Browse Articles

Real-world patient characteristics, outcomes, and resource utilization of chimeric antigen receptor (CAR) T cell therapy across Foundation for the Accreditation of Cellular Therapy (FACT) and non-FACT treatment centers in large B-cell lymphoma (LBCL).

7023 Background: CAR T cell therapy has transformed the LBCL treatment landscape and is now being offered in some non-FACT accredited centers. We evaluated clinical characteristics, AEs, time to next treatment (TTNT), and health care resource utilization (HCRU) of patients with LBCL who received CAR T cell therapy from FACT versus non-FACT centers. Methods: This retrospective cohort study used the Komodo Health Claims Database (01/2015–08/2025). Adults with LBCL receiving CAR T cell therapy were identified via International Classification of Diseases, Ninth/Tenth Revision, diagnosis and procedure codes. Centers were classified as FACT or non-FACT based on public records. Cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and infections were assessed within 15 and 30 days after infusion. TTNT was estimated using KM methods. All-cause HCRU was reported as per patient per month (PPPM) to adjust for variation in follow-up duration; inpatient utilization was assessed by length of stay (LOS). Comparisons used chi-square test. Results: Among 6857 CAR T cell therapy−treated eligible patients with LBCL (FACT, n = 6748; non-FACT, n = 109), demographics and characteristics were comparable between cohorts; mean Charlson Comorbidity Index score was 4.6 versus 4.9, respectively. Significantly more patients treated at FACT sites traveled > 50 miles compared with those treated at non-FACT sites (43% vs 31%; P < 0.05); median distance traveled was 34 versus 17 miles, respectively. Rates of CRS (44% vs 40%), ICANS (21% vs 24%), and infections (39% vs 36%) within 15 days after infusion were similar between cohorts (FACT vs non-FACT, respectively); rates were also comparable within 30 days. Median (95% CI) TTNT was numerically lower in the FACT-treated (23 months [21–25]) versus non-FACT–treated cohort but not statistically significant (42 months [18–not estimable]; P = 0.20; estimates limited by small sample size); 12-month TTNT rates were 58% versus 67%, respectively. Excluding infusion visits, FACT-treated patients had marginally higher postinfusion HCRU (PPPM) over 1 year, including inpatient (0.93 vs 0.61; P = 0.52), outpatient (3.84 vs 3.16; P < 0.05), and ICU visits (0.13 vs 0.07; P < 0.05). Standardized 1-year inpatient LOS was 18.4 versus 15.9 days, respectively ( P = 0.58). Among patients treated in an inpatient setting, HCRU including infusion visit exhibited a similar trend. Conclusions: In this real-world LBCL cohort, clinical characteristics, safety, TTNT, and HCRU were generally comparable between FACT- and non-FACT– accredited centers. Despite the non-FACT sample size and claims-based limitations, these findings suggest patients have similar outcomes across both types of authorized treatment centers.

Prognostic and predictive impact of baseline gene expression (exp) in the NATALEE trial of adjuvant (adj) ribociclib (RIB) + nonsteroidal aromatase inhibitor (NSAI) in HR+/HER2− early breast cancer (EBC).

501 Background: In the NATALEE clinical trial, RIB + NSAI significantly improved invasive disease–free survival (iDFS) vs NSAI alone in patients (pts) with stage II/III HR+/HER2− EBC. We report on the prognostic and predictive value of baseline gene exp in NATALEE. Methods: Pts were randomized 1:1 to RIB + NSAI or NSAI alone. Men and premenopausal women received goserelin. Eligible pts had anatomical stage IIA (if N0 with additional risk factors [G3, or G2 with Ki67 ≥20% or high genomic risk] or N1 [1-3 axillary lymph nodes]), IIB, or III disease per AJCC (8th ed). Gene exp in surgical samples was profiled by NanoString BC360 panel. PAM50-based intrinsic subtype × treatment (tx) interaction was estimated by likelihood ratio test. Prognostic and predictive effects of PAM50 subtypes and genomic risk/proliferation signature scores created from gene exp data were assessed with Cox proportional hazards models. Differences in genomic risk and proliferation scores were analyzed by Wilcoxon test. Associations between gene exp and RIB benefit were estimated with Cox models. Results: In all, 3022 baseline surgical samples were analyzed. iDFS benefit with RIB + NSAI was consistent in the biomarker (hazard ratio [HR], 0.72) and intent-to-treat populations (HR, 0.71). PAM50 subtype distribution was comparable across tx arms and differed between N0 and N1-N3 in pts with luminal A (LumA; 50% vs 68%), luminal B (lumB; 41% vs 26%), and basal-like (BSL; 6.4% vs 2.5%) disease, with similar percentages for HER2-enriched (HER2E; 2.5% vs 3.0%). PAM50 subtypes were strongly prognostic (HRs vs LumA: LumB, 1.39; HER2E, 2.62; BSL, 3.92). RIB had benefit across all PAM50 subtypes (HRs: LumA, 0.77; LumB, 0.71; HER2E, 0.50; BSL, 0.42), with no significant subtype × tx interaction ( P = .34). Higher genomic risk signature or proliferation signature scores showed a trend for increased RIB benefit, again with no significant interaction. Pts with N0 vs N1-N3 had significantly higher genomic risk scores and proliferation scores. Exploratory analysis of the predictive effect of gene exp on RIB benefit identified several genes for which higher (eg, CEACAM6 , NOD2 , and GPX3) or lower exp (eg, GATA3 , SLC39A6 , and MAPT ) was associated with increased RIB benefit. Conclusions: In this analysis of NATALEE, which examined the largest dataset of surgical tumor samples from any adj CDK4/6i trial in HR+/HER2− EBC, RIB had benefit across all PAM50 subtypes, with a trend for increased benefit in pts with higher genomic risk signature or proliferation signature scores. Baseline exp levels of several genes were associated with differential RIB benefit in EBC, showing potential predictive and prognostic value. The findings reinforce the therapeutic benefit of RIB in combination with ET across HR+/HER2− EBC populations. Clinical trial information: NCT03701334 .

Development of human B7H3/IL13Ra2 bispecific armored CAR-T for treatment of glioblastoma.

2056 Background: Glioblastoma (GBM) remains a highly lethal malignancy driven by infiltrative growth, molecular complexity, immune evasion, and therapeutic resistance. The limited efficacy of current treatments reflects antigen heterogeneity, an immunosuppressive tumor microenvironment, and restricted delivery across the blood–brain barrier with targeted therapy. Although earlier CAR-T therapies demonstrated preliminary activity in GBM, durable efficacy remains elusive. We have developed EPC-003, a fully human bispecific B7-H3/IL13Rα2 CAR-T engineered with a multi-mechanism armor to mitigate antigen heterogeneity, modulate the tumor microenvironment, and enhance persistence via central memory T-cell enrichment. Methods: Human anti-IL13Rα2, anti-B7-H3, and anti-PD-L1 scFvs were discovered from proprietary human B-cell libraries using mRNA display platform. A multi-mechanism armor was engineered by fusing the anti-PD-L1 scFv to a fine-tuned, immune cell-type specific IL-2 variant, identified through the unique cytokine engineering platform. These binding and functional modules were systematically optimized to generate EPC-003, a bispecific tandem CAR targeting IL13Rα2 and B7-H3 and incorporating a secreted multi-mechanism armor. CAR mechanisms, anti-tumor activity, and preclinical toxicity were evaluated. A proprietary clinical manufacturing process was established to produce a central memory T cell enriched CAR-T product. Results: The secreted armor of EPC-003 suppressed regulatory T-cell activation while selectively activating central memory T-cells, with the potential to enhance CAR-T cell persistence. In a 7-day G-Rex manufacturing process, EPC-003 demonstrated promising druggability with robust and reproducible CAR expression, and the proprietary cytokine cocktail consistently enriched the product to >65% central memory CAR-T cells. In orthotopic GBM models, intracranial administration of EPC-003 (0.4 × 10⁶ and 1.2 × 10⁶ CAR-T cells) induced tumor regression and showed dose-dependent anti-tumor activity. In preclinical toxicity studies, EPC-003 exhibited a favorable safety profile, with no body weight loss, cytokine release syndrome, or systemic clinical signs. No treatment-related pathological changes were observed across 25 examined organs. Immunohistochemistry revealed no evidence of brain hemorrhage in treated groups, with minimal monocyte infiltration in the pia mater observed only at the high dose. Conclusions: EPC-003, a multi-mechanism armored bispecific CAR-T, demonstrated favorable preclinical safety, developability, robust anti-tumor activity, and potential durability. These data support its advancement into an investigator-initiated clinical trial for the treatment of glioblastoma.

Pulmonary immune-related adverse events post-immune checkpoint inhibitors (ICI): Real-world experience.

11166 Background: Immunotherapy (IT) has transformed cancer treatment and is often better tolerated than chemotherapy; however, immune-related pulmonary adverse events (Pulm-AE) have emerged as clinically significant and potentially treatment-limiting toxicities that may impact morbidity, treatment continuity, and survival. Real-world comparative data on Pulm-AE risk remain limited. We evaluated the incidence, cumulative risk, severity, and clinical outcomes of Pulm-AEs in patients receiving IT versus non-IT systemic therapies. Methods: We conducted a retrospective cohort study of 5,556 adult cancer patients treated at the Cleveland Clinic between 2010–2022. Included cancers were bladder (stage II–IIIA n = 476; IV n = 158), endometrial IV (n = 157), esophageal/gastric (II–III n = 797; IV n = 590), head & neck IV (n = 36), renal (III n = 88; IV n = 223), metastatic melanoma (n = 45), and lung cancers: non-squamous NSCLC (IIIB n = 206; IV n = 1,609), squamous NSCLC (IIIB n = 182; IV n = 366), and SCLC IIIB–IV (n = 623). Patients receiving IT (± chemotherapy or radiation) were compared with non-IT regimens and followed from treatment initiation to Pulm-AE, death, or last encounter. Pulm-AEs included pneumonitis, pleural effusion ± pleuritis, and interstitial lung disease. Data were collected on demographics, CTCAE grade, timing, management, and outcomes. Incidence rates per 100 person-years (py) were estimated using Poisson regression, cumulative incidence (CIR) using Kaplan–Meier methods, and adjusted hazard ratios (HRs) using time-dependent Cox models. Results: Of 5,556 patients, 2,133 (38%) received IT, including 1,291 (60%) as first-line therapy; 99.9% of IT exposure was ICI. The cohort was 38% female, 87% White, with a median age of 66 years. Over a median follow up of 14 months (CI: 6-35), 127 Pulm-AEs occurred, including 51 among first-line IT recipients. Pulm-AE incidence was higher with IT than non-IT (0.2 vs 0.06 per 100 py; P < 0.05), driven primarily by pneumonitis (0.16 vs 0.04 per 100 py; P < 0.05). At 24 months, CIR for Pulm-AEs was 5.5% with first-line IT versus 2.0% without (HR 3.50, P < 0.001); pneumonitis CIR was 4.3% versus 1.3% (HR 5.21, P < 0.001). Among pneumonitis cases, 86% were CTCAE grade 2–4, 81% required steroid therapy, and 28% resulted in permanent IT discontinuation, frequently necessitating long-term immunosuppression. Other Pulm-AEs in the IT & non-IT groups were pleural effusion (n = 10, 24), pleuritis without effusion (n = 0, 2), and interstitial lung disease (n = 0, 2). Conclusions: Receipt of IT was associated with a significantly increased risk of Pulm-AEs, primarily clinically significant pneumonitis. These toxicities were common (~7% by 24 months), frequently severe, and often led to irreversible damage and treatment cessation, underscoring the need for vigilant monitoring, early recognition, multidisciplinary management, and prompt intervention to minimize morbidity.

Race, neighborhood deprivation, and mortality in prostate cancer: A real-world analysis from the MedStar Health Network.

e17137 Background: The Area Deprivation Index (ADI), a validated measure of neighborhood socioeconomic disadvantage, demonstrates race-specific associations with prostate cancer (PC) risk. Studies have shown neighborhood deprivation independently increases PC risk and mortality among Black men, a relationship not observed in White men. We evaluated the associations between race, ADI, and all-cause mortality among men with prostate cancer within the MedStar Health Network. Methods: This is a retrospective cohort study of 4115 PC patients (46.1% Black, 40.4% White, and 13.5% Other) within the MedStar Health Network (2016-2024). Each patient was assigned an ADI score based on their residential zip code that was ranked relative to the national level and further categorized into quartiles. Chi-square tests were used to assess associations between race and ADI quartile (Q1 = least deprived and Q4 = most deprived), including pairwise comparisons between racial groups. Multivariable logistic regression models, including an interaction term between race and ADI, were used to assess differential associations with mortality. Results: We included 1973 patients in the analysis (41.6% Black, 44.5% White, and 14.0% Other) residing in Q1 (53.4%) and Q4 (46.6%). There was a significant association between race and ADI (χ² p < 0.001) with Black patients disproportionately represented in Q4. Pairwise comparisons demonstrated significant differences between Black versus White patients (p < 0.001) and Black versus Other patients (p < 0.001), while White versus Other patients did not differ significantly (p = 0.473). In multivariable logistic regression, residence in Q4 was independently associated with higher odds of mortality (OR 1.45, 95% CI 1.17–1.79, p < 0.001). When stratified by race, race was not significantly associated with mortality among Black (OR 1.17, p = 0.333), White (OR 1.55, p = 0.055) or Other (OR 0.99, p = 0.976) patients in Q4. Conclusions: We found that Black men with PC are disproportionately represented in the most deprived ADI quartile (Q4) compared to White Men. While residence in the most disadvantaged neighborhoods was independently associated with higher odds of mortality in the cohort, this association did not reach statistical significance within individual racial groups. This outcome contrasts prior studies that show neighborhood deprivation is associated with increased all-cause mortality specifically within Black men. Our findings suggest that neighborhood deprivation contributes to PC mortality disparities through complex mechanisms that extend beyond race alone. Targeted interventions addressing neighborhood-level socioeconomic disadvantage may help reduce disparities in prostate cancer outcomes across all racial groups.

Clinical and demographic characteristics in ameloblastoma patients: A single-center study.

e18146 Background: Ameloblastomas account for 13-58% of odontogenic tumors. They can be unicystic, extraosseous/peripheral, or metastatic. Treating an ameloblastoma involves surgically removing the tumor and performing reconstruction at the same time. These tumors are locally aggressive, have high recurrence rates, and can metastasize at a rate of 1%. Treating ameloblastoma remains challenging due to its high recurrence rate and extensive tissue defects. Recent molecular advances strongly indicate the potential for targeted therapy with better outcomes in ameloblastomas. These tumors often have mutations in genes within the mitogen-activated protein kinase (MAPK) pathway. About 96% of ameloblastomas with BRAFV600E mutations are found in the mandible. There have been reports of notable treatment responses using dual BRAF/MEK inhibitors, dabrafenib and trametinib, in patients with multiple lung metastases. This study aimed to explore the demographic and clinicopathological characteristics of patients with ameloblastoma. Methods: In our study, patients diagnosed at Çukurova University between 2010 and 2023 were included, and data from 78 treated patients were retrospectively analyzed. Patient age, gender, tumor location, histological subtypes, presence of recurrence, BRAF mutation, and Ki67 value were recorded. Results: Among the patients, 51.3% (40) were male and 48.7% (38) were female. The median age at diagnosis for patients was 35 years (range 12-70 years). Tumors were located in the mandible in 69 patients and in the maxilla in 9 patients. There are 17 patients with unicystic, 4 with desmoplasty, 2 with intracystic intraluminal conditions, 1 with multicystic, and 4 with solid ameloblastoma histology. BRAF mutation was tested in seven patients, and it was found in five. One patient received BRAF-targeted therapy for metastatic disease. 7 patients experienced a recurrence of the disease during follow-up. Discussion: Ameloblastoma more commonly occurs in the mandible, but it can also be found in the maxilla. In our study, 88% of the patients had the tumor localized to the mandible. In our study, the unicystic type made up 21% of the patients and was the most frequently identified histological subtype. The BRAF mutation is the most frequently identified mutation in patients with ameloblastoma. In our study, we examined the BRAF mutation in 7 patients, and a BRAF mutant was found in 5 of them. The BRAF mutation might be linked to the frequency of recurrence and metastasis occur. Conclusions: Limited data exist on factors affecting the recurrence of ameloblastoma, a locally aggressive odontogenic tumor, and on treatments for metastatic disease. Our focus was to review current treatment methods and emerging strategies by analyzing the demographic and clinicopathological characteristics of ameloblastoma patients.

Induction adebrelimab combined with chemotherapy followed by response-adaptive concurrent chemoradiotherapy guided by PET-CT in locally advanced unresectable esophageal squamous cell carcinoma: A prospective, single-arm, phase II study.

TPS2692 Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced unresectable esophageal cancer. Currently, data on PD-L1 inhibitors combined with chemoradiotherapy in this setting still remain limited. Furthermore, the efficacy of induction immunotherapy prior to CCRT, and the utility of PET-CT assessment to guide subsequent CCRT regimens, have not been explored. This study aims to evaluate the efficacy and safety of induction adebrelimab (an anti-PD-L1 antibody) combined with chemotherapy, followed by a PET-CT guided adaptive chemotherapy regimen during CCRT for locally advanced unresectable esophageal squamous cell carcinoma (ESCC). Methods: This single-arm, open-label, exploratory study will recruit 36 patients with locally advanced unresectable ESCC (clinical stage T1N+M0 or T2-4bNxM0) who have not received prior antitumor treatment. Patients will undergo 2 cycles of induction therapy with adebrelimab (1200 mg, d1, iv, q3w) plus the TP regimen (nab-paclitaxel 180 mg/m² or paclitaxel 135 mg/m², d1, iv; carboplatin AUC=5, d1, iv, q3w). Following induction, response will be assessed via PET-CT. Responders (defined as SUV reduction ≥35% or partial response ) will continue with the TP regimen (nab-paclitaxel 60 mg/m² or paclitaxel 50 mg/m², d1, iv; carboplatin AUC=2, d1, iv, qw for 5 cycles) during concurrent radiation (50.4–60 Gy/28–33f). Non-responders will switch to the FP regimen (fluorouracil 750–1000 mg/m², civ 96h; cisplatin 75 mg/m², d1, iv, q4w for 2 cycles) during concurrent radiation. All patients will proceed to maintenance therapy with adebrelimab following CCRT until disease progression or unacceptable toxicity. The primary endpoint is the 1-year progression-free survival (PFS) rate. Secondary endpoints include the clinical complete response (cCR) rate, objective response rate (ORR), disease control rate (DCR), duration of response (DoR), PFS, overall survival (OS), and safety profile. Clinical trial information: NCT07112833 .

Prophylactic peptide vaccine targeting resistance mutations in advanced ALK-positive lung cancer: Primary analysis from the ARCHER trial.

8517 Background: Acquired resistance to targeted therapy remains a major challenge in ALK-positive NSCLC and is often mediated by mutations in the ALK kinase domain. Prophylactic immune targeting of common ALK resistance mutations represents a novel strategy to delay or prevent the emergence of ALK inhibitor resistance. Methods: We conducted a first-in-human phase 1b clinical trial of a prophylactic peptide vaccine (ALK-Vac) in advanced ALK-positive NSCLC patients without progression on standard-of-care tyrosine kinase inhibitor (TKI) therapy. Patients continued their ALK TKI and received ALK-Vac, consisting of synthetic long peptides targeting seven common ALK resistance mutations (I1171T, I1171N, I1171S, L1196M, G1202R, D1203N, E1210K) plus poly-ICLC adjuvant. ALK-Vac was administered subcutaneously on days 1, 4, 8, 15, and 22 (priming) and weeks 12 and 20 (boost). Primary objectives were safety and vaccine-specific T cell responses assessed by IFN-γ ELISpot. Exploratory objectives included molecular and immune-phenotype dynamics assessed by ultrasensitive cell-free DNA (cfDNA) duplex sequencing and CyTOF mass cytometry. Results: Fifteen patients were enrolled and all completed the planned ALK-Vac regimen. Most patients (13/15, 87%) were receiving first-line TKI therapy. Concomitant TKIs included alectinib (7/15, 47%), lorlatinib (5/15, 33%), and brigatinib (3/15, 20%). At enrollment, median TKI duration was 43.7 months (range 4.6-74.2) and 67% of patients had no measurable disease. Treatment-related adverse events (TRAEs) were primarily grade 1 (93% of patients); most commonly injection site reactions (93%), fatigue (60%), and flu-like symptoms (40%). No grade ≥ 3 TRAEs were observed. T cell responses (≥2-fold increase in SFU) were detected in 71% (10/14) of evaluable patients, with a median 11.9-fold increase. Responses were observed to G1202R, L1196M, and D1203N (each 10/14, 71%), E1210K (9/14, 64%), and I1171N/S/T (each 7/14, 50%). With a median follow-up of 11.5 months, the disease control rate was 93% (14/15). One patient who achieved robust immune response against multiple resistance mutations developed oligoprogression on alectinib 8.5 months after starting ALK-Vac; molecular profiling of this lesion identified an emergent KRAS G12D mutation without detectable ALK resistance mutation. Conclusions: ALK-Vac was well-tolerated and induced vaccine-specific T cell responses in a minimal residual disease setting, demonstrating feasibility of prophylactic targeting of ALK resistance mutations as an adjunct to TKI therapy and supporting a broader immune-interception framework potentially applicable to other oncogene-driven NSCLC. Comprehensive cfDNA and immune-phenotyping analyses will be reported. Clinical trial information: NCT05950139 .

Cellulose nanocrystals: A versatile biobased nano material

Pb‐Rich Buried Interface Promoting Upward Unidirectional Crystallization for Efficient and Stable Carbon‐Based Perovskite Solar Cells and Mini‐Modules

ABSTRACT Improving the crystalline quality of perovskite films is the most effective approach for constructing high‐performance carbon‐based perovskite solar cells (C‐PSCs). In particular, highly (100)‐oriented monolayer perovskite films can effectively suppress defect‐induced recombination while enhancing charge transport, thereby reducing non‐radiative recombination losses in C‐PSCs. In this work, we propose a scalable strategy for constructing a Pb‐rich modified buried interface with abundant Pb sites, which promotes perovskite nucleation and induces an upward unidirectional crystallization process, resulting in large‐grained, (100)‐oriented perovskite films. Moreover, the Pb‐rich interface layer of Pb 10 (PO 4 ) 6 O exhibits better lattice matching with perovskite, significantly alleviating interfacial lattice strain at the buried interface. As a result, the fabricated C‐PSCs achieved a champion efficiency of 21.56%, as well as an efficiency of 18.12% for the carbon‐based mini‐module (10.08 cm 2 ), which is among the best reported efficiencies for hole transport layer‐free planar C‐PSCs. In addition, the maximum power point tracking of unencapsulated devices offered an outstanding T 90 lifetime exceeding 1000 h under the ISOS‐L‐1I standard protocol. These results confirm that the above strategy possesses excellent scalability and strong potential for large‐area perovskite photovoltaics.

Programming Cascade Catalysis in Multielement Dual‐Heterostructured Catalysts Through Gradient Adsorption Potentials

ABSTRACT Catalytic reactions involving multiple intermediates are fundamentally constrained by the limited functionality of single active sites. While multi‐site catalysts provide a promising route to decouple complex reaction steps, the rational design and realization of architectures that enable rapid and directional inter‐site intermediate spillover remains largely unexplored and highly challenging. Here, we report a strategy to program intermediate spillover and cascade catalysis in multielement dual‐heterostructured catalysts through gradient adsorption potentials. Using the acidic oxygen evolution reaction as a model, a dual‐heterostructured RuIr–Mo/WVOx catalyst is precisely engineered to integrate an oxyphilic WVOx matrix for rapid water dissociation, a Mo bridge for efficient * OHspillover, and a RuIr alloy for accelerated oxidation. Guided by first‐principles screening and differences in elemental reducibility, a continuous gradient adsorption sequence (WVOx → Mo → RuIr) is constructed from a multielement architecture, enabling directional * OH transport across cooperatively coupled active centers with balanced energetics for cascade catalysis. As a result, the optimized catalyst delivers an overpotential of 183 mV at 10 mA cm − 2 and sustains stable operation for 450 h at 100 mA cm − 2 , outperforming single‐interface and commercial benchmarks. This work establishes gradient adsorption engineering as a general design framework for programming cascade catalysis in multistep reactions.

Real-world utilization of upfront genomic testing in newly diagnosed non–small cell lung cancer in a rural state.

e23377 Background: Comprehensive genomic testing (NGS) to inform biomarker-driven therapy is a standard recommendation in patients with metastatic non-small cell lung cancer (NSCLC). There is emerging evidence to support testing in early-stage NSCLC. Maine has a high incidence of lung cancer and is the most rural state with the oldest population in the U.S. Real-world genomic test utilization in this setting has not been well-characterized. Methods: We conducted a retrospective study of adults with biopsy-confirmed stage IB-IV NSCLC diagnosed between April 2020 and September 2024 in the MaineHealth Cancer Care Network. NGS results closest to diagnosis were obtained from Tempus (Chicago, IL) and demographic and clinical data from our tumor registry and EMR. Zip codes were used to determine rurality. Utilization was compared across subgroups using Wilcoxon rank-sum and Chi-square tests. Results: Among 1,024 patients with stage IB-IV NSCLC, 435 (42.5%) underwent upfront genomic testing with a median age of 69 years; 53.1% female, 98.6% white, and 55.6% Medicare enrollees. Compared with those who did not receive testing, tested patients were younger (69 vs. 72 years), more often adenocarcinoma (70.6% vs. 45.7%), and more often former (69.2% vs. 63.3%) or never smokers (10.8% vs. 5.4%). In stage IV disease (N = 621), testing was more common at the academic cancer center compared to community sites (60.8% vs. 52.8%, p = 0.045). In early-stage disease (IB-III, N = 403) and adenocarcinoma (N = 576), testing was more frequent among urban residents (80.6% vs 71.7%, p = 0.044; 70.6% vs. 61.9%, p = 0.029, respectively). In squamous cell carcinoma (SCC, N = 252), testing was more common at community sites (44.9% vs. 31.9%, p = 0.04). Testing rates trended up from 2020 to 2024 in stage IV disease and adenocarcinoma, but remained variable in early-stage disease and SCC as depicted in the table. Conclusions: Fewer than half of patients with stage IB-IV NSCLC underwent upfront comprehensive genomic profiling across a statewide network. Testing was less common among rural residents and those treated at community sites in early stage, stage IV, and adenocarcinoma. Patients with SCC were more likely to be tested in the community, possibly reflecting practice variation or small sample size. While testing rates increased in stage IV disease and adenocarcinoma over time, patterns in early-stage and SCC fluctuated, likely influenced by evolving guideline recommendations. Our findings highlight gaps in access to precision oncology in Maine and underscore the need for improvements, such as the implementation of reflex testing algorithms, enhanced physician and patient awareness, and financial support. Year Stage IV Adenocarcinoma Early-Stage SCC 2020 (Apr-Dec) 33.9% 37.9%, 33.3%, 32.4% 2021 42.1% 41.6% 19.2% 25.5% 2022 46.5% 60.6% 43.3% 33.9% 2023 49.6% 66.4% 54.8% 47.1% 2024 (Jan-Sep) 51.4% 55.9% 38.7% 37.3%

Efficacy and safety of bevacizumab biosimilars in metastatic colorectal cancer: A pairwise and network meta-analysis.

e15566 Background: Colorectal cancer (CRC) is a significant contributor to cancer-related mortality worldwide. Bevacizumab is an established VEGF inhibitor for the management of metastatic CRC in addition to doublet chemotherapy. The data pertaining to comparison of biosimilars is limited. Methods: A systematic search after protocol registration (CRD420251179090) was conducted across PubMed, Cochrane, Google Scholar, Clinicaltrials.gov to identify relevant published articles or conference abstracts of randomized studies. The primary outcomes were objective response rate (ORR) and incidence of grade 3 or higher adverse events (AEs). Secondary outcomes were overall survival (OS), progression-free survival (PFS). Data was pooled as odds ratios (ORs) for binary outcomes and hazard ratio (HR) for time-to event outcomes with 95% confidence intervals (CIs). A pairwise and network meta-analysis was performed. Pooled estimates were generated using the Mantel–Haenszel method with random-effects models in RevMan 5.4. Analyses were stratified by the type of doublet chemotherapy, Oxaliplatin-based (O) or Irinotecan-based (I) regimen, with heterogeneity assessed using I² statistics. A network meta-analysis using the Bayesian approach was performed using the gemtc package in R v4.5.2. Ranking of biosimilars was done using the Surface Under the Cumulative Ranking Curve (SUCRA) values, with reference bevacizumab as the control. Results: Data from a total of 7 randomized studies with 1428 patients was pooled and analyzed. The ORR of all biosimilars together was comparable to the reference molecule (OR 0.94 95%CI 0.73-1.21, I 2 = 0%) as well as between the two chemotherapy regimens (OR O: 0.91 95%CI 0.70-1.18, I 2 = 0% and I: 1.32 95%CI 0.51-3.43, I 2 = 26%). The incidence of Grade 3 or higher AEs was also comparable between all biosimilars together and reference bevacizumab and between the chemotherapy regimens (OR 0.99 95%CI 0.76-1.30, I 2 = 0%; O: 1.07 95%CI 0.79-1.44, I 2 = 0%, I: 0.74 95%CI 0.41-1.33, I 2 = 0%). Survival outcomes did not differ significantly between biosimilar and reference bevacizumab (OS: HR 0.93 95%CI 0.70-1.24, I 2 = 0%; PFS: HR 1.02 95%CI 0.80-1.30, I 2 = 0%). Indirect comparison of individual biosimilars demonstrated clinical equivalence to one another for both ORR as well as the incidence of grade 3 or higher AEs. For ORR, BE1040V ranked highest (0.78 95% Crl -0.56, 2.19; SUCRA: 83.01%) in terms of efficacy. For grade 3 or higher AEs, DRL_BZ ranked highest (-0.68 95% Crl -0.51,1.93; SUCRA: 84.6%) in terms of safety. Conclusions: This analysis highlights biosimilar molecules of bevacizumab to bear clinical comparability to the reference molecule with BE1040V and DRL_BZ proving most effective for ORR and grade 3 AEs respectively. These findings emphasize the use of bevacizumab biosimilars in patients with metastatic CRC, guiding discretion of individualized treatment decisions.

Phase 2 study of YL201, an anti-B7H3 antibody–drug conjugate (ADC), in heavily pretreated metastatic castration-resistant prostate cancer (mCRPC).

5015 Background: The treatment of mCRPC remains challenging, especially for patients who progressed on androgen receptor axis-targeted therapy (ARAT) with or without taxane-based chemotherapy. YL201 is a B7H3-targeting ADC with promising activity in advanced solid tumors. Here, we report the safety and preliminary efficacy of YL201 monotherapy in heavily pretreated mCRPC patients from a phase 2 study. Methods: Patients with mCRPC who had an ECOG PS of 0 or 1 and progressed on ≥1 prior line of ARAT and ≤2 lines of chemotherapy were enrolled and treated with YL201 intravenously Q3W at 2.0 or 2.4 mg/kg until disease progression or unacceptable toxicity. Primary endpoints were objective response rate (ORR) and radiographic progression-free survival (rPFS) per RECIST v1.1 and PCWG3 criteria. Secondary endpoints included PSA 50 response rate, duration of response (DoR), overall survival (OS), and safety. Results: As of 12 December 2025, 82 patients were enrolled (34 at 2.0 mg/kg; 48 at 2.4 mg/kg) with a median follow-up of 12.2 months (95% CI: 11.2–13.4). The median age was 67.0 years, 65.9% had an ECOG PS of 1, and 43.9% had visceral metastases (22.0% with liver metastasis) at study entry. Patients had a median of 4 prior line of therapy (range: 1–8), with 100% having received ARAT and 70.7% having received taxane-based chemotherapy. Across both dose levels, confirmed PSA 50 response rate was 38.5% (95% CI: 27.7–50.2), with a median duration of PSA response of 13.6 months (95% CI: 6.9–NR). Confirmed ORR was 29.5% (95% CI: 18.5–42.6), with a median DoR of 9.9 months (95% CI: 6.5–NR). Median rPFS was 9.1 months (95% CI: 7.4–12.0), while median OS remained immature. Higher PSA 50 response rate, ORR and rPFS were observed at 2.4 mg/kg compared with 2.0 mg/kg (48.9% vs . 24.2%, 33.3% vs . 24.0%, 11.8 vs . 9.0 months, respectively). Notably, in patients with baseline visceral metastases, YL201 still showed encouraging efficacy with a confirmed PSA 50 response rate of 54.5%, confirmed ORR of 28.6%, and median rPFS of 11.8 months at 2.4 mg/kg. Membrane B7H3 expression was detected in most tumor samples (median H-score: 185; range: 0–290), with no association observed between response and B7H3 expression level. Treatment-related adverse events (TRAEs) of grade ≥3 occurred in 43.9% of patients. The most common grade ≥3 TRAEs included neutropenia (29.3%), anemia (22.0%), leukopenia (18.3%), and thrombocytopenia (9.8%). No interstitial lung disease or pneumonitis was observed. The rate of treatment discontinuation due to TRAEs was 1.2%, and no treatment-related deaths were reported. Conclusions: YL201 showed promising antitumor activity and manageable safety profile in heavily pretreated mCRPC patients. These findings support further development of YL201 in mCRPC, especially for those who progressed after ARAT with or without taxane-based chemotherapy, and those with visceral metastases. Clinical trial information: NCT06241846 .

Tumor and immune microenvironment remodeling with neoadjuvant trastuzumab deruxtecan in HER2-positive gastric cancer: Exploratory analyses from the phase 2 EPOC2003 study.

3129 Background: We previously reported the efficacy and safety of neoadjuvant trastuzumab deruxtecan (T-DXd) for HER2-positive gastric and gastroesophageal junction adenocarcinoma (EPOC2003) (Takahari et al., ASCO GI 2024). This exploratory analysis aimed to investigate the associations of baseline molecular features of the tumor, the immune landscape, and their longitudinal changes with the therapeutic efficacy of T-DXd. Methods: Tumor samples were collected at baseline, pre-cycle 2, post-cycle 3 (before surgery), and at surgery. We performed bulk/single-cell RNA sequencing (scRNA-seq) and multiplex immunohistochemistry to identify correlates of pathological response. Responders were defined as patients achieving a major pathological response according to the Becker criteria. Blood samples were collected at baseline and post-cycle 3 for circulating tumor DNA (ctDNA) analysis using a clinically validated, tumor-informed, personalized assay (Signatera, Natera, Inc.). Results: Baseline HER2 expression did not differ between responders (n= 4) and non-responders (n= 22). In the post-treatment sample analysis, a decreasing trend in proliferation index was observed in responders, whereas this trend was not observed in non-responders, suggesting preferential elimination of proliferative tumor cells by T-DXd. Early on-treatment samples (pre-cycle 2 or post cycle 3) tended to demonstrate upregulation of cytokine signaling, inflammatory, immune response signatures, and CD8+ T cell density in both tumor and stroma regardless of response. Notably, scRNA-seq revealed an expansion of neutrophils, which was more pronounced in responders with a stronger baseline interferon signature. These post-treatment neutrophils displayed upregulated migration, phagocytosis, and degranulation signatures, indicative of enhanced neutrophil mediated anti-tumor activity following T-DXd. ctDNA testing was performed in 18 patients, with a baseline positivity rate of 94.4% (17/18). All responders (3/3) achieved ctDNA clearance after cycle 3, compared with only 35.7% (5/14) of non-responders. Conclusions: Neoadjuvant T-DXd therapy induced biological remodeling of the tumor and immune microenvironment. Together with on-treatment ctDNA kinetics, these findings suggest distinct response-associated biological patterns and may help guide future treatment optimization for HER2-positive gastric and gastroesophageal junction adenocarcinoma. Clinical trial information: NCT05034887 .

Predictors of Gleason score concordance after radical prostatectomy: A SEER analysis.

e17146 Background: Discrepancies between clinical Gleason score (cGS) and pathological Gleason score (pGS) can alter prostate cancer prognosis and management. This study aims to quantify the concordance between cGS and pGS by identifying independent preoperative predictors of pathological upgrading and downgrading in a large population-based cohort. Methods: A retrospective cohort analysis was performed using the Surveillance, Epidemiology, and End Results (SEER) database on 59,567 men diagnosed with prostate adenocarcinoma between 2018-2022, who underwent radical prostatectomy with complete clinical and pathological data. The primary outcome was concordance between cGS and pGS. A multinomial logistic regression was performed to determine predictors of Gleason score upgrading and downgrading. Covariates included age, race/ethnicity, preoperative PSA, clinical T-stage, time to treatment, cGS, and the percent of positive biopsy cores. Results: Overall, 70.1% of patients had concordant GS, while 16.1% were upgraded and 13.8% were downgraded. Agreement between cGS and pGS was moderate (weighted kappa = 0.507). Among cGS 6 tumors, 67.0% were upgraded, while 57.5% of cGS 8 tumors were downgraded. In contrast, cGS 7 demonstrated the highest concordance rate of 90.5%. Upgrading was significantly associated with increasing preoperative PSA levels (OR 1.02 per ng/mL; p < 0.001) and prolonged interval from diagnosis to treatment (OR 1.03 per month; p < 0.001). Compared to Non-Hispanic White patients, Hispanic patients demonstrated a 12% increased odds of upgrading (OR 1.12; p = 0.011), while Non-Hispanic Black patients showed a 10% decreased likelihood (OR 0.90; p = 0.016). Downgrading was most strongly predicted by higher initial cGS (OR 5.23; p < 0.001) and lower clinical T-stage (T1-T3 versus T4; p < 0.001). Specifically, clinical T2 disease showed the highest likelihood of downgrading relative to T4 disease (OR 3.49; p < 0.001). Conclusions: Biopsy results often underestimate prostate cancer severity, with nearly one in six patients harboring more aggressive disease than initially detected, while high-risk clinical scores often overestimated pathological severity. These findings underscore the need for accurate risk stratification to avoid both undertreatment in high-risk groups and potential overtreatment in those with overestimated risk.

Trends and disparities in liver cancer–related mortality in adults with psychoactive substance use disorder in the United States, 1999–2023.

e16157 Background: Liver cancer mortality remains a major public health burden in the United States despite advances in prevention and treatment. Psychoactive substance use disorder (PSUD) is an increasingly prevalent comorbidity; however, national trends and disparities in liver cancer mortality among adults with PSUD remain poorly characterized. Methods: We conducted a retrospective analysis of liver cancer-related deaths among U.S. adults aged 25 years and older with PSUD from 1999 to 2023 using Centers of Disease Control (CDC) Wide Ranging Online Data for Epidemiological Research (WONDER) mortality database. Age-adjusted mortality rates (AAMRs) were calculated per 100,000 population and stratified by census region, state, urban–rural status, sex, and race/ethnicity. Temporal trends were assessed using Joinpoint regression to estimate average annual percent change (AAPC). Statistical significance was determined using p-value (<0.05). Results: Overall liver cancer related AAMR per 100,000 among adults with PSUD significantly increased from 0.15 in 1999 to 1.02 in 2023 (AAPC: 7.47; 95% CI: 6.33 to 8.61; p < 0.000001). The overall mortality burden was higher in males. However, females experienced larger rises in mortality (AAPC: 10.03; 95% CI: 8.85 to 11.24; p < 0.000001) as compared to males (AAPC: 7.30; 95% CI: 5.78 to 8.84; p < 0.000001). Marked racial disparities were observed, with non-Hispanic Black and non-Hispanic White individuals experiencing the highest mortality rates with persistent increases over time, while Hispanic/Latino populations exhibited modest and variable trends. A substantial geographic variability was observed, with the greatest increases in the Midwest and the South. State-level analysis revealed higher mortality rate in Oregon (1.27) followed by Washington (1.12) and Texas (1.06) respectively. Both rural and urban areas experienced a sharp rise in mortality with AAPC being slightly higher in rural areas (AAPC: 10.34) as compared to urban areas (AAPC: 9.67). Conclusions: Liver cancer mortality among U.S. adults with PSUD has risen markedly over the past two decades, with substantial demographic and geographic disparities. These findings highlight the need for integrated liver cancer screening and substance use disorder interventions targeting high-risk populations. Variables AAMR (95% CI) in 2023 AAPC (95% CI) Overall 1.02 (0.98 –1.05) 1999-2023: 7.47* (6.33 – 8.61) Female 0.42 (0.39 – 0.46) 1999-2023: 10.03* (8.85 – 11.24) Men 1.69 (1.62 –1.76) 1999-2023: 7.30* (5.78 – 8.84) White 1.05 (1.0 –1.09) 1999-2023: 9.52* (8.08 – 10.98) Black / African Americans 1.22 (1.09 – 1.35) 1999-2023: 6.59* (5.50 – 7.68) Hispanics / Latinos 0.75 (0.65 – 0.84) 1999-2023: 1.26 (-1.01 – 3.60) AAMR (95% CI) in 2020 AAPC (95% CI) Rural 1.51 (1.39 – 1.62) 1999-2020: 10.34* (5.05 – 15.90) Urban 0.92 (0.82 – 0.95) 1999-2020: 9.67* (7.32 – 12.06)

Outcomes with first-line (1L) platinum-based chemotherapy (PBC) and avelumab 1L maintenance in locally advanced or metastatic urothelial carcinoma (la/mUC) by <i>NECTIN4</i> and <i>HER2</i> RNA expression: Exploratory analyses from JAVELIN Bladder 100.

4575 Background: Nectin-4 and HER2 are relevant therapeutic targets and potential biomarkers for the treatment of la/mUC. NECTIN4 and HER2 RNA expression are heterogeneous in UC tumors, with highest expression observed in luminal molecular subtypes. We report exploratory biomarker analyses from the JAVELIN Bladder 100 phase 3 trial evaluating response to 1L PBC and survival outcomes with avelumab administered as 1L maintenance treatment in subgroups defined by tumor NECTIN4 and HER2 RNA expression. Methods: In JAVELIN Bladder 100 (NCT02603432), patients (pts) with unresectable la/mUC without progression after 4-6 cycles of 1L PBC were randomized 1:1 to receive avelumab + best supportive care (BSC) or BSC alone. Biomarker analyses were performed using existing whole transcriptome profiles generated using RNA sequencing, and transcript levels were quantified using Personalis ACE technology. NECTIN4 and HER2 RNA expression were assessed as continuous variables for subgroups defined by response to 1L PBC and as dichotomous variables (median and lower quartile split) for stratified survival analyses. Results: In biomarker-assessable pts (n=560) who had complete response (CR; n=149), partial response (n=261), or stable disease (SD; n=150) to 1L PBC, no significant differences in tumor NECTIN4 RNA expression were observed, whereas slightly higher tumor HER2 RNA expression was observed in pts who had CR vs SD. Overall, when defined by median split, 201 pts (35.9%) had high NECTIN4 /high HER2 RNA expression, 202 (36.1%) had low NECTIN4 /low HER2 , 78 (13.9%) had high NECTIN4 /low HER2 , and 79 (14.1%) had low NECTIN4 /high HER2 . Molecular subtype was non-luminal in 20.4%, 87.1%, 55.1%, and 50.6%, respectively. The table shows overall survival (OS) with avelumab + BSC vs BSC alone in subgroups defined by combined high or low NECTIN4 / HER2 expression. OS improvements with avelumab + BSC vs BSC alone were observed across subgroups defined by high or low NECTIN4 / HER2 RNA expression alone. Conclusions: Exploratory analyses from JAVELIN Bladder 100 showed that pts with low NECTIN4 and low or high HER2 RNA expression had pronounced OS with avelumab 1L maintenance vs BSC alone. Results are hypothesis generating. Clinical trial information: NCT02603432 . Avelumab + BSC BSC High NECTIN4 /high HER2 n=100 n=101 Median OS (95% CI), mo 23.0 (17.8-30.9) 14.3 (10.8-21.3) HR (95% CI) 0.73 (0.52-1.02) Low NECTIN4 /low HER2 n=105 n=97 Median OS (95% CI), mo 29.8 (20.1-46.9) 18.8 (13.9-29.4) HR (95% CI) 0.78 (0.55-1.11) High NECTIN4 /low HER2 n=39 n=39 Median OS (95% CI), mo 18.4 (13.0-NE) 17.4 (14.0-NE) HR (95% CI) 0.84 (0.47-1.50) Low NECTIN4 /high HER2 n=40 n=39 Median OS (95% CI), mo 31.1 (20.6-NE) 15.8 (9.3-41.9) HR (95% CI) 0.66 (0.38-1.15) Stratified subgroups defined by median split are shown. HR, hazard ratio; mo, months; NE, not estimable.

Quantitative pathology biomarkers for platinum resistance in ovarian cancer.

5520 Background: Despite serving as the first-line systemic treatment for high-grade serous ovarian cancer, roughly 20% of patients fail to respond to platinum-based chemotherapy. However, there is a paucity of biomarkers which correlate to platinum resistance. Effective biomarkers would allow for individualized risk profiling and early identification of patients who may benefit from treatment escalation. Quantitative pathologic biomarkers have shown prognostic utility in several cancers and offer a potential low-cost approach to address challenges in assessing platinum resistance. We examined the utility of machine learning (ML)-derived pathologic biomarkers in identifying platinum-resistant ovarian cancer. Methods: Our multi-institutional dataset included 158 whole-slide images (WSIs) obtained from resection of primary ovarian cancer, with 86 (54%) in the training cohort and 72 (46%) in the validation cohort. Our dataset included 112 (71%) platinum-sensitive and 46 (29%) platinum-resistant WSIs. The CLAM deep learning framework and CONCH visual-language foundation model were utilized to segment tissue, generate 256 x 256 image patches, and extract 512-dimensional features from each patch. Non-linear dimensionality reduction, employing Uniform Manifold Approximation and Projection (UMAP), was applied to cluster training samples, and validation samples were projected onto the learned low-dimensional space. Samples were stratified into predicted-sensitive and predicted-resistant cohorts based on similarity to training-derived clusters, and clinical characteristics were compared using a two-tailed t-test and chi-square tests. Results: UMAP analysis identified distinct phenotypes associated with platinum sensitivity and resistance. At the image level, UMAP-defined phenotypes exhibited high predictive ability. Of the predicted-sensitive images in the validation cohort, 79% showed platinum sensitivity. UMAP-defined phenotypes demonstrated moderate patch-level accuracy in identifying platinum-sensitive samples (training accuracy 69%, validation accuracy 65%). Additionally, clinical correlates to pathology-based predictions were investigated. Predicted-resistant patients were significantly older (median age, 69 years [IQR 59.5–76.26] vs. 62 years [IQR 55–68], p = .021) and more frequently higher-staged (IIIC/IV 89% vs. 77%, p = .087) compared to predicted-sensitive patients. Conclusions: ML-derived pathologic biomarkers can aid in the identification of platinum-resistant ovarian cancer. Our future work will evaluate the relationship between quantitative biomarkers and known clinical predictors of platinum resistance, such as CA-125 and the extent of residual disease at cytoreduction. Integrating multimodal biomarkers in clinical decision-making practices will allow for improved risk stratification and individualized treatment for patients.

Miconazole as a repurposed therapeutic candidate for prostate cancer.

e17130 Background: Prostate cancer remains a leading cause of cancer-related morbidity and mortality worldwide, despite significant advances in diagnosis and therapy. Current treatment options are often associated with long-term adverse effects and the development of therapeutic resistance, underscoring the need for alternative treatment strategies. Drug repurposing of FDA-approved compounds represents a promising approach to rapidly identify novel anticancer agents with established safety profiles. In this study, we explored the anticancer potential of selected FDA-approved antifungal drugs as repurposed therapeutics for prostate cancer. Methods: Five antifungal agents, natamycin, terbinafine, ketoconazole, miconazole, and clotrimazole, were evaluated for anticancer activity in prostate cancer (C4-2 and DU145) cell lines using CCK-8 cell viability, colony formation, and invasion and migration assays. Proteomic profiling was performed to identify differentially expressed proteins, followed by pathway enrichment analysis to elucidate affected signaling networks. The most effective compound was further investigated using confocal and scanning electron microscopy, flow cytometry, and Western blotting to assess cellular morphology, cell-cycle distribution, and apoptosis. Molecular docking studies were conducted to evaluate binding interactions between miconazole and key proteins involved in cell-cycle regulation and apoptosis. Results: Among the tested antifungal agents, miconazole exhibited the strongest anticancer activity, significantly reducing cell viability, clonogenic survival, and invasive and migratory capacities of prostate cancer cells. Proteomic analysis confirmed significant modulation of proteins associated with cell-cycle control and apoptosis, with pathway enrichment highlighting prostate cancer and p53 signaling pathways. Mechanistic studies revealed that miconazole induced marked morphological and nuclear alterations, caused G0/G1 cell-cycle arrest through downregulation of cyclin D3, CDK2, CDK4, and PCNA, and promoted apoptosis via activation of p53-associated pathways, including upregulation of p53, p21, p27, cleaved PARP, and cleaved caspase-3. Molecular docking demonstrated strong binding affinities of miconazole toward PARP1 and cyclin D3, supporting its mechanistic role in growth inhibition and apoptosis induction. Conclusions: This study demonstrates that miconazole possesses potent anticancer activity against prostate cancer cells and highlights its potential as a repurposed therapeutic agent.