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Change in relative cerebral blood volume as a biomarker for early response to bevacizumab in patients with recurrent glioblastoma: ECOG-ACRIN EAF151.
2016 Background: Bevacizumab therapy (Bev) for recurrent glioblastoma (rGBM) has not demonstrated improved overall survival (OS) in randomized clinical trials. However, single-center and preliminary multi-center studies suggest that relative cerebral blood volume (rCBV) measured with dynamic susceptibility contrast MRI (DSC-MRI) at baseline or shortly after treatment initiation may predict response to Bev. The primary aim of ECOG-ACRIN EAF151 was to evaluate whether early binary change in rCBV, assessed 2–3 weeks after initiation of Bev-containing therapy, identifies patients with an OS benefit of ≥4 mos. Pre-specified secondary aims assessed baseline rCBV; post-hoc exploratory analyses examined early post-Rx rCBV. Methods: A prospective, phase II multi-center trial without randomization enrolled subjects with rGBM receiving their first Bev-containing therapy. Progression was determined by local sites (RANO criteria; MRI within 28 days of registration, ≥42 days since end of chemoradiation). Baseline (S0) and follow-up (S1) DSC-MRI were performed before the first Bev infusion (within 3 days), and 12-25 days post-infusion but before the second infusion. Anatomic MRI and DSC-MRI (double-dose Gadavist injection, full-dose preload) complied with recommended protocols. Mean normalized (nRCBV) and standardized (sRCBV) rCBV were extracted from contrast-enhancing tumor ROIs. A 2-sided logrank test (α=0.1) was used to test the primary aim (change in mean nRCBV from S0 to S1, ≥0 vs. <0). Cox regression with restricted cubic splines was used to assess the association between continuous rCBV markers and OS. Results: 146 subjects were accrued from 33 sites. 134 completed S0 and 118 completed both S0 and S1. After exclusion of uninterpretable scans, 107 were evaluable for change in rCBV, and 124 for baseline rCBV. There was no statistically significant difference in OS between subjects with binary increase (n=40; median OS 8.0 mos [90% CI 5.5–9.2]) vs. decrease (n=67; 7.9 mos [90% CI 6.3–10.3]) in mean nRCBV (p=0.67). Based on the spline fits, we observed a strong nonlinear association between OS and continuous nRCBV and sRCBV at both S0 and S1: low marker values are associated with lower risk, but beyond a threshold, higher values are not associated with greater risk. As an exploratory analysis, we estimated optimal cut points (nRCBV: S0=1.11, S1=1.16; sRCBV: S0=1.13, S1=0.99) and found that subjects whose S1 rCBV decreased below threshold had a median OS 2.7 mos (nRCBV, HR 0.61 [90% CI 0.41–0.88]) and 5.2 mos (sRCBV, HR 0.43 [90% CI 0.28–0.63]) longer than subjects whose rCBV either increased or did not decrease below threshold. Conclusions: EAF151 prospectively evaluated whether DSC-MRI markers predict OS in patients with rGBM treated with Bev. Although the change in these markers was not predictive, both baseline and early post-Rx markers were predictive of OS. Clinical trial information: NCT03115333 .
Spatial multiomic profiling to identify de-differentiated tumor phenotypes and exhausted T cell niches in rhabdoid and sarcomatoid RCC.
4557 Background: Rhabdoid and sarcomatoid (S/R) differentiation are high-grade dedifferentiated states that can arise across renal cell carcinoma (RCC) subtypes. Although associated with poor patient prognosis, S/R RCC paradoxically exhibits increased sensitivity to immune checkpoint blockade. The mechanisms underlying this aggressive, yet immunotherapy-responsive phenotype remain unclear. Spatial multi-omic profiling offers a powerful framework to interrogate tumor-intrinsic and microenvironmental programs that account for this phenotype. Here, we applied spatial multi-omic analyses to treatment-naïve clear cell RCC specimens from seven patients, enabling direct comparison of sarcomatoid, rhabdoid, and clear cell regions captured within the same tissue sections. Methods: Hematoxylin and eosin (H&E)–stained sections from seven FFPE patient samples were reviewed and annotated by a genitourinary pathologist to identify discrete regions of sarcomatoid, rhabdoid, or clear cell morphology. Annotated FFPE samples were processed by Singular Genomics using the G4X spatial multi-omic platform, which enables quantification of 315 RNA transcripts, 14 protein targets, and fluorescent H&E imaging. Results: Initial spatial multi-omic profiling resolved distinct tumor regions with clear cell biology alongside areas exhibiting rhabdoid or sarcomatoid features. Comparative analysis of immune infiltrates across these regions revealed enrichment of both T cells and B cells within rhabdoid regions. In addition, T cells localized to rhabdoid and sarcomatoid regions displayed distinct phenotypic states compared with those in clear cell regions. Differential gene expression (DGE) analysis of T cells from rhabdoid and sarcomatoid regions relative to clear cell RCC demonstrated upregulation of activation markers ( CD69 , IL2RA ), exhaustion markers ( LAG3 , PDCD1 ), and cytotoxic genes ( GZMA , GZMK , NKG7 ). Parallel analysis of tumor cell transcriptional programs further highlighted distinct tumor biology across histologic regions. Sarcomatoid tumor cells exhibited increased expression of genes associated with cellular stress, inflammation, and epithelial–mesenchymal transition (EMT), including IGFBP7 and FOS . In contrast, rhabdoid tumor cells showed upregulation of antigen-presentation machinery ( HLA-A , TAP1/2 ) along with elevated expression of EMT-associated genes ( MET , VCAM1 , and CD44) . Conclusions: Spatial multi-omic analysis of S/R RCC revealed distinct immune and transcriptional programs across sarcomatoid, rhabdoid and clear cell regions. T cells within S/R regions exhibited activated and exhausted phenotypes, while tumor cell characterization of S/R cells reveals upregulation of stress, inflammatory and antigen-presentation machinery, features that may underlie the sensitivity of S/R RCC to immune checkpoint inhibitors.
Disparities in race and insurance status among hospitalized patients with pancreatic cancer and protein–energy malnutrition: A nationwide analysis, 2016–2022.
11052 Background: Protein–energy malnutrition (PEM) is frequently encountered in patients with pancreatic cancer and is associated with worse clinical outcomes. Although sociodemographic differences in malnutrition risk have been described, it is unclear whether racial and insurance-based disparities persist after accounting for clinical complexity, socioeconomic factors, and hospital characteristics. We sought to identify independent predictors of PEM among hospitalized patients with pancreatic cancer using a nationally representative inpatient cohort with multivariable adjustment for relevant covariates. Methods: We conducted a retrospective cohort study using the National Inpatient Sample (NIS) from 2016 to 2022. Adult hospitalizations with pancreatic cancer were identified using ICD-10-CM code C25, and PEM was defined using ICD-10-CM codes E40–E46. Multivariable regression models evaluated independent predictors of PEM and its associations with in-hospital mortality, length of stay, discharge disposition, and hospital charges. Models adjusted for demographic factors, comorbidities, and hospital characteristics, with survey weights applied to generate national estimates. Results: Among an estimated 263,890 hospitalizations for pancreatic cancer, 37% were associated with PEM. After adjustment, Black patients (adjusted odds ratio [aOR] 1.39, 95% CI 1.31–1.48) and Asian/Pacific Islander patients (aOR 1.41, 95% CI 1.27–1.56) had higher odds of PEM compared with White patients. Medicaid insurance was associated with increased odds of PEM (aOR 1.12, 95% CI 1.03–1.22), whereas private insurance was associated with lower odds (aOR 0.85, 95% CI 0.80–0.91) relative to Medicare. Higher comorbidity burden (Charlson Comorbidity Index ≥3) was the strongest predictor of PEM (aOR 1.54, 95% CI 1.45–1.64). Median household income was not independently associated with PEM. PEM was more common in urban hospitals and those with larger bed size. Conclusions: In this national inpatient cohort, PEM was common among patients hospitalized with pancreatic cancer and demonstrated racial and insurance-based disparities that persisted after adjustment for income, comorbidities, and hospital characteristics. These findings highlight potential gaps in nutritional risk recognition and underscore the importance of standardized inpatient nutritional screening and targeted interventions for high-risk populations. Variable aOR 95% CI P value Age 50–64 1.20 1.03–1.38 0.016 Age ≥65 1.25 1.08–1.46 0.004 Female sex 0.94 0.91–0.98 0.006 Black race 1.39 1.31–1.48 <0.001 Asian/Pacific Islander 1.41 1.27–1.56 <0.001 Other race 1.23 1.10–1.38 <0.001 Medicaid insurance 1.12 1.03–1.22 0.010 Private insurance 0.85 0.80–0.91 <0.001 Charlson Index ≥3 1.54 1.45–1.64 <0.001
Effects of upfront dual immunotherapy on overall survival in patients with metastatic non-small cell lung cancer with no targetable mutations or PD-L1 expression.
e20588 Background: Upfront treatment decision for patients with metastatic Non-Small Cell Lung Cancer (NSCLC) with no targetable mutations and no Programmed Death Ligand 1 (PD-L1) expression remains controversial. Although FDA approved, the combination of conventional chemotherapy and PD-1/L-1 antibody has shown mixed results as multiple sub-groups analyses of clinical trials failed to show a benefit in PD-L1 negative tumors. Conversely, a combination of 2 checkpoint inhibitors, ipilimumab and nivolumab (ipi+nivo), is not Food and Drug Administration approved for these tumors but is an option in the NCCN guidelines. To our knowledge, this is the first large-scale study to address survival outcomes between upfront chemotherapy-immunotherapy (ChemoIO) vs dual immunotherapy alone in metastatic NSCLC. Methods: A retrospective cohort study using TriNetX Research Network, a federated platform of HIPAA-compliant patient records from 159 healthcare organizations (HCO) from the Global Collaborative Network was carried out. Patients with NSCLC and no targetable mutation defined as HER2, MET variant, EGFR, ALK, RET, EGFR, BRAF, ROS1, NTRK1/2/3 and no PDL1 were identified. Outcomes were compared of first-line ipi+nivo vs ChemoIO (pembrolizumab plus cisplatin, carboplatin, paclitaxel, pemetrexed or a combination of these). Cohorts were balanced for age and sex. Overall survival (OS) was assessed via Kaplan-Meier analysis. Results: Between May 2020 and December 2025, 739 patients received ChemoIO and 173 ipi+nivo across 26/24 HCO. After balancing, cohorts totaled 172 each. Patients diagnosed with NSCLC with no targetable mutation and no PDL1 expression who received first line treatment with dual immunotherapy had superior OS than those who were treated with ChemoIO [p = 0.0001]. The survival probability at 6-, 12- and 24- months for ipi+nivo vs ChemoIO was noted to be 88% vs 74%, 81% vs 66%, and 68% vs 51%, respectively. In comparison to ChemoIO, patients with ipi+nivo had more hospitalizations but similar incidence of emergency department visits. There was a tendency for longer time to second line of therapy for ipi+nivo, which was not yet statistically significant. Conclusions: Patients with metastatic NSCLC with no targetable mutations and no PDL1 expression who received dual immunotherapy in the first line setting had superior survival than those treated with ChemoIO. Our results show a very significant survival difference in favor of combination immunotherapy, indicating that further investigation of the best initial therapy for these patients is urgently needed. Dual immunotherapy was associated with higher rates of healthcare utilization, perhaps suggesting a need for proactive recognition of possible side effects and implementation of standardized protocols to assist with their management.
Assessing breast density: Are convolutional neural networks the only path?
e12558 Background: Beyond reducing image interpretability, high breast density is an independent risk factor for breast cancer. It is increasingly considered in personalized screening strategies and decisions regarding supplemental imaging. Because breast density influences both the sensitivity of mammography and the patient’s overall risk of developing breast cancer, its accurate assessment is clinically important. Most of present days systems for breast density assessment are convolution neural networks (CNN) whose inputs are the mammograms. Because their numbers of connection weights are huge and because the features their density assignment decisions rely on are not explicit and up to now cannot be explained, CNN can hardly meet the prime requirements of reproducibility, transparency and testability for trustworthy applications of artificial intelligence in healthcare. Methods: We analyzed the 7,622 cranio-caudal images of VinDr-Mammo dataset from Siemens Mammomat device only, for quality uniformity concern. In each mammogram we removed the image background and artefacts. Then, in this very large region of interest we extracted four easy and fast to compute markers of low and high density tissues: Marker M1 was the bimodality of the pixel intensity histogram. From this marker we defined 4 ranges of pixel intensities: the very dark range of intensities (VDRI), and the dark (DRI), bright (BRI) and very bright (VBRI) ones. Marker M2 was the heterogeneity of BRI. Markers M3 and M4 were the ratio of BRI over DRI heterogeneities and that of VBRI over VDRI. The heterogeneity of an intensity range was the Shannon entropy of its pixel intensities distribution. The four markerswere input to a deep learning classifier of only 256 parameters: 4 input cells one per marker, a single hidden layer of 16 cells, and the output layer of one cell per BIRADS A to D breast density category. Results: Markers M1 to M4 were relevant features for breast density assessment because of their very high correlations with subsets of BIRADS breast density categories. They were interpretable in terms of breast tissues and were fast to compute. The classifier was small, easy to simulate in open source machine learning environments, and the learning too was very fast on regular personal computers. The computational efficiency of both the markers and the classifier allowed assessing the performance robustness by cross validation procedures. The design achieved performances that were at the level of most of CNN designs. In A-B versus C-D category assessment: Acc = 94.25% ± 0.027, F1 = 93.86 ± y, AUC = 94.82 ± 0.045. In A-B-C-D: Acc = 83.18 ± 0.100, F1 = 81.40 ± 0.117, AUC = 89.57 ± 0.154. Conclusions: Our design offers a simple, transparent, and efficient alternative to CNN-based breast density classifiers. It is suited for clinical integration and may support consistent patient stratification for supplemental screening. The codes are publicly available to ensure reproducibility.
Impact of Medicaid expansion on five-year mortality among patients with melanoma in the United States.
e21603 Background: Melanoma survival depends on early diagnosis and timely access to definitive surgery and modern systemic therapies, including immune checkpoint inhibitors. Insurance-related barriers may therefore exert an ample influence on outcomes in melanoma. While Medicaid expansion under the Affordable Care Act (ACA) improved insurance coverage nationally, its effect on long-term melanoma survival and associated racial inequities remains insufficiently characterized. Methods: Using the National Cancer Database (2006-2023), we identified adults aged 40-64 years with a primary diagnosis of melanoma. A difference-in-differences design compared 5-year overall mortality between states that implemented Medicaid expansion by January 2014 (expansion states) and non-expansion states, which are yet to implement the policy. Models adjusted for demographic, clinical, and socioeconomic factors. Pre-specified subgroup analyses assessed heterogeneity by race and ethnicity. Results: The cohort included 288,494 patients with melanoma (mean [SD] age, 54.5 [6.8] years), of whom 171,805 (59.6%) resided in expansion states. Following ACA implementation, expansion states experienced substantially greater reductions in uninsurance and larger increases in Medicaid coverage compared with non-expansion states. Medicaid expansion was associated with a 1.1%-point absolute reduction in 5-year mortality, corresponding to approximately 1,900 fewer deaths among patients in expansion states (95% CI, ~1,030-2,405). Significant racial and ethnic heterogeneity was observed (χ² = 56.1; P < 0.001). Hispanic patients experienced the largest survival benefit (-7.0% points; 95% CI, -9.1 to -4.8), followed by non-Hispanic other racial groups (-4.1; 95% CI, -8.0 to -0.3). More modest improvements were seen among non-Hispanic White patients (-0.8; 95% CI, -1.2 to -0.3). Notably, no survival benefit was observed among non-Hispanic Black patients (-0.5; 95% CI, -6.2 to 5.2). Conclusions: Medicaid expansion was associated with meaningful improvements in long-term melanoma survival, reinforcing the central role of insurance access in a disease where outcomes hinge on early detection and timely treatment. However, the absence of benefit among Black patients underscores persistent structural barriers that are not mitigated by coverage expansion alone. These findings highlight the need for targeted, equity-focused interventions across the melanoma care continuum to ensure that advances in cancer policy and treatment translate into equitable survival gains.
A phase 3 randomized, open-label study of pasritamig (JNJ-78278343), a T-cell engager targeting human kallikrein-2, with docetaxel versus docetaxel for metastatic castration-resistant prostate cancer.
TPS5139 Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with high morbidity and a median overall survival of approximately two years. Human kallikrein 2 (KLK2) is highly and specifically expressed in normal and malignant prostate tissue, including late stage mCRPC. Pasritamig (PAS) is a first-in-class bispecific T-cell-engager that simultaneously binds KLK2 on prostate cancer cells and CD3 receptor complexes on T cells. In the Phase 1b study (NCT05818683), pasritamig was combined with docetaxel (DOCE) to treat patients with mCRPC. The safety profile of PAS+DOCE was shown to be consistent with previous studies of DOCE and no cytokine release syndrome of any grade was reported (0 of 51 patients). Promising anti-tumor activity was observed in both taxane-naïve and heavily pretreated patients. Methods: This global, randomized, open-label, phase 3 study (NCT07225946) evaluates the efficacy and safety of PAS in combination with DOCE versus DOCE alone in adult participants (≥18 years) with mCRPC. Approximately 800 participants will be randomized 1:1. Stratification factors include sites of metastases (on conventional imaging), lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, and prior poly(ADP-ribose) polymerase (PARP) inhibitor use. Key inclusion criteria are histologically or cytologically confirmed adenocarcinoma of the prostate, evidence of metastatic disease, and PSA or radiographic disease progression on 1-2 novel ARPI for any stage of prostate cancer. Key exclusion criteria include prior treatment with T-cell redirecting therapies, chemotherapy, or radiopharmaceutical therapy, uncontrolled central nervous system metastases, or significant comorbidities that could interfere with study participation. PAS is administered in the outpatient setting at a target dose of 300 mg IV Q6W with two step-up doses of 3.5 mg IV on day 1 and 18 mg IV on day 8. Participants in the DOCE alone arm will also receive continuous prednisone per label. The primary endpoint is radiographic progression-free survival assessed by blinded independent central review per Prostate Cancer Working Group 3 and RECIST v1.1 criteria. Key secondary endpoints include overall survival, time to symptomatic progression, time to subsequent therapy, and time to skeletal-related event. Safety, pharmacokinetics, biomarkers, and quality of life assessments will also be evaluated. The study is currently enrolling patients in the North and Latin Americas, European Union and Asia Pacific regions. Clinical trial information: 78278343PCR3003 .
Treatment selection for first- and second-line therapy and survival outcomes in advanced biliary tract cancer: A large real-world retrospective analysis.
e16197 Background: Biliary tract cancer (BTC) is an aggressive malignancy with constrained therapeutic options. This study aims to observe temporal changes in first-line and second-line treatment strategies for advanced biliary tract cancer (BTC) in real-world settings and evaluate overall survival outcomes across different therapeutic approaches. Methods: This multicentre retrospective study collected clinical and pathological features, treatments, response and survival data from patients with advanced BTC between 2011 and 2024. Kaplan-Meier curves, log-rank tests, propensity score matching and cox regression were used for analysis. Results: Among 1,656 BTC patients, progressive and sustained improvements were observed across first-line treatment modalities: chemotherapy, chemo-immunotherapy, and chemo-immuno-angiogenic therapy (median progression-free survival [mPFS]: 5.5 vs. 6.4 vs. 7.8 months, P < 0.001; median overall survival [mOS]: 11.6 vs. 13.4 vs. 15.3 months, P = 0.001), with particularly pronounced benefits in ICC and GBC patients. Within the chemo-immuno-angiogenic group, gemcitabine plus oxaliplatin (GEMOX)-based regimens outperformed gemcitabine plus cisplatin (GC)-based regimens (mOS: 19.3 vs. 11.3 months, P = 0.005). In second-line treatment (n = 647), immunotherapy-based regimens demonstrated superior efficacy versus chemotherapy-based approaches (mPFS: 4.7 vs. 3.8 months; P = 0.003; mOS: 9.6 vs. 8.1 months; P = 0.027). Among second-line fluorouracil-based chemotherapy regimens, taxane combinations demonstrated numerically superior OS (15.5 months; P = 0.217). Notably, continued immunotherapy after first-line immunotherapy demonstrated significantly better outcomes than switching to non-immunotherapy regimens (mPFS: 4.1 vs. 2.6 months, P = 0.029). Conclusions: Sequential addition of immunotherapy and anti-angiogenic agents to first-line chemotherapy yielded incremental survival benefits, particularly for ICC and GBC, with chemotherapy backbone selection influencing outcomes in combination regimens. In second-line setting, immunotherapy-based regimens outperformed chemotherapy, and maintaining immunotherapy across treatment lines further improved outcomes. These findings provide actionable guidance for optimizing treatment sequencing strategies throughout patients' treatment course.
Postoperative adjuvant donafenib-based therapy for patients with hepatocellular carcinoma at high risk of recurrence.
e16256 Background: The 5-year recurrence rate after radical resection for hepatocellular carcinoma (HCC) is as high as 70%, with early recurrence within 2 years portending a poor prognosis for high-risk patients. Given the lack of a globally standardized adjuvant therapy, this study aimed to evaluate the efficacy and safety of donafenib as postoperative treatment in this patient population. Methods: This retrospective study included patients with HCC and high-risk recurrence factors who underwent surgical resection at Beijing Ditan Hospital, Capital Medical University, between December 2023 and October 2025. High-risk recurrence factor was defined as the presence of one or more of the following: (a) multiple tumors; (b) tumor diameter > 5 cm; (c) satellite nodules; (d) microvascular invasion (MVI); (e) Edmondson-Steiner grade III–IV; or (f) a pathological margin < 1 cm. Following surgery, patients received adjuvant therapy with donafenib. Primary outcomes were recurrence-free survival (RFS), secondary outcomes included the 1-year RFS rate, overall survival (OS) and safety. Results: A total of 37 patients were included in this study. Among them, 54.1% had a tumor diameter > 5 cm, 27.0% presented with multiple tumors, and 59.5% were classified as Edmondson-Steiner grade III–IV, 45.9% of patients exhibited MVI (M1 or M2). Overall, 27 patients carried two or more high-risk factors. 24 patients received donafenib monotherapy, while 13 were treated with donafenib-based combination therapy (combined with TACE and/or PD-1 inhibitors). At a median follow-up of 12.2 months, 4 patients experienced recurrence, and all recurrences were intrahepatic. The median RFS has not yet been reached, with a 1-year RFS rate of 86.4% (95% CI 74.6% - 100.0%). The 1-year OS rate was 96.6% (95% CI 90.1% - 100.0%). While patients with a single high-risk factor had a 1-year RFS rate of 100.0%, those with ≥2 factors had a rate of 82.3%, Notably, all four recurrent patients had ≥2 high-risk factors. Among 27 patients with ≥2 high-risk factors, 19 received donafenib monotherapy and 8 received combination therapy. The 6- and 12-month RFS rates were 81.9% and 81.9%, respectively, in the monotherapy group, compared with 100.0% and 85.7% in the combination therapy group. No significant change from baseline in albumin-bilirubin (ALBI) score was observed after any treatment cycle (all P > 0.05). The scores remained stable at -2.7 ± 0.5 (baseline), -3.0 ± 1.2 (cycle 1, P = 0.41), -2.8 ± 0.4 (cycle 2, P = 0.47) and -2.8 ± 0.3 (cycle 3, P = 0.25). Treatment-emergent adverse events (TEAEs) occurred in 87.0% of patients, with Grade 3 AEs in 27.0% (n = 10). No Grade 4 or 5 AEs were observed. The most common AEs were increased ALT, anemia, and thrombocytopenia. Conclusions: In summary, adjuvant donafenib shows promise for reducing recurrence with an acceptable safety profile in high-risk HCC patients after radical resection.
National burden of cholangiocarcinoma in the United States: A 20-year analysis of temporal trends and racial disparities (2005–2024).
e16493 Background: Cholangiocarcinoma (CCA) is an uncommon but highly lethal malignancy with rising global concern, yet long-term U.S. epidemiologic data remain limited. Understanding contemporary trends in incidence, prevalence, demographic patterns, and racial or ethnic disparities is critical to guide prevention and early detection. We examined 20-year temporal patterns in CCA using a large real-world U.S. dataset. Methods: We conducted a retrospective cohort study using the TriNetX U.S. Collaborative Network (2005–2024). Adults with ≥1 ICD-10-CM code for intrahepatic or extrahepatic CCA were included. Annual incidence and prevalence proportions, mean age at diagnosis, and demographic distributions were assessed. Temporal trends were analyzed using the Mann–Kendall test and Sen’s slope. Sex-stratified incidence trajectories were evaluated using Joinpoint regression (log-linear model; ≤3 Joinpoints). Race-stratified incidence rate ratios (IRRs) were estimated using Poisson regression with White patients as reference, adjusting for calendar year. Results: Among 111,355,335 individuals, 51,218 were diagnosed with CCA (0.046%). Incidence increased sixfold from 0.002% in 2005 to 0.012% in 2024 (τ = 0.923, p = 1.19×10⁻⁷), with a consistent annual rise of 4.70×10⁻⁶ (95% CI, 3.85×10⁻⁶–5.56×10⁻⁶). Prevalence increased more than fivefold (0.006% to 0.032%; τ = 0.992, p < 2.22×10⁻¹⁶). Mean age at diagnosis rose from 61.6 to 67.5 years, surpassing 65 years after 2015–2017, indicating progressive aging at presentation. Joinpoint analysis demonstrated distinct acceleration phases in 2007–2012 (APC 21.88%, p < 0.05) and 2021–2024 (APC 15.84%, p < 0.05), separated by a prolonged plateau. Sex-specific slopes were parallel despite persistently higher absolute incidence in males. Compared with White patients, incidence was significantly higher among Asian (IRR 1.205, 95% CI 1.156–1.257) and American Indian/Alaska Native patients (IRR 1.214, 95% CI 1.082–1.361), lower among Black patients (IRR 0.663, 95% CI 0.642–0.684), and comparable among Native Hawaiian/Other Pacific Islander patients. Incidence rose in both Hispanic and non-Hispanic populations, with consistently higher absolute rates among non-Hispanic patients. Conclusions: CCA incidence and prevalence increased substantially over 20 years in the United States, with aging at diagnosis and persistent racial disparities. These findings underscore a growing national burden and highlight the need for targeted prevention and early detection strategies.
Neoadjuvant immunotherapy combined with concurrent chemoradiotherapy for locally advanced esophageal squamous cell carcinoma: A prospective, single-arm, phase II trial.
e16095 Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). In the era of immunotherapy, it is worth exploring whether the combination of CCRT and immunotherapy can improve efficacy. This study aimed to evaluate the efficacy and safety of preoperative anti-PD-L1 Immunotherapy combined with CCRT in ESCC. Methods: In this phase II trial, patients (pts) with resectable, locally advanced ESCC received neoadjuvant durvalumab (1500mg, Q4W) combined with CCRT (41.4Gy/23f with weekly paclitaxel/carboplatin), followed by surgery. Co-primary endpoints were the objective response rate (ORR, irRECIST) and pathologic complete response (pCR, CAP). Secondary endpoints included safety, surgical outcomes, disease-free survival (DFS), and overall survival (OS) (NCT04568200). Results: As of January 26, 2026, 34 pts were enrolled. Among the 27 pts who completed neoadjuvant therapy and were evaluable for efficacy, the ORR was 88.9% (comprising 1 complete, 22 partial responses, 3 stable disease and 1 progression disease), and the disease control rate (DCR) was 96.3%. The neoadjuvant therapy was completed in a median of 32 days. The regimen was manageable, with 24 pts (90.3%) completing the full radiotherapy course, and all pts completing two cycles of immunotherapy. The median interval from the completion of radiotherapy to surgery was 51.5 days. Of the 27 evaluable patients, 23 were deemed eligible for surgery. Ultimately, 22 pts underwent McKeown minimally invasive esophagectomy, all of whom achieved R0 resection. Pathologic assessment of these surgical specimens showed a primary tumor pCR rate of 50% (11/22) and a pCR rate in both primary tumor and lymph nodes (ypT0N0) of 36.4% (8/22). The major pathologic response (MPR) rate was 72.7% (16/22). The median number of lymph nodes harvested was 44 (range, 25-63). At a median follow-up of 10.7 months, the estimated 1-year DFS rate was 86.3% in the surgical cohort (n=22), and the 1-year OS rate was 97.1% in the intention-to-treat population (n=34). Common AEs included leukopenia/neutropenia (n=14), radiation esophagitis (n=7), pneumonia (n=2), intestinal obstruction(n=1), myocardial infarction due to coronary heart disease (n=1). Two patients contracted COVID-19. No new safety signals were identified. Conclusions: Anti-PD-L1 Immunotherapy combined with CCRT in locally advanced ESCC might be a useful treatment option with highly promising efficacy and manageable safety. Clinical trial information: NCT04568200 .
Interim analysis of TAD: A phase 2 single-arm open-label study of combination therapy of transarterial chemoembolization and ablation with durvalumab in unresectable hepatocellular carcinoma.
e16296 Background: Transarterial chemoembolization (TACE) combined with ablation has been used to treat unresectable hepatocellular carcinoma (HCC) to enhance local tumor control. We initiated the TAD study of TACE in combination with ablation followed by durvalumab to evaluate the safety and efficacy in patients with unresectable HCC. Methods: This phase 2, single-arm study is designed to investigate the safety and efficacy of TACE plus ablation followed by durvalumab in patients with unresectable HCC who are unsuitable for surgical resection. Approximately 30 patients are planned for enrollment. After TACE, patients undergo ablation and then receive durvalumab 1500 mg Q4W until disease progression or death. Patients achieving complete remission (CR) after 1 year of durvalumab discontinue treatment per protocol. Treatment may be extended up to 2 years if imaging shows viable lesions. Tumor assessment is performed according to mRECIST by independent radiologists. The primary endpoint is adverse events of special interest (AESIs). The secondary endpoints are adverse events (AEs), progression-free survival (PFS), Time to progress (TTP) and overall survival (OS). Results: The interim analysis (IA) was conducted. At this IA, 30 patients (SS set) were enrolled, and the cutoff date was 10th Dec 2025. There were 24 patients (FAS and PP set) received TACE plus ablation and at least 1 cycle of durvalumab, with 12 patients receiving durvalumab for ≥1 year. The median follow-up was 27.6 months (range, 11.9-53.0). Among the 30 patients (SS set), 14 (46.7%) reported grade 1–2 AESIs possibly related to durvalumab: 7 (23.3%) elevated liver enzymes, 6 (20.0%) elevated lipase, 4 (13.3%) abnormal thyroid function, 2 (6.7%) elevated amylase, 2 (6.7%) rashes, and 1 (3.3%) interstitial pneumonia. However, only the 1 patient with interstitial pneumonia required oral corticosteroids for management. Additionally, 7 patients (23.3%) reported grade 3 elevated liver enzymes, attributed to TACE or ablation. No grade 4 AEs or AE-related death occurred. Serious AEs were reported in 6 patients (20.0%), none considered treatment related. No patients discontinued durvalumab due to treatment-related AEs (TRAEs). In the PP set, the objective response rate (ORR) was 100% (24/24), including CR in 70.8% (17/24) and PR in 29.2% (7/24). Additionally, the median PFS (events occurred in 15 patients) and TTP were both 12.5 months (95% CI: 9.4–15.6), with a 1-year PFS rate of 58.3%. As of the last follow-up, 2 patients had died of disease progression, and the median OS was not reached. Conclusions: TACE in combination with ablation followed by durvalumab demonstrated an manageable safety profile without unexpected toxicity, and a promising early efficacy in this interim analysis. The trial is ongoing, and OS benefits will be reported with further follow-up. Clinical trial information: NCT04517227 .
Inferring molecular signatures in colorectal cancer directly from routine whole-slide images.
3522 Background: Molecular profiling has advanced colorectal cancer (CRC) research but remains limited in the clinic due to cost and tissue constraints. In contrast, haematoxylin and eosin (H&E) whole-slide images (WSIs) are routinely available. Recent deep learning studies show that molecular signatures can be inferred from morphology. However, prediction of patient level pathway activity remains underexplored despite their pathobiological significance as coordinated drivers of cancer risk. Methods: We developed SPARROW, a neural network trained to predict over 200 molecular signatures from WSI graph representation of tumour, stroma, lymphocytic and mucosal regions in resection specimens. SPARROW was trained on TCGA (n = 585) and externally validated in the PETACC3 trial dataset (n = 1,160). It predicts pathway enrichment scores, point mutation and clinically actionable CRC subtypes. Results: As shown in the table below, SPARROW accurately predicts key molecular features of CRC directly from routine H&E slides and generalizes robustly to the independent PETACC3 trial. The strongest concordance was observed for biologically and clinically relevant programmes, including intrinsic consensus molecular subtype 3 (iCMS3) genes, Fetal enteric progenitor pathway genes, a 22-gene YAP/TAZ transcriptional target signature and epithelial-specific high-risk gene set (epiHR) activity. SPARROW also showed good performance for clinically used classifications, including iCMS/CMS subtypes, interferon phenotype and BRAF mutation status. Importantly, image-derived molecular scores were predictive of relapse free survival as well. Conclusions: SPARROW demonstrates that key molecular features of CRC, including transcriptomic subtypes and genomic alterations, are robustly encoded in and learnable from routine H&E histology. This enables histology to serve as a cost-effective and rapid surrogate for predicting key molecular signatures and actionable molecular subtypes while also allowing mining of spatially localised image signatures associated with transcriptional programmes. Molecular Signature TCGA (4-fold CV) PETACC3 (external) Relapse Free Survival Analysis (PETACC3) iCMS3 (ρ) 0.64 ± 0.05 0.66 HR=1.2*, 95% CI:1.04-1.38 Fetal Mustata (ρ) 0.47 ± 0.06 0.61 HR=1.74*, 95% CI:1.45-2.08 YAP_22 (ρ) 0.41 ± 0.07 0.49 HR=2.54*, 95% CI:2.03-3.18 EpiHR (ρ) 0.40 ± 0.08 0.45 HR=1.59*, 95% CI:1.31-1.92 iCMS2 vs iCMS3 (AUC) 0.90 ± 0.02 0.92 HR=1.12, 95% CI:1.00-1.26 CMS (4 groups) (AUC) 0.84 ± 0.01 0.84 HR=6.3* (CMS4 vs other), 95% CI:3.92-10.01 Interferon (High/Low) (AUC) 0.82 ± 0.08 0.88 HR=1.14, 95% CI:0.86-1.05 BRAF Mutation (AUC) 0.82 ± 0.07 0.80 HR=2.12*, 95% CI:1.13-4.29 *p-value <0.05 based on log-rank test using median pathway score.
Gaps in patient-facing information on artificial intelligence in cancer care: A cross-sectional analysis.
9000 Background: Artificial intelligence (AI) is increasingly integrated into cancer care and is also widely accessed by patients seeking information about their diagnoses and treatments. While AI has the potential to improve care delivery and patient engagement, inadequate or misleading patient education may introduce safety risks. We assessed the availability, readability, and quality of publicly available online patient-facing information about AI in cancer care. Methods: We conducted a cross-sectional analysis of online patient-facing information related to AI in cancer care. Using common cancer- and AI-related keywords identified using Google Trends, we searched Google and YouTube on August 6, 2025. The first 170 webpages and 150 videos were screened for relevance and patient-facing intent; scientific or industry-facing content was excluded. Eligible webpages and videos were independently evaluated by two reviewers with discrepancies resolved by a third. Webpage readability was assessed using validated indices (Flesch–Kincaid [FK], Gunning Fog [GF], and SMOG). Content was evaluated for discussion of key AI safety concepts including clinician oversight, transparency, bias, and hallucination or misinformation risk. Quality of consumer health information was assessed for both webpages and videos using the DISCERN instrument, with scores ≥ 4 (of 5) indicating high quality. Descriptive statistics were used to summarize findings. Results: Of the 170 webpages screened, 52 (31%) met inclusion criteria. Most content focused on breast cancer (n=30, 58%) or was pan-tumor (n=22, 42%). Median readability corresponded to a college-level reading standard, with median grade levels of 12.8 (IQR: 11.6-14.1), 14.8 (IQR: 13.5-16.5), and 14.2 (IQR: 13.6-15.6) based on FK, GF, and SMOG indices, respectively. Most webpages discussed clinician oversight (n=41, 79%) and/or transparency (n=41, 79%), and over half addressed bias (n=29, 56%); however, few discussed hallucination or misinformation risk (n=8, 15%). Only 33% (n=17) of webpages met criteria for high-quality information. Of the 150 videos, 29 (19%) met inclusion criteria. Median view count was 127 (IQR: 23-1000). Few (n=11, 38%) were classified as high quality based on DISCERN scores. Conclusions: Publicly available, patient-facing information about AI in cancer care is limited, difficult to read, and often of low quality. Inadequate discussion of AI-related risks, particularly hallucinations or misinformation, may leave patients poorly informed as they encounter or independently use AI-based tools. These findings highlight the need for accessible, high-quality educational resources that clearly explain the clinical role of AI in oncology and provide guidance for safe patient engagement.
Impact of CAPOX combined with traditional Chinese medicine (TiaoPi AnChang Decoction) on disease-free survival in patients with stage III or high-risk stage II colorectal cancer: An updated report of a randomized, double-blind, placebo-controlled trial.
3645 Background: Colorectal cancer (CRC) at early and mid-stages has significantly different prognoses from advanced CRC. Preventing the progression to advanced disease after surgery is crucial for improving survival and reducing healthcare burden. Multiple retrospective studies have shown that Tiaopi Anchang Decoction (TPACD), an oral formula of edible botanical drugs, can reduce recurrence and metastasis risk in CRC when combined with CAPOX. However, the evidence is limited by confounding factors and reporting biases. This study aims to test the hypothesis that CAPOX combined with TPACD can further improve disease-free survival (DFS) in patients with stage III or high-risk stage II CRC. Methods: The study recruited patients from 4 departments of China-Japan Friendship Hospital. It enrolled stage III or high-risk stage II CRC patients undergoing CAPOX and randomly assigned patients in a 1:1 ratio to either the TPACD group (30 mL orally, twice daily) or the placebo group (matched placebo). The trial duration covered 4 chemotherapy cycles, during which CAPOX-induced adverse reactions, quality of life (QoL), safety, and survival outcomes were assessed. The primary endpoint was DFS, while the secondary endpoints included overall survival, the incidence of CAPOX-induced adverse reactions, and QoL score (EORTC QLQ-C30). Kaplan-Meier analysis and Cox proportional hazards regression model were used to evaluate the correlation between CAPOX combined with TPACD and DFS. Results: From December 2022 to September 2024, 496 patients were screened, and 108 were enrolled. The 108 patients were randomly assigned in a 1:1 ratio to the TPACD group or placebo group. 42% were female, the average age was 58 years, and 66% had stage III disease. The interim report has confirmed that TPACD is safe, significantly reduced CAPOX-induced adverse reactions, and improved QoL. Median follow-up time was 28 months, with 17 DFS events (4 TPACD, 13 placebo) and no deaths. Kaplan-Meier analysis estimated 2-year DFS rates of 93.3% for TPACD and 74.7% for placebo. Log-rank testing revealed a statistically significant difference between the two groups ( χ² = 5.329, P = 0.021). CAPOX combined with TPACD significantly reduced the occurrence of DFS events (multivariable hazard ratio [HR] 0.23, 95% confidence interval [CI] 0.073-0.736, P = 0.01) and this effect was not influenced by age, sex, primary tumor site, or TNM stage ( P interaction > 0.05). Conclusions: For patients with stage III and high-risk stage II CRC, TPACD is a well-acceptable complementary therapy. The combination of CAPOX and TPACD not only reduces CAPOX-induced adverse reactions and improves QoL, but also further extends the DFS. Further disclosure of survival data could help optimize adjuvant chemotherapy regimens for CRC. Clinical trial information: ChiCTR2200065759.
Targeted sensorimotor training vs. general aerobic exercise for chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.
e24175 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity in breast cancer patients receiving taxane-based regimens. While pharmacological efficacy remains limited, exercise is a promising adjunct therapy. However, the optimal modality remains undefined. This meta-analysis evaluates the efficacy of specific exercise modalities: targeted sensorimotor training (SMT) versus general aerobic/resistance training (GAT) in reducing CIPN symptom burden. Methods: This systematic review and meta-analysis of randomized controlled trials (RCTs) followed a formal study protocol developed prior to implementation in accordance with PRISMA guidelines and reviewed by the Departmental Research Committee at Chitwan Medical College Teaching Hospital. Data were sourced from PubMed, EMBASE, and the Cochrane Library. The primary endpoints were sensory and motor symptom scores. Statistical analysis used a random-effects model to calculate Standardized Mean Differences (SMD) and 95% Confidence Intervals (CI). Methods for handling missing data included available-case analysis. Risk of bias was assessed using the Cochrane RoB 2.0 tool. To account for confounding by intervention type, pre-specified subgroup analyses were conducted to differentiate between targeted SMT and GAT protocols. Results: Eight RCTs (N = 722) were included. Exercise resulted in a significant reduction of overall sensory symptoms (SMD -0.72 [-1.24 to -0.20]; P = 0.006) and motor symptoms (SMD -0.76 [-1.23 to -0.28]; P = 0.002). In subgroup analyses, targeted sensorimotor training significantly improved sensory (SMD -0.99 [-1.55 to -0.44]; P = 0.0005) and motor outcomes (SMD -1.07 [-1.36 to -0.78]; P < 0.00001). Conversely, general aerobic protocols did not significantly reduce sensory (SMD -0.34 [-1.11 to 0.44]; P = 0.40) or motor symptoms (SMD -0.03 [-0.43 to 0.37]; P = 0.87). Autonomic symptoms were significantly improved (SMD -0.69 [-1.10 to -0.28]; P = 0.001). Overall CIPN burden was significantly lower in exercise groups (SMD -1.34 [-1.88 to -0.80]; P < 0.00001), with patient-reported outcomes (SMD -1.64) showing higher sensitivity than physician-reported scores (SMD -0.14). Conclusions: Exercise significantly alleviates CIPN, but efficacy is modality-dependent. Targeted sensorimotor and hand-foot exercises provide robust benefits for sensory and motor dysfunction, whereas general aerobic activity may not be sufficient for symptom-specific reduction. These findings support the integration of structured, targeted exercise into supportive care for taxane-treated patients.
Real-world comparison of enzalutamide and darolutamide for non-metastatic castration-resistant prostate cancer: A multicenter retrospective study.
e17048 Background: Although enzalutamide and darolutamide share a common mechanism of action targeting the androgen receptor pathway, they differ in their molecular structure and pharmacological properties, which may influence their efficacy and safety. However, real-world evidence directly comparing these agents in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) remains limited. Methods: In this multicenter retrospective study, data from 198 patients who received enzalutamide or darolutamide as their first androgen receptor signaling inhibitor (ARSI) during treatment for nmCRPC, were analyzed. Adverse events (AEs) and prostate-specific antigen (PSA) responses were compared. Progression of PSA and development of metastases were assessed using the Fine-Gray sub-distribution hazards model, adjusting for death as a competing risk. Results: In the cohort, 94 (47%) patients received enzalutamide and 104 (53%) received darolutamide. Incidence rates of any-grade AEs and grade ≥3 AEs were similar between the two groups ( P = 0.968 and P = 1.000, respectively). The rates of any PSA response, decline in PSA ≥50%, and decline in PSA ≥90% did not differ significantly between the two groups ( P = 0.130, P = 0.687, and P = 0.171, respectively). In multivariable analyses, ARSI type was not significantly associated with progression of PSA (reference, enzalutamide; sub-distribution hazard ratio [SHR], 1.153; P = 0.620) or development of metastases (reference, enzalutamide; SHR, 0.815; P = 0.510). Conclusions: Enzalutamide and darolutamide had comparable safety and oncological outcomes in patients with nmCRPC. These findings support the use of either agent as an appropriate first ARSI treatment. Multivariable analysis for progression of PSA. Factor P value SHR 95% CI Biopsy Gleason score ≥8 0.120 1.857 0.859–4.015 Clinical stage at initial diagnosis cT4 or cN1 0.420 1.290 0.694–2.397 History of radical treatment Positive 0.073 0.594 0.036–1.051 Number of therapies prior to ARSI treatment Continuous 0.210 1.197 0.903–1.588 PSA doubling time <3.3 months 0.078 1.606 0.949–2.720 Relative dose intensity Continuous 0.660 1.377 0.325–5.831 ARSI type Darolutamide 0.620 1.153 0.659–2.018 ARSI, androgen receptor signaling inhibitor; CI, confidence interval; PSA, prostate-specific antigen; SHR, sub-distribution hazard ratio.
Knowledge, attitude, and practices of residents towards venous thromboembolism prophylaxis among cancer patients at Quirino Memorial Medical Center.
e22552 Background: The risk of venous thromboembolism (VTE) is higher in individuals with cancer than in those without cancer across all age categories. Thromboembolism in people with cancer still remains a major health problem and is a leading cause of mortality after cancer itself, despite being a largely preventable disease. The study was conducted to assess the knowledge, attitude and practices of Quirino Memorial Medical Center residents towards venous thromboembolism prophylaxis among cancer patients. Methods: This study is a cross-sectional study design where in Quirino Memorial Medical Center residents were given with VTE knowledge, attitude and practices questionnaire adopted with permission from Mukisidi, et. al. used in the study published in Orient Journal of Medicine last 2016. The VTE knowledge was identified using frequencies and percentage. The Pearson’s chi-squared test of independence was used to test the association between the respondents’ categorical data and the groups. Results: Of the 100 respondents, 70% has satisfactory knowledge about VTE. Most (99%) believe that prophylaxis is clinically important among cancer patients to reduce morbidity and mortality. However, sixty-nine (69%) recognized that the institution has no formal VTE prophylaxis policy. Most of the respondents prescribed VTE prophylaxis and combination of different intervention (anticoagulants and compression stockings) is the most commonly used prophylaxis. Conclusions: Most of the residents in the Quirino Memorial Medical Center are knowledgeable about VTE and agreed that prophylactic measures were important for cancer patients but despite that, practice on VTE prophylaxis was sub-optimal and the contributory factor include absence of strong institutional policy/guidelines on VTE prophylaxis. These underscores the need for guidelines and improved attitude towards VTE prophylaxis.
Fern-EC-01 (BNT323-01): A phase 3 trial of trastuzumab pamirtecan (HER2 ADC) versus investigator’s choice of chemotherapy in patients with previously treated, HER2-expressing, recurrent endometrial cancer (EC).
TPS5645 Background: Despite advancements in frontline therapies for EC, treatment options for recurrent/refractory disease remain limited. HER2 overexpression in EC is associated with rapid disease progression, tumor invasiveness, a high risk of recurrence, and poor prognosis. Trastuzumab pamirtecan (T-Pam; BNT323/DB-1303) is an investigational HER2-targeting antibody-drug conjugate (ADC) with a DNA topoisomerase I inhibitor payload and a drug-to-antibody ratio of ~8. In a phase 1/2a trial (NCT05150691), T-Pam demonstrated encouraging clinical benefit in patients with HER2-expressing EC, efficacy was observed across all HER2 expression levels and patient subgroups with a manageable safety profile. Methods: Following a protocol amendment, this open-label, randomized, multi-site, phase 3 trial (Fern-EC-01; BNT323-01) is enrolling patients with recurrent, HER2 expressing EC (assessed by central laboratory testing using IHC) who have measurable disease defined by RECIST v1.1, an ECOG PS of 0-2, and have received ≥1 prior line of platinum-based therapy (in any setting) and prior immune-checkpoint inhibitor treatment. Up to three lines of prior therapy are permitted. Prior hormonal therapy and radiation are allowed but do not count as prior lines of therapy. Prior exatecan-containing treatment is not allowed. All patients will receive treatment until RECIST v1.1 defined progressive disease, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met. The trial is enrolling two cohorts. In Cohort 1, ≈420 patients with HER2-expressing (IHC 1+ or 2+) EC will be randomized 2:1 to evaluate the efficacy and safety of T-Pam vs investigator’s choice of chemotherapy (doxorubicin, paclitaxel, or docetaxel in case of contraindication to paclitaxel and availability at the site). Stratification is based on HER2 expression (IHC 1+; 2+) and prior lines of therapy (1; 2+). The primary endpoint for Cohort 1 is progression-free survival (PFS) by blinded independent central review (BICR); overall survival is a key secondary endpoint. In Cohort 2, ≈60 patients with HER2 IHC 3+ EC will receive T-Pam; the primary endpoint for this cohort is objective response rate by BICR. Enrollment is ongoing globally. Clinical trial information: NCT06340568 .
Updated efficacy and safety of first-line PD-1 inhibitors plus metronomic oral vinorelbine in elderly patients with advanced NSCLC.
e20590 Background: Elderly patients (≥70 years) with metastatic non-small cell lung cancer (NSCLC) face challenges with standard chemotherapy due to poor performance status, comorbidities, and limited social support. Metronomic chemotherapy (MCT), using low-dose continuous cytotoxic agents, shows promising safety and anti-angiogenic, immunomodulatory effects. This phase II study updates efficacy and safety of PD-1 inhibitors combined with metronomic oral vinorelbine (mOV) as first-line therapy in elderly metastatic NSCLC patients. Methods: Elderly patients (≥70 years) with untreated locally advanced or metastatic NSCLC, without EGFR mutations, ALK fusions, or ROS1 fusions, and ECOG performance status 0-1, received PD-1 inhibitors combined with mOV (30 mg, three times weekly on days 1, 3, and 5), followed by PD-1 inhibitor maintenance until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: From March 2021 to November 2025, 54 patients (median age 79 years, 79.6% male) were enrolled. After a median follow-up of 10.1 months, median PFS was 8.37 months (95% CI, 5.47–22.90) and median OS was 22.87 months (95% CI, 12.93–NR). The ORR was 25.9% (95% CI, 14.96%–39.65%) and DCR was 75.9% (95% CI, 62.36%–86.51%). Thirty-nine patients (72.2%) experienced at least one AE, with immune-related pneumonitis being the most frequent (18.5%). Grade 3–4 AEs occurred in 5 patients (9.3%), mainly immune-related pneumonitis, myocarditis, hepatitis, enteritis, and myositis, and bone marrow suppression. PD-L1-positive patients (TPS ≥1, 28 patients, 51.9%) had similar PFS (8.40 vs. 8.37 months) but significantly improved OS (30.17 months, 95% CI, 21.10–NR) compared to PD-L1-negative patients (20 patients, 37%), whose median OS was 13.13 months (95% CI, 8.60–NR). Patients with high PD-L1 expression (TPS ≥50%, 11 patients, 20.4%) showed the greatest benefit, with a median PFS of 25.83 months (95% CI, 20.30–NR) and a median OS not reached, along with ORR of 36.4%. Among patients aged ≥80 years (n = 22), median PFS was 8.97 months (95% CI, 3.53–NR) and median OS was 13.13 months (95% CI, 5.60–NR), with ORR of 18.2%. Sixteen patients (72.7%) experienced at least one AE, with grade 3-4 AEs observed in one patient (4.5%, myelosuppression). Conclusions: PD-1 inhibitors combined with mOV as first-line therapy provided significant survival benefits and acceptable tolerability in elderly patients with driver gene–negative metastatic NSCLC, particularly those with high PD-L1 expression. Similar efficacy and safety were observed in patients aged ≥80 years. Research Sponsor: National High-Level Hospital Clinical Research Funding (BJ-2023-073) and Beijing Medical Award Foundation Grant (YXJL-2020-0785-0251). Clinical trial information: ChiCTR2300074586;ChicTR21000 49487.