(n = 171) NIVO(n = 170) HR (95% CI) mPFS (95% CI), mo CR/PR NR (NE) NR (60.8–NE) 0.82 (0.43–1.54) SD 33.1 (5.8–NE) 9.2 (4.4–22.1) 0.52 (0.24–1.14) All lines (n = 296) (n = 286) mPFS (95% CI), mo 1 metastatic site at BL NR (NE) 60.8 (26.3–NE) 0.51 (0.33–0.77) ≥2 metastatic site at BL 59.2 (38.4–NE) 23.0 (11.8–NE) 0.70 (0.51–0.97) mOS (95% CI), mo CR/PR NR (NE) NR (NE) 0.92 (0.46–1.83) SD NR (35.3–NE) 26.8 (15.7–48.9) 0.43 (0.23–0.80) 1 metastatic site at BL NR (NE) NR (NE) 0.52 (0.31–0.88) ≥2 metastatic site at BL NR (NE) NR (NE) 0.68 (0.46–0.99) BL, baseline; m, median; NE, not estimable; NR, not reached.
The 31-gene expression profile for identification of real-world node-negative patients with stage I-IIA cutaneous melanoma who have a higher risk of death: A SEER collaboration.
e21593 Background: Most patients with stage I-IIA (tumor stage T1-T3a) cutaneous melanoma (CM) have good overall outcomes, and current guidelines do not recommend increased surveillance or systemic therapies for these patients with early-stage disease. However, a significant subset (~16%) of sentinel lymph node negative patients who are ineligible for advanced imaging experience metastasis and/or melanoma-specific death. In collaboration with the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, we analyzed whether the 31-gene expression profile (31-GEP) identifies early-stage patients at increased risk of melanoma-specific mortality (MSM) or all-cause mortality (ACM) who may benefit most from more risk-aligned disease management plans. Methods: We analyzed data from node-negative patients with stage I-IIA CM who were clinically tested with the 31-GEP (2013-2019) and linked to the SEER registry database (n = 8,896). Five-year melanoma-specific survival (MSS) and overall survival (OS) were estimated using Kaplan-Meier analysis and compared between groups using the log-rank test. Multivariable Cox regression analysis was used to evaluate significant predictors of MSM and ACM (*p < 0.05, **p < 0.001). Results: The 31-GEP significantly stratified risk of death in node-negative patients with stage I-IIA CM (p < 0.001). The 5-year MSS for a Class 1A result was 98.8% compared with 96.1% for Class 1B/2A and 93.4% for Class 2B results. The 31-GEP also significantly stratified 5-year OS (p < 0.001) for Class 1A (93.5%), Class 1B/2A (88.7%), and Class 2B (81.1%). In multivariable analysis, 31-GEP Class 1B/2A (HR = 2.34*), Class 2B (HR = 2.94*), and age (HR = 1.04**) were significant predictors of MSM. The 31-GEP Class 2B (HR = 1.68*), Breslow thickness (HR = 1.23*), and age (HR = 1.09**) were significant predictors of ACM. Conclusions: In a large, real-world cohort of patients with early-stage, node-negative CM, the 31-GEP identified patients at increased risk of death, including melanoma-specific death. These patients with lower-stage disease and a high-risk 31-GEP result may benefit from more intensive surveillance and follow-up schedules. No variable was more predictive of death from melanoma than Class 2B results, even Breslow thickness. Critically, these findings suggest that a reconsideration of current indications for adjuvant therapies, including the highest risk 31-GEP signature, may be warranted.
Condensate-driven transcriptional reprogramming to define core vulnerabilities in esophageal and gastric cancers.
e15119 Background: Biomolecular condensates organize key nuclear functions through phase separation, yet their roles in gastrointestinal tumorigenesis remain poorly defined. Integrating multi-omics profiling, functional genomics, and biophysical modeling, we reveal that esophageal and gastric cancers share a condensate-enriched transcriptional architecture driven by intrinsically disordered regulators of transcription, RNA processing, and replication stress. Methods: RNA-seq data from GTEx and TCGA were normalized and analyzed for differential expression in esophageal and gastric cancers. Condensate-related genes were defined using GO terms and assessed with DepMap dependency data. To identify those proteins able to form biomolecular condensates on their own, we employed a machine-learning predictor (1), high-resolution coarse-grained molecular dynamics simulations (2) and experimental in vitro characterization of single-protein condensates via turbidity at 340 nm. Results: Transcriptomic analyses identified a hyperactive transcriptional state with upregulation of condensate-associated genes, including TOPBP1 and CHERP. Dependency mapping demonstrated that these scaffolds are essential for tumor cell viability, defining a conserved condensate core across tumor types. Machine-learned predictions and coarse-grained molecular dynamics confirmed their high intrinsic disorder and low saturation concentration to undergo phase-separation, consistent with autonomous condensate formation and with our in vitro estimation of the saturation concentration of CHERP. Furthermore, expression profiling showed that TOPBP1 and CHERP are activated during tumorigenesis and downregulated in metastasis, reflecting adaptive remodeling of nuclear condensates during disease progression. Conclusions: Together, these findings establish condensate organization as a fundamental mesoscale principle in upper gastrointestinal cancers and nominate condensate scaffolds as tractable therapeutic vulnerabilities. References: R Tejedor A, Aguirre Gonzalez A, Maristany MJ, Chew PY, Russell K, Ramirez J, Espinosa JR, Collepardo-Guevara R. Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates. ACS Cent Sci. 2025 Feb 11;11(2):302-321. doi: 10.1021/acscentsci.4c01617. PMID: 40028356; PMCID: PMC11869137. Von Bülow S, Tesei G, Zaidi FK, Mittag T, Lindorff-Larsen K. Prediction of phase-separation propensities of disordered proteins from sequence. Proc Natl Acad Sci U S A. 2025 Apr;122(13):e2417920122. doi: 10.1073/pnas.2417920122. Epub 2025 Mar 25. PMID: 40131954; PMCID: PMC12002312.
Phase I trial of combination gemcitabine (gem) and nab-sirolimus (nab-S) in advanced leiomyosarcomas (LMS) or advanced soft-tissue sarcomas (STS) with <i>TSC1/2</i> alterations: Preliminary results.
11578 Background: Advanced LMS has limited effective therapies, with gem-based regimens being the most prescribed. Preclinical data suggest gemcitabine induces activation of the PI3K–mTOR pathway, supporting combination strategies with mTOR inhibition. Nab-S is a nanoparticle albumin-bound, IV formulation of sirolimus and has demonstrated greater intratumoral accumulation and antitumor activity in preclinical models compared to conventional mTOR inhibitors. Methods: This investigator-initiated, single-center phase I study evaluates gem (900mg/m2) plus nab-s (dose levels [DL]: DL1=75mg/m2 or DL2=100mg/m2) in patients (pts) using a Bayesian optimal interval (BOIN) design. Primary objective was to estimate the maximum tolerated dose (MTD) of the combination based on cycle 1 dose-limiting toxicities (DLT). Secondary objectives were to estimate objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Responses were assessed by RECIST1.1 and adverse events (AE) graded per CTCAEv5. Results: As of 01/22/26, all 12 pts initially planned for accrual have completed the DLT period. The original dosing schedule consisted of drug administration on Days 1 and 8 of a 21-day cycle. After the first 6 pts were enrolled, the protocol was amended to administer drugs on Days 1 and 15 of a 28-day cycle. This modification was implemented for all pts due to hematologic toxicities. While expected based on the known safety profile of nab-s and of gem, this frequently prevented Day 8 administration under the original schedule. All pts had advanced LMS, 10 pts were female and 7 had uterine LMS, the median age at time of consent was 55 yo. Three pts were included at DL1, and there was no DLT. DL2 included 9 pts: only one pt experienced a DLT of mucositis and diarrhea grade (Gr) 3 lasting for 3 days. The most frequent treatment-related Gr3-4 AE was thrombocytopenia. One pt had Gr3 pneumonitis attributed to gem and discontinued trial after 2 cycles. There was no other concern for safety. Ten pts were evaluable for response (1 pt died of disease and 1 pt chose to discontinue the trial before their first evaluation). ORR is 30% (n=3/10) at time of data cutoff and 90% pt had clinical benefit: 6 pts had stable disease with 5 pts experiencing shrinkage of disease (range: -8% to -21%) and 1 pt with 0% change. Only 1 pt had progressive disease as best response. With a median follow-up of 4 months (mo) for PFS, the median PFS (95% confidence interval [CI]) is 8.38 (1.68, not reached) mo, the 3-mo PFS (95% CI) is 78% (36%,94%), and the 6-mo PFS (95% CI) is 58% (16%,85%). With a median follow-up of 5.8 mo for OS, the 6-mo OS (95% CI) is 80% (39%,95%). Conclusions: The MTD was determined to be gem 900mg/m2 with nab-s 100mg/m2 on Days 1 and 15 of a 28-day cycle. Based on this preliminary safety and efficacy, an expansion with an additional 6 pts at this DL is ongoing. Clinical trial information: NCT06308419 .