Browse Articles

Extended monitoring and biomarker analysis in metastatic melanoma patients treated with TIL therapy and conditioning-replacing igrelimogene litadenorepvec virotherapy: Pre-infusion immune cell and cytokine profiles associated with survival.

2538 Background: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can be effective in metastatic melanoma, but its routine use is limited by the need for lymphodepleting chemotherapy and systemic high-dose IL-2. To reduce toxicity while preserving antitumor activity, a strategy pairing TIL therapy with the oncolytic adenovirus igrelimogene litadenorepvec (TILT-123) was assessed. This virus selectively replicates in malignant tissue and drives local expression of TNF and IL-2 within tumors, functionally replacing the need for pre-infusion chemotherapy and post-infusion IL-2 administration. Methods: Seventeen patients with advanced melanoma resistant to immune checkpoint inhibitors were treated and sampled (NCT04217473). Treatment with igrelimogene litadenorepvec started upon tumor biopsy collection for TIL manufacturing took place and eventually followed by autologous TIL infusion around 36 days after. Hypotheses generated during data analysis were validated using additional patient datasets (NCT04695327, NCT05271318). Results: The regimen was well tolerated, with no dose-limiting toxicities. Objective response rate was 11.7%, with disease control in 35% by RECIST 1.1 and 47% by PET; metabolic responses were seen in 27%. Among those patients, higher baseline expression of epidermal and hepatocyte growth factors (EGF and HGF respectively) was associated with poorer prognosis. Higher than median HGF was negatively correlated with survival (p=0.032). Additionally, patients that achieved disease stabilization or better had a lower presence of circulating MDSCs (p=0.017). The link between growth hormones, MDSCs and disease progression was extrapolated to a larger dataset including other patients treated with igrelimogene litadenorepvec to find out the same trend for survival (HGF; p = 0.003, EGF; p = 0.029). In parallel, baseline circulating young memory T cells (CD27+CD28+CD8+) and an early expansion of NK cells (CD45+CD56+CD3-) correlated with a lower chance of progressing (T cells p=0.005, NK cells p=0.003). Conclusions: Combining TILT-123 with TIL therapy was safe and produced meaningful clinical activity in checkpoint inhibitor-refractory melanoma, especially in patients with lower HGF and EGF at baseline and a higher presence of young memory T cells and NK cells. In this clinical set-up, adapting the inclusion exclusion criteria to select patients with those defined immune system features, could help improve efficacy beyond. This approach may substantially broaden the feasibility and accessibility of TIL-based immunotherapy, especially due to the omission of the toxic conditioning regimens. Clinical trial information: NCT04217473 .

Real-world adoption and pathological insights of neoadjuvant chemoimmunotherapy in resectable NSCLC: Single-institution experiences and perspectives.

e20077 Background: Since March 2022, neoadjuvant or perioperative PD-(L)1 inhibitor plus platinum-based chemotherapy has become standard of care for resectable stage II–III non-small cell lung cancer (NSCLC). However, real-world implementation has been variable, and resistance mechanisms remain poorly understood, particularly among patients who fail to achieve pathologic complete response (pCR). We therefore evaluated institutional uptake, outcomes, and translational correlates of neoadjuvant therapy in resectable NSCLC. Methods: We retrospectively identified patients with resectable stage IB–IIIB NSCLC treated at a single academic center between January 2022 and December 2025 using surgical and pharmacy databases. Actionable genomic alterations (AGAs) were identified via next-generation sequencing (NGS) according to NCCN guidelines. Clinicopathologic characteristics, treatment patterns, surgical outcomes, and pathologic responses were summarized descriptively. To explore resistance mechanisms and inform adjuvant strategies, paired resected tumor and tumor-draining lymph node specimens were analyzed using Xenium single-cell spatial transcriptomics with a customized 480-gene panel. Results: Among 62 patients (median age at diagnosis 69.2 years; 58.1% male), 12 harbored AGAs and 4 progressed or were lost to follow-up. Forty-six (74.2%) received neoadjuvant therapy and 32 (51.6%) underwent surgical resection. Thirty-six patients received neoadjuvant chemoimmunotherapy, of whom 26 (72.2%) proceeded to surgery; among these, pCR was achieved in 7 (26.9%), pathologic downstaging without pCR in 14 (53.8%), stable disease in 4 (15.4%), and pathologic progression in 1 (3.8%). All 6 patients who received neoadjuvant chemotherapy without immunotherapy underwent surgery, with pCR in 1 (16.7%), pathologic downstaging without pCR in 4 (66.7%), and stable disease in 1 (16.7%). Preliminary spatial transcriptomic analyses of paired tumor and lymph node specimens (n = 6) demonstrated increased immune cell activation following chemoimmunotherapy. Resistant tumors showed higher RNA expression of TROP2, MET, HER2, NECTIN4, and EGFR compared with sensitive tumors; validation studies are ongoing. Conclusions: In this single-institution cohort, neoadjuvant chemoimmunotherapy demonstrated meaningful clinical effectiveness while highlighting persistent gaps in adoption. Translational analyses suggest actionable targets in resistant disease, underscoring the importance of personalized adjuvant strategies for patients with residual tumors. Overall, these findings emphasize the need for integrated multidisciplinary workflows and biomarker-driven approaches to improve outcomes in resectable NSCLC.

Shared treatment decision-making between physicians and their patients with metastatic urothelial carcinoma: Results of a real-world survey in Europe and the United States.

e16581 Background: Metastatic urothelial carcinoma (mUC) is associated with poor prognosis, but recent treatment (tx) approvals have changed the therapeutic landscape. Patient (pt) involvement in cancer tx decisions has been shown to improve quality of life and support informed consent. However, there is a paucity of data on pt involvement in tx decisions for mUC. We aimed to address this data gap by exploring the concordance between pt- and physician-reported pt involvement in mUC tx decisions. Methods: Data were drawn from the Adelphi Real World mUC Disease Specific Programme, a cross-sectional survey of medical oncologists/urologists and their pts with mUC in Europe and the US, from Dec 2023 to Jul 2024. Physicians reported pt demographics and pt involvement in mUC tx decision-making. Pts voluntarily reported their involvement in tx decision-making. Alignment on pt involvement was measured between matched response options from pts and physicians using a weighted Cohen’s κ coefficient, with level of concordance categorized using the Landis and Koch (1977) scale. Results: Overall, 100 physicians reported data for 452 pts with mUC who provided details on their involvement in tx decisions. Mean (SD) pt age was 68.7 (8.2) years; most pts were male (69%) and White (97%) and had a caregiver (69%). Only 18% of pts reported being involved in the final tx decision in some way, ranging from 10% in Spain (n = 11/106) to 33% in the UK (n = 9/27). In contrast, physicians reported that 42% of pts were involved in the tx decision in some way, ranging from 33% in Spain (n = 35/106) to 48% in Italy (n = 32/66) and the UK (n = 13/27). Across the 335 pts with matched pt-physician responses, concordance on pt involvement in the tx decision was moderate (κ = 0.4621). Most commonly, 61% of pts (n = 206) reported that they discussed all tx options with the physician, but the physician made the final decision. For these pts, 77% of their physicians (n = 159) agreed exactly. A fifth of pts (20% [n = 68]) reported that their physician made the tx decision with no input from them. For these pts, 50% of their physicians (n = 34) agreed exactly, and 38% of their physicians (n = 26) reported discussing the tx options with the pt but said that the physician made the final decision themselves. Overall, exact agreement between pts and physicians on pt involvement was observed for 69% of pts. Conclusions: Despite just under half of physicians reporting that the pt was involved in the tx decision, only 1 in 5 pts reported the same. This discordance between physicians and pts highlights the need to strengthen existing pt-physician relationships, to move toward a shared decision-making model and facilitate true informed consent. With the expansion of tx options, each with distinct benefit-risk profiles, supporting pts with mUC to take an active role in their tx is important to ensure clinical and personal goals are met.

New evidence for Early Pleistocene use of fire at Wonderwerk Cave (South Africa)

Tracing the earliest evidence of burning in archaeological contexts is essential for understanding the emergence of fire use—an innovation that underpinned critical behavioral and biological developments in the genus Homo . However, identifying unambiguous traces of early fire use remains challenging. To enhance detection of incipient burning in early occupation layers, we introduce a rapid, non-invasive protocol based on bone luminescence properties, validated through comparison with Fourier Transform Infrared spectroscopy (FTIR). Using these methods, we provide evidence for fire use in two Early Pleistocene (Acheulean) deposits at Wonderwerk Cave (South Africa), extending the chronology of one of the world’s earliest paleo-fire records. This combined approach improves the resolution with which early fire use can be identified and opens new avenues for investigating the emergence of pyrotechnology in deep time.

Green synthesis of Alternanthera sessilis-derived silver nanoparticles: Dual action against pathogenic microbes and organic dye pollutants

Robust Shape‐Memory Chiral Photonic Elastomers With Multi‐Stimuli Responsiveness

ABSTRACT Stimuli‐responsive materials are pivotal for advanced photonics, yet achieving ones with multiple‐dimensional manipulation and high robustness remains a challenge. Here, we present a shape‐memory chiral photonic platform with multi‐stimuli‐responsiveness by sophisticatedly controlling the crosslinking chemistry and density of a triplet–triplet annihilation upconversion featured cholesteric elastomer. A thermally resettable shape memory effect on structural colors is induced by force in the elastomer with an oligomer‐lowered crosslinking density, which also exhibits exceptional stretchability and enhanced optics, a remarkable 259 nm blueshift over 215% strain. The covalent incorporation of annihilators secures homogeneity and stability of the system. The material possesses programmable optical properties, including chirally, thermally, and mechanically regulated structural colors and photoactivated luminescence, enabling high‐dimensional information encryption with accessibility to scalable spray‐printing. This work provides a versatile material strategy for cutting‐edge optical encryption and paves the way for next‐generation wearable sensors, adaptive optical devices, and interactive camouflage technologies.

Efficacy and safety of photothermal biomodulated platelet-rich plasma versus standard platelet-rich plasma for facial rejuvenation: a prospective split-face randomized study

Abstract Autologous platelet-rich plasma (PRP) regenerative properties are used to treat clinical manifestations of skin aging. This study assessed the efficacy and safety of photothermal biomodulated PRP (PTBM-PRP) compared to standard PRP for skin rejuvenation. Prospective, split-face, randomized study including Thai volunteers (30–60 years) with Fitzpatrick skin type III-IV and moderate severity photoaging or higher conducted at Siriraj Hospital (Bangkok, Thailand). Face sides were randomized to receive intradermal autologous PTBM-PRP or PRP injections in three sessions at one-month intervals, with follow-up visits at one, three, and six months. PRP was preconditioned using the MCT System (Meta Cell Technology, Sant Cugat del Vallès, Spain) preset with the Exosomes program (467 nm continuous light [1 J/cm 2 ], 37 °C, 10 min). We evaluated changes in skin surface characteristics, pigmentation, redness, and biomechanical properties (i.e., firmness, elasticity, and viscoelasticity), perceived facial improvement, and perceived pain. We included 28 volunteers (96.4% women) with a mean (SD) age of 40.82 (8.95) years and mostly skin type IV (67.86%). PTBM-PRP decreased fine lines maximum depth ( p  = 0.041) and indentation index ( p  = 0.005), folds maximum depth ( p  = 0.032) and indentation index ( p  < 0.001), and wrinkles maximum depth ( p  = 0.024) and indentation index ( p  = 0.041) in the periorbital area. PRP transiently decreased folds indentation index ( p  = 0.008) and wrinkles maximum depth ( p  = 0.0499) (PTBM-PRP vs. PRP wrinkles maximum depth p  = 0.038 and indentation p  = 0.018). Improvements in pigmentation, redness, and biomechanical properties were similar for both treatments. Patients perceived both treatment effects mostly as good or excellent improvement, with slightly favorable pain scores for PTBM-PRP vs. PRP, particularly at visit 3 ( p  = 0.006). Compared to standard PRP, PTBM-preconditioned PRP for facial skin rejuvenation results in greater improvements in fine lines, folds, and wrinkles parameters, with sustained effects for more than six months, supporting a PTBM protocol use to enhance the regenerative capacity of PRP in skin rejuvenation.

Analysis of ligand recognition by choline O-acetyltransferase reveals thiol-reactive assay interference and weak ligand affinity in solution

Clinical genomic and quantitative IHC–driven target identification to enable precision, tumor-selective activation of SynchroLINK T2X antibody-drug conjugates.

e15043 Background: Conventional antibody–drug conjugates (ADCs) rely on single-step payload release and are often limited by off-tumor toxicity and variable therapeutic index. SynchroLINK T2X ADCs are designed for precision, tumor-selective activation through sequential intracellular processes. We sought to identify tumor-specific biological features supporting this activation paradigm using integrative genomic analysis and quantitative immunohistochemistry (IHC) to inform patient selection and target prioritization. Methods: Large-scale transcriptomic datasets from human tumors and matched normal tissues were analyzed to identify cancer-enriched expression patterns of genes associated with intracellular ADC processing and activation. Candidate targets were prioritized based on differential tumor-to-normal expression and pathway coherence. Quantitative IHC was performed on tumor tissue microarrays using analytically validated monoclonal antibodies. Digital image analysis with cytoplasmic-specific algorithms was used to generate H-scores, enabling objective assessment of protein abundance and spatial distribution across tumor types. Results: Genomic analyses revealed distinct tumor-enriched expression profiles for multiple biological components implicated in sequential ADC activation, with limited expression in corresponding normal tissues. Co-expression analyses demonstrated coordinated upregulation of these features across several solid tumor indications. Quantitative IHC confirmed robust, cytoplasmically localized protein expression in tumors, with significantly lower expression in adjacent normal tissues. Digital H-score distributions supported clear tumor-normal separation and revealed inter-tumoral heterogeneity consistent with a precision-based activation model. Integration of genomic and IHC data enabled identification of tumor subsets predicted to support efficient, sequential activation of SynchroLINK T2X ADCs. Conclusions: Integrative genomic and quantitative IHC analyses identify tumor-specific biological features that support precision, tumor-selective activation of SynchroLINK T2X ADCs. These findings provide a translational framework for patient selection and support a novel activation paradigm with potential to improve the therapeutic index of ADC-based cancer therapies.

Clinical characteristics, molecular features, and treatment of primary central nervous system melanoma.

9523 Background: Primary Central Nervous System (CNS) Melanoma is a rare and aggressive malignancy, comprising 1% of melanoma cases and 0.07% of brain tumors. Due to its rarity, its natural history, molecular features and optimal management remain poorly defined. Methods: We retrospectively reviewed patients at our institution between January 1998 and October 2025 with primary CNS melanoma or melanocytoma with melanoma transformation. Clinical characteristics, molecular profiling, treatments and survival outcomes were collected. Overall survival (OS) and progression free survival (PFS) were estimated using Kaplan-Meier curves. Results: Nineteen patients were identified, including eight (42%) with melanocytoma to melanoma transformation. Median time of transformation was 34.4 months. Thirteen (68%) patients were female with a median age at diagnosis of 59.3 years. Common presenting symptoms were sensory disturbances (58%), pain (53%), motor deficits (37%) and nausea or vomiting (32%). At diagnosis, location of disease was spinal (n=12), intracranial (n=6) and multifocal (n=1). Thirteen patients had leptomeningeal involvement. Molecular profiling was performed in 15 patients, revealing mutations in GNAQ (n=7), GNA11 (n=3), CKIT (n=2), BAP1 (n=1), EIF1AX (n=1), and BRAF v600 (n=1). Thirteen (68%) patients underwent subtotal resection (STR), five (26%) gross total resection (GTR) and one radiation only. Median resected tumor size was 1.7 cm. Seventeen (94%) patients had recurrence at a median of 9.1 months, and four patients underwent repeat surgery. Fourteen (74%) patients received adjuvant radiation and 14 (74%) received immunotherapy, most commonly ipilimumab with nivolumab (71%). Nine patients received chemotherapy: temozolomide (n=5), bevacizumab (n=2) and one each of intrathecal IL-2, tebentafusp, imatinib and encorafenib with binimetininb. Four patients received chemotherapy before immunotherapy. Median OS from diagnosis of CNS melanocytoma or melanoma was 50.9 months (13.4 – 80). Median OS from time of transformation to melanoma or CNS melanoma diagnosis was 24.0 months (11.9 – NA). One-, three- and five-year OS rates were 73%, 53% and 40% respectively. GTR was associated with increased median OS compared to STR (80.0 vs 19.7 months, p= 0.02). Age at diagnosis, immunotherapy, chemotherapy, adjuvant radiation, STR with or without radiation, disease location, leptomeningeal involvement, tumor size >3cm and presence of GNAQ mutation were not associated with survival. Median PFS was 3 months with chemotherapy and 5.7 months with immunotherapy. Conclusions: To our knowledge, this is the largest single center study of primary CNS melanoma. Outcomes remain poor, with survival primarily associated with GTR. The predominance of GNAQ and GNA11 alterations with rare BRAF v600 mutations highlight the distinct biology of primary CNS melanoma and need for novel targeted therapies.

Brain metastases in upper gastrointestinal tumours: A multi-centre, retrospective analysis of clinical predictors and outcomes in a multi-ethnic Asian cohort.

e16079 Background: Gastric and esophageal cancers are the 5th and 11th most common worldwide, but brain metastasis (BM) in upper gastrointestinal (UGI) cancers is rare, with a reported 1–3% incidence. Identifying clinicopathological predictors is critical to improve both surveillance and management given this poor prognosis. We aim to evaluate risk factors for BM and determinants of overall survival (OS) and progression-free survival (PFS) in patients with metastatic UGI cancers. Methods: We conducted a multi-centre retrospective analysis of 803 patients with Stage IV Gastric, Esophageal and Gastro-Esophageal Junction cancers diagnosed in 2000–2024 across four tertiary hospitals in Singapore. Patients with de novo metastatic and recurrent disease were included. Logistic regression was used to identify predictors of BM development. OS and PFS were analysed using Cox proportional hazards models. OS was defined as time from diagnosis of BM to death from any cause. PFS was defined as time from diagnosis of BM to first documented disease progression. Results: Median age at cancer diagnosis was 65.3 years. Most patients were male (65.7%), Chinese (77.7%) with ECOG 0 or 1 (68.8%). Primary tumour sites were gastric (66.8%), esophageal (17.8%) and GEJ (14.7%). BM occurred in 77 patients (9.6%). Histological subtypes were predominantly adenocarcinoma (55.8%) and SCC (15.6%). On univariate analysis, age > 65 years (OR 0.54, p = 0.03) and diagnosis after 2010 (OR 0.34, p = 0.02) were associated with lower odds of BM, while T4 disease increased BM risk (OR 2.37, p = 0.03). On multivariable analysis, only age remained significant. HER2 and PDL-1 status were not associated with BM development. Median OS following BM diagnosis was 8.2 months (95% CI 5.4-12.1). Median Follow Up Time was 65.4 months (95% CI 49.8-∞). Among patients with BM, multivariable analysis demonstrated poorer OS with esophageal primary (v. GEJ, HR 2.76, p < 0.01), PDL CPS < 1 (HR 4.95, p < 0.01), HER2+ (HR 5.81, p < 0.01), leptomeningeal disease (HR 6.27, p < 0.01), multifocal BM (HR 1.96, p = 0.02), symptomatic BM (HR 4.05, p = 0.03) and absence of prior systemic therapy (HR 3.43, p < 0.01). Surgical resection of BM (HR 0.49, p = 0.05) and N0 disease (HR 0.20, p < 0.01) were associated with improved OS. On univariate analysis, ECOG > 1 (HR 2.14, p = 0.04), T4 disease (HR 2.41, p = 0.01) and multifocal BM (HR 1.89, p = 0.02) were associated with a poorer PFS, while N0 disease was associated with improved PFS (HR 0.36, p < 0.01). On multivariate analysis, HER2+ (HR 5.21, p < 0.01) and absence of previous systemic therapy (HR 1.72, p = 0.04) were also associated with poor PFS. Conclusions: In our cohort, the higher incidence of BM (9.6%) as compared to published series deserve further validation and investigation. Multimodality treatment - systemic therapy and surgical resection of BM - are associated with improved outcomes.

NRG1 fusions in non–small cell lung cancer (NSCLC): Prevalence, clinical and molecular features from a real-world cohort profiled with DNA plus RNA-based sequencing.

e15111 Background: NRG1 gene fusions are rare oncogenic drivers in non-squamous NSCLC, occurring in approximately 0.2–0.3% of cases and enriched in invasive mucinous adenocarcinoma (IMA). Their true incidence may be underestimated by DNA-only NGS. Following FDA approval of a bispecific HER2-HER3 antibody for NRG1 fusion–positive tumors, we evaluated the prevalence, clinicopathologic, and molecular characteristics of these cases in a real-world Brazilian cohort systematically profiled with integrated DNA and RNA sequencing. Methods: We retrospectively analyzed all non-squamous NSCLC samples tested at the centralized molecular laboratory of Oncoclínicas Medicina de Precisão (OCPM) from February 2022 to December 2025. Only tumors with successful paired DNA- and RNA-based NGS were included. Demographic, clinical, histologic, molecular, and outcome data were collected from institutional records. Results: Among 1,536 patients, 12 (0.8%) harbored NRG1 fusions. Median age was 66 years; 83% were female. Six were former and five never-smokers. Eight of 12 had stage IV disease at diagnosis; Central nervous system (CNS) metastases were present in 2 patients (25%). Ten tumors (83%) were IMAs, all PD-L1 negative and TMB-low. TP53 was the most frequent co-mutation (50%) and a co-occurring KRAS mutation was identified in one patient. CD74 (n = 5) and SLC3A2 (n = 3) were predominant fusion partners, with single cases involving WRN, LIPE, VAMP2, and SDC4. Among metastatic patients, first-line therapies included chemoimmunotherapy (n = 5), chemotherapy alone (n = 2), and radiotherapy for CNS disease (n = 1). None received HER2-HER3–directed therapy. After a median follow-up of 7.3 months, median overall survival for stage IV patients was 7.9 months (95% CI, 5.4–NA). Conclusions: NRG1 fusions were identified in 0.8% of NSCLC, exceeding historical estimates and underscoring the importance of RNA-based NGS for fusion detection. The clinical and molecular profile mirrored prior reports, with predominant female patients, IMA histology, PD-L1 negativity, and low TMB. Outcomes were poor in metastatic patients lacking access to targeted therapy, supporting the need for broader implementation of RNA sequencing and availability of anti-HER3 agents.

The efficacy of trastuzumab deruxtecan after HER2-TKI exposure in HER2 exon 20 insertion–positive non–small cell lung cancer: Results from a large-scale nationwide genomic screening (LC-SCRUM-Asia).

8531 Background: Although reduced efficacy of HER2-TKIs after trastuzumab deruxtecan (T-DXd) has been reported in HER2 exon 20 insertion–positive non–small cell lung cancer (NSCLC), the efficacy of T-DXd following prior HER2-TKI exposure remains unclear. Methods: We identified patients with HER2 exon 20 insertion–positive NSCLC treated with T-DXd from two cohorts: the National Cancer Center Hospital East (N = 26,971) and the LC-SCRUM-Asia (N = 20,902). Clinical outcomes (ORR, DCR, and PFS) were evaluated across three groups based on prior HER2-TKI therapy: (1) HER2-TKI-naïve patients (naïve cohort), (2) those treated with selective HER2-TKIs (zongertinib or severtinib) (selective TKI cohort), and (3) those treated with non-selective pan-HER2-TKIs (such as poziotinib, afatinib, and others) (non-selective TKI cohort). Results: Of 77 patients (0.2%) included, 60 in the naïve cohort, 7 in the selective TKI cohort, and 10 in the non-selective TKI cohort. Overall, the median age was 60 years (range, 44–76), and 56% of patients were female. By NGS analysis, all tumors harbored ERBB2 exon 20 insertions within the tyrosine kinase domain; the YVMA subtype was the most common (57%). T-DXd was administered as a median fourth-line therapy (range, 2–8). Baseline clinical and genomic characteristics were generally comparable across the three groups. According to prior HER2-TKI exposure, the ORR was 60% (36/60) in the naïve cohort, 29% (2/7) in the selective TKI cohort, and 60% (6/10) in the non-selective TKI cohort. The DCRs were 83% (50/60), 71% (5/7), and 80% (8/10), respectively. Median PFS with T-DXd was 9.9 months in the naïve cohort, compared with 6.5 months in the selective TKI cohort and 5.3 months in the non-selective TKI cohort. The 6-month PFS rate was 72%, 71%, and 50%, respectively. Among 10 patients who did not achieve an objective response to prior HER2-TKIs (best response of stable or progressive disease), 6 achieved a partial response with subsequent T-DXd. Conclusions: Although prior HER2-TKI exposure, particularly selective HER2-TKIs, may attenuate the efficacy of T-DXd in HER2 exon 20 insertion–positive NSCLC compared with HER2-TKI–naïve patients, T-DXd retained clinically meaningful activity in a subset of patients, including those who did not achieve objective responses to prior HER2-TKIs.

ASC4Kids-2: Asciminib in pediatric chronic myeloid leukemia with or without T315I.

TPS6606 Background: Adenosine triphosphate (ATP)-competitive tyrosine kinase inhibitors (TKIs), including imatinib, dasatinib, nilotinib, and bosutinib, are the standard of care for pediatric patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP), with efficacy and safety profiles generally comparable to those observed in adults. However, TKIs can cause long-term adverse effects in pediatric pts, including delayed growth and development. Effective therapies that minimize long-term adverse effects in pediatric pts are needed. No TKI is approved for pediatric pts with the T315I mutation, which is linked with lower progression-free and overall survival. Asciminib represents an alternative to ATP-competitive TKIs that works by Specifically Targeting the ABL Myristoyl Pocket (STAMP). Asciminib is approved for adults with newly diagnosed and previously treated CML-CP (at 80 mg daily), and those harboring T315I (at 200 mg twice daily). In ASC4Kids (NCT04925479), asciminib was well-tolerated and efficacious in pediatric pts resistant or intolerant (R/I) to 1 prior TKI without T315I. Here, we describe ASC4Kids-2 (NCT07354074), a phase 2 study evaluating asciminib in pediatric pts with CML-CP. Methods: Approximately 50 pediatric pts aged 1 to <18 years with Philadelphia chromosome positive (Ph+) CML-CP who are (1) newly diagnosed without known T315I, (2) R/I to ≥1 prior TKI without known T315I, or (3) with T315I irrespective of prior TKIs, will be enrolled in this multicenter, open-label, single-arm study. Asciminib will be administered at 80 mg once daily, or at 200 mg twice daily for pts with T315I using the adult formulation under fasting conditions, or as a body weight–based pediatric formulation (2.6 mg/kg once daily or 6.5 mg/kg twice daily for pts with T315I, rounded to the nearest 5 mg) in the fed state. ASC4Kids-2 consists of a 22-day screening period followed by a treatment period with visits at weeks 1, 2, 4, 8, 12, 24, 36, and 48, then every 12 weeks. A posttreatment follow-up period includes a 30-day safety follow-up call and survival assessments every 12 weeks until study end, which is 240 weeks after the last pt receives the first dose. The primary objective is to assess treatment efficacy via MMR at week 48 (defined as the proportion of pts who meet MMR criteria at week 48, excluding those who discontinued earlier or lost response at/before week 48). Secondary endpoints include MMR at week 96; hematologic, cytogenetic, and molecular responses at and by scheduled time points; time to response, progression, or treatment failure; duration of response; event-free and overall survival; growth and sexual maturation (assessed via height, weight, bone age measured by x-ray, and Tanner staging); safety; and pharmacokinetic parameters. Clinical trial information: NCT04925479 .

Trends in infection-related mortality among older adults with multiple myeloma in the United States over the last two decades.

e19553 Background: Multiple myeloma (MM) is associated with profound immune dysfunction and treatment-related immunosuppression, increasing susceptibility to infection-related mortality. However, national trends and demographic and geographic disparities in infection associated deaths among MM patients remain incompletely characterized. This study evaluated long-term mortality patterns from 1999 to 2023. Methods: CDC WONDER data was extracted using ICD-10 codes for MM (C90.0) and infectious causes including sepsis (A40–41), fungal infections (B35–49), pneumonia (J12–J18), and urinary tract infections (N39.0). Age-adjusted mortality rates (AAMR) per 1,000,000, standardized to the 2000 U.S. population, were calculated among adults aged ≥65 years. Temporal trends were assessed using Joinpoint regression from the year 1999 to 2023. Analyses were stratified by sex, race, states and place of death. Results: A total of 37,560 infection associated deaths occurred among MM patients. Most deaths occurred in medical facilities (77.8%), followed by nursing or long-term care facilities (7.7%). Overall AAMR decreased from 1999 to 2018, increased transiently during 2018 to 2021 (APC 3.63%), and then declined sharply to near pre-2018 levels. Among males, AAMR declined from 55.2 in 2004 to 40.9 in 2012 (APC −3.81%; p<0.05), followed by reversal with an increase to 42.3 in 2020. Female mortality demonstrated a sustained downward trend, decreasing from 31.4 in 2004 to 23.1 in 2011 (APC −3.37%; p<0.05) and further to 20.6 in 2023 without reversal. Across racial groups, Non-Hispanic Black populations consistently exhibited nearly double the AAMR compared with other groups. From 1999 to 2012, AAMR declined significantly among both Non- Hispanic Black (APC −3.02%; p<0.05) and Non-Hispanic White populations (APC −3.30%; p<0.05), followed by stabilization among Non-Hispanic Whites and a modest increase among Non-Hispanic Blacks. In contrast, Hispanic or Latino populations demonstrated a sustained decline from 1999–2023 (APC −1.29%;p < 0.05). State-level AAMRs varied widely, with rates in the District of Columbia nearly threefold higher than in Maine. Conclusions: Infection related mortality among older adults with MM declined during the early study period but demonstrated a subsequent resurgence, with marked racial and geographic disparities persisting. These findings highlight ongoing vulnerability among high-risk populations and underscore the need for targeted infection prevention strategies and improved access to supportive oncology care.

Comparison of survival outcomes in <i>ALK</i> fusion–positive advanced non–small cell lung cancer patients diagnosed by next-generation sequencing or RT-PCR: A propensity score–weighted analysis.

e20669 Background: Although ALK inhibitors significantly improve the prognosis of ALK fusion-positive non-small cell lung cancer (NSCLC) patients, different ALK fusion detection methods may be used in clinical practice. Reverse-transcription polymerase chain reaction (RT-PCR) detects known, predefined fusion sites, while next-generation sequencing (NGS) can identify other rare or unknown fusion subtypes. Both methods are widely used in China. This study aims to explore the differences in efficacy of ALK inhibitors in patients identified by RT-PCR versus NGS and to investigate the impact of ALK fusion patterns and molecular characteristics on prognosis. Methods: We retrospectively analyzed 153 patients with advanced ALK -positive NSCLC who received first-line targeted therapy, identified by RT-PCR (n = 71) or NGS (n = 82). Inverse probability of treatment weighting (IPTW) was applied, incorporating covariates such as clinical characteristics and treatment drugs. Cox models were used to compare progression-free survival (PFS) and overall survival (OS) between the two groups. In the NGS group, fusion patterns were defined as: classic fusion (containing only EML4-ALK fusion), non-classic fusion (containing no EML4-ALK fusion), and complex fusion (containing both types). Cox regression models were used to evaluate the prognostic factors. Risk factors for early treatment failure (PFS &lt; 12 months) were analyzed. Statistical tests were two-sided, with P &lt; 0.05 considered significant. Results: The median PFS of patients in the NGS group was significantly shorter than that in the RT-PCR group (19.0 vs. 48.0 months; HR, 2.73; P &lt; 0.001), and their OS was also worse (NR vs. NR; HR, 2.18; P = 0.035). Univariate analysis showed that patients in the non-classic fusion group (n = 13) had worse median PFS compared to the classic fusion group (n = 34) (13.0 vs. 23.1 months; HR, 2.14; P = 0.038). However, multivariate analysis confirmed that only TP53 mutation was an independent risk factor for PFS (HR, 4.36; P &lt; 0.001) and OS (HR, 6.14; P = 0.005). Additionally, TP53 mutation (OR, 4.50; P = 0.023), co-existing other gene mutations (OR, 3.00; P = 0.044), and non-V1/V2/V3 EML4-ALK fusion variants (OR, 7.50; P = 0.023) were potential risk factors for early treatment failure. Conclusions: This study suggests that ALK -positive patients identified by NGS may differ in treatment response and prognosis from those identified by RT-PCR, with significantly worse PFS and OS. ALK fusion patterns themselves are not strong independent prognostic factors. TP53 mutations, other co-existing mutations, and rare non-V1/V2/V3 EML4-ALK fusion variants are noteworthy risk markers that may guide intensified monitoring and treatment strategies for high-risk patients. Further research is needed to confirm these findings.

A retrospective analysis of cardiovascular outcomes in patients with prostate cancer treated with upfront gonadotropin-releasing agonist versus antagonists utilizing real-world data.

e17101 Background: Prostate cancer is commonly treated with androgen deprivation therapy (ADT). This is achieved using gonadotropin-releasing hormone (GnRH) agonists such as leuprolide or GnRH antagonists such as degarelix and relugolix. While GnRH agonists have been widely used for decades, antagonists offer more rapid testosterone suppression and avoid the initial testosterone surge associated with agonists. Although there is data to suggest that GnRH antagonists may have better cardiovascular safety compared to agonists, the available evidence is conflicting. Therefore, leveraging real-world data may provide important insights into outcomes across broader patient populations. Methods: We utilized the TriNetX global federated health research network which included 115 different healthcare organizations. By utilizing ICD-10 and ICD oncology codes, patients with prostate cancer were identified and separated into two cohorts based on time to initiation of either leuprolide (GnRH agonist arm), or degarelix or relugolix (GnRH antagonist arm) within 1 year of the index diagnosis event. Propensity score matching (PSM) was conducted based on age, race and stage of prostate cancer (Stage I to IV). Primary outcome measure of interest was major adverse cardiovascular events (MACE), a composite of myocardial infarction, cerebrovascular infarction and all-cause mortality. Cox-proportional hazards model for major adverse cardiovascular events (MACE) was performed with covariates including age, race, heart failure, personal history of malignant neoplasm, cerebral infarction, dementia, chronic pulmonary disease, liver disease, diabetes and chronic kidney disease. Results: 108,064 patients with prostate cancer treated with GnRH agonists and 12,242 such patients who received GnRH antagonists were identified. 12,242 patients were matched 1:1 based on PSM per cohort. Baseline characteristics including age and race were well balanced in the matched cohorts. MACE occurred in 2,554 (22.56%) of patients in the GnRH agonist arm versus 1,618 (15.02%) of patients in the GnRH antagonist arm HR 1.649, 95% CI 1.539-1.766, p &lt; 0.0001). All-cause mortality was similarly higher in patients in the GnRH agonist arm (2,330 patients or 19%) versus the GnRH antagonist arm (1,589 patients or 13%) (HR 1.58, 95% CI 1.472-1.691, p &lt; 0.0001). Cox-proportional hazards model showed statistically significant increase in MACE associated with treatment with GnRH agonists compared to GnRH antagonists (HR 1.16, 95% CI 1.11-1.21, p &lt; 0.0001). Conclusions: Treatment with GnRH agonists was associated with significantly higher rates of MACE and all-cause mortality compared with GnRH antagonists among patients with prostate cancer. Prospective randomized studies are needed to inform individualized treatment decisions.

Baseline autoantibodies and treatment outcomes in metastatic melanoma treated with anti–PD-1 or ipilimumab combination immunotherapy.

e21505 Background: B cells can exert both pro- and anti-tumor effects depending on the cancer type, disease stage, and the tumor microenvironment. They may enhance anti-tumor immunity through antigen presentation, antibody production that activates effector pathways, and the formation of tertiary lymphoid structures. However, the role of autoantibodies (AAbs) in predicting response to immune checkpoint inhibitors remains poorly understood. Methods: Baseline serum from 166 patients with stage IV melanoma who received either pembrolizumab (pembro, n=101) or ipilimumab plus nivolumab (ipi/nivo, n=65) was analyzed to identify AAbs associated with overall response rate (ORR), progression free (PFS) and overall survival (OS). AAbs were measured using an 832-antigen immuno-oncology array. Analyses were performed separately for each treatment group. AAbs associated with ORR were identified by Significance Analysis of Microarrays (SAM; d-score ≥1.8, p &lt; 0.05). The proportional hazard ratio (HR) was calculated for AAbs associated with PFS and OS by Cox regression analysis (p&lt;0.05). PFS and OS were measured from treatment initiation until progression and/or death. For each treatment and outcome, the 10 AAbs with the highest HR and p&lt;0.05 were selected, prioritising overlapping markers. Results: In pembro-treated patients, AAbs to ECE1 and TNFRSF1B were positively associated with PFS and OS, whereas AAbs to DHFR and ACPP were negatively associated. ECE1 generates endothelin peptides that drive tumor growth and angiogenesis, and TNFRSF1B (TNFR2) supports immunosuppressive Treg activity in the TME. Anti-IL4R was associated with longer OS. In the ipi/nivo cohort, anti-TNFRSF10B was positively associated with ORR and PFS, while anti-PLEKHM2 was negatively associated. TNFRSF10B (DR5) mediates TRAIL-induced apoptosis in cancer cells. AAbs to IL27 and IFNL2 were linked to longer OS, anti-LAG3 to longer PFS, and AAbs to ADRA1A to shorter PFS. LAG3 is an inhibitory checkpoint targeted in cancer therapy to enhance T-cell activation. IL4R supports Th2-skewed, protumor signaling, while IL27 and IFNL2 can promote anti-tumor T-cell responses. Conclusions: We identified baseline AAb profiles associated with clinical outcome in patients treated with mono or combined immune checkpoint blockade (ICB), indicating antigen-specific immune effects that may be either anti- or pro-tumorigenic. These findings highlight a role for B cells and AAbs in melanoma immunotherapy and suggest opportunities to target B cell–related pathways. AAbs to cytokines and receptors, including IL27, IFNL2, ADRA1A, ECE1, TNFRSF10B, TNFRSF1B, and IL4R, support a potential modulatory function in ICB response. Functional validation is needed to clarify their impact on anti-tumor immunity and outcomes.

Emotional burnout among oncology clinicians in Russia: Results of a national cross-sectional survey.

9014 Background: International reports suggest a high prevalence of burnout in oncology, but contemporary Russian data are limited. Methods: Anonymous online survey (June 7-14, 2025) of oncology clinicians and trainees assessing emotional exhaustion in the prior 4 weeks, related symptoms, coping strategies, and free-text views on drivers/mitigation. Results: 735 respondents participated (medical oncologists 46.0%, surgical oncologists 23.9%, radiation oncologists 11.6%, trainees 9.0%); 78.5% worked in public hospitals and 69.0% had no managerial role. Emotional exhaustion was reported "often" by 326 (44.4%) and "constantly" by 152 (20.7%); 157 (21.4%) reported episodic exhaustion, 74 (10.1%) rare, and 26 (3.5%) none. Patient detachment was reported sometimes by 291 (39.6%), often by 221 (30.1%), and as near-constant disengagement by 42 (5.7%). Frequent thoughts about leaving clinical work were reported by 275 (37.4%) (additional 243, 33.1% only in exceptionally difficult moments). Excessive workload was perceived often/constantly by 458 (62.3%); lack of time for breaks/recovery by 629 (85.6%) at least sometimes. Common coping strategies included sleep/rest by 592 (80.5%), support from close ones by 437 (59.5%), physical activity by 385 (52.4%), and hobbies by 251 (34.1%); 198 (26.9%) reported alcohol/medications. In free-text drivers (n=569), the most cited themes were leadership/management issues (33.7%), time/workload pressure (21.1%), patient/relative conflict and complaints (19.3%), and paperwork (12.5%); proposed mitigation included protected rest/work-life boundaries (26.3%) and workload reduction/staffing/process optimization (20.8%). Conclusions: Two-thirds of respondents reported frequent/constant emotional exhaustion, accompanied by patient detachment and high intent to leave clinical work. Findings support prioritizing organization-level interventions and protected recovery time alongside accessible support resources.

An open-label, first-in-human study of SKB500 in patients with locally advanced or metastatic solid tumors.

3011 Background: SKB500 is an antibody drug conjugate (ADC) composed of an antibody targeting the B7 homolog 3 (B7-H3), which is overexpressed in many types of solid tumors, conjugated to a topoisomerase I inhibitor payload via a cleavable pyrimidine-tripeptide linker. We hereby report initial results of the FIH study (NCT06736327). Methods: This phase 1 study comprised dose-escalation, dose-expansion, and indication-expansion phases to evaluate the safety, tolerability, pharmacokinetics, and efficacy of SKB500. Patients (pts) with unresectable solid tumors refractory to standard treatment will be enrolled and receive SKB500 at doses ranging from 2 to 18 mg/kg every three weeks (Q3W) until disease progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate (ORR) assessed by investigators per RECIST v1.1. Results: As of Dec 23, 2025, 150 pts were treated with SKB500 across all dose levels (2-18 mg/kg). No dose-limiting toxicities (DLT) were observed during dose escalation. Based on preliminary data, the recommended phase 2 dose (RP2D) was established as 12 mg/kg. Among 97 pts treated at 12 mg/kg, the median treatment duration was 6.7 weeks. Treatment-related adverse events (TRAEs) occurred in 70 pts (72.2%), with most frequent (≥20%) being anemia (35.1%), nausea (34.0%), and white blood cell count decreased (24.7%). Grade ≥3 TRAEs occurred in 16 pts (16.5%), with most frequent being anemia, lymphocyte count decreased, pneumonia, and asthenia (each 3.1%). Pneumonitis occurred in 2 pts (2.1%; both grade 1). Both pneumonitis and grade ≥ 3 hematologic toxicities demonstrated low occurrence rates. No TRAEs led to treatment discontinuation or death. Among 55 pts treated at 12 mg/kg who had at least 6 weeks of follow-up (≥2 prior lines: 34.5%; prior platinum: 98.2%; prior IO therapy: 76.4%), the ORR was 54.5% (30/55) and the DCR was 92.7% (51/55). In tumor-specific subgroups, the small cell lung cancer (SCLC) cohort (n = 21) achieved an ORR of 71.4% (15/21) and a DCR of 100% (21/21), while the esophageal squamous cell carcinoma (ESCC) cohort (n = 18) showed an ORR of 55.6% (10/18) and a DCR of 88.9% (16/18). Conclusions: SKB500 demonstrated a manageable safety profile and promising antitumor activity in patients with treatment-refractory advanced solid tumors, with notable efficacy in SCLC and ESCC cohorts, supporting further clinical development. Clinical trial information: NCT06736327 .