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Transcriptomic signature of temozolomide treatment-effect heterogeneity in IDH-wildtype glioblastoma.

2084 Background: Adjuvant temozolomide (TMZ) is standard of care for IDH-wildtype glioblastoma (GBM), yet clinical benefit is heterogeneous and not fully explained by MGMT promoter methylation. We developed a transcriptomic signature specifically predicting TMZ benefit rather than overall prognosis using a causal inference framework. Methods: Transcriptomic and clinical data from 448 patients with histologic grade 4 IDH-wildtype GBM treated with radiotherapy alone or radiotherapy plus TMZ across six cohorts were analyzed. A training set (N=322; TCGA, CGGA-325/693, GLASS) and an independent validation set (N=126; GSE7696, CGGA-301) were used. Data were normalized, batch-corrected, and screened for outliers. To address non-random treatment assignment, inverse probability of treatment weighting (IPTW) based on propensity scores from age, sex, and MGMT status was applied. A 15-gene Temozolomide Sensitivity Score (TSS) was derived using univariate prognostic filtering followed by LASSO modeling of gene-by-treatment interactions. Final gene weights were obtained from a doubly adjusted multivariable Cox model incorporating IPTW and clinical covariates. Performance was assessed by comparing adjusted hazard ratios (HRs) for TMZ benefit across TSS-defined subgroups. Results: Five genes emerged as significant independent modulators of TMZ response: C2CD4A, SLC35E3, and DNASE1L3 predicted sensitivity, whereas APOBEC3B and PMAIP1 predicted resistance. In the training cohort, TSS-sensitive patients derived significant benefit from TMZ (median overall survival, 21.0 vs 7.7 months; adjusted HR, 0.20; 95% CI, 0.10–0.39; P<0.001), whereas TSS-resistant patients did not (14.4 vs 13.1 months; adjusted HR, 0.89; 95% CI, 0.53–1.51; P=0.674), with a significant difference in treatment effect (P<0.001). Validation confirmed these findings: TSS-sensitive patients benefited (21.9 vs 12.8 months; adjusted HR, 0.32; 95% CI, 0.16–0.62; P<0.001), while TSS-resistant patients did not (13.7 vs 15.1 months; adjusted HR, 1.25; 95% CI, 0.70–2.23; P=0.453), showing differential efficacy (P=0.003). Age, sex, and MGMT status were balanced between groups. Conclusions: A 15-gene transcriptomic signature developed through causal inference and interaction modeling is associated with differential temozolomide benefit in IDH-wildtype glioblastoma independent of MGMT status. This signature may identify patients less likely to benefit from temozolomide, offering a promising tool for de-escalation strategies and enrollment in precision clinical trials.

The PROFOUND study: A large-scale prospective multicenter case-control trial of a multi-cancer early detection (MCED) test in China.

10541 Background: Early cancer detection reduces morbidity and mortality, but current recommended screening in China misses many lethal cancers. Emerging liquid biopsy-based MCED tests have the potential to increase the number of screen-detected cancers when added to recommended screening. In this study, we evaluate the performance of a MCED test tailored to 16 cancer types covering 85% of China's total cancer incidence, including malignancies without recommended screening tests in the large-scale, prospective, multicenter case-control PROFOUND study. Methods: A total of 10,541 participants from over 50 sites nationwide were enrolled, with the cohort comprised by a training set (7,487 participants: 4,448 cancer, 3,039 non-cancer) and a test set (3,054 participants: 1,740 cancer, 1,314 non-cancer). It included 16 major cancer types encompassing diverse pathological subtypes, with stage I-III cases accounting for 83.31% of all cancer samples. All cancer cases were confirmed via pathological diagnosis. Blood samples underwent targeted methylation profiling and were analyzed with the Genie-ADLA AI algorithm to train, validate and independently verify the MCED assay, as well as assess its clinical performance (sensitivity, specificity, tissue-of-origin [TOO] prediction accuracy). Results: In the validation set, specificity was 99.03% (95% CI: 98.27%–99.51%), overall sensitivity was 70.63% (95% CI: 67.23%–71.67%) and sensitivity for stage I–III cancers was 66.03% (95% CI: 63.53%–68.46%). The overall TOO prediction accuracy reached 85.21% (95% CI: 83.05%–87.20%). For the five highest-mortality cancers (liver, colorectal, esophageal, gastric and lung cancer), sensitivities were 87.85%, 90.48%, 83.78%, 72.85% and 69.54% respectively. Sensitivities of lung adenocarcinoma and non-adenocarcinoma were 48.75% and 92.96%, respectively. Among them, non-adenocarcinoma is more likely to be missed in recommended screening tests. For cancers without recommended screening (pancreatic, ovarian, gallbladder cancer, lymphoma), sensitivities reached 64.75%, 87.88%, 100% and 74.72%, respectively. Conclusions: Powered by the Genie-ADLA AI algorithm, the PROFOUND study's MCED assay demonstrated robust performance including high sensitivity, specificity and TOO prediction accuracy for 16 cancer types (including cancers do not have recommended screening). It may serve as a complementary tool to augment recommended screening and revolutionize early cancer detection paradigms. A prospective interventional clinical study covering 16 cancer types will be launched to further validate MCED's clinical effectiveness. Clinical trial information: NCT06217900 .

Cabozantinib plus nivolumab (C+N) versus sunitinib (S) in patients with advanced renal cell carcinoma (aRCC) and liver metastasis: Subgroup analysis of the phase 3 CheckMate-9ER trial.

4530 Background: In the phase 3 CheckMate 9ER trial (NCT03141177), C+N treatment significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs S in patients with first-line aRCC, including those with baseline LM (Motzer et al. Ann Oncol 2026). We performed exploratory analyses of outcomes in additional subgroups including patients with no LM (NLM) and those with LM plus other metastatic sites. Methods: 651 patients with clear-cell aRCC were randomized 1:1 to C (40 mg QD) + N (240 mg Q2W) or S (50 mg QD for 4 weeks of 6-week cycles). PFS (primary endpoint) and ORR were per RECIST v1.1 by blinded independent central review. Median f-u was 67.6 mo. Patient subgroups analyzed included those with LM or NLM at baseline and those with bone, lung, lymph node (LN), or adrenal gland metastasis in addition to LM. Results: 129 patients had LM at baseline. Baseline characteristics were generally consistent between treatment arms among patients with LM and NLM. A PFS and OS benefit with C+N vs S was observed in patients with LM and NLM (Table). Both subgroups experienced greater ORR and longer duration of response (DOR) with C+N vs S. Although outcomes were less favorable in those with vs without LM, and least favorable in those with both LM and bone metastasis, the relative benefit with C+N vs S was consistent across metastatic site subgroups. The safety profile among patients with LM was generally consistent with the overall population. Presence of LM did not negatively impact C dose exposure (median daily dose 31.8 mg in LM; 26.3 mg in NLM). Conclusions: Treatment with C+N vs S improved efficacy outcomes in patients with first-line aRCC irrespective of LM at baseline. Among patients with LM, a consistent benefit was observed regardless of concomitant metastasis in bone, lung, LN, or adrenal gland. Clinical trial information: NCT03141177 . Efficacy by metastatic sites. Subgroup(C+N v S) LM + Any Site(s) a (n=73 v n=56) NLM(n=250 v n=272) LM + Bone(n=15 v n=17) LM + Lung(n=46 v n=43) LM + LN(n=31 v n=27) LM + Adrenal Gland(n=8 v n=6) mPFS, mo 10.9 v 6.2 b 18.4 v 9.2 6.9 v 3.8 9.1 v 4.1 9.7 v 6.2 32.0 v 2.0 PFS HR (95% CI) 0.55 (0.37, 0.82) b 0.59 (0.48, 0.71) 0.77 (0.33, 1.76) 0.50 (0.32, 0.80) 0.65 (0.36, 1.17) 0.18 (0.04, 0.78) mOS, mo 37.6 v 22.1 b 49.5 v 39.7 20.9 v 12.7 40.1 v 13.4 34.8 v 13.4 46.3 v 2.0 OS HR (95% CI) 0.65 (0.43, 0.97) b 0.83 (0.66, 1.03) 0.57 (0.26, 1.24) 0.49 (0.30, 0.79) 0.59 (0.33, 1.05) 0.10 (0.02, 0.53) ORR, % 52 v 21 b 57 v 29 40 v 18 52 v 23 48 v 19 88 v 17 mTTR, mo 2.8 v 4.0 2.8 v 5.4 2.9 v 3.0 2.8 v 3.5 2.8 v 4.1 2.8 v 11.1 mDOR, mo 20.7 v 17.8 22.1 v 15.2 12.6 v 6.4 23.1 v 15.8 33.0 v 17.9 41.5 v NR a Only 7 patients had liver-only disease (n=2, C+N; n=5, S), precluding meaningful analysis of this subgroup. b Motzer et al. Ann Oncol 2026. m, median; NR, not reached; TTR, time to response.

From local pixels to global patterns: Vision transformer–based modeling for lung cancer classification on computed tomography.

e20014 Background: Lung cancer remains the leading cause of cancer-related mortality worldwide, driven largely by delayed diagnosis and variability in interpretation of computed tomography (CT) imaging. Although convolutional neural networks (CNNs) have shown strong performance in pulmonary lesion analysis, their reliance on localized receptive fields may limit modeling of global anatomic context, particularly for heterogeneous tumors and lesions with diffuse margins. Vision Transformers (ViTs) introduce an attention-based paradigm that enables global contextual reasoning across entire images. We evaluated a Vision Transformer B/16 (ViT-B/16) model for lung cancer classification on CT imaging. Methods: A publicly available lung CT dataset comprising 5,000 images was analyzed, including malignant lung cancer, benign pulmonary lesions, and normal lung findings. Images were stratified into training (80%) and validation (20%) cohorts with class balancing applied to the training set. A ViT-B/16 model pretrained on ImageNet was fine-tuned for multi-class classification. Input images (224×224) were partitioned into non-overlapping 16×16 patches and embedded into a token sequence with positional encodings and a learnable class token. The architecture employed 12 transformer encoder blocks with multi-head self-attention and feed-forward layers. Performance was assessed using accuracy, sensitivity, specificity, precision, F1 score, confusion matrix analysis, and area under the receiver operating characteristic curve (AUROC). Results: The Vision Transformer achieved a validation accuracy of 97% with balanced class-wise performance. Sensitivity for malignant lung cancer exceeded 96%, with specificity of 98% for benign and normal findings. Attention-based global modeling reduced misclassification of lesions with complex spatial patterns and diffuse margins, a known limitation of purely convolutional architectures. Performance was comparable to high-performing CNN models, although achieved with higher parameter count and computational cost. Conclusions: Vision Transformer–based modeling enables accurate lung cancer classification on CT by leveraging attention-driven global contextual understanding beyond localized feature extraction. While less computationally efficient than optimized CNNs, ViTs offer complementary strengths in modeling complex spatial relationships and provide interpretable attention mechanisms. These findings support further investigation of transformer architectures in lung cancer screening, diagnostic triage, and AI-assisted radiologic workflows.

A prospective, single-arm, phase II exploratory clinical study on the efficacy and safety of neoadjuvant adebrelimab combined with cisplatin and docetaxel in patients with clinical stage IVB oral squamous cell carcinoma.

6048 Background: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck. Stage IVB OSCC had long been considered unresectable with extremely poor prognosis, and mainstream guidelines encourage exploring new therapies via clinical trials. This study aimed to evaluate the efficacy and safety of adebrelimab plus cisplatin/docetaxel as neoadjuvant therapy for stage IVB OSCC (NCT06277791). Methods: IVB OSCC patients aged 18–75 years were enrolled and received 2 cycles of neoadjuvant immunochemotherapy (adebrelimab 1200 mg + cisplatin 75 mg/m²/docetaxel 75 mg/m², q3w). Three weeks after neoadjuvant treatment, patients underwent extended primary tumor resection and radical neck dissection, followed by adjuvant radiotherapy/chemoradiotherapy. The primary endpoint was pathological response rate (pCR+MPR); secondary endpoints included radiographic response, R0 resection rate, and safety. Results: 28 patients were enrolled between June 2023 and January 2026. The mean age was 47.8 years, with a male predominance (25, 89.3%). Primary tumors were mainly located in the buccal mucosa (14, 50.0%) and tongue (10, 35.7%). Smoking, alcohol consumption, and betel nut chewing histories were noted in 75.0%, 42.9%, and 64.3% of patients, respectively. Most had an ECOG performance status of 1 (75.0%). 8 cases (28.6%) were classified as cT4b and 20 cases (71.4%) as cN3b at baseline. Three patients (10.7%) were excluded from efficacy analysis due to insufficient data. In the evaluable population (n=25), no complete response (CR) was observed; 8 (28.6%) achieved partial response (PR), 14 (50.0%) stable disease (SD), and 3 (10.7%) progressive disease (PD), with an overall objective response rate (ORR) of 32.0% (8/25). Subgroup ORRs were 33.3% (2/6) for cT4b and 31.6% (6/19) for cN3b. Pathological assessment was available for 25 patients: based on the combined pathological assessment of the primary tumor and lymph nodes, 15 (60.0%) achieved MPR, 1 (4.0%) pCR, resulting in a 64.0% pathological response rate. For subgroups, the pathological response rate was 50.0% in 6 evaluable cT4b (2 MPR, 1 pCR) and 68.4% in 19 evaluable cN3b (13 MPR, no pCR). The R0 resection rate was 100% among 25 surgical patients. Treatment-related adverse events (TRAEs) were mostly grade 1–2. Grade 3 TRAEs occurred in 2 cases (7.2%), with no grade 4/5 events. At data cutoff (median follow-up: 12.0 months), 3 deaths occurred. The estimated 1-year OS rate was 87.9%, with subgroup rates of 89.1% for cN3b (median follow-up: 12.0 months) and 87.5% for cT4b (median follow-up: 19.4 months). Conclusions: Neoadjuvant adebrelimab combined with chemotherapy achieves a high pathological response rate in stage IVB OSCC, with manageable adverse events and favorable safety. Clinical trial information: NCT06277791 .

ctDNA clearance durability and progression-free survival in unresectable or metastatic cutaneous malignancies.

9591 Background: Circulating tumor DNA (ctDNA) has emerged as a sensitive biomarker for disease monitoring and prognostication across malignancies. Yet, the clinical relevance of sustained ctDNA negativity (“clearance”) as a guide for immunotherapy duration in advanced cutaneous cancers remains poorly defined. This study evaluated the prognostic impact of durable ctDNA clearance in patients with unresectable or metastatic skin cancers treated with immune checkpoint inhibitors (ICIs). Methods: A single-institution retrospective study was performed using a personalized ctDNA assay (Signatera, Natera Inc.) on prospectively collected plasma from patients with stage III–IV unresectable cutaneous malignancies receiving ICIs every 3-6 weeks. ctDNA clearance was defined as a change from ctDNA-positive to ctDNA-negative on at least two consecutive samples obtained ≥4 weeks apart during ICI therapy and categorized as transient (<12 months) or sustained (≥12 months). Demographics and clinical characteristics were summarized with descriptive statistics; progression-free survival (PFS) was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were calculated with Cox proportional hazards models. Results: Among 75 patients (stage III: 23%, stage IV: 77%), most were male (72%) and had melanoma (87%), with a median age of 72 years and median follow-up of 20.4 months. Median ICI treatment duration was 6.9 months; all patients received ICIs, most commonly relatlimab/nivolumab (49%) or pembrolizumab (40%). Median ctDNA clearance duration was 8.2 months. Patients with sustained ctDNA clearance (n=25) experienced markedly improved 12-month PFS compared with those with transient clearance (n=50) (92.0% [95% CI, 71.6–97.9] vs 58.1% [95% CI, 42.6–70.8]). In a multivariable model adjusting for age, malignancy type, and treatment regimen, transient ctDNA clearance was associated with significantly worse PFS than sustained clearance (HR 12.1; 95% CI, 2.7-53.4). Conclusions: Sustained ctDNA clearance (≥12 months) is strongly associated with superior PFS in advanced cutaneous malignancies treated with ICIs, underscoring its potential as a dynamic biomarker to inform the treatment duration. Validation in larger, multi-institutional cohorts is warranted to confirm these findings and refine cDNA-guided immunotherapy strategies.

Predictors of surgery refusal and disease-specific survival outcomes in inflammatory breast cancer: A nationally representative cohort study.

e12725 Background: Inflammatory breast cancer (IBC) is a rare but highly aggressive subtype of breast cancer characterized by rapid progression, early metastatic potential, and poor survival compared to non-IBC subtypes. Approximately 10% of breast cancer-related deaths are related to IBC, which accounts for less than 5% of all breast cancer subtypes in the country. Multimodal therapy, including systemic treatment and surgery when indicated, remains central to optimizing disease-specific outcomes; however, not all patients undergo recommended surgical management. In this study, we utilized the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the association between refusal of recommended surgery and disease-specific mortality as well as identify independent predictors of surgical refusal. Methods: The SEER database was queried to identify females diagnosed with histologically-confirmed cases of invasive IBC (ICD-O-3 histology code 8530/3; primary site codes C50.0-50.9) who either received or refused recommended surgery between 2000-2022. Patients with an unknown status of treatment were excluded. Statistical analysis was conducted using SPSS version 29.0.2 and included multivariable binary logistic regression and multivariable cox regressions (significance p < 0.05). Results: A total of 4052 patients were identified, of which the greatest number were non-Hospanic White (66.5%), ages 50-59 (30.3%), resided in urban communities (86.9%), and underwent recommended surgery (98.0%). Multivariable Cox regression adjusting for age, race and ethnicity, annual income, rural-urban living, disease stage at diagnosis, and tumor grade revealed that refusal of recommended surgery was independently associated with a +104% increased disease-specific mortality risk (aHR 2.04; 95% CI 1.27-3.27) compared to those who underwent recommended surgery. Given the observed increase in disease-specific mortality, we next sought to identify independent predictors of recommended surgery refusal. Multivariable binary logistic regression adjusting for the same covariates revealed that Asian and Pacific Islander (API) racial groups were independently associated with +300% greater odds of refusing recommended surgery (aOR 4.00; 95% CI 1.02-15.63). Conclusions: The study highlights significant racial disparities related to surgery refusal, which may help inform patient counseling within affected subgroups and prompt further investigation of barriers contributing to refusal of potentially life-saving treatment. These patterns may reflect underlying sociocultural factors influencing medical decision-making. Our findings are also consistent with prior literature demonstrating higher rates of surgery refusal among API patients across multiple malignancies, including prostate, lung, liver, and gastric cancers.

Demographic and clinical factors impacting survival in malignant pheochromocytoma: A population-based analysis.

e22605 Background: Malignant pheochromocytoma is a rare and potentially aggressive neuroendocrine tumor arising from chromaffin cells. While overall survival (OS) is often favorable compared to other malignancies, a subset of patients experiences progressive disease. Existing literature has primarily focused on clinical and pathological prognostic factors, such as tumor size, location, and genetic markers. However, a significant gap remains in the large-scale epidemiological assessment of how demographic and socioeconomic factors influence patient outcomes. Furthermore, real-world evidence on the impact of specific treatment modalities, particularly in the context of these demographic variables, is limited. This study utilizes a national population-based registry to investigate the association between demographic factors, treatment approaches, and survival in malignant pheochromocytoma. Methods: Patients diagnosed with malignant pheochromocytoma from 2000 through 2022 were identified from the Surveillance, Epidemiology, and End Results (SEER) database using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) histology code 8700/3. Overall survival was analyzed using Cox proportional hazard regression models in GraphPad Prism. Results: The study cohort included 996 patients. Over a median follow-up of 22 months, 305 deaths occurred. In terms of demographic factors, Older age (≥65 years) was associated with significantly worse survival (HR 1.9, 95% CI 1.3-2.7, p = 0.0003). Patients with a household income below $80,000 had an increased hazard of death (HR 1.8, 95% CI 1.3-2.5, p = 0.0009) compared to those with higher income. For clinical factors, as expected, disease stage strongly predicted outcome: distant spread (HR 5.1, 95% CI 3.3-8.1, p < 0.0001) and regional spread (HR 1.8, 95% CI 1.1-2.9, p = 0.0172) conferred worse survival compared to localized disease. Treatment with surgery was strongly associated with better survival (HR 0.4, 95% CI 0.26-0.61). Receipt of chemotherapy was associated with poorer survival (HR 1.9, 95% CI 1.1-3.0, p = 0.0127), likely reflecting its use in more aggressive disease. Conclusions: Malignant pheochromocytoma often follows an indolent course with good overall survival, though prognosis declines sharply with distant metastasis. This analysis identifies age and lower socioeconomic status as significant demographic predictors of worse mortality, suggesting healthcare disparities. Surgery remains the cornerstone of effective management. The association of chemotherapy with poorer survival likely indicates its application in advanced, high-risk cases rather than a negative treatment effect, highlighting the need for effective systemic therapies.

Final results of a phase 2 trial of cabozantinib plus nivolumab (CaboNivo) in patients with non–clear cell renal cell carcinoma (nccRCC).

4521 Background: CaboNivo improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) over sunitinib in a phase 3 trial for metastatic clear cell RCC. (Choueiri NEJM 2021). We previously reported on 47 patients (pts) treated on a phase 2 trial of CaboNivo for nccRCC. We now present final results on all 60 pts accrued to the study. Methods: Pts had advanced nccRCC, 0 or 1 prior systemic therapies excluding prior immune checkpoint inhibitors and measurable disease by RECIST. Cabo 40 mg/day plus Nivo 240 mg every 2 weeks or 480 mg every 4 weeks was given across two cohorts. Cohort 1: papillary, unclassified, or translocation associated RCC (tRCC); Cohort 2: chromophobe RCC. The primary endpoint was ORR by RECIST; secondary endpoints included PFS, OS, and safety. Cohort 1 was a single stage design that met its primary endpoint and was expanded to produce more precise estimates of ORR. Cohort 2 was a Simon two-stage design that closed early for lack of efficacy and slow accrual. Results: Of 60 pts, 53 were included in Cohort 1, of whom 16 had papillary RCC, 16 unclassified RCC with papillary features (UCPF), 8 FH-deficient, 8 unclassified without papillary features (UC), and 5 tRCC. In Cohort 1, 39 (74%) pts were previously untreated, and 14 (26%) pts had 1 prior line: 10 (19%) received prior VEGF-targeted therapy and 8 (15%) received prior mTOR-targeted therapy. For Cohort 1 (Table), the ORR was 43% (95% CI 30-58), including 88% in pts with FH-deficient RCC. Median PFS (mPFS) in Cohort 1 was 11 months (95% CI 8-14), median OS was 28 months (95% CI 21-37), and there were 43 deaths after a median follow-up of 50 months for survivors. 7 pts with chromophobe RCC were enrolled in Cohort 2 with 5 achieving stable disease (SD) but no objective responses observed. Adverse events were similar to the previously reported cohort and cabozantinib and nivolumab were discontinued for toxicity in 22 (42%) and 20 (38%) pts, respectively. Conclusions: Final results from this phase 2 trial in nccRCC confirm efficacy and acceptable safety of CaboNivo in pts with metastatic papillary, unclassified, or tRCC histologies with a particularly high ORR in FH-deficient RCC. These results justify CaboNivo as a standard first-line treatment option for these pts. In contrast, objective responses were not observed in chromophobe RCC. Clinical trial information: NCT03635892 . Cohort 1 outcomes. Outcome All Pts(n=53) 1 st -line(n=39) 2 nd -line(n=14) Papillary(n=16) UCPF(n=16) FH-def(n=8) UC(n=8) tRCC(n=5) ORR, %(95% CI) 43(30-58) 46(30-63) 36(13-65) 31(11-59) 38(15-65) 88(47-100) 50(16-84) 20(1-72) CR, n (%) 1 (2) 1 (3) 0 1 (6) 0 0 0 0 PR, n (%) 22 (42) 17 (44) 5 (36) 4 (25) 6 (38) 7 (88) 4 (50) 1 (20) SD, n (%) 27 (51) 19 (49) 8 (57) 10 (63) 10 (62) 1 (12) 2 (25) 4 (80) PD, n (%) 3 (6) 2 (5) 1 (7) 1 (6) 0 0 2 (25) 0 mPFS, mo.(95% CI) 11(8-14) 11(8-16) 14(5-23) 11(7-25) 10(5-13) 16(5-37) 8(1-34) 14(5-41)

The CNS exile: An AI-driven audit of active brain metastasis exclusions in modern NSCLC immunotherapy clinical trials.

e13746 Background: Up to 50% of patients with metastatic non-small cell lung cancer (NSCLC) will develop brain metastases in their disease course, with 10% to 20% having them at the time of diagnosis. While modern immunotherapy (IO) agents demonstrate meaningful intracranial efficacy, clinical trial (CT) eligibility criteria often mandate central nervous system (CNS) stability or exclude CNS disease entirely. This study utilized a large language model (LLM) to audit whether eligibility criteria in the modern IO era have evolved to include patients with active or untreated CNS metastases in the advanced/metastatic setting. Methods: Interventional phase I to phase III CTs involving "immunotherapy" in "NSCLC stage IV" were extracted from ClinicalTrials.gov from 2016 to 2025. Using each trial’s inclusion and exclusion criteria, a LLM (Gemini 2.5-Flash) was used to classify CNS metastases eligibility into four categories: 1) total exclusion (explicitly excludes history of CNS metastases), 2) treated/stable only (only allowed if CNS metastases have been treated and are stable), 3) active allowed (explicitly allow active, asymptomatic, or untreated CNS metastases), and 4) silent (CNS metastases policy not mentioned). The accuracy of LLM categorization was validated via manual review of 30 randomly sampled trials, yielding 100% agreement. Results: In this CT cohort (n = 71), only 16.9% of trials explicitly permitted patients with active/untreated CNS metastases. 14.1% of trials did not have a statement regarding CNS metastases and were categorized as silent. The majority (63.4%) of CTs required treated/stable brain metastases, with 8.5% explicitly excluding those with brain metastases. Temporal analysis revealed a non-significant 2.3% decrease in the number of clinical trials allowing for active/untreated metastases (p = 0.21). Conclusions: Even when analysis is restricted to advanced/metastatic NSCLC trials, where brain metastases are a common clinical reality, 69% of modern IO protocols will explicitly exclude patients with active CNS disease. This "CNS exile" creates a profound evidence-practice gap, generating pivotal trial data that is not representative of a significant portion of the patient population. Future protocols must explicitly expand inclusion for stable, untreated CNS metastases to improve equity and real-world applicability. CNS eligibility policy in metastatic NSCLC trials by year, 2016-2025 (%). Year ACTIVE ALLOWED SILENT TOTAL EXCLUSION TREATED STABLE Total (N) 2016 33.3 0 66.6 0 3 2017 11.1 11.1 0 77.8 9 2018 42.9 0 14.3 42.9 7 2019 25 16.7 0 58.3 12 2020 0 0 14.3 85.7 7 2021 12.5 12.5 0 75 8 2022 16.7 33.3 0 50 6 2023 0 25 0 75 4 2024 33.3 0 0 66.7 6 2025 0 33.3 0 66.7 9 Total 16.9 14.1 5.6 63.4 71

Age-specific trends in liver cancer mortality in the United States, 1999–2023: A Joinpoint regression analysis.

e16334 Background: Liver cancer remains a leading cause of cancer-related mortality in the United States. Although overall mortality has increased over the past two decades, age-specific patterns and demographic disparities are not fully characterized. Here, we analyzed U.S. liver cancer mortality trends from 1999 to 2023, with a focus on age-related, racial and ethnic, and geographic differences. Methods: Mortality data for U.S. adults aged ≥25 years from 1999 to 2023 were obtained from the CDC WONDER database (ICD-10 codes C22.0–C22.9). Age-adjusted mortality rates (AAMRs) were standardized to the 2000 U.S. population. Joinpoint regression was used to estimate annual percent change (APC) and average annual percent change (AAPC) across age groups, sex, race/ethnicity, U.S. census regions, and levels of urbanization. Results: From 1999 to 2023, overall liver cancer AAMRs increased from 6.95 to 10.1 per 100,000. Marked age-specific differences were observed. Mortality among adults aged 45–54 and 55–64 years peaked in the mid-2010s and subsequently experienced significant declines through 2023 (recent APCs < −4.5% for both groups; P < 0.001). Specifically, while the overall AAPC for the 55–64 age group was +1.89%, mortality significantly reversed after 2016 (APC, −4.59%). In contrast, mortality continued to rise among older adults, including those aged 65–74 years (AAPC, +2.26%), 75–84 years (AAPC, +1.69%), and aged ≥85 years (AAPC, +1.77%) (all P < 0.001). Differences in mortality trends were also identified across racial and ethnic groups. Sustained increases were observed among Non-Hispanic White individuals (AAPC, +1.89%; P < 0.001), while Hispanic/Latino populations experienced declines after 2013 (APC, −0.67%; P = 0.003). Non-Hispanic Black individuals demonstrated a significant decrease in mortality between 2017 and 2020 (APC, −3.82%; P = 0.03). Regionally, liver cancer mortality declined in the Northeast after 2013 (APC, −0.66%; P < 0.001), whereas no significant post-peak declines were observed in the South or West. Conclusions: U.S. liver cancer mortality trends exhibit substantial heterogeneity by age, race and ethnicity, and geographic region. The recent, sharp declines among middle-aged adults (APCs < −4.5%) likely reflect the success of large-scale viral hepatitis screenings and highly effective antiviral therapies, whereas continued increases among older adults may relate to the cumulative impact of metabolic risk factors and delayed diagnosis. Persistent racial and regional disparities highlight the need for targeted, age-specific prevention and surveillance strategies.

Rationale and study design of the KOV-HIPEC-04: A phase III randomized controlled trial in primary stage three and four ovarian cancer after interval cytoreductive surgery (FOCUS).

TPS5643 Background: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) during interval cytoreductive surgery increases progression-free and overall survival for patients with stage III ovarian cancer in two randomized controlled trials (OV-HIPEC-01 and KOV-HIPEC-01). This trial aims to identify the survival benefit of HIPEC in stage III & IV ovarian cancer in the era of maintenance therapy of bevacizumab and/or PARP inhibitors. Methods: Ovarian cancer patients will be randomized at the time of interval cytoreductive surgery with achieving complete cytoreduction or cytoreduction with no more than 2.5mm size of residual disease to receive HIPEC (41.5 cisplatin 75mg/m 2 , 90 minutes) or not (Control arm). After recovery from surgery, patients will receive postoperative platinum-based adjuvant chemotherapy followed by maintenance therapy with PARP inhibitor or bevacizumab. The primary objective of the trial is to evaluate OS in two groups. Secondary objectives are PFS, cancer-specific survival, time to first subsequent therapy (TFST), safety, CA-125 KELIM, and quality of life. Assuming that the enrollment period is 5 years and the follow-up period is 3 years, the total number of events required is 263. Based on the log-rank test, the total number of subjects required to prove HR 0.67 with a two-sided alpha of 0.05 and 90% power is 494. Considering 5% drop-out, 520 patients are finally studied. Clinical trial information: NCT05827523 .

Camrelizumab combined with capecitabine as maintenance therapy for metastatic nasopharyngeal carcinoma: A phase II single-arm clinical trial.

e18016 Background: Metastasis is the main cause of death in nasopharyngeal carcinoma (NPC). The current first-line treatment for metastatic NPC involves gemcitabine, cisplatin, and camrelizumab followed by camrelizumab maintenance. This phase II trial evaluates the efficacy and safety of camrelizumab combined with capecitabine as a novel maintenance therapy strategy after systemic treatment. Methods: This study enrolled 20 patients with metastatic nasopharyngeal carcinoma, comprising 11 with synchronous metastases and 9 with asynchronous (post-treatment) metastases. All patients received systemic therapy with camrelizumab (200mg d1) plus gemcitabine (1000 mg/m² d1 and 8) and cisplatin (80 mg/m² d1) intravenously every 3 weeks (4-6 cycles), followed by maintenance therapy with camrelizumab (200mg d1) plus capecitabine (1000 mg/m² bid d1–14). The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included the 18-/24-month PFS rate, 12-/18-/24 month overall survival (OS) rate, and the incidence of adverse events. Results: As of December 31, 2025, 20 patients were enrolled, with a median age of 41 years (range: 26–62). Among them, 15 were male and 5 were female; 8 had a history of smoking; 18 tested positive for EB virus after metastasis; 6 patients underwent induction chemotherapy, and 9 underwent definitive radiotherapy prior to the development of metastasis. Two patients received 5 cycles of systemic therapy, while the remaining 18 completed 6 cycles. Additionally, liver metastasis was observed in 10 patients (50%), bone metastasis in 9 (45%), and lung metastasis in 6 (30%). All patients were alive, and the 12-month PFS rate (systemic therapy + maintenance therapy) was 81.48%. The median survival was not yet reached. The objective response rate (ORR) was 100%. Treatment-emergent adverse events (TEAEs) of any grade occurred in all 20 patients, with all patients experiencing at least one grade ≥3 event. The most common grade ≥3 TEAEs included anemia (55%), neutropenia (55%), thrombocytopenia (25%), elevated aspartate aminotransferase (5%), and diarrhea (5%). Once maintenance therapy is started, the adverse reactions are significantly alleviated. Conclusions: Camrelizumab combined with capecitabine as maintenance therapy effectively prolongs survival time in patients with metastatic nasopharyngeal carcinoma, demonstrating favorable efficacy and safety. Enrollment is ongoing, and further validation of specific data is awaited. Clinical trial information: ChiCTR2500111883.

Intismeran Autogene Plus Pembrolizumab Versus Pembrolizumab Alone in High-Risk Resected Melanoma: 5-Year Update of the Randomized Phase IIb KEYNOTE-942 Study

Intismeran autogene (intismeran; formerly V940 or mRNA-4157) is an mRNA-based individualized neoantigen therapy. We report 5-year outcomes of intismeran plus pembrolizumab from the phase IIb KEYNOTE-942 study (ClinicalTrials.gov identifier: NCT03897881 ). Eligible patients with resected stage IIIB to IV cutaneous melanoma were randomly assigned 2:1 to receive nine doses of intramuscular intismeran 1 mg once every 3 weeks plus 18 doses of intravenous pembrolizumab 200 mg once every 3 weeks or 18 doses of intravenous pembrolizumab 200 mg once every 3 weeks. The primary end point was recurrence-free survival (RFS); secondary end points included distant metastasis-free survival (DMFS) and safety. Five-year analyses were descriptive. Among 157 randomly assigned patients (intismeran plus pembrolizumab, n = 107; pembrolizumab, n = 50), the median planned follow-up at data cutoff (December 15, 2025) was 60.3 (range, 50.5-76.4) months. Intismeran plus pembrolizumab continued to prolong RFS (hazard ratio [HR], 0.510 [95% CI, 0.294 to 0.887) and DMFS (HR, 0.411 [95% CI, 0.200 to 0.843]), with a favorable trend in overall survival (HR, 0.471 [95% CI, 0.165 to 1.345]) versus pembrolizumab. Safety profile continued to be manageable, with no new safety signals. Intismeran plus pembrolizumab was associated with increased T-cell receptor clonality and novel clonotypes versus pembrolizumab; greater novel clone expansion was observed in patients without versus with recurrence in the combination arm. After a 5-year follow-up, intismeran plus pembrolizumab demonstrated sustained, durable treatment benefits versus pembrolizumab alone in resected high-risk melanoma.

Barriers to comprehensive genomic profiling implementation in Japan and perspectives on systemic reform: A longitudinal analysis of nationwide physician surveys (2019–2025).

e15083 Background: Comprehensive Genomic Profiling (CGP) was reimbursed in Japan in 2019. By 2025, physician awareness reached approximately 90%, whereas implementation rates remained limited to 10–30% across cancer types. In Japan, CGP requires mandatory Expert Panel (EP) review, and reimbursement is restricted to patients who have completed or are expected to complete standard therapies. This study examined temporal changes in barriers to CGP implementation from 2019 to 2025 and assessed the impact of Japan-specific institutional requirements on clinical practice. Methods: Web-based surveys were conducted once or twice annually from 2019 among physicians registered with Plamed Inc., collecting approximately 1,000 responses per wave. Using anonymized data, temporal trends were analyzed for perceived challenges to CGP implementation, factors required to promote CGP uptake, burden associated with EP meetings, and time required for EP-related tasks. Results: CGP implementation increased from approximately 1–5% in 2019 to 10–30% in 2025 but remained limited.In 2019, frequently cited challenges included uncertainty in identifying treatment options, lack of experience in explaining results to patients, and burden related to explaining hereditary findings to families, each reported by approximately 50% of physicians.By 2025, the main challenges shifted to low treatment reach (with only ~10% of tested patients leading to treatment), high costs including patient out-of-pocket burden, and prolonged turnaround time (TAT) of 2–3 months, each selected by approximately 30% of respondents and consistently high since 2022.To promote future CGP uptake, physicians emphasized simplifying procedures and reducing operational burden. EP meetings were identified as a major source of burden, with approximately 90% reporting EP-related burden since 2022, particularly for case preparation. No meaningful reduction in EP-related workload was observed over time. Conclusions: Key barriers to CGP implementation in Japan include low treatment reach, financial burden, and prolonged TAT. Mandatory EP review represents a significant operational burden and may contribute to procedural complexity and delayed result delivery. Policy discussions are ongoing regarding flexibilization of EP operations and expansion of eligible EP-performing institutions. Additionally, allowing CGP prior to completion of standard therapy may expand patient eligibility and improve treatment access. As physician awareness and willingness continue to increase, comprehensive systemic reforms addressing EP processes and testing timing are essential to further promote CGP adoption in Japan.

Climate and regional plant richness drive diet specialization in butterfly caterpillars

Burden of adolescent and young adult lung cancer in South Asia: 1990−2023.

e22596 Background: Lung cancer is the leading cause of cancer mortality worldwide. South Asia, the world’s most populous region, bears a significant yet understudied burden of adolescent and young adult (AYA) lung cancer. Methods: Using the Global Burden of Disease 2023, we report incidence rate (IR) and mortality rate (MR) per 100,000 and deaths attributable to risk factors for AYA (ages 15–49) lung cancer in South Asia (Bangladesh, Bhutan, India, Nepal, and Pakistan) from 1990–2023, stratified by sex. Global and GBD super-region estimates were used as comparators. Results: Global IR and MR declined to 3.2 (−24%) and 2.5 (−27%) in 2023, respectively; however, South Asia, despite having the second-lowest IR (1.9) and third-lowest MR (1.6) in 2023, was the only GBD super-region with increasing IR (+68%) and MR (+65%) from 1990–2023, driven by rising female IR (+96%) and MR (+92%). In South Asia, IR and MR were double in males (IR 2.5; MR 2.1) compared with females (IR 1.3; MR 1.0). In 2023, IR and MR were highest in Bangladesh (IR 3.4; MR 2.8) and Bhutan (IR 2.6; MR 2.1), and lowest in Pakistan (IR 1.8; MR 1.5), India (IR 1.7; MR 1.5), and Nepal (IR 1.7; MR 1.4). Male rates were highest in Bangladesh (IR 4.8; MR 3.9), while female rates were highest in Bhutan (IR 2.4; MR 2.0). Pakistan was the only country where female rates exceeded male rates (IR 2.2 vs 1.5; MR 1.8 vs 1.3). All countries had increasing IR and MR, with the largest in Bhutan, where rates rose by over 200% in all populations. In 2023, 71% of male and 57% of female deaths in South Asia were attributable to modifiable risks. In males, behavioral risks predominated (50%), driven by tobacco (39%), while environmental and occupational risks contributed 42%, including particulate matter pollution (31%). Among females, environmental and occupational risk were dominant (39%), exceeding behavioral risks (28%), with particulate matter pollution contributing 33% and tobacco 15%. From 1990-2023, risk attributable deaths decreased (–5.8% males; –9.9% females). Tobacco risk decreased by 20% in males and 29% in females, driven by India and Nepal. Males had increases in occupational exposure to asbestos (+102%), diesel engine exhaust (+34%), and silica (+31%). Females had increases in all occupational exposures, with the highest increases in Bangladesh (131–203%) and Pakistan (199–281%). Ambient particulate matter attributable deaths increased by 93% in males and 121% in females, peaking in Bhutan (+186% males, +264% females). Conclusions: Despite low IR and MR, South Asia is the only GBD super-region with rising AYA lung cancer burden from 1990-2023, driven largely by rising female burden. Declines in tobacco-attributable mortality have been offset by rapid growth in ambient particulate matter pollution and occupational carcinogens, with marked country-level heterogeneity. Sex- and country-specific prevention strategies are needed that extend beyond tobacco control to address other exposures.

Prostate cancer screening in Nigeria: Findings from a multi-city community-based PSA testing outreach.

e13597 Background: Prostate cancer is the most frequently diagnosed cancer and the leading cause of malignancy-related mortality among Nigerian men. The rising incidence and mortality rates across Africa are largely attributed to late-stage presentation and a lack of early detection infrastructure. Prostate-specific antigen (PSA) testing provides a cost-effective method to identify high-risk individuals (PSA > 4 ng/mL). This study analyzes PSA data from a multi-site screening event to identify health trends and inform future screening strategies in resource-limited settings. Methods: In February 2023, a community outreach event ("More Time for Life") screened 262 men for prostate cancer and comorbidities across three Nigerian cities: Abuja (n = 86), Lagos (n = 56), and Port Harcourt (n = 120). PSA values were analyzed using STATA to generate descriptive statistics across age cohorts (40–49, 50–59, 60–69, and 70–79). Results: PSA levels increased with age across all screening sites, correlating with established clinical trends. While men with elevated blood pressure generally had higher PSA levels, a t-test (p = 0.83) showed no statistically significant association, likely due to the limited sample size. Geographic disparities were significant: the proportion of men with PSA > 4 ng/mL in Port Harcourt was nearly three times higher than those in Abuja. Additionally, Port Harcourt recorded the highest average BMI among participants. All individuals identified with elevated PSA levels were referred to tertiary centers for further clinical assessment. Conclusions: This community-based screening outreaches demonstrate the feasibility of multi-city PSA testing to identify geographic and demographic patterns of prostate cancer risk in resource-limited settings. Significant geographic variations in PSA levels suggest that environmental factors, such as high levels of air pollution in regions like Port Harcourt, may influence cancer risk and merit further investigation. These findings underscore the potential for self-care and out-of-facility interventions to enhance chronic disease management and early cancer detection.

Comparative efficacy and safety of neoadjuvant immunochemotherapy, chemoradiotherapy, and chemotherapy in resectable locally advanced esophageal squamous cell carcinoma: A network meta-analysis of randomized controlled trials.

e16140 Background: Neoadjuvant chemoradiotherapy (NCRT) followed by surgery is currently the standard of care for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC). Recently, neoadjuvant immunochemotherapy (NICT) has emerged as a highly promising strategy, demonstrating potent antitumor activity and a manageable safety profile. Due to the lack of large-scale, head-to-head randomized controlled trials (RCTs) directly comparing NICT with NCRT, the optimal neoadjuvant strategy remains clinically debated. This network meta-analysis aims to compare the survival outcomes, pathological responses, and safety profiles among NICT, NCRT, and neoadjuvant chemotherapy (NCT) to guide individualized treatment decisions. Methods: We systematically searched PubMed, Embase, and the Cochrane Library for eligible RCTs published from January 2000 to December 2025. Study quality was assessed using the Cochrane Risk of Bias tool 2.0. A frequentist network meta-analysis based on a random-effects model was performed to comprehensively evaluate overall survival (OS), pathological complete response (pCR), and grade ≥3 treatment-related adverse events (TRAEs). Treatment ranking probabilities were estimated using P-scores. Results: Seven RCTs involving 1,362 patients were included. For OS, compared with surgery alone (S), NICT demonstrated the most pronounced survival benefit (HR 0.36, 95% CI 0.17 – 0.76), followed by NCRT (HR 0.62, 95% CI 0.50 – 0.78) and NCT (HR 0.75, 95% CI 0.58 – 0.98). The P-score ranking indicated that NICT had the highest probability of being the optimal treatment for improving OS (P-score 0.97). In contrast, pCR rates were highest with NCRT (OR 10.07 vs. NCT, 95% CI 4.51–22.48), followed by NICT (OR 4.14, 95% CI 2.01–8.55). Both OS and pCR showed low heterogeneity (I² = 0%). Regarding safety, NICT showed a grade ≥3 TRAE profile comparable to that of NCT (P-score: 0.47 vs. 0.53). Conclusions: NICT and NCRT offer distinct therapeutic advantages in LA-ESCC. While NCRT remains superior for achieving pathological complete response, NICT provides a more pronounced long-term survival benefit and favorable systemic tolerability. These findings suggest that NICT may be the preferred neoadjuvant strategy for maximizing OS in LA-ESCC, whereas NCRT retains value for local tumor downstaging. Nevertheless, further well-designed randomized studies are warranted to validate these results, given the limitied number of included trials.

Coping strategies adopted by caregivers of pediatric oncology patients navigating the economic burden of treatment in a tertiary cancer care center: A qualitative thematic analysis.

e22004 Background: Economic distress due to cost of cancer treatment is a significant challenge for patients and caregivers. It impacts treatment adherence, quality of life, and emotional well-being, often leading to need for coping strategies that differ across sociocultural contexts, especially in pediatric cancers. Research on coping strategies used to navigate treatment costs is especially important in LMICS like India to plan healthcare delivery and policy. Methods: We conducted a qualitative study using semi-structured interviews with 10 parents/caregivers of pediatric cancer patients (< 18 years) to understand coping strategies used to navigate through their financial burdens during treatment. Interviews were recorded and transcribed verbatim and thematic analysis was performed using manual coding to identify common codes and themes on unique strategies used to address financial burdens. Results: All participants reported significant financial strain on their families due to the cancer treatment of their ward, which led to various coping strategies that cane grouped under the following 4 themes: (1) financial coping (selling of personal assets, taking loans and mortgages, relying on family and friends, support from charities, NGOs and government schemes, change of jobs and home, reduce/cut non-medical expenses),(2) emotional and social isolation, (3) discontinuation of education and (4) effect on siblings of the patient. Conclusions: The families of pediatric oncology patients in India face acute financial toxicity that extends beyond the medical bills which includes loss of income, educational disruption, and social isolation. The coping strategy themes identified from this study can help guide pediatric cancer care implementation and policies in India and similar LMIC countries.