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A randomized phase III trial investigating platinum and taxane chemotherapy in metastatic castration-resistant prostate cancer (mCRPC) patients with alterations in DNA damage response (DDR) genes (OPTION-DDR) CCTG-PR-25 NCT06439225.
TPS5143 Background: Outcomes for patients (pts) with mCRPC after androgen receptor pathway inhibitors (ARPI) remain poor. There are numerous treatment options, including single agent docetaxel, however overall survival (OS) after ARPI is between 12-19 months. Thus, management of mCRPC post-ARPI represents an area of unmet need. 25% of pts have alterations in DDR genes, which may be a biomarker for sensitivity to treatment with platinum agents. Carboplatin has been previously evaluated in smaller trials in pts with mCRPC and shows promise in patients with DDR gene alterations. PR-25 leverages standard of care testing for DDR genes to evaluate in a rigorous manner whether addition of carboplatin to docetaxel improves overall survival (OS) in pts with DDR gene alterations and mCRPC. Methods: PR-25 is a phase III randomized controlled trial led by the Canadian Cancer Trials Group comparing docetaxel to docetaxel and carboplatin in pts with DDR alterations. Pts must receive prior ARPI for mCRPC and demonstrate radiographic or PSA progression prior to enrollment. Qualifying DDR gene alterations include: BRCA1, BRCA2, ATM, ATR, BRIP1, BARD1, CDK12, CHEK1, CHEK2, ERCC2, FANCA, FANCC, FANCD2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L. The primary endpoint is OS. Secondary endpoints include radiographic progression free survival (PCWG3 and RECIST 1.1), PSA response, time to next systemic therapy, patient reported quality of life and economic evaluation. Statistical design: The target accrual is 236 patients over 3.25 yrs with 2 year follow-up to detect a HR of 0.65 in OS, using a type 1 error rate of 5% (2 sided) and power of 80%. Conduct to Date: Study activation – October 2024. First patient enrolled - December 2024. Accrual to date: 10. Clinical trial information: NCT06439225 .
Epidemiological trends and burden of esophageal cancer mortality in South Asia: A retrospective analysis from 1990 to 2023 with advanced machine learning forecasting to 2050.
e16055 Background: Esophageal cancer remains a major cause of cancer mortality in South Asia, with marked geographic and sex-specific heterogeneity. Comprehensive evaluations integrating long-term trends with advanced forecasting are scarce. We examined temporal patterns of esophageal cancer mortality across South Asia from 1990–2023 and projected future burden through 2050. Methods: Age-standardized mortality rates (ASMRs) were analyzed using population-based estimates for South Asia and individual countries from 1990–2023, using the Global Burden of Disease 2023 database. 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 applied to forecast ASMRs to 2050 with uncertainty intervals (UI). Results: At the regional level, esophageal cancer mortality increased significantly from 1990–2023 (both sexes EAPC 1.80; 95% CI 1.35–2.25), with faster rises among males (EAPC 2.09; 1.69–2.49) than females (1.49; 0.99–2.01). South Asian ASMRs (both sexes) rose from 4.35 per 100,000 in 1990 to 8.14 in 2023. Male ASMRs increased from 4.44 to 8.79, while female ASMRs rose from 4.24 to 7.51. India demonstrated the steepest increase in mortality (both sexes EAPC 2.25; 1.71–2.81), with parallel rises in males (2.42; 1.92–2.92) and females (2.13; 1.51–2.76). Bangladesh showed a pronounced male predominance (male EAPC 1.59; 1.42–1.76 vs female 0.71; 0.43–0.99). Bhutan exhibited divergent trends, with declining female mortality but increasing male mortality. Nepal showed near-stable overall trends, and Pakistan experienced modest overall increases. Forecasts indicate continued increases across South Asia, with both-sex ASMRs projected to reach 15.60 by 2050. Male ASMRs are projected to rise to 14.49 (95% UI 1.93–27.04) and female ASMRs to 24.05 (6.90–41.19), reflecting widening sex disparities and increasing uncertainty. Conclusions: Esophageal cancer mortality has increased substantially across South Asia over the past three decades, with pronounced male predominance and striking inter-country heterogeneity. Projections suggest a rapidly escalating future burden, underscoring the urgent need for targeted prevention, and early detection. Location Sex EAPC Lower 95%CI Upper 95%CI Bangladesh Both 1.19 0.98 1.40 Bangladesh Female 0.71 0.43 0.99 Bangladesh Male 1.59 1.42 1.76 Bhutan Both 0.32 0.20 0.44 Bhutan Female -0.34 -0.53 -0.15 Bhutan Male 1.08 1.01 1.16 India Both 2.25 1.71 2.81 India Female 2.13 1.51 2.76 India Male 2.42 1.92 2.92 Nepal Both 0.00 -0.20 0.19 Nepal Female -0.38 -0.60 -0.17 Nepal Male 0.36 0.18 0.55 Pakistan Both 0.26 0.15 0.37 Pakistan Female -0.12 -0.28 0.03 Pakistan Male 0.61 0.47 0.74 South Asia Both 1.80 1.35 2.25 South Asia Female 1.49 0.99 2.01 South Asia Male 2.09 1.69 2.49
Transcriptomic profiling in advanced hepatocellular carcinoma to identify biomarkers for immunotherapy response and mechanisms of acquired resistance.
4146 Background: Immune checkpoint inhibitors (ICI) are the standard of care for advanced HCC, yet validated biomarkers for response and mechanisms of acquired resistance remain undefined. We utilized transcriptomic profiling to identify predictive mRNA expression signatures and characterize evolution of the tumor microenvironment (TME) under therapeutic pressure. Methods: RNA-sequencing was performed on 35 HCC samples, comprising a cohort of 20 patients (16 pre-treatment + 4 treatment-naive tumors) and an independent cohort of 11 post-progression tumors (Post-IO). Patients received first-line atezolizumab/bevacizumab (n = 9), durvalumab/tremelimumab (n = 4), or nivolumab/ipilimumab (n = 3). 29 validated immune and stromal gene signatures were quantified (Bagaev, Cancer Cell 2021). Differential expression was assessed using Welch’s t-test and permutation testing. Survival outcomes were correlated with gene signatures using Cox regression and Kaplan-Meier estimation. Results: Comparison of the pre-IO exposure (n = 20) vs post-IO (n = 11) cohorts revealed significant TME remodeling. Acquired resistance was driven by the evolution of a "hypovascular immune desert," characterized by statistical downregulation of antigen presentation (MHC-II, P = 0.04) and angiogenesis (P = 0.04). Regarding baseline prediction to universal IO regimen (all 3 regimens), high tumor proliferation rate (HR 4.79, P = 0.007; mPFS 2.6 vs 10.0 m), Th2 signature (HR 22.5, P = 0.01), and Treg traffic (HR 15.6, P = 0.01) strongly correlating with inferior outcomes; high macrophage/DC traffic predicted favorable outcomes (HR 0.18, P = 0.04; mPFS 7.4 vs 3.4 m). Distinct from these universal IO predictors, we utilized permutation testing to differentiate regimen-specific signals, identifying higher myeloid cell traffic (P = 0.007) and higher angiogenesis (P = 0.02) at baseline as unique biomarkers of response exclusively in anti-CTLA4 regimens. Transcriptomic profiles of post-transplant recurrences (n = 4) were statistically indistinguishable from the pre-IO cohort. Conclusions: Advanced unresectable HCC shows distinct tumor states linked to immunotherapy benefit versus early resistance, and these states evolve with treatment. Our findings support a biology-driven framework for predicting response, understanding resistance, and prioritizing rational combination strategies to improve durable disease control.
Renal safety and clinical outcomes of enfortumab vedotin plus pembrolizumab in urothelial carcinoma patients with chronic kidney disease.
e16564 Background: Urothelial carcinoma (UC) predominantly affects older adults with a high burden of comorbidities, particularly chronic kidney disease (CKD), which affects 30–40% of patients at diagnosis and is more prevalent in advanced disease. Enfortumab vedotin plus pembrolizumab (EV+P) has become a frontline standard for advanced UC; however, patients with moderate-to-severe CKD were underrepresented in pivotal trials. Enfortumab vedotin targets Nectin-4 expressed in renal tubular epithelium, and immune checkpoint inhibitors are associated with immune-mediated nephrotoxicity, raising concern for renal vulnerability in patients with reduced renal reserve. Real-world data evaluating renal and clinical outcomes of EV+P in patients with baseline CKD are limited. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network, identifying adult patients with UC treated with EV+P between January 2020 and December 2025. Baseline CKD status (stages 3–5; eGFR < 60 mL/min/1.73 m²) was determined by diagnostic codes and laboratory data obtained prior to EV+P initiation.Patients were stratified into CKD and non-CKD cohorts. Propensity score matching (1:1) was performed for demographics, comorbidities, laboratory values, and prior therapies. Outcomes assessed within 180 days of treatment initiation included overall survival (OS), major adverse kidney events (MAKE; composite of acute kidney injury, dialysis initiation or dependence, or death), and selected treatment-related toxicities. Kaplan–Meier and Cox proportional hazards models were used. Results: After matching, 386 patients were included in each cohort (median age 75 years), with well-balanced baseline characteristics (all post-matching standardized mean differences < 0.1). Prior to matching, patients with CKD had a higher burden of cardiovascular comorbidities. Baseline renal function differed by design, with lower mean eGFR and higher serum creatinine in the CKD cohort. Overall survival was similar between CKD and non-CKD cohorts (HR 0.96; 95% CI, 0.69–1.35; p = 0.83), with 180-day survival rates of 79.9% and 79.3%, respectively. Patients with CKD had a higher incidence of MAKE, reflected by lower 180-day event-free survival (49.4% vs 59.1%; HR 1.41; 95% CI, 1.13–1.76; p = 0.002). Treatment-related toxicities were also more frequent in the CKD cohort (HR 1.35; 95% CI, 1.05–1.74; p = 0.020), with a higher mean number of toxicity events (4.3 vs 3.4). Conclusions: In this large real-world analysis, EV+P use was associated with comparable short-term overall survival in UC patients with and without CKD but with higher rates of renal events and treatment-related toxicities among patients with baseline CKD. These findings support the use of EV+P in select UC patients with CKD, with close monitoring of renal function and treatment-related toxicity.
Efficacy and safety of ivonescimab combined with liposomal irinotecan in patients with small-cell lung cancer (SCLC) progressing after first-line chemoimmunotherapy: A multicenter, phase 2 study.
8007 Background: SCLC patients (pts) progressing after first-line platinum-based chemoimmunotherapy have limited effective treatment options and poor prognosis. This study evaluated the efficacy and safety of ivonescimab combined with liposomal irinotecan in this setting. Methods: This phase 2, multicenter, single-arm trial enrolled SCLC pts who progressed during or after platinum-based chemoimmunotherapy. Eligible pts were required to be ≥18 years of age and have an ECOG PS of 0 or 1. Pts received ivonescimab (20 mg/kg, IV, Q3W) plus liposomal irinotecan (56.5 mg/m², IV, Q2W) until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival (PFS) rate (ClinicalTrials.gov: NCT06478043). Results: Between October 22, 2024 and August 27, 2025, 60 pts were included in the intention-to-treat population. Median age was 62.0 years (range: 38-75), 56 (93.3%) were male, and 53 (88.3%) had ECOG PS 1. At baseline, 35.0% and 26.7% of pts had liver and brain metastases, respectively. A total of 63.3% of pts had a chemotherapy-free interval of more than 90 days. As of December 15, 2025, with a median follow-up time of 7.3 months (95% CI: 6.0-9.0), the 6-month PFS rate was 72.0% (95% CI: 57.0-82.6). Median PFS was 9.8 months (95% CI: 6.7-13.4), and median OS was not reached. The confirmed objective response rate was 61.7% (95% CI: 48.2-73.9; all partial responses) and the disease control rate was 91.7% (95% CI: 81.6-97.2). In subgroup analysis, the median PFS was 11.9 months (95% CI: 7.3-NE) for patients with a CFI ≥90 days and 7.0 months (95% CI: 4.4-NE) for those with a CFI < 90 days. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 16 pts (26.7%). The most common grade ≥3 TRAEs were decreased neutrophil count (8.3%), decreased white blood cell count (8.3%), fatigue (6.7%), and diarrhea (3.3%). TRAEs led to treatment interruption in 31.7% and chemotherapy dose reduction in 25.0% of pts. No patient discontinued all treatment drugs due to TRAEs; discontinuation of ivonescimab alone occurred in 6 pts (10%). Immune-related AEs occurred in 33.3 % of pts, with grade 3 events in 8.3%. No grade ≥4 irAEs or treatment-related deaths were reported. Conclusions: Ivonescimab combined with liposomal irinotecan demonstrated encouraging antitumor activity with a manageable safety profile as a second-line treatment for SCLC pts after platinum-based chemoimmunotherapy. These results support further investigation in randomized controlled trials. Clinical trial information: NCT06478043 .
Impact of concomitant medications on immune checkpoint inhibitor outcomes in sarcoma.
11553 Background: Immune checkpoint inhibitors (ICIs) are an established treatment for many malignancies, with an emerging role in sarcoma. While the impact of concomitant medications (CM) on ICIs has been described in other cancers, it has not been evaluated in sarcoma. We assessed the association between CM use and ICIs outcomes in sarcoma patients. Methods: This pooled post hoc analysis included 7 investigator-initiated phase II ICI-based trials enrolling patients with metastatic sarcoma between April 1, 2017, and May 30, 2024. Patients receiving ≥1 dose of ICIs were included. CM taken within 30 days prior to treatment initiation were defined as baseline; PRN medications were excluded. CM were recorded at each cycle through end of treatment and categorized by medication class; supplements/herbal agents included vitamins, minerals, probiotics, botanicals, amino acids, and other dietary substances. For progression-free survival (PFS), baseline and on-treatment CM were analyzed as time-dependent covariates using Cox proportional hazards models. Overall survival (OS) analyses were limited to baseline CM. Logistic regression evaluated associations between baseline CM and objective response (ORR) and immune-related adverse events (irAEs). Toxicity was graded per CTCAE v5.0. Results: A total of 321 patients (median age, 58 years) were included. The most common histologies were liposarcoma (all subtypes, 22%), undifferentiated pleomorphic sarcoma (22%), and leiomyosarcoma (19%); 46% had received ≥3 prior lines of therapy. ICI was combined with cytokine/oncolytic therapies (43%), targeted agents (38%), or chemotherapy (19%). After a median follow-up of 47.4 months, ORR was 18%, median PFS was 3.9 months (95% CI, 3.09–5.32), and median OS was 19.9 months (95% CI, 17.5–22.9). Grade ≥3 irAEs occurred in 25% of patients, most commonly hematologic (6%) and hepatic (5%). On-treatment use of supplements/herbal agents was associated with longer PFS (HR 0.64, 95% CI 0.50–0.82; p<0.01), while on-treatment anti-infective use was associated with shorter PFS (HR 1.55, 95% CI 1.06–2.25; p=0.02); baseline anti-infective use was not associated with PFS. Baseline supplement/herbal use was associated with longer OS (HR 0.69, 95% CI 0.53–0.90; p<0.01), whereas baseline non-opioid (HR 1.54, 95% CI 1.10–2.16; p=0.01) and opioid analgesic use (HR 2.14, 95% CI 1.45–3.14; p<0.01) were associated with shorter OS. Baseline antihistamine use showed a trend toward increased gastrointestinal irAEs (OR 2.37, 95% CI 0.97–5.98; p=0.06). No CM class was associated with ORR. Conclusions: Concomitant medication use is associated with differential ICI outcomes in metastatic sarcoma and warrants prospective evaluation. CM Timing Outcome HR SH OT PFS 0.64 AI OT PFS 1.55 AI BL PFS 1.37* SH BL OS 0.69 Non-OA BL OS 1.54 OA BL OS 2.14 *Not statistically significant; SH = Supplements/herbal agents, AI = Anti-infectives, OA = Opioid analgesia, OT = on-treatment, BL = Baseline.
Breast cancer risk in MSH2 and MSH6 Lynch syndrome female patients: A single-institution retrospective analysis.
e22655 Background: Lynch syndrome (LS) is a germ pathogenic mutations involving DNA Mismatch Repair (MMR) genes and is associated with an increased risk of several malignancies including gastrointestinal, genitourinary, gynecologic, skin, and brain cancers. Despite immense advancement in the knowledge available regarding molecular basis of breast cancer development, no biomarker is used in disease management except BRCA1 and BRCA2. Human MSH6 protein is one of the most important mismatch repair proteins in the post-replicative DNA mismatch repair system (MMR)’s, and plays a core role in repairing mismatched DNA bases In the process of DNA mismatch binding dissociation, the encoded protein can heterodimerize with MSH2 to form mismatch recognition complex, and exchange ADP and ATP as bidirectional molecular switch. Functioning of mismatch repair proteins involves 2 central dimers MutLα (MLH1 and/or PMS2) and MutSα (MSH2 and/or MSH6). Intact MSH2 and MLH1 are compulsory to maintain the stability of MSH6 and PMS2 respectively. However, MLH1 and MSH2 stability can be maintained in the absence of MSH6 or PMS2 because role is compensated by other mismatch repair proteins. Therefore, expression analysis of particular proteins by immunohistochemistry can lead to precise estimation of affected mismatch repair deficiency. Mismatch repair deficient phenotype may be developed during chemotherapeutic treatment. Methods: From the Santa Maria alle Scotte Hospital registry, we retrospectively identified female patients with LS diagnosed showed by the detection of a germ heterozygous pathogenic or likely-pathogenic variant in MLH1, MSH2, MSH6 or PMS2 on molecular genetic testing within April 2017 to June 2025. We compared our sample size to SEER of 2017 NCI database. Results: Overall, 50 female patients with LS were identified. Of those, 13 (26%) had primary BC (95% CI 1.463% to 26.7189% Chi-squared 5.95 p<0.0001 ). Among the BC LS patients, 91% (12 ) have a hormone receptor positive tumor and BC is the only diagnosis of cancer to date. 7 patients (45%) with BC LS have germinal MSH6 mutation, 4 of 13 patient has MSH2 alteration. MSH2 and MS6 patients have a more aggressive breast cancer with local relapse disease and distant metastases. Median age at diagnosis is 54.5 years, median follow up is 8 years: All patients are still alive and under treatment. Conclusions: In our single institution analysis, 26 % of female patients with LS developed BC. Our study suggests that MSH6 and MH2 mutations are closely linked to the occurrence, progression and metastasis of breast cancer. Further investigation with prospective clinical studies with larger samples is warranted to validate our data.
Differential impact of <i>TP53</i> and <i>KRAS</i> pathogenic variants on overall survival in advanced ovarian carcinoma.
5583 Background: Advanced epithelial ovarian carcinoma, including high grade serous ovarian carcinoma (HGSOC), clear cell ovarian carcinoma (CCOC), endometrioid ovarian carcinoma (EOC) and mucinous ovarian carcinoma (MOC), frequently presents in advanced stages and is associated with poor outcomes. In addition to common germline mutations in BRCA1/2 , many patients also harbor TP53 and KRAS pathogenic variants (PVs) in their tumors. However, the role of these genomic alterations in advanced epithelial ovarian cancer remains unclear. Methods: Our study examined a large cohort of patients (n = 1060) with advanced epithelial ovarian cancer with genomic profiling performed using next-generation sequencing (StrataNGS). Cox regression modeling was used to examine the associations between TP53 and KRAS PVs and overall survival (OS), adjusting for covariates including age, race/ethnicity, performance status, Charlson Comorbidity Index, and other genomic alterations. Results: Our cohort included HGSOC (n = 924), CCOC (n = 66), EOC (n = 42), and MOC (n = 28). Median OS was 33.4, 33.8, 25.1 and 66.8 months for HGSOC, CCOC, MOC and EOC, respectively. In the CCOC group, TP53 PVs were associated with worse OS (hazard ratio [HR] = 3.23, [95% confidence interval [CI], 1.05-9.89]), while KRAS PVs were associated with better OS (HR = 0.29, [95% CI ,0.09-0.89]). In patients with HGSOC 71.3% had TP53 PVs, whereas 8.0% had KRAS PVs. KRAS PVs were associated with better OS (HR = 0.72, [95% CI, 0.50-1.02]) in HGSOC. TP53 PVs were associated with worse OS only within the sub-cohort that also harbored KRAS PVs (HR = 3.42, [95% CI, 1.13-10.33]. TP53 PVs were not associated with OS in the KRAS wild-type sub-cohort (HR = 0.95, [95% CI, 0.72-1.25]). Our finding that TP53 PVs were associated with worse OS in KRAS PVs sub-cohort was confirmed by interaction analysis (HR = 2.06, [95% CI, 0.98-4.35]). There was no OS difference between TP53 gain-of-function versus non-gain-of-function PVs in HGSOC patients. Conclusions: In our large study cohort of patients with advanced epithelial ovarian carcinoma, we found that TP53 and KRAS PVs were differentially associated with OS. Surprisingly, KRAS PVs were associated with higher OS in HGSOC while TP53 PVs were associated with worse OS only in conjunction with KRAS PVs, highlighting the need to deepen our understanding of the oncogenic role KRAS plays in ovarian epithelial carcinoma. Further mechanistic studies to understand the roles of these common mutations in ovarian cancers could provide deeper insights.
Neoadjuvant (NA) chemoradiotherapy (CTRT) plus avelumab (Ave) in locally advanced rectal cancer (LARC): 4-year outcomes of the phase II AVANA trial and their association with computational pathology.
3632 Background: The AVANA trial investigated the addition of PD-L1 inhibitor Ave to NA CTRT in LARC. Here, we report long-term survival and explore its association with tumor microenvironment (TME) features assessed through computational pathology. Methods: AVANA is a multicenter, single-arm, phase II trial enrolling patients (pts) with LARC defined by at least one high-risk feature (cN+, cT4, or high-risk cT3). Pts received NA CTRT combined with six cycles of Ave, followed by surgery. Primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Multiplex immunofluorescence was performed on baseline biopsies and surgical specimens using CODEX platform (Akoya). A deep-learning pipeline using a spatially constrained convolutional neural network for cell detection and a classifier for cell labeling was applied, allowing identification of eight cell populations: cancer cells, normal epithelial cells, fibroblasts, lymphocytes (lym), neutrophils (neu), macrophages, endothelial (endo) cells and myocytes. Cell infiltrates were dichotomized as high or low using optimal cutpoints derived from maximally selected rank statistics. Cell density maps were generated to identify differences in cellular configurations between baseline and surgical specimens. Results: The primary endpoint was met, with a pCR of 21.8% (22/101 pts). At a median follow-up of 51.8 months, 26 of 101 pts had a progression event and the 48-month PFS rate was 74.7% (95% CI: 65.0–82.2). Thirteen deaths occurred, yielding a 48-month OS rate of 87.6% (95% CI: 79.1–92.7). Age (≥70 vs <70; p=0.371), sex (p=0.897), ECOG PS (0 vs 1; p=0.899), cN positivity (p=0.716), cT stage (1-2 vs 3-4; p=0.264), or mismatch repair status (dMMR vs pMMR; p=0.274) were not associated to PFS. Digital whole-slide images of diagnostic biopsies and surgical specimens were available for 87/101 pts (86.1%). In post-treatment surgical specimens, high neu (p=0.00025) and high lym infiltrate (p=0.0038) correlated with better PFS, whereas high endo cell infiltrate was associated to shorter PFS (p<0.0001). Comparisons between baseline and post CTRT+Ave tissues showed that increased endo cell density in surgical specimen relative to baseline biopsies had worse PFS (p=0.0070), while increased neu to cancer cell ratios [HR 0.50 (95% CI: 0.21-1.18); p=0.108] and increased neu density [HR 0.22 (95% CI: 0.03-1.65; p=0.106] showed trends toward better PFS, although not statistically significant. Conclusions: AVANA demonstrates the feasibility and activity of adding ICIs to standard CTRT in LARC. Computational pathology analyses suggest that dynamic changes in TME cellular composition could be associated with long-term outcomes, supporting its potential role for pts stratification. Clinical trial information: NCT03854799 .
Geographic variation in outcomes and resource utilization among U.S. hospitalizations for tumor lysis syndrome.
e13718 Background: Tumor lysis syndrome (TLS) is a life threatening oncologic emergency. Geographic differences in U.S. hospital systems may influence patient outcomes and cost, but national comparisons remain limited. Methods: We analyzed 73,975 weighted TLS hospitalizations in the Nationwide Inpatient Sample, stratified by hospital region (Northeast, Midwest, South, West). Categorical outcomes were compared using Pearson chi square tests, and continuous variables were evaluated with Welch ANOVA and Games–Howell post hoc testing. Results: In-hospital mortality was highest in the Northeast at 26.1% compared with 21.5% in the Midwest, 21.5% in the South, and 20.2% in the West (p < 0.001). Congestive heart failure was most common in the Northeast and Midwest (19.0% and 19.3%, respectively) and lowest in the West (13.7%, p < 0.001). Acute kidney injury was frequent in all regions but peaked in the Northeast and Midwest (68.4% and 69.1%) and was lowest in the West (61.3%, p < 0.001). Sepsis occurred in roughly one quarter of admissions with slightly higher rates in the Northeast and West (p = 0.001), and organ failure was most common in the Midwest (78.8%) and least common in the West (72.9%, p < 0.001). Mechanical ventilation ranged from 15.9% in the Northeast to 13.9% in the West (p < 0.001), and vasopressor use ranged from 6.9% in the Northeast to 4.2% in the West (p < 0.001). Electrolyte derangements showed consistent geographic gradients: hyperkalemia (31.3% Midwest vs. 25.3% West), hypocalcemia (12.9% Midwest vs. 9.7% Northeast), hyperphosphatemia (25.3% Midwest vs. 20.6% Northeast), and hyperuricemia (16.5% Midwest vs. 10.3% Northeast) all peaked in the Midwest (all p < 0.001). Frailty or malnutrition/sarcopenia was highest in the Midwest (24.5%) and lowest in the South (20.4%, p < 0.001). Mean age was greatest in the Northeast (61.6 years) and lowest in the West (55.7 years, p < 0.001). Length of stay was longest in the Northeast (15.4 days) and shortest in the Midwest (13.2 days, p < 0.001). Total hospital charges were highest in the West (mean $295,043) despite this region having the youngest patients and the lowest comorbidity burden, and lowest in the Midwest ($188,425, p < 0.001). The Charlson Comorbidity Index was highest in the Midwest (6.99) and lowest in the West (6.32, p < 0.001). Conclusions: The Northeast experiences the highest mortality, longest hospital stays, and heavy critical care utilization, while the Midwest carries the greatest burden of chronic kidney disease, metabolic complications, and frailty but the lowest costs. The West, despite younger and less comorbid patients, incurs the highest charges. These findings highlight the need to investigate regional practice patterns and system factors that may underlie these disparities and to target quality improvement efforts accordingly.
Velzatinib (IDRX-42) as 1L or 2L therapy for advanced gastrointestinal stromal tumors (GISTs) by <i>KIT</i> mutation status: A subset analysis of the phase 1/1b StrateGIST 1 study.
11501 Background: Most GISTs present with activating KIT mutations (exons 9/11) initially responsive to imatinib, but many progress due to diverse KIT resistance mutations (largely in exons 13/14/17/18). Velzatinib (subject to USAN approval), a novel selective KIT inhibitor, has broad mutation coverage and robust in vitro/vivo preclinical activity in models with mutations relevant to 1 st - (1L) and 2 nd -line (2L) GIST. We present results from StrateGIST 1 evaluating the safety and efficacy of velzatinib in patients (pts) with advanced GIST as 1L or 2L therapy by KIT mutation status. Methods: The study design of StrateGIST 1 has been previously described (Schöffski et al. J Clin Oncol 2024). We present updated safety and efficacy data for 1L and 2L pts by KIT mutation status treated with velzatinib at the recommended phase 1b dose (RP1bD) of 300-mg tablet or exposure-equivalent 400-mg capsule. Results: As of December 15, 2025, 18 pts in 1L and 46 pts in 2L received velzatinib at the RP1bD and were evaluable for the efficacy analysis. In 2L pts, median follow-up (mFU) was 14.7 (95% CI: 12.9, 18.4) mo and median progression-free survival (mPFS) was 13.7 (95% CI: 7.4, 18.4) mo. In 1L, the mFU was 6.4 (95% CI: 1.8, 11) mo, and all pts (18/18) had a reduction in tumor volume, of whom 11 (61%) experienced unconfirmed responses, including 1 complete and 10 partial responses (Table 1). As of the cutoff date, 17 1L pts remained on study treatment. Treatment was well tolerated, with low rates of dose reductions (1L: 0%; 2L: 6%) and withdrawals (1L: 0%; 2L: 4%) due to AEs. Conclusions: Velzatinib exhibited promising activity and tolerable safety as 1L and 2L therapy across clinically relevant KIT mutations for pts with advanced GIST. These data support further study of velzatinib, including in 1L pts, to address the need for therapeutic options with broad coverage of clinically relevant GIST mutations. This study (NCT05489237) is funded by GSK. Clinical trial information: NCT05489237 . Clinical activity and response by mutation status per mRECIST v1.1. a 1Ltotal(n=18) 2Ltotal(n=46) 2LEx 9mutation only(n=8) 2LEx 11mutation only(n=14) 2LEx 11+ATP-binding pocket resistance mutation (13/14)(n=14) 2LEx 11+activation loop resistance mutation (17/18)(n=3) 2LOther(including ≥2 resistance mutations)(n=7) Best overall response, n (%) Complete response 1 (6) 2 (4) 0 1 (7) 0 0 1 (14) Partial response 10 (56) 14 (30) 5 (62) 2 (14) 5 (36) 1 (33) 1 (14) Stable disease 7 (39) 25 (54) 3 (38) 8 (57) 8 (57) 2 (67) 4 (57) Progressive disease 0 5 (11) 0 3 (21) 1 (7) 0 1 (14) Not evaluable 0 0 0 0 0 0 0 Objective response rate, n (%)(95% CI) 11 (61)(35.7, 82.7) 16 (35)(21.4, 50.2) 5 (62)(24.5, 91.5) 3 (21)(4.7, 50.8) 5 (36)(12.8, 64.9) 1 (33)(0.8, 90.6) 2 (29)(3.7, 71) a In an efficacy-evaluable population defined as all pts with ≥1 postbaseline disease assessment or prior clinical progression or death.
Profile and clinical outcomes of patients with thoracic tumors discussed at a tumor board in Brazil.
e23137 Background: The thoracic oncology tumor board is a multidisciplinary forum essential for discussing and defining the best therapeutic strategies in complex cases of lung cancer and other thoracic tumors. Bringing together specialists in medical oncology, thoracic surgery, radiation therapy, radiology, and pathology, the tumor board aims to optimize individualized approaches, considering aspects such as staging, histology, biomarkers, and the patient's clinical conditions. This work aims to analyze the main clinical decisions made in a thoracic oncology tumor board, highlighting the impact of interdisciplinary collaboration on the quality of care and oncological outcomes. Methods: This is an epidemiological observational study, with case discussion of adult patients, over 18 years of age, with tumor located in the thorax, staging I-IV. 72 clinical cases discussions over 12 month period, from jan 2025 to dec 2025, in bi-weekly meetings in the participation multidisciplinary teams. Results: Most of the cases discussed were female and non-smokers. Approximately 70% of the cases were advanced or metastatic disease, with 82% being adenocarcinomas. PET-CT scans were used for staging in more than 80% of patients, and in 47% of cases, the management was modified after PET_TC analyses. The vast majority, 95%, were patients with private health insurance, and only 22% did not have a molecular profile at the time of clinical discussions. The main molecular alterations found were PD-L1 positivity and EGFR AGA in 20%. Despite the majority of patients having metastatic disease, a multidisciplinary approach was adopted in 30% of surgical procedures and 15% of radiotherapy. Tumor board evaluation led to management modifications in 72% of cases, demonstrating the importance and impact of multidisciplinary in thoracic oncology. Conclusions: In real-world thoracic tumor board experience in Brazil, MDT discussion led to management changes in 72% of cases, frequently driven by PET-CT based reassessment (47% changed after PET review) and occasional diagnostic reclassification (including benign diagnoses). The date support tumor board review as a pragmatic quality-improvement strategy in lung cancer care, reducing the time to treatment initiation and guiding management with an interdisciplinary perspective.
Real-world use of fruquintinib in refractory metastatic colorectal cancer in the United States.
e15713 Background: Fruquintinib demonstrated overall survival benefit in heavily pretreated metastatic colorectal cancer (mCRC) in FRESCO and FRESCO-2. The FDA approved fruquintinib on Nov 8, 2023 for adult patients with mCRC after standard chemotherapy plus anti-VEGF therapy, with anti-EGFR therapy when appropriate (e.g., RAS wild-type). Observed geographic variation in post-approval uptake suggests potential disparities in the delivery of evidence-based medicine across U.S. regions. Methods: We conducted a retrospective cohort study using Epic Cosmos, a database of over 300 million patient records from over 1,500 hospitals nationwide. We identified adults with metastatic colorectal cancer (mCRC) with prior standard systemic therapy exposure and recorded fruquintinib exposure following FDA approval beginning Nov 8, 2023. Fruquintinib uptake was analyzed by U.S. Census region and state, expressed as the proportion of eligible mCRC patients receiving fruquintinib within each geography. Results: Among 116,116 pre-treated mCRC patients, 6,722 (5.79%) had recorded fruquintinib exposure during the post-approval period. Uptake varied nearly five-fold across states (2.27%–11.33%) (Table). High-uptake states were disproportionately concentrated in the central U.S./Midwest, whereas multiple low-uptake states were observed in the West and Northeast, suggesting broader regional variation beyond state-to-state differences. Conclusions: In a large national EHR-derived cohort of pre-treated mCRC patients after U.S. approval, fruquintinib uptake demonstrated substantial geographic variation. These findings raise concern for inequities in delivery of evidence-based later-line therapy and highlight the need to identify modifiable system- and site-level drivers (e.g., access, referral patterns, treatment infrastructure) to promote equitable adoption. Fruquintinib uptake among eligible metastatic colorectal cancer patients by U.S. state. Rank Geography Eligible mCRC (N) Fruquintinib uptake (%) Overall Overall 116,116 5.79 Top 1 Oklahoma 1,236 11.33 2 Kansas 1,312 10.75 3 Indiana 2,448 10.70 4 Missouri 1,521 9.47 5 Connecticut 2,208 9.24 Bottom 1 Washington 1,232 2.27 2 Nevada 441 2.72 3 Rhode Island 476 2.73 4 Tennessee 1490 2.82 5 Maine 614 2.93 Fruquintinib uptake is reported as the proportion of eligible pre-treated metastatic colorectal cancer (mCRC) patients with recorded fruquintinib exposure following U.S. FDA approval. States are ranked by uptake percentage.
An early resistance genomic state (ERGS) as an identifier of primary CDK4/6 inhibitor failure in HR+/HER2− metastatic breast cancer.
1086 Background: CDK4/6 inhibitors combined with endocrine therapy are the standard first-line treatment for patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer (mBC). However, a substantial subset of patients experience early disease progression, and there are currently no clinically practical tools available at treatment initiation to identify patients unlikely to derive lasting benefit. In this study, we attempt to define a clinically actionable genomic resistance phenotype using routine tumor sequencing. Methods: We conducted a retrospective real-world analysis using the MSK CHORD 2024 cohort, including 1,690 patients with HR+/HER2− mBC treated with first-line CDK4/6 inhibitors (palbociclib, ribociclib, or abemaciclib). An Early Resistance Genomic State (ERGS) was pre-specified based on alterations in five genes with established roles in endocrine and cell-cycle resistance: TP53, ESR1, RB1, PTEN, and NF1. The primary endpoint was time to first documented progression following CDK4/6 initiation, with early progression defined as progression within 6 months. Multivariable Cox proportional hazards models were adjusted for age, visceral disease, and central nervous system (CNS) involvement. Model performance was assessed using internal validation with resampling. Results: ERGS alterations were present in 41% of patients. ERGS demonstrated a graded, dose-dependent association with progression risk. Compared with ERGS-negative patients, those with one ERGS alteration had a 29% higher risk of progression (Hazard Ratio (HR) = 1.29, 95% CI: 1.15-1.45), those with two alterations had a 58% higher risk (HR = 1.58, 95% CI: 1.30-1.91), and those with three or more alterations had more than double the risk (HR = 2.19, 95% CI: 1.24-3.87; global log-rank p<0.0001). Twelve-month progression rates were 48%, 62%, 71%, and 85% across ERGS 0, 1, 2, and ≥3 groups, respectively. The prognostic impact of ERGS remained consistent across endocrine partner (aromatase inhibitor vs fulvestrant) and metastatic pattern subgroups. Incorporation of ERGS significantly improved model discrimination beyond clinical covariates alone, increasing the concordance index from 0.61 to 0.85 in internal validation analysis. Conclusions: ERGS defines a systems-level intrinsic CDK4/6 resistance phenotype identifiable using routine tumor sequencing at treatment initiation. This parsimonious genomic state provides clinically meaningful risk stratification beyond standard clinicopathologic features and identifies patients unlikely to derive lasting benefit from CDK4/6-based therapy. Therefore, ERGS may serve as a practical biomarker to prioritize enrollment on escalated first-line trials or alternative therapeutic strategies in HR+/HER2− metastatic breast cancer.
RACED: Reduction of cervical cancer disparities— Racial literacy as a strategy to foster a race-conscious oncology.
e13609 Background: The RACED project aims to reduce racial inequities in cervical cancer care at the Instituto do Câncer do Estado de São Paulo (ICESP). This initial phase evaluated a racial literacy course for hospital staff, designed to mitigate barriers associated with structural, institutional, and interpersonal racism prior to patient inclusion in oncological navigation. Methods: Using a pragmatic implementation design, we delivered a multidisciplinary course focused on health equity, critical race theory, and implicit bias. We evaluated acceptability, adherence, and feasibility, alongside immediate effects on self-reported knowledge, attitudes, and practices. Pedagogical strategies included interactive lectures and case discussions. Results: Four classes were conducted with approximately 100 participants each. Participants included a high proportion of leadership and director roles (46.1%), followed by attending and resident physicians (15.4%). While overall adherence was low relative to the total number of employees, results showed an expanded understanding of barriers faced by Black women and improved skills in culturally sensitive communication and active listening. The topics covered in the course were: 1- critical race theory; 2- intersectionality in healthcare for Black and LGBT+ populations; 3- structural racism in healthcare and equity policies; and 4- implicit biases and disparities in cancer care. Comparing pre- and post-course questionnaires, participants chiefly increased their knowledge and skills on race-conscious care. Detailed participant profiles and educational impact are shown in Table 1. Conclusions: Preliminary findings suggest that while team engagement remains a challenge, racial literacy training is a viable implementation strategy for quaternary services. The course addresses implications for reflective practice and the potential for replicability and scalability in other healthcare settings, contributing to the advancement of implementation strategies aimed at promoting racial equity in oncology care. Participant profile and professional background and educational impact on racial equity literacy. Category Group/ Classification Value Demographics Mean Age 35 years Professional Role Leadership & Directors 32,7% Attending & resident physicians 15.4% Nursing, Physiotherapy, Pharmacy, and Administration. 38.5% Race / Ethnicity White 60.4% Brown (Pardo) 21.8% Black 13.9% Asian 4.0% Indigenous 0% Difference between post-test (n=88) and pre-test (n=101) score I can differentiate structural, institutional, and interpersonal racism. +1,21 I grasp intersectionality in healthcare. +1,34 I know the National Black Health Policy +1,38 I am able to consider my clinical decisions through a racial equity lens +0,59 I am committed to institutional change. +0,69
Career destination effects of receipt of the American Society of Clinical Oncology Young Investigator Award.
9022 Background: Successful funding during training has long been recognized as a predictor for a career in academic medicine. 1 Among hematology and medical oncology fellows, the American Society of Clinical Oncology Young Investigator Award (ASCO YIA) often serves as a fellow’s first attempt to obtain extramural research funding. Whether receipt of the ASCO YIA predicts for an academic career in hematology and medical oncology is unknown. Methods: A retrospective, exploratory analysis was conducted using data from 15 consecutive graduating classes from the fellowship program of a large destination cancer center. For each graduate, data regarding submission of an ASCO YIA proposal and the results of each submission were collected. To determine if receipt of the ASCO YIA correlated with an early career and retention in academia, we explored data on each graduate’s initial and current job placement. Correlation of each physician's area of subspecialization compared to the focus of the ASCO YIA proposal was also investigated. Results: From 2011-2025, a total of 214 graduates were identified, and 211 (98.6%) applied for the ASCO YIA. Eighty-three (39%) applicants were awarded the ASCO YIA. Among the entire cohort of applicants for the ASCO YIA, 157 (74%) graduates sought an initial career in academia. Of the fellows who were awarded the ASCO YIA, 74 of 83 (89%) started their careers in academia compared to 83 of 128 (65%) for those who were not awarded the ASCO YIA (odds ratio [OR], 4.46; 95% confidence interval [CI], 2.04 to 9.74; P = 0.0002). Of the fellows awarded the ASCO YIA, 66 of 83 (80%) currently remain in academia compared to 51 of 128 (40%) for those who were not awarded the ASCO YIA (OR, 2.57; 95% CI, 0.29 to 1.60; P = 0.0038). Of the fellows who were awarded the ASCO YIA and sought careers in academia, 69 of 74 (93%) began their academic career in the same subspecialty as the focus of their ASCO YIA proposal, and 59 of 66 (89%) remain in that subspecialty. Conclusions: Among applicants for the ASCO YIA, recipients are more likely than non-recipients to begin careers in academic hematology and medical oncology positions and to remain in academia. In addition, early funding through the ASCO YIA predicts for retention of academic hematologists/oncologists in their subspecialty of early research and funding. These results emphasize the need for enhanced funding to support these awards with a goal of promoting early careers in academic hematology and medical oncology. To further validate these results, a multi-institutional analysis is planned. Reference: 1. Brass LF, Akabas MH, Burnley LD, Engman DM, Wiley CA, Andersen OS. Are MD-PhD programs meeting their goals? An analysis of career choices made by graduates of 24 MD-PhD programs. Acad Med. 2010;85(4):692–701.
A novel regimen of liposomal irinotecan plus capecitabine as total neoadjuvant therapy for locally advanced rectal cancer (LipCap): A phase II trial.
e15640 Background: Clinical data on the participation of liposomal irinotecan in neoadjuvant therapy for locally advanced rectal cancer (LARC) is still limited worldwide. This prospective phase II trial aims to evaluate the efficacy and safety of liposomal irinotecan in this treatment field, with the goal of establishing a novel therapeutic option for LARC. Methods: Patients diagnosed with LARC (cT3-4NanyM0) were enrolled. Treatment commenced with long-course concurrent chemoradiotherapy (LCRT, 50.4Gy/28f). The concurrent chemotherapy regimen consisted of capecitabine (625 mg/m²bid on days of radiotherapy) and liposomal irinotecan (50 mg/m²on the first and 14th days of radiotherapy). After completing LCRT, consolidation chemotherapy comprising 4-6 cycles of liposomal irinotecan plus capecitabine was administered. The primary endpoint was the rate of pathological complete response (pCR). Secondary endpoints encompassed the rates of major pathological response (MPR) and clinical complete response (cCR), the incidence of adverse events (AEs), as well as 3-year progression-free survival and overall survival. The trial was registered with ClinicalTrials.gov (identifier: NCT06210971). Results: Between February 2024 and March 2025, 60 patients were enrolled and initiated neoadjuvant chemoradiotherapy. Of these, 57 proceeded to consolidation chemotherapy upon completion of the initial phase. Ultimately, 47 patients underwent surgical resection, all of whom achieved R0 resection. Pathological evaluation confirmed a pCR in 10 (21.3%) surgical patients and a MPR (defined as TRG 0–1) in 23 (48.9%). Among the 10 patients who did not undergo surgery, 3 achieved a cCR, resulting in an overall complete response rate (pCR + cCR) of 21.7% (13/60) for the entire cohort. The incidence of grade 3–4 AEs was 16.7%, with the most common being diarrhea (10.0%) and leukopenia (5.0%). Other notable AEs included anemia (3.3%), thrombocytopenia (1.7%), and neutropenia (0%). Conclusions: Combining a promising pathological response with a more manageable toxicity profile, this regimen offers a well-tolerated and effective alternative for TNT in LARC. Clinical trial information: NCT06210971 . Baseline characteristics of eligible patients. Characteristic Total (n = 60) Sex Male 44 (73.3%) Female 16 (26.7%) Age Median (Range) 60 (31-74) Clinical T stage cT3 46 (76.7%) cT4 14 (23.3%) Clinical N stage N0 3 (5%) N1 13 (21.7%) N2 44 (73.3%) Clinical stage II 3 (5%) III 57 (95%) Distance from primary tumor to anal verge ≤5cm 27 (45.0%) 5-10cm 33 (55.0%) EMVI Positive 19 (31.7%) Negative 41 (68.3%) MRF Positive 25 (41.7%) Negative 35 (58.3%) EMVI, extramural vascular invasion; MRF, mesorectal fascia.
Safety and preliminary efficacy of OH2 combined with BS006 sequential intratumoral injection in patients with advanced solid tumors: An open-label, dose-escalation phase Ib/II study.
2590 Background: The immunosuppressive (“cold”) tumor microenvironment (TME) limits patient response to checkpoint inhibitors. Oncolytic viruses (OVs) can selectively replicate in tumor cells, leading to robust TME-remodeling. Reported here is the first clinical evaluation of a dual TME-modulating strategy based on an oncolytic HSV2 platform, whereby OH2, a clinically validated oncolytic HSV2 expressing GM-CSF, which enhances tumor lysis, antigen release, and dendritic cell recruitment in the TME, is co-injected with BS006, a second HSV2-based OV, which expresses a PD-L1/CD3 bispecific antibody that can redirect bystander T cells to tumor cells in the TME. Methods: BS008-001 is a multicenter, open-label phase Ib /II trial in heavily pre-treated patients with advanced solid tumors. Patients received biweekly sequential intratumoral injections of OH2 (fixed dose: 10⁷ CCID₅₀/mL) followed by BS006 (dose escalation: 10⁶–10⁷ CCID₅₀/mL), with identical volumes being injected at the same lesion. The primary endpoint is safety and tolerability; secondary endpoints included efficacy outcomes assessed by RECIST 1.1/iRECIST. Results: As of January 5, 2026, a total of 15 patients with a mean age of 59.3 were enrolled (4 soft tissue sarcoma, 3 colorectal cancer, 2 melanoma, 2 biliary tract tumors, 2 breast cancer, 1 pancreatic cancer, and 1 liver cancer). 93.3% of the patients had a baseline ECOG score of 1. The mean maximum diameter of the target lesion at baseline was 91.3 mm. 100% of the patients had distant metastases to internal organs such as the liver and lungs. Safety: Incidence of TRAEs in the Safety Set was 53.3% (8/15) with mild grade 1-2 reactions, including fever (40.0%) and decreased lymphocyte count (20.0%). 1 patient developed Grade ≥3 TRAE (6.7%), but no DLT-causing AEs or premature withdrawal from the trial occurred. Efficacy: In the 13 patients with evaluable advanced multi-line solid tumors, ORR was 7.7% and DCR 38.5%. 1 melanoma patient achieved 1 PR after 11 treatments, with the total diameter of the target lesions significantly decreasing by 70.8% to 30.4 mm; another melanoma patient received 39 doses over a treatment duration of 18.9 months (SD), whereas 1 subject with leiomyosarcoma achieved SD and survived for 27.1 months. While the mOS of the 15 patients has not yet been reached, landmark 1-year OS is 78% (95% CI: 47%-92%), with 3 patients still on treatment. Conclusions: Sequential intratumoral administration of OH2 and BS006 in heavily pre-treated patients is feasible and safe and results in reasonable DCR, with some patients achieving long-term clinical benefits. This study supports the clinical relevance of an HSV2-based platform combination of 2 oncolytic viruses encoding GM-CSF and T-cell redirected bispecific antibodies to warm up the cold TME. Further clinical research of the platform is warranted.
Pharmacokinetic variability with pembrolizumab dosage switching and its impact on immune-related adverse events in patients with non-small cell lung cancer.
12138 Background: Pembrolizumab 400 mg every 6 weeks (Q6W) was approved based on population pharmacokinetic (pop-PK) modeling rather than direct pharmacokinetic measurements, leaving its real-world concentrations insufficiently characterized. The impact of concentration changes when switching from 200 mg every 3 weeks (Q3W) to Q6W on immune-related adverse events (irAEs) remains unclear. Methods: We retrospectively identified patients with advanced non-small cell lung cancer who switched pembrolizumab from Q3W to Q6W between March 2017 and September 2023. Serum concentrations were quantified by liquid chromatography–tandem mass spectrometry; pop-PK analysis estimated maximum concentration (eCmax) and trough concentration (eCtrough). Inter-cycle variability was expressed as percentage coefficient of variation (%CV) using all available Q3W cycles. Early irAEs were defined as events within 126 days. In exploratory analysis, associations between pop-PK metrics and after switching irAEs (including pneumonitis) were evaluated using Wilcoxon rank-sum tests and multivariable logistic regression. Clinical correlates of %CV-eCmax were examined using multivariable stepwise linear regression. Results: Seventy-nine patients switched, and pop-PK analysis was feasible in 66. Median age was 70 years, 50 were male and 62 had a smoking history. Median Q3W cycles were 6 (range, 1–37) and median follow-up after switching was 463 days. After switching, 42 patients developed new or worsened irAEs, with 16 pneumonitis, and 22 had early irAEs, with 12 early pneumonitis. First-dose 400 mg eCmax and cross-regimen exposure ratios were not associated with the occurrence of irAEs. Among 64 patients who received ≥2 cycles of Q3W, those who developed irAEs after switching showed higher %CV-eCmax during Q3W (p = 0.036). Similar associations were observed for early irAEs (p = 0.024), pneumonitis (p = 0.023), and early pneumonitis (p = 0.007). %CV-eCtrough during Q3W was not associated with irAEs after switching (irAEs, p = 0.24; early irAEs, p = 0.13; pneumonitis, p = 0.16), with an association observed only for early pneumonitis (p = 0.044). High %CV-eCmax during Q3W was associated with increased odds of irAEs (odds ratio [OR] 8.4, p = 0.02), pneumonitis (OR 14.3, p = 0.03), early irAEs (OR 15.2, p = 0.017), and early pneumonitis (OR 30.0, p = 0.03). No significant associations were observed between %CV-eCtrough and irAEs or early irAEs. Higher platelet count and renal dysfunction were independently associated with increased %CV-eCmax. Conclusions: Higher inter-cycle variability in eCmax during 200 mg Q3W was associated with an increased risk of new or worsened irAEs, particularly pneumonitis, after switching to 400 mg Q6W. These findings suggest that inter-cycle variation in Cmax may be an important safety consideration when transitioning to a 400 mg Q6W regimen.
Uterine cancer mortality and demographic disparities in the United States in relation to female obesity.
e17616 Background: Uterine Cancer is the sixth most common cause of death in women. The incidence and mortality rates of uterine cancer have increased 0.7% and 1.1% per year respectively over the past two decades. We evaluated long-term mortality trends across age, race/ethnicity, urbanization and geography using national surveillance data. Additionally, we assessed recent trends in female obesity prevalence to provide insight into observed mortality patterns. Methods: We used the data from CDC WONDER from 1999-2020 to calculate age-adjusted mortality rates stratified by age, sex, race and urbanization. Uterine Cancer deaths were identified using ICD 10 codes C54-C55 and obesity was identified using ICD code E66. Temporal trends were assessed using Joinpoint regression to estimate annual percent changes (APC) and average annual percent change (AAPC) with 95% confidence interval. Results: Overall joinpoint regression identified a single inflection point in 2009. Mortality declined between 1999 and 2009 (APC -0.46%, 95% Cl -0.76 to -0.16; P = 0.005) followed by a significant increase from 2009-2020 (APC 1.53%, 95% Cl 1.32 -1.74; P <0.001), resulting in an overall rise in mortality (AAPC 0.58%, 95% Cl 0.41-0.74; P <0.001). Age stratified analysis shows sustained increase among women aged 25-64 years throughout the study period (AAPC range 1.39% -1.96%; P <0.001). Among women aged 45-84 years, inflection points occurred between 2005 and 2009, after which mortality increased significantly. A marked rise was seen in women aged 65-74 years after 2008 (APC 2.33%; P <0.001), while those aged 75-84 years had increase in mortality after 2009 (APC 1.40%; P <0.001). Racial disparities were evident with increasing mortality among Asian and Pacific Islander, Hispanics, Black and White women (AAPC 2.15%, 1.14%, 0.85%, 0.44% respectively; all P <0.001). Urbanization showed significant increase post 2009 across central, large fringe and medium metropolitan areas (AAPC range 0.40%- 0.80%; P <0.006). Geospatial mapping shows higher mortality clustering in parts of Midwest, Northeast and Southeast regions. In parallel, analysis of female obesity prevalence demonstrated a significant increase post 2010 (APC 6.38% , Cl 5.24-7.53; P <0.0001), with a greater increase noted in recent years, indicating a marked acceleration in the burden of obesity in past few years. Conclusions: This mortality burden likely reflects the obesity epidemic and increasing metabolic disease, resulting in estrogen exposure and insulin resistance, compounded by delayed diagnosis in the absence of effective screening. A shift towards aggressive histologic subtypes and persistent racial, socioeconomic and geographic inequities further amplify these trends. Hence, there is a need for equitable access to guideline-based care and further research.