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Long-term survivorship rates among previously treated advanced melanoma patients achieving objective response (OR) with lifileucel.
9592 Background: Durability of response and associated long-term survival benefits of modern cancer therapies are often manifested as plateaus in duration of response (DoR) and overall survival (OS) curves for responders. In the single-arm, Phase 2 C-144-01 trial, unresectable/metastatic melanoma patients who progressed on immune checkpoint inhibitors (ICIs) showed durable clinical responses to lifileucel—an FDA-approved autologous T-cell therapy. This analysis evaluated the association between achieving an OR with lifileucel and possibility of being a long-term survivor (LTS) in the C-144-01 study. Methods: Mixture cure models (MCMs) were applied to analyze OS and DoR outcomes for patients who achieved confirmed OR by committee review among those receiving lifileucel within commercial specifications in Cohorts 2 and 4 (overall cohort; n=106, median follow-up: 47.4 months, OR rate 35.8%). In both analyses, LTS were subject to only non–melanoma-related mortality whereas non-LTS were subject to both melanoma- and non–melanoma-related mortality. In the DoR analysis, LTS were also assumed to remain in response until death. For LTS, OS/DoR outcomes were assumed to follow the survival trend of age- and sex-adjusted US general population, and derived from published lifetables whereas for non-LTS, they are modeled by parametric distributions. Fraction of LTS and OS/DoR distributions for non-LTS were estimated simultaneously via maximum likelihood methods. Candidate MCMs were evaluated based on statistical fit criteria, visual agreement with observed OS/DoR data, and underlying hazards. Results: Exponential MCM and gamma MCM provided best fits to the observed DoR and OS data, respectively, and estimated the fractions of LTS (95% CI) among responders as 52% (34.0%–69.4%) and 50.4% (31.3%–66.7%) from the OS and DoR data, respectively. Estimated fractions of LTS across clinically plausible models ranged between 48.4%–52.9% in the OS analysis and 50.4%–51.1% in the DoR analysis. Best-fitting MCMs projected 10-year mean OS and DoR as 70.7 and 62.2 months, respectively, and 10-year OS and DoR rates as 46.7% and 45.3%, respectively. Smoothed OS and DoR hazards derived from the observed data displayed convergence to general population mortality rates by the end of follow-up indicating maturity and suitability of data for modeling with MCMs. Conclusions: Responders had significantly higher fraction of LTS than the overall cohort, underscoring the importance of achieving OR to lifileucel for its long-term survival benefit. Estimated fractions of LTS from OS and DoR were robust to model choice, consistent with each other, and when scaled by OR rate, aligned with previously reported fractions of LTS from progression-free survival and OS for the overall cohort. Results support clinical potential of lifileucel for addressing unmet need in post-ICI advanced melanoma.
Early immune recovery during adjuvant anti–PD-1 as a predictor of early recurrence in resected stage II–III melanoma.
e21545 Background: Early identification of patients at risk of recurrence during adjuvant anti–PD-1 remains an unmet need. We tested whether a longitudinal Time-in-Range (TIR) metric capturing time spent in an “immune-recovered” state during weeks 0–12 predicts early post-landmark recurrence. Methods: Consecutive AJCC 8th stage II–III melanoma patients receiving adjuvant nivolumab or pembrolizumab (n = 74) underwent routine CBC monitoring approximately every 2 weeks during weeks 0–12 (median 7 measurements/patient). The immune-recovered range was prespecified as NLR < 3 AND ALC ≥1.0×10⁹/L. TIR(0–12) was calculated using interval-based time-weighting between consecutive measurements. Secondary prespecified dynamics included ALC slope (0–12) and time-adjusted RMSSD of log(NLR). To mitigate guarantee-time bias, we applied a 12-week landmark: patients recurring before week 12 were excluded, and the primary endpoint was early recurrence from week 12 to month 12; secondary endpoint was 12-month RFS. Parsimonious models adjusted for stage and ulceration; sensitivity analyses tested alternative thresholds (NLR < 4; ALC ≥0.8×10⁹/L) and exclusion of intercurrent infection/inflammation in weeks 0–12. Results: Median age was 61 years (IQR 53–68.8); stage III 52.7%; ulceration 45.9%; nivolumab 55.4%. Intercurrent infection/inflammation in weeks 0–12 occurred in 17.6%. Overall 12-month recurrence was 24/74 (32.4%). Early recurrence < 12 months occurred in 13/74 (17.6%). One patient recurred before week 12; 73 comprised the landmark cohort, with 12/73 (16.4%) early post-landmark recurrences. Median TIR was 0.0% in early post-landmark recurrences versus 18.5% in non-recurrences. In adjusted logistic regression, higher TIR was associated with lower odds of early post-landmark recurrence (OR 0.74 per +10% TIR, 95% CI 0.57–0.95). Categorized for interpretability, the highest TIR tertile had lower early recurrence than the other tertiles combined (4.2% vs 24.0%; adjusted OR 0.06, 95% CI 0.007–0.59). Discrimination remained favorable after bootstrap optimism correction (AUC 0.83). Secondary dynamics were directionally consistent (lower ALC slope, higher NLR volatility among early recurrences). Twelve-month RFS was 78.3% overall and 95.8% in the highest TIR tertile; associations were consistent when excluding intercurrent infection/inflammation. Conclusions: A simple longitudinal metric—time spent in an immune-recovered range during the first 12 weeks of adjuvant anti–PD-1—was independently associated with early post-landmark recurrence, suggesting an actionable early window for risk-adapted surveillance. External validation is warranted.
Clinical validation of an AI-based prognostic assay for stage I-II cutaneous melanoma.
9578 Background: In early-stage cutaneous melanoma (CM), AJCC staging demonstrates limited ability to identify patients at elevated recurrence risk who may benefit from adjuvant therapy or intensified surveillance. We evaluated DiaSurv, an AI-based prognostic assay analyzing standard H&E whole-slide images (WSI) to refine risk stratification in stage I-II melanoma. Methods: DiaSurv was validated on a retrospective cohort of 456 stage I-II primary CM patients with 5-year follow-up at Gustave Roussy. The algorithm assigns high- or low-risk scores based solely on primary tumor WSI analysis. Kaplan-Meier analysis estimated 5-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). Log-rank tests compared survival between risk groups. Multivariable Cox regression assessed independent prognostic value after adjusting for clinicopathological factors (Breslow thickness, ulceration, age, sex, tumor location, histological subtype, mitotic count). Results: Among 456 stage I-II patients (109 recurrences, 67 distant metastases, 57 deaths), DiaSurv classified 285 (62.5%) as low-risk and 171 (37.5%) as high-risk. Low-risk patients had significantly better 5-year outcomes compared to high-risk patients: RFS 92% vs 38% (HR = 7.71, 95%CI 4.86-12.23, p < 0.001), DMFS 94% vs 55% (HR = 10.39, 95%CI 5.31-20.36, p < 0.001), and OS 96% vs 71% (HR = 8.12, 95%CI 4.10-16.07, p < 0.001). In multivariable analysis, DiaSurv was independently associated with all endpoints (RFS: HR = 2.43, p = 0.006; DMFS: HR = 3.71, p = 0.002; OS: HR = 3.78, p = 0.003). In the clinically relevant stage I-IIA subgroup (n = 368), DiaSurv identified 86 patients (23.4%) with high-risk profiles despite favorable AJCC staging. These patients had markedly inferior outcomes compared to the 282 low-risk patients: 5-year RFS 71% vs 92% (HR = 4.85, p < 0.001), DMFS 77% vs 96% (HR = 5.48, p < 0.001), and OS 84% vs 96% (HR = 4.39, p < 0.001). The NPV of low-risk classification at 5 years in stage I-IIA was 92.2% for RFS, 96.5% for DMFS, and 96.5% for OS which is in line or superior to some commercially available gene-expression profiling assays. Conclusions: In early-stage melanoma (I-IIA), where adjuvant therapy is not currently standard, DiaSurv identifies nearly one-quarter of patients with a high-risk profile and significantly elevated recurrence rates. This AI-based assay provides actionable prognostic information beyond AJCC staging to guide decisions regarding adjuvant therapy consideration, sentinel lymph node biopsy, and surveillance intensity.
Actionable genomic alterations and survival in <i>KRAS</i> wild-type pancreatic ductal adenocarcinoma: Analysis of the MSK-CHORD 2024 clinico-genomic cohort with spotlight on <i>NRG1</i> fusions.
4222 Background: Pancreatic ductal adenocarcinoma (PDAC) is predominantly driven by KRAS mutations; however, approximately 10% of tumors are KRAS wild-type (KRAS-WT). Among these, NRG1 gene fusions have recently gained heightened clinical relevance following the FDA’s accelerated approval of zenocutuzumab for NRG1 fusion–positive PDAC after prior therapy. Contemporary real-world data characterizing actionable alteration yield and outcomes in KRAS-WT PDAC remain limited. Methods: We analyzed patients with PDAC (OncoTree: PAAD) from MSK-CHORD 2024. KRAS status was defined by the presence or absence of pathogenic KRAS somatic mutations. NRG1 fusions were identified through structural variant analysis. A predefined clinically actionable alteration set included NRG1 and NTRK1–3 fusions, MSI-H/dMMR, BRCA1/2 or PALB2 alterations, ERBB2 amplification, and BRAF V600E mutation. The primary endpoint was overall survival (OS) from the date of molecular profiling. Secondary endpoints included prevalence of actionable alterations within KRAS-WT PDAC and enrichment of NRG1 fusions by KRAS status. Results: Among 2,703 patients with PDAC, 2,424 (89.7%) had KRAS mutations and 279 (10.3%) were KRAS-WT. NRG1 fusions were identified exclusively within KRAS-WT tumors (4/279; 1.43%) and were absent among KRAS-mutant PDAC. As summarized in Table 1, 25 of 279 KRAS-WT PDAC patients (9.0%) had at least one clinically actionable genomic alteration. These included NRG1 and NTRK fusions, MSI-H/dMMR, homologous recombination repair gene alterations, ERBB2 amplification, and BRAF V600E mutation. Median OS differed substantially by KRAS status. Patients with KRAS-WT PDAC demonstrated longer survival compared with those with KRAS-mutant disease (26.3 vs 14.9 months). Patients with NRG1 fusion–positive PDAC had a median OS of 22.9 months, acknowledging limited sample size (n=4). Conclusions: KRAS-WT PDAC accounts for approximately one-tenth of cases and is associated with significantly longer overall survival compared with KRAS-mutant disease. Nearly 1 in 10 KRAS-WT tumors harbored clinically actionable genomic alterations, including NRG1 fusions, now linked to an FDA-approved targeted therapy. These findings support routine comprehensive molecular profiling, including fusion detection, in KRAS-WT PDAC and underscore the clinical relevance of precision oncology approaches in this distinct subgroup. Genomic characteristics and actionable alterations in KRAS–wild-type PDAC (MSK-CHORD 2024). Characteristic KRAS-Mutant PDAC (n=2,424) KRAS–Wild-Type PDAC (n=279) Median OS, months 14.9 26.3 Any actionable alteration* — 25 (9.0%) NRG1 fusion 0 (0%) 4 (1.43%) NTRK1–3 fusion — 3 (1.08%) MSI-H/dMMR — 2 (0.72%) BRCA1/2 mutation — 6 (2.15%) PALB2 mutation — 1 (0.36%) ERBB2 amplification — 5 (1.79%) BRAF V600E — 7 (2.51%)
Randomized phase III study of nivolumab after surgery and adjuvant chemotherapy in NSCLC (ECOG-ACRIN EA5142, ALCHEMIST).
8000 Background: The NCI’s ALCHEMIST program has screened thousands of patients with resected lung adenocarcinoma for mutations in EGFR and ALK. EA5142 studied the efficacy of adjuvant nivolumab after standard of care adjuvant therapy in patients with resected lung adenocarcinoma without sensitizing EGFR and ALK alterations and squamous cell carcinoma. Methods: Patients enrolled in the ALCHEMIST screening trial (A151216) with resected NSCLC tumors at least 4 cm and/or lymph node positive (N1/2) (for lung adenocarcinoma, without sensitizing EGFR and ALK alterations), were centrally tested for tumor cell PD-L1 expression using the DAKO 28-8 clone. After completion of all planned adjuvant therapy (chemotherapy and/or post-operative radiation) patients were randomized 1:1 to adjuvant nivolumab 480 mg IV every 4 weeks for up to 1 year or best supportive care. Patients were stratified by tumor histology, stage (AJCC 7 th edition IB/IIA vs IIB/IIIA), prior adjuvant treatment, and PD-L1 status (<1% vs ≥1%). The primary study endpoints were disease free survival (DFS) in all patients and in patients with high tumor PD-L1 expression (≥50%). Overall survival was powered to be tested hierarchically, if DFS was positive. Results: Between July 2016 and October 2019, 935 patients were randomized across 378 sites. The treatment arms were balanced for age (median 66 years), sex (52% male), smoking status (10% never smoked), histology (29% squamous), stage and PD-L1 expression (29% PD-L1 high). With a median follow-up of 72.6 months, nivolumab did not improve DFS in the intention to treat population (median DFS 71.3 months vs. 68.8 months in observation arm), hazard ratio (HR) 0.97 (95% CI 0.81-1.17, p=0.78) or the PD-L1 ≥50% subset (median DFS 89.8 months vs. 78.5 months in observation arm), HR 0.86 (95% CI 0.59-1.25, p=0.43). In multivariate analysis, adjusting for age, gender, and smoking history, the DFS HR was 0.99 (95% CI 0.82-1.19, p=0.89) in all randomized patients and 0.82 (95% CI 0.56-1.2, p=0.31) in the PD-L1 ≥50% subset. As the primary recurrence endpoint included any lung cancer, including new primaries, a sensitivity analysis was performed excluding new primary lung cancers, DFS HR 0.97 (95% CI 0.80-1.18, p=0.76) in all patients and HR 0.88 (95% CI 0.60-1.30, p=0.52 in the ≥50% subset. The median duration of treatment with adjuvant nivolumab was 9.4 months (range 0-12.7 months). The most common reasons for nivolumab discontinuation were adverse event (29%), patient withdrawal (11%), and disease progression while on treatment (10%). Treatment related grade 3-5 toxicities were reported in 25% of patients: Grade 3: 23%, Grade 4: 2%, Grade 5: <1%. Conclusions: In patients with resected NSCLC (≥4cm or LN+, EGFR/ALK -) adjuvant nivolumab did not improve DFS, irrespective of tumor PD-L1 expression. Clinical trial information: NCT02595944 .
PTHrP-associated gene programs in cancer cachexia and hypercalcemia and therapeutic targeting with anti-PTHrP antibody.
e16413 Background: Parathyroid hormone-related protein (PTHrP), a ligand of parathyroid hormone receptor-1 (PTH1R) encoded by PTHLH , is abundantly secreted by diverse cancers and mediates tumor progression and malignancy-associated hypercalcemia, making it an attractive therapeutic target. In pancreatic cancer (PC), PTHLH is frequently co-amplified with KRAS and promotes disease progression and cachexia through disruption of adipose de novo lipogenesis. However, PTHrP-associated gene programs relevant to cancer cachexia and hypercalcemia remain poorly defined. This study investigated PTHrP-associated genes and evaluated the effects of the PTHrP-targeting antibody BGM-2121 on tumor growth, cachexia, and hypercalcemia. Methods: The prognostic impact of PTHLH expression across cancer types was assessed using the Kaplan–Meier Plotter database. Correlations between PTHLH and selected gene expression profiles in pancreatic cancer were analyzed across two independent cohorts (n = 177 and 96) from cBioPortal. The antitumor efficacy of BGM-2121 was evaluated in PC cell line–derived xenograft (CDX) models and patient-derived xenograft (PDX) models. The effects of BGM-2121 on cancer-associated cachexia and hypercalcemia were assessed in relevant animal models. Results: High PTHLH mRNA expression was significantly associated with poor overall survival in over 350 patients with lung, liver, gastric, or colorectal cancers (p < 0.002) and with inferior overall and disease-free survival in pancreatic cancer (p < 0.0001). Co-expression analyses from two independent cohorts identified significant positive correlations between PTHLH and cachexia- or hypercalcemia-associated genes, including ACKR3/CXCR7 , ANGPTL2 , IL11 , TGFB1 , MMP2 , and MMP14 . Several of these genes have been reported as downstream targets of PTHrP signaling, supporting a functional role of PTHrP in cancer-associated cachexia and hypercalcemia. BGM-2121 treatment demonstrated significant antitumor activity in two CDX models (CFPAC-1 and BxPC3) and two PDX models of PC. In 786-O xenografts, BGM-2121 significantly suppressed cachexia and normalized serum calcium levels. Conclusions: These findings define PTHrP-associated gene programs linked to cancer cachexia and hypercalcemia and demonstrate the therapeutic potential of PTHrP blockade. The PTHrP-targeting antibody BGM-2121 suppresses tumor growth and alleviates systemic complications in preclinical models, supporting PTHrP as a promising target for cancers with aggressive progression and metabolic dysregulation.
What is the optimal timing of radiotherapy and immunotherapy in lung cancer? A meta-analysis of randomized trials using reconstructed Kaplan–Meier data.
e20076 Background: The increasing use of combined radiotherapy (RT) and immunotherapy (IO) in lung cancer is driven by evidence that RT can enhance immune activation by increasing neoantigen release, particularly when IO is given before RT. However, RT may also induce vascular damage and immunosuppressive changes that could reduce IO efficacy when administered after RT. These opposing effects create uncertainty regarding the optimal sequencing of RT and IO, supporting the need for systematic evaluation using randomized evidence. Methods: We searched PubMed, Web of Science, Scopus, and the Cochrane Library from inception through November 8, 2025, and evaluated overall survival (OS), progression-free survival (PFS), pneumonitis, and immune-related pneumonitis. Analyses were conducted in R using random-effects models, pooling categorical outcomes as risk ratios (RR) and time-to-event outcomes as hazard ratios (HR) with 95% confidence intervals (CI); when Kaplan–Meier curves (KM) were reported, individual patient data were reconstructed to generate pooled survival curves and study-stratified Cox models for comparisons across treatment strategies. Results: Across 20 randomised controlled trials including 4,309 patients, IO–RT–based combination therapy significantly improved PFS compared with monotherapy (HR 0.74, P < 0.01), with benefit mainly driven by regimens incorporating chemotherapy. The greatest PFS and overall survival benefits were observed when immunotherapy was administered after radiotherapy (PFS HR 0.67, P = 0.0024; OS HR 0.69, P = 0.0021), whereas no significant benefit was seen with prior or concurrent immunotherapy; subgroup differences by timing were significant for OS ( P < 0.0001). Combination therapy was associated with a higher risk of any-grade pneumonitis (RR 1.56, P = 0.01), but no significant increase was observed for grade 3–4 (RR 1.30, P = 0.25), grade 5 pneumonitis ( P = 0.16), or immune-related pneumonitis (any grade P = 0.07; grade 3–4 P = 0.91), with no effect of IO–RT sequencing. Reconstructed KM analyses showed that IO given before RT was associated with significantly worse PFS, while concurrent and post-RT IO had similarly improved PFS, with prior IO conferring markedly higher risk compared with concurrent (HR 5.16) or post-RT IO (HR 4.31) and no significant difference between concurrent and post-RT timing (HR 1.20). Conclusions: IO–RT–based combination therapy provides superior progression-free and overall survival compared with monotherapy, especially if associated with chemotherapy. The greatest benefit is observed when immunotherapy is administered after radiotherapy. Pneumonitis rates did not differ meaningfully between treatment approaches, and safety outcomes were comparable regardless of IO–RT sequencing.
ILF2 as a predictor of cisplatin resistance and clinical outcomes in intrahepatic cholangiocarcinoma.
3122 Background: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive biliary tract cancer with increasing global incidence and limited therapeutic options, partly due to the low prevalence of actionable genomic alterations such as FGFR2 fusions (~10%) and IDH1 mutations (~13%). Using single-cell transcriptomic analyses, we identified recurrent amplification at chromosome 1q21.3 as a dominant genomic alteration in iCCA tumor cells. Given our prior evidence linking 1q21.3 amplification to DNA damage–response (DDR) processes and chemotherapy resistance in multiple cancer types, we focused on Interleukin enhancer binding Factor 2 (ILF2), a gene within 1q21.3, and systematically evaluated its multi-omic features and clinical relevance in iCCA using multiple independent clinical datasets. Methods: Single-cell RNA sequencing datasets were analyzed using Single-Cell Variational Aneuploidy (SCEVAN) to identify recurrent chromosomal alterations. Bulk RNA and DNA sequencing datasets were assessed for ILF2 copy number variation (CNV) and mRNA expression. Clinical validation was performed using independent iCCA cohorts from Keio University and SJCI (n=67) and a public dataset (GSE89748; n=49). In vitro assays validated the functional role of ILF2 in DDR and cisplatin sensitivity of iCCA cell lines (n=3). Results: SCEVAN analysis of GSE125449 (n=8) and GSE138709 (n=5) revealed that 1q21.3 was the only common highest amplified region of iCCA tumor cells (29.7% and 31.1%, respectively). TCGA-CHOL dataset (n=32) demonstrated that ILF2 CNV amplification occurred in 46.7% of cases and was strongly correlated with increased ILF2 mRNA expression (r = 0.730, p < 0.001), which was significantly higher in tumor tissue than normal liver tissue in iCCA patients (p < 0.001). In the iCCA validation cohort (n=67) and GSE89748 dataset (n=49), ILF2 mRNA level upregulation was significantly associated with shorter recurrence-free survival (log-rank test; p < 0.001 and p = 0.047, respectively), and independently predicted recurrence risk (multivariate Cox regression analysis HR = 4.63, 95% CI 1.71 – 12.6, p = 0.003 and HR = 2.73, 95% CI 1.10 – 6.80, p = 0.031, respectively). Consistently, ILF2 protein expression as assessed by multiplex immunofluorescence was significantly lower in FFPE tumor tissues from cisplatin responders than non-responders of iCCA patients (p < 0.001, n=16). Across iCCA cell lines, ILF2 interacted with DDR–related factors to suppress R-loop and γH2AX activities; both events are involved in promoting cisplatin resistance. Conclusions: ILF2 is a frequent novel functional gene strongly associated with adverse clinical outcomes and cisplatin resistance of iCCA. This supports its role as a clinically relevant and theranostic biomarker related to DDR in iCCA patients.
Cigarette smoking on outcomes with osimertinib in <i>EGFR</i> -mutated non–small cell lung cancer: A real-world analysis.
e20680 Background: Osimertinib is a preferred therapy for patients with EGFR-mutated non–small cell lung cancer (NSCLC). However, while the effect of cigarette smoking has been evaluated in clinical trials, there is limited data on real-world populations. This study evaluated whether smoking history influences overall survival (OS) and time to next treatment (TTNT) among patients treated with osimertinib. Methods: We conducted a retrospective cohort study using the TriNetX database, including adults (≥18 years) with EGFR-mutated NSCLC who initiated osimertinib between 2015 and 2024. Patients were stratified by smoking history (current or former smokers vs never smokers). Cohorts were matched 1:1 using propensity scores based on age, sex, race, ethnicity, metastatic status, and comorbidities. Primary outcomes were OS and TTNT. TTNT was defined as time from osimertinib initiation to receipt of any subsequent antineoplastic therapy, with follow-up starting 14 days after osimertinib initiation to avoid misclassification. Kaplan–Meier methods and log-rank testing were used. A sensitivity analysis excluding smoking-related comorbidities was performed to assess the impact of overadjustment. Results: Before matching, 1,748 smokers and 5,249 never smokers were identified; after matching, 1,612 patients remained in each cohort. Mean age after matching was 67.8 years in smokers and 68.1 years in never smokers, with a consistent 60% female distribution. In the primary matched analysis, there was no significant difference in OS between smokers and never smokers (5-year OS 32% vs 32%; median OS 37.7 vs 38.3 months; p = 0.824). TTNT was also similar between groups (99 vs 101 days; p = 0.637). In the sensitivity analysis excluding smoking-related comorbidities, smokers demonstrated inferior OS, with lower 5-year survival and shorter median OS (32% vs 34%; 37.4 vs 41.2 months; p = 0.046), while TTNT remained unchanged (99 vs 102 days; p = 0.545). Conclusions: In a large real-world cohort of EGFR-mutated NSCLC patients treated with osimertinib, smoking history was not associated with differences in OS or TTNT when smoking-related comorbidities were balanced. However, when real-world comorbidity burden was retained, smokers experienced significantly worse survival. These findings suggest that smoking-related comorbidities, rather than smoking history alone, may drive inferior outcomes and should be considered in prognostication and patient counseling.
Locally advanced or metastatic thyroid cancer treated with donafenib with or without chemotherapy: A real-world study.
e18019 Background: Neoadjuvant therapy is often required for patients (pts) with locally advanced thyroid cancer (LATC). Our prior research demonstrated that anlotinib combined with chemotherapy exhibited favorable efficacy and safety as a first-line treatment for anaplastic thyroid carcinoma (ATC) and primary squamous cell carcinoma of the thyroid. Donafenib, another small-molecule, multi-targeted tyrosine kinase inhibitor, has shown significant clinical benefit in patients with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). This study aims to evaluate the efficacy and safety of donafenib alone or in combination with chemotherapy in patients with LATC or metastatic thyroid cancer (TC). Methods: This real-world, observational study included pts with LATC or metastatic TC who received either donafenib monotherapy or donafenib in combination with chemotherapy at the Department of Head-Neck and Thyroid Surgery, The First Affiliated Hospital of USTC, between June 1, 2024, and October 25, 2025. All enrolled pts underwent multidisciplinary team (MDT) evaluation before treatment initiation. Donafenib plus chemotherapy was considered in cases of high tumor burden (e.g., causing dyspnea) or in patients who had previously received combination chemotherapy. The primary endpoint was objective response rate (ORR). Secondary endpoints included R0/R1 resection rate, progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and treatment-related adverse events (TRAEs). Tumor responses were assessed according to RECIST v1.1 criteria. Results: Among the 15 patients analyzed, 12 had DTC and 3 had ATC. The median age was 70 years (range, 30.0–76.0). 40% (6/15) had undergone prior surgery, and 33.3% (5/15) had previously received radioiodine (iodine-131) therapy. 86.7%(13/15) of pts had stage IV disease (other 2 pts were in stage I becease of age under 55) . As of data cutoff (December 30, 2025), the median follow-up duration was 8.73 months. Based on RECIST 1.1, the best ORR was 20%, and the DCR was 93.3% ( 3 pts with partial responses, 11 pts with stable disease [SD] ). Notably, target lesions in 6 SD pts shrank by 21.1%–27.4%. Of the 13 pts with locally advanced thyroid cancer (LATC), 5 underwent subsequent surgery, and 80% (4/5) achieved R0/R1 resection. Among pts who did not undergo surgery, median PFS had not yet been reached. The 6-month PFS rate was 88.9%. TRAEs occurred in 66.7% (10/15) of pts. Grade ≥3 TRAEs were observed in 2 pts (13.3%). No treatment-related deaths were reported. Conclusions: This real-world study suggests that donafenib either as monotherapy or in combination with chemotherapy is both effective and well-tolerated in patients with locally advanced or metastatic thyroid cancer.
SCIntMatch: A probabilistic soft-matching framework for integrating single-cell genomes and transcriptomes to dissect adaptive resistance in patients with esophageal cancer.
e16012 Background: Adaptive resistance remains a major barrier to effective radiation therapy in esophageal cancer. While scDNA-seq reveals clonal architecture and scRNA-seq captures phenotypic states, linking specific genotypes to transcriptional programs remains challenging. Current methods often rely on hard clustering assignments that fail to capture the uncertainty and noise inherent in single-cell data. We developed SCIntMatch, a novel probabilistic soft-matching framework, and applied it to dissect resistance mechanisms in longitudinally sampled esophageal tumors. Methods: SCIntMatch utilizes an optimal transport formulation to probabilistically map scRNA-seq profiles onto ground-truth scDNA-seq clonal landscapes. Unlike discrete assignment methods, our algorithm optimizes a global reconstruction loss in copy-number space and applies a softmax function to generate continuous probability scores for every cell-to-clone pairing. This allows the model to handle ambiguity by assigning "soft" weights rather than forcing rigid classifications. We validated the framework on a high-complexity "ground truth" breast cancer dataset before applying it to paired pre- and mid-treatment samples from esophageal cancer patients. Results: In technical validation, SCIntMatch successfully resolved complex subclonal architectures, demonstrating robust specificity in distinguishing normal diploid cells from the tumor mass. The soft-matching probabilities effectively captured the signal of different subclones, enabling the dissection of subtle evolutionary trajectories that hard-clustering methods missed. Applying SCIntMatch to the esophageal cohort revealed distinct resistance landscapes. The tool revealed distinct resistance landscapes across the cohort. In one non-responder, the tool linked persistent resistant clones to a specific transcriptional program characterized by upregulated oxidative phosphorylation and downregulated interferon/inflammatory responses. In another, SCIntMatch resolved intra-patient heterogeneity, distinguishing a 'stress-adapted' persistent clone (enriched for EMT, mTORC1, and NFκB) from a genetically distinct 'newly emerged' clone that exhibited a purely proliferative phenotype. Conclusions: SCIntMatch provides a rigorous probabilistic framework for resolving genotype-phenotype links. By replacing rigid clustering with soft-weighted assignments, we successfully identified coexisting intrinsic (metabolic adaptation) and adaptive (proliferative emergence) resistance mechanisms, highlighting the utility of probabilistic integration for precision oncology.
Early detection of second primary solid tumors in patients with an index solid malignancy.
e13792 Background: Multiple primary malignant neoplasms (MPMN) are defined as two or more independent malignant tumors with distinct histopathology arising in different organs or tissues. This study aims to analyze the early detection of second primary solid tumors in patients followed after an index solid malignancy. Methods: A retrospective study included 513 patients with solid tumors who developed a second primary solid malignancy treated at the Henry Moore Oncology Institute (October 2012 to August 2025). Patients with index tumors stage I-III were selected. Second tumors were classified as synchronous (≤6 months) or metachronous ( > 6 months). Detection was categorized as screening-based or symptomatic. Age, sex, carcinogen exposure, and genetic factors were evaluated. Results: Among 513 patients, 464 (90%) had an index tumor stage I-II. Median age at first tumor was 60 years (r = 16-88); 240 were women. Most frequent index tumors were breast (n = 136), colorectal (n = 80), prostate (n = 67), and renal (n = 36). Median follow-up was 61 months (r = 0-123). Second tumors were synchronous in 100 and metachronous in 364 patients, with a median interval of 55 months (r = 7-111). Overall, 332 second tumors were considered preventable and detected by screening, while 132 were non-preventable. Preventable tumors were significantly more frequently diagnosed at early stages (p < 0.001). Conclusions: This is the largest reported cohort of patients with second primary solid tumors in Argentina. Most index tumors were diagnosed at early stages. The majority of preventable second tumors were detected at early stages, supporting the role of effective treatments, structured follow-up, and modern imaging in improving early detection, curative potential, and survival Stage distribution of second primary tumors according to preventability. Tumor site Non-preventable Preventable Stage 0 I II III IV Total Breast 0 76 11 30 23 6 6 76 Colorectal 0 75 3 5 20 33 14 75 Prostate 0 62 2 24 24 5 7 62 Lung 0 54 2 8 5 15 24 54 Renal 51 0 4 37 4 4 2 51 Others 81 65 14 47 20 20 40 146 Total 132 332 36 151 96 88 93 464
Updated design of INVOKE: A phase 1 study of OKN4395, a first-in-class EP2/EP4/DP1 triple prostanoid receptor antagonist, in patients with advanced solid tumors.
TPS2681 Background: The immunosuppressive pathway of prostaglandin E 2 (PGE 2 ), part of the cyclooxygenase (COX) pathway, is upregulated in certain cancers and has been implicated in tumor evasion of CD8 T, NK, and dendritic immune cells, allowing tumor growth and metastasis (Jin et al., 2023). COX2 inhibitors, aspirin and nonsteroidal anti-inflammatories (NSAIDS) have shown some survival benefit in patients with gastrointestinal cancer and others (Cao et al., 2016; Martling et al., 2025; Takiuchi et al., 2018; Zhang et al., 2025); however, results are inconsistent, likely due to toxicity limiting complete blockade of the pathway, highlighting the need for more potent but selective inhibitors. OKN4395 is a first-in-class, highly selective, equipotent inhibitor of EP2, EP4, and DP1, downstream receptors for COX-derived PGE 2 , and PGD 2 , respectively. DP1 has described roles in immunosuppression and inhibition of apoptosis, supporting the therapeutic rationale (Luo et al., 2024; Peinhaupt et al., 2017). OKN4395 is hypothesized to modulate the tumor microenvironment to allow an effective immune response as monotherapy, and to potentiate the effect of immunotherapies such as checkpoint inhibitors, both of which are evaluated in INVOKE. Tumor types for INVOKE were selected using previously presented multimodal artificial intelligence (AI) drug-matching algorithms (Grimaldi, et al., 2025). Methods: INVOKE (OKN-4395-121; NCT06789172) is a Ph1a/1b, first-in-human study of OKN4395 (oral, BID) as monotherapy (mono) or in combination with a PD1 checkpoint inhibitor (combo), in patients with advanced solid tumors. Ph1a is a Bayesian dose escalation in mono with a new parallel substudy, followed by combo dose confirmation, primarily assessing safety, establishing the Ph1b dose. Response will be assessed in updated Ph1b (cohorts of n=20): select sarcomas (mono), non-small cell lung (combo), colorectal (combo), and gastric cancer (combo). Key inclusion criteria include COX-active (Ph1a) or above-listed (Ph1b) tumors, performance status 0-1, biopsy-amenable lesions, and adequate organ function. Active CNS metastases, upper GI bleed risk factors, untreated H. pylori infection, and concomitant NSAIDs/COX inhibitors/prostaglandins are exclusionary. A new and innovative 3-period, crossover substudy in parallel with Ph1a will explore the intra-participant effects of food and gastric pH on OKN4395 pharmacokinetics. Trial data, paired pre- and on-treatment biopsies, and exploratory biomarkers will be used to enhance development using advanced agentic AI systems, including a synthetic digital twin control arm, novel methodology of which is submitted to this meeting as well. Ph1a of the study is currently recruiting in the US, UK, and Australia. Dose Level 5 concluded in December 2025 with no DLTs to that date. Clinical trial information: NCT06789172 .
Evaluation of clinicopathological features and prognosis of patients with small cell carcinoma of gastrointestinal system origin.
e16481 Background: Small cell carcinoma of gastrointestinal origin is a rare, highly aggressive neuroendocrine malignancy that can arise throughout the gastrointestinal tract. It is characterized by early dissemination and poor clinical outcomes compared with conventional gastrointestinal carcinomas. Due to its rarity, clinicopathological characteristics, treatment patterns, and prognostic factors remain poorly defined, underscoring the need for large population-based studies. In this study, we aimed to describe the characteristics of patients with small-cell carcinoma of the gastrointestinal tract. Methods: This retrospective cohort study analyzed Surveillance, Epidemiology, and End Results (SEER) database data to identify patients diagnosed with primary gastrointestinal small cell carcinoma between 2000 and 2022. Demographic, clinicopathological, and treatment variables were extracted for analysis. Survival outcomes were assessed using Kaplan–Meier estimates, and independent prognostic factors were evaluated through multivariate Cox proportional hazards regression. Results: We analyzed data from 2791 patients. Patients aged 60 years and older (71.6%) and male patients (57.5%) were more prevalent. The most common sites of small cell carcinoma in the gastrointestinal system were the colon (29%), pancreas (21.4%), esophagus (16.9%), and stomach (9.7%). The metastatic disease rate at diagnosis was 57.4%. 20.5% of patients underwent cancer-related surgery. 24.1% of patients received radiotherapy, and 61% received chemotherapy. In patients with metastases, the most common metastatic sites were the liver (51.3%), bone (12.4%), lung (11.9%), and brain (3.4%). 2118 (75.9%) patients died due to small-cell carcinoma of the gastrointestinal system. The median survival time was 8 months (95% confidence interval, 7.5-8.4). The 1, 3, and 5-year survival rates were 38.1%, 15%, and 11.8%, respectively. Factors affecting survival were evaluated using multivariate analysis, and the results were as follows: age (p = 0.171), gender (p = 0.111), origin (p = 0.193), tumor site (p = 0.001), surgery (p < 0.001), radiotherapy (p < 0.001), chemotherapy (p < 0.001), and initial stage (p < 0.001). Conclusions: Patients with gastrointestinal small cell carcinoma had a high rate of metastatic disease at diagnosis and a poor prognosis. Prognosis varied depending on the tumor site. Tumors of unknown primary site and liver origin had the worst prognosis. Primary tumor surgery, chemotherapy, and radiotherapy were identified as independent prognostic factors.
Conditioning intensity and post-transplant outcomes in acute myeloid leukemia: A real-world analysis.
e18573 Background: The choice of conditioning intensity for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (allo-HCT) is influenced by multiple factors, including disease risk, remission status, patient fitness, and center-specific practice patterns. While myeloablative (MAC) and reduced-intensity conditioning (RIC) regimens have been extensively compared, less is known about their real-world effectiveness when accounting for contemporary patient selection and disease risk. Methods: We performed a retrospective analysis of adult patients with AML who underwent allo-HCT at the University of Kentucky between Jan 2015 and Jan 2025. Baseline demographics, disease characteristics, ELN risk classification, conditioning intensity, and transplant outcomes were collected. Overall survival (OS) was calculated from the time of transplant, and relapse outcomes were assessed longitudinally. Results: A total of 147 patients were included. Median age was 57 years (IQR 43–64), and 53% were male. Median follow-up from diagnosis was 59 months (IQR 47.7–77), with a median OS from transplant of 66 months (IQR 43.3–NR). ELN risk was favorable in 22%, intermediate in 28%, and unfavorable in 50%. Transplant occurred in first complete remission (CR1) in 61% and in second complete remission CR2 in 22% of patients. Conditioning regimens included RIC in 53% (FluBu2 45%, FluMel 49%, FluTreosulfan 6%), MAC in 32% (FluBu4 78%, TBI/etoposide 9%, other TBI-based regimens 13%), and non-myeloablative regimens in 5.4%. Post-transplant relapse occurred in 32% of patients. ELN risk distribution was similar between MAC and RIC groups (unfavorable risk: 53% vs 48%, p=0.2). Patients receiving MAC were younger than those receiving RIC (median age 48 vs 60 years, p<0.01). Median time to relapse was not reached in either group (MAC 95% CI 13–NR vs RIC 95% CI 34–NR; p=0.6). Conclusions: In this real-world cohort, conditioning intensity was not associated with differences in relapse timing despite clear differences in patient age and selection. These findings suggest that reduced-intensity conditioning provides comparable disease control to myeloablative approaches in appropriately selected patients with AML, supporting risk-adapted conditioning strategies in contemporary practice.
Expression of FGFR2b and HER2 in gastric cancer: Implications for targeted therapy selection.
e16106 Background: FGFR2b and HER2 are clinically relevant therapeutic targets in gastric cancer (GC), with multiple targeted agents demonstrating efficacy in biomarker-selected patient populations. HER2 testing is well established in routine clinical practice, while FGFR2b has recently emerged as a promising target, particularly for antibody–drug conjugate–based therapies. However, the real-world prevalence of FGFR2b expression and its relationship to HER2 status remain incompletely defined. This study aimed to characterize the expression patterns of FGFR2b and HER2 in a cohort of gastric cancer cases to inform biomarker testing strategies and therapeutic development. Methods: Tissue microarrays from 103 patients with histologically confirmed gastric cancer, were evaluated by immunohistochemistry (IHC). FGFR2b expression was assessed using a validated monoclonal antibody and scored based on membranous staining intensity and extent. FGFR2b positivity was defined as ≥10% of tumor cells exhibiting 2+ or 3+ membranous staining. HER2 status was determined using standard clinical IHC criteria in accordance with established gastric cancer guidelines, with 2+ or 3+ staining considered positive. All cases were independently reviewed by board-certified pathologists to ensure consistency. Results: HER2 positivity was identified in 13.6% (14/103) of gastric cancer cases, consistent with reported prevalence in unselected GC populations. FGFR2b expression was detected in 3.88% (4/103) of cases. The low observed frequency of FGFR2b positivity is likely influenced by the application of stringent scoring thresholds and the limited cohort size, rather than reflecting true biological absence. Co-expression of FGFR2b and HER2 was uncommon, suggesting that these biomarkers define largely distinct therapeutic subsets. No consistent association between biomarker expression and histologic subtype was observed in this cohort. Conclusions: FGFR2b and HER2 identify distinct and potentially actionable subsets of gastric cancer. While HER2 remains a more prevalent biomarker, FGFR2b may define a smaller but clinically relevant population for emerging targeted therapies. The low FGFR2b prevalence observed in this study highlights the importance of standardized assessment criteria and larger, well-powered studies to more accurately define its expression landscape and therapeutic relevance in gastric cancer. These findings underscore the value of comprehensive biomarker profiling in gastric cancer and support further evaluation of FGFR2b and HER2 in larger, clinically annotated cohorts.
Initial results from EXCEED, a phase 1 study of LY4101174, an antibody-drug conjugate targeting Nectin-4, in participants with advanced or metastatic urothelial carcinoma.
4517 Background: Enfortumab vedotin plus pembrolizumab (EVP) is the current first-line standard of care for locally advanced / metastatic urothelial carcinoma (mUC). However, subsequent treatment options are limited, representing an urgent and growing unmet need. Preclinical data suggest that EV resistance may be payload mediated and consequently Nectin-4 remains a viable target for alternative therapies. LY4101174 is a next generation anti-Nectin-4 ADC comprising a humanized IgG1 antibody conjugated to the topoisomerase I inhibitor, exatecan, via a maleimide-ß-glucuronide poly-sarcosine linker and a homogeneous drug antibody ratio of 8. Here, we report the initial clinical data from the phase 1 dose escalation cohort of EXCEED (NCT06238479). Methods: Adults with locally advanced / mUC or other selected solid tumors were eligible. Participants (pts) must have received or were ineligible for available standard therapies, and have ECOG PS 0-1. Dose escalation utilized a Bayesian optimal interval design. Key endpoints were safety, PK, and antitumor activity of LY4101174 per RECIST v1.1. Results: As of 3 Dec 2025, 143 pts (86 mUC, 57 non-UC tumors) were treated across 6 dose levels (DLs) of LY4101174 (0.8-3.2 mg/kg Q2W or 2.4-4.0 mg/kg Q3W IV). Median age was 68 (range, 30-85), 60% ECOG PS 1. Median prior lines of therapy was 4 (range, 1-10), 92% of mUC pts had received prior EV (19% [15/79] had discontinued EV due to treatment-related toxicity). LY4101174 and total antibody exhibited mostly linear, dose-proportional PK up to 4.0 mg/kg, and up to 3.2 mg for exatecan. At 3.2 mg/kg Q2W, 3 of 6 pts experienced DLTs (neutropenia [grades 3 and 4], febrile neutropenia, and thrombocytopenia [both grade 3]) prompting a schedule change to 3.2 mg/kg Q3W for continued escalation. The most common treatment-emergent AEs (TEAEs) across Q3W DLs were anemia (71%), fatigue (55%), nausea (49%), neutropenia (36%), thrombocytopenia (31%), diarrhea (26%), vomiting (25%), and decreased appetite (23%). The most common grade ≥3 TEAEs were anemia (47%), neutropenia (29%), thrombocytopenia (21%), febrile neutropenia and leukopenia (10% each); prophylactic granulocyte colony stimulating factor (G-CSF) was required at DL 4.0 mg/kg Q3W. TRAEs led to dose reduction in 24% and discontinuation in 2%. In the 66 efficacy evaluable mUC pts treated with 2.4-4.0 mg/kg Q3W (92% [61/66] EV-pretreated), ORR was 18% (12/66) and DCR was 70% (46/66) with 12 PR (8 confirmed, 4 ongoing and pending confirmation) and 34 SD. Median follow-up was 4.9 months (95% CI, 1.4-NE). Conclusions: LY4101174 has demonstrated clinical activity at Q3W dose levels, including in EV pre-treated mUC, suggesting Nectin-4 remains an important therapeutic target. Dose and duration on treatment were mainly limited by grade ≥3 hematologic toxicity requiring the use of prophylactic G-CSF. Clinical trial information: NCT06238479 .
Real-world effectiveness and safety of elranatamab in patients with relapsed/refractory multiple myeloma: Preliminary results from the prospective, non-interventional MagnetisMM-16 study.
e19507 Background: Elranatamab is a B-cell maturation antigen–CD3 bispecific antibody approved for the treatment of adult patients with relapsed or refractory multiple myeloma (RRMM) in several countries. The efficacy and safety of elranatamab were demonstrated in previous clinical trials, and real-world data for elranatamab are currently being accumulated. This interim analysis provides an early look into the results from a real-world primary data collection study of elranatamab in patients with RRMM. Methods: MagnetisMM-16 (EUPAS106401) is a prospective, international, multicenter, non-interventional post-authorization safety study evaluating the effectiveness and safety of elranatamab in patients aged ≥18 years with RRMM treated in real-world settings. Patients are being recruited from hematology/oncology clinics, primary care settings, and academic centers in the United Kingdom, Germany, Spain, and Italy. Investigators were asked in the study protocol to follow recommendations in the local health authority–approved product label, including infection precautions and antimicrobial prophylaxis. This interim analysis is based on a September 15, 2025 data cut and describes preliminary results. Results: A total of 52 patients were included in the analysis. The median age of patients was 70.0 years (range, 48.0-87.0), 59.6% were male, and 88.5% were white. The patients were heavily pre-treated with more than half of the patients (61.5%) receiving ≥4 prior lines of therapy, 94.2% were double-class exposed to prior anti-CD38 and proteasome inhibitor, and 84.6% were triple-class exposed to prior anti-CD38, proteasome inhibitor, and immunomodulatory therapy. International Staging System disease stage at baseline was reported for 32 patients, 46.9% (n=15) had stage III and 34.4% (n=11) had stage II disease. The most common (≥10%) comorbidities were hypertension (32.6%), atrial fibrillation (16.3%), chronic kidney disease (11.6%), and type 2 diabetes mellitus (14.0%). Conclusions: Real-world effectiveness and safety data for elranatamab will be presented for this heavily pre-treated RRMM patient population at the congress. Clinical trial information: EUPAS106401.
Cumulative low-dose ionizing radiation exposure in frequent emergency department encounters and implications of carcinogenic risk.
e23157 Background: Repeated low-dose ionizing radiation (IR) over short intervals can accumulate causing DNA damage and increased long-term carcinogenic risk. Frequent emergency department (ED) users may represent an underrecognized population at risk for clinically significant cumulative radiation exposure. We quantified cumulative IR exposure among frequent ED users and identified demographic and clinical factors associated with elevated exposure relevant to malignancy risk. Methods: 714 patient records were abstracted from 404,000 ED encounters (June 2021–June 2023). Encounters per patient over 2 years were stratified by frequency. 20 patients per stratum were randomly sampled for 1–25 visits and all patients with > 25 visits were included (n = 214) Radiologic imaging type and anatomic region were recorded, cumulative IR exposure was calculated using a standardized dosage table (mSv). Demographics and comorbidities were abstracted. Patients were categorized by cumulative exposure ≥100 mSv vs < 100 mSv, 50 mSv was considered a clinically significant annual threshold. Linear regression modeled encounters required to reach high-risk thresholds. Results: Mean age 48 ± 19 years, 60.6% female, 63.6% White, Medicaid predominated. Mean ED encounters: 22 ± 21, mean CT scans: 11 ± 12 per patient. Mean cumulative IR: 114 ± 129 mSv. Regression modeling demonstrated that approximately 17 ED encounters over 2 years sufficient to reach 100 mSv. Age weakly correlated with IR (r = 0.185, p < 0.001), females had higher exposure (p = 0.04), race differences were not observed. Total imaging strongly correlated with cumulative IR (r = 0.842, p < 0.001). Psychiatric/behavioral health diagnoses including mood disorders, anxiety, chronic pain, substance use and nonadherence were significantly associated with exposure ≥100 mSv (all p < 0.05). Conclusions: Among very frequent ED users, particularly socioeconomically disadvantaged females with psychiatric comorbidities, cumulative IR exposure was substantial with approximately half of patients exhibiting exposure ≥100 mSv a dose range linked to higher risk of solid and hematologic malignancies. Although 95.3% of encounters and 99.6% of patients were not at concern a small but clinically meaningful subset accrued high exposure. Emerging data suggest that cumulative exposures near 50 mSv may also confer deleterious risk. Findings identify an underrecognized at-risk population and support targeted imaging stewardship to mitigate long-term oncologic risk.
Nutraceutical therapies for radiation-induced injury: A systematic review and meta-analysis.
e24196 Background: Radiation-induced edema and necrosis are common, dose-limiting toxicities. Corticosteroids remain first-line therapy but are associated with significant morbidity and limited long-term tolerability. Dietary and herbal agents with antioxidant, anti-inflammatory, and neurovascular protective properties are suggested as adjunct or steroid-sparing agents, yet systematic analysis of their overall efficacy is unclear. Methods: A systematic search of PubMed, Embase, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted from inception through December 2025. Eligible studies included randomized trials and observational studies evaluating non-traditional dietary or herbal interventions for radiation-induced cerebral edema or injury. The primary outcome was radiographic improvement of cerebral edema on MRI, harmonized as any MRI-documented reduction or resolution of edema or necrosis. A random-effects comparative meta-analysis was performed for controlled studies with extractable binary outcomes, excluding case reports. A secondary random-effects, single-arm meta-analysis of proportions was conducted for Boswellia serrata , including observational cohorts and case series. Studies without MRI-based cerebral toxicity endpoints were synthesized qualitatively. Results: Eleven studies encompassing more than 400 patients met the inclusion criteria. Boswellia serrata was the most frequently evaluated intervention, followed by dl-3-n-butylphthalide, vitamin E, omega-3 fatty acids, melatonin, multi-herbal formulations, and integrative multi-compound regimens. In a comparative meta-analysis of two controlled studies, dietary and herbal interventions were associated with a significantly higher likelihood of radiographic improvement in cerebral edema compared with standard therapy or placebo (pooled risk ratio 1.60, 95% CI 1.12–2.30; I² = 0%). In a secondary, single-arm, meta-analysis of five Boswellia serrata studies, the pooled radiographic response rate was 56.2% (95% CI 45.0%–67.1%). Across other studies, neurologic and cognitive improvement and steroid-sparing effects were commonly reported, while serious treatment-related adverse events were uncommon. Integrative oncology approaches combining Boswellia serrata with other natural compounds were also associated with improved survival and reduced steroid dependence in longitudinal observational studies. Conclusions: Dietary and herbal interventions, particularly Boswellia serrata , are associated with meaningful radiographic and clinical improvement in radiation-induced cerebral edema and brain injury, with favorable safety profiles. These findings support further prospective randomized trials and suggest a potential adjunctive role for non-pharmacologic therapies in managing radiation-related neurotoxicity.