Browse Articles

Alpha-emitting radionuclide or beta-emitting radionuclide combined with metastasis-directed stereotactic body radiotherapy for oligorecurrent prostate adenocarcinoma (ANDROMEDA): A phase II trial.

TPS3175 Background: The recent LUNAR study (NCT05496959) found that adding beta-emitting 177 Lutetium-PNT2002 ( 177 Lu-PSMA) to stereotactic body radiation therapy (SBRT) more than doubled median progression-free survival (PFS) compared to SBRT alone in oligorecurrent hormone-sensitive prostate cancer (orHSPC), hazard ratio (HR)=0.37. However, the relative efficacy compared to novel alpha-emitting 225 Actinium-PSMA-617 ( 225 Ac-PSMA) is unknown. The hypothesis is that 225 Ac-PSMA will improve PFS by treating more micrometastases, given its higher radiobiologic effectiveness. We aim to compare the relative benefit of 2 cycles of 177 Lu-PSMA versus 1 cycle of 225 Ac-PSMA followed by SBRT metastasis-directed therapy (MDT). Methods: ANDROMEDA (NCT07150715) is a phase II, non-blinded, single-center randomized trial for individuals with orHSPC and 1-5 PSMA-avid metastases outside the prostate/prostate bed (N1 and/or M1). Eligibility criteria include testosterone >150 ng/dL, ≥18 years, and ECOG performance status ≤2. Exclusion criteria include de novo metastatic disease, castrate-resistance (testosterone <50 ng/mL with rising PSA), ADT/chemotherapy within 6 months of enrollment, and neuroendocrine histology. Participants are randomized 1:1 to 2 cycles 177 Lu-PSMA (7.4 GBq/cycle, 6 weeks apart) or 1 cycle of 225 Ac-PSMA (8 MBq, once), followed by SBRT to all lesions 1-2 weeks after radioligand therapy infusion. The primary endpoint of PFS is defined as the time from randomization to either 1) a new PSMA-avid lesion or 2) PSMA-PET local progression (>30% SUV increase or >20% increase in the sum of the longest lesion diameters) with a PSA rise. For those alive without progression, PFS will be censored at the time of the last scan. All randomized subjects will be analyzed based on intent-to-treat. Secondary endpoints include 24-month disease burden by PSMA-PET, physician-scored toxicity, patient-reported quality of life, ADT-free survival, local control of SBRT lesions at 24 months after last radionuclide infusion, and time-to-progression (locoregional, distant, new metastasis). We hypothesize that the 24-month post-SBRT PSA-based recurrence rate of 177 Lu-PSMA will be ~50%, which will be reduced with 225 Ac-PSMA to ~30% (PFS HR~0.51). We anticipate an accrual time of 1.5 years and a median follow-up time of 24-months. A sample size of 96 patients (48 per arm) would provide 80% power to detect the expected difference in PFS at a 0.1 alpha level. Assuming a 10% drop-out/screen failure rate, the target trial accrual is 107 patients. Early stopping guidelines include monitoring site-specific grade 4-5 toxicity with a safety threshold of 20% from the time of the first enrolled patient, which would trigger halting the trial and safety consultation. ANDROMEDA is currently open for enrollment. Clinical trial information: NCT07150715 .

Prevalence and regional variation of cervical cancer in Nigeria: A systematic review and meta-analysis (2010–2025).

e17519 Background: Cervical cancer remains a leading cause of cancer-related morbidity and mortality among women in low- and middle-income countries, including Nigeria. Despite its preventability, evidence on the national and regional burden of cervical cancer in Nigeria remains fragmented and highly variable. This systematic review and meta-analysis aimed to estimate the pooled prevalence of cervical cancer in Nigeria and examine regional variations across the country’s geopolitical zones. Methods: Following PRISMA 2020 guidelines, we systematically searched PubMed, Web of Science Core Collection, Web of Science CAB International, Embase, and Google Scholar for observational studies published between January 2010 and December 2025 that reported cervical cancer prevalence in Nigeria. A random-effects meta-analysis was performed to estimate the pooled prevalence with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran’s Q and I² statistics. Subgroup analyses were conducted by geopolitical zone. Robustness was evaluated through leave-one-out sensitivity analysis, and publication bias was assessed using funnel plots and Egger’s regression test. Results: Eighteen studies met the inclusion criteria, representing all six geopolitical zones. Individual prevalence estimates ranged from 1.25% to 62.7%. The pooled prevalence of cervical cancer was 12% (95% CI: 8–19%), with very high heterogeneity (I² = 98.7%, p < 0.0001). Higher pooled prevalence estimates were observed in the South-South and South-East zones, while lower estimates were seen in northern regions. Sensitivity analysis demonstrated stable pooled estimates (range: 11%–14%) with no single study exerting undue influence. There was no evidence of publication bias (Egger’s test: p = 0.855). Conclusions: Cervical cancer prevalence in Nigeria remains high, with marked regional disparities and substantial heterogeneity driven by differences in study setting, screening coverage, and healthcare access. These findings highlight persistent gaps in prevention, early detection, and surveillance. Scaling up HPV vaccination, expanding equitable screening programs, and strengthening population-based cancer registries are urgently needed to support progress toward the WHO cervical cancer elimination targets.

Dyadic exercise intervention for LGBTQ+ cancer survivors: Associations with health-related quality of life, fatigue, and inflammation biomarkers.

12041 Background: Mixed training (aerobic/resistance) exercise is a key adjuvant therapy in exercise oncology; it decreases cancer mortality and improves patients' quality of life, in part by modulating the tumor microenvironment, regulating the HPA axis, and inflammatory pathways. LGBTQ cancer survivors and their partners frequently experience excessive fatigue, insomnia, impaired health-related quality of life (HRQOL), and relationship stress, yet remain underrepresented in exercise oncology research. Methods: We conducted an RCT with 70 LGBTQ+ cancer survivor-partner dyads (N = 140) to compare a 6-week home-based dyadic exercise program (EXCAP-PA) against a survivor-only intervention. Analyses focused on changes from baseline to post-intervention. Primary outcomes included the Survivor Profile of Mood States (POMS) Fatigue and PROMIS global health change to assess HRQOL. ANCOVA-style linear models regressed change scores on treatment arm and baseline values. Mediation analyses assessed whether changes in dyadic support, cortisol, and C-reactive protein (CRP) mediated the effect of treatment on fatigue and HRQOL. Results: Among 56 survivor–partner dyads with analyzable data, delivery of EXCAP-PA was feasible in this LGBTQ+ population. Both survivors and partners in each arm demonstrated improved HRQOL; however, the treatment arm did not significantly predict changes in PROMIS global health for survivors (survivors: B = 0.10, SE = 0.39, p = 0.80; partners: B = 0.03, SE = 0.41, p = 0.94). Baseline symptom burden strongly influenced outcomes: higher baseline fatigue was associated with greater reductions in POMS Fatigue–Inertia (B = −0.55, SE = 0.15, p < 0.001), indicating that participants with the highest fatigue experienced the largest improvements. In the CRP model (n ≈ 44), higher baseline CRP was significantly associated with greater subsequent decreases in log-transformed CRP (B = −0.37, SE = 0.17, p = 0.04). The model relating fatigue change to baseline fatigue, baseline CRP, and CRP change explained a substantial proportion of variance (R² = 0.29; F(3,40) = 5.42, p = 0.003), whereas baseline cortisol was not significantly related to fatigue change. Although mediation analyses using changes in dyadic support, log-transformed CRP, or log-transformed cortisol as mediators of treatment arm effects on fatigue or HRQOL yielded small, non-significant indirect effects, the outcomes are consistent with a beneficial effect in which dyadic processes and reduced inflammation improve symptoms and HRQOL. Conclusions: Dyadic EXCAP-PA proved feasible for LGBTQ+ survivor–partner dyads. Although this pilot is underpowered to detect significant effects on global health, fatigue, or inflammation, the findings highlight high-symptom/high-CRP survivors as a priority subgroup for future, larger dyadic exercise trials.

Characterization of tumor immune microenvironment and real-world efficacy of first-line immunotherapy in <i>BRAF</i> -mutant non–small cell lung cancer.

e20607 Background: The efficacy of immune checkpoint inhibitors (ICIs) in BRAF-mutant non-small cell lung cancer (NSCLC) remains under debate compared to driver-gene wild-type (WT) populations. To elucidate the biological basis of clinical responsiveness, this study integrated a comprehensive analysis of the tumor immune microenvironment (TIME) with real-world outcomes of first-line ICI-based therapy in BRAF-mutant NSCLC. Methods: In this single-center study, for cohort I, we characterized the TIME of 63 surgically resected NSCLC samples (BRAF V600E, n = 31; WT, n = 32) using RNA sequencing and multiplex immunofluorescence (MIF) stained with CD8, CD68, CD163, CD57, PD-1, and PD-L1 antibodies. In cohort II, we conducted a real-world analysis of 110 advanced NSCLC patients treated with first-line ICI monotherapy or combination therapy. Patients were stratified into BRAF V600E (n = 14), BRAF non-V600 (n = 14), and WT (n = 82) groups to evaluate objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs). Results: In cohort I, RNA sequencing identified only 77 differentially expressed genes between BRAF V600E and WT. Analysis of immune-related signatures, including most infiltrating immune cell subtypes and tertiary lymphoid structures, indicated that BRAF V600E mutation status had minimal impact on TIME characteristics. MIF revealed significantly higher proportions of CD68+CD163- tumor-associated macrophages in the BRAF V600E group across tumor, stroma, and total regions. However, the proportions of CD8+, CD8+PD-L1+, and CD8+PD-1+ tumor-infiltrating lymphocytes showed no significant disparity between BRAF V600E and WT groups. In cohort II, baseline characteristics were comparable. The BRAF V600E group achieved an ORR of 35.7% and DCR of 85.7%, which were consistent with the BRAF non-V600 (ORR 28.6%, DCR 78.6%) and WT groups (ORR 42.7%, DCR 87.8%). The BRAF-mutant cohort (n = 28) showed no statistically significant difference compared to the WT cohort (n = 82) in median OS (36.73 vs. 55.62 months; P = 0.60) or median PFS (12.75 vs. 18.30 months; P = 0.25). Further subtype stratification revealed comparable OS between BRAF V600E and non-V600 groups (NR vs 35.84 months; P = 0.74). Notably, BRAF V600E patients exhibited a numerically longer median PFS compared to non-V600 patients (25.63 vs. 9.61 months; P = 0.11). Safety profiles were manageable, with Grade ≥3 TRAEs occurring in only 7.1% of V600E patients. Conclusions: The TIME was generally similar between the BRAF V600E mutant and driver gene wild-type groups. Clinically, BRAF-mutant patients derive similar survival benefits from first-line ICI-based therapy as the wild-type population, supporting the use of immunotherapy in this subgroup.

The CONVERGE study: A phase II, single-arm trial of adebelimab combined with targeted therapy and liposomal irinotecan-based chemotherapy for conversion surgery in unresectable MSS colorectal cancer liver metastases.

3604 Background: Liver metastasis is a key poor prognostic factor for colorectal cancer (CRC). Microsatellite stable (MSS) CRC predominates and is poorly responsive to single-agent immunotherapy. Only 10%–20% of patients with initially unresectable MSS colorectal cancer liver metastases (CRLM) are eligible for upfront curative resection, and conventional chemo-targeted therapy yields a conversion resection rate of merely 15%–30%. This phase II study evaluated the efficacy and safety of adebelimab (a PD-L1 inhibitor) plus molecularly stratified targeted therapy and liposomal irinotecan-based chemotherapy for unresectable MSS CRLM, focusing on hepatic metastatic lesion control (ChiCTR2600117031). Methods: This single-center, open-label phase II trial enrolled 45 patients with unresectable MSS CRLM (ECOG PS 0-1, no prior systemic anti-tumor therapy). Patients received adebelimab (1200mg IV, Q2W) + stratified targeted therapy (cetuximab for RAS/BRAF wild-type left-sided tumors; bevacizumab otherwise) + liposomal irinotecan-based chemotherapy (Q2W) for up to 12 cycles. Primary endpoint: conversion-to-resection rate. Secondary endpoints: ORR, DCR, R0 resection rate, hepatic metastasis pathological response, and safety (NCI-CTCAE v5.0). Efficacy was assessed per RECIST v1.1. Results: As of January 20, 2026, 42 patients were included in baseline analysis (median age 57.6±11.1 years, 64.3% male; mean hepatic metastasis diameter 37.21±19.00 mm, max 82.79 mm). Among 35 efficacy-evaluable patients, ORR was 45.7% (95% CI: 28.8%–63.4%) and DCR was 88.6% (95% CI: 73.3%–96.8%). Fourteen patients underwent surgery (conversion rate 45.2%, 95% CI: 27.3%–60.0%), all completing simultaneous resection of hepatic metastases and primary tumors. Of these 14 patients, 5 (35.7%) achieved hepatic TRG 0 (complete pathological regression) and 12 (85.7%) achieved R0 resection (95% CI: 49.2%–95.3%). For safety, 95.2% (40/42) of patients had AEs. Common (≥10%) all-grade AEs were mainly hematological (leukopenia 23.8%, myelosuppression 21.4%). Grade 3 AEs were rare (predominantly leukopenia 14.3%), and no grade 4 AEs occurred. No any-grade immune-related AEs were reported. Conclusions: Adebelimab combined with molecularly stratified targeted therapy and liposomal irinotecan-based chemotherapy shows substantial efficacy and favorable safety for unresectable MSS CRLM, with excellent hepatic metastasis control. Its high conversion-to-resection rate and 35.7% hepatic TRG 0 rate confirm potential for deep pathological response. This regimen warrants further investigation as a promising conversion therapy for unresectable MSS CRLM. Genomic sequencing of successfully converted patients is ongoing to elucidate therapeutic mechanisms. Clinical trial information: ChiCTR2600117031.

Cost-effectiveness analysis of teclistamab plus daratumumab in relapsed or refractory multiple myeloma.

11038 Background: Relapsed or refractory multiple myeloma (RRMM) remains a significant therapeutic and economic challenge as patients progress through successive lines of therapy. Teclistamab, a CD3×B-cell maturation antigen (BCMA) bispecific antibody, has demonstrated deep and durable responses in heavily pretreated patients in the phase 1–2 MajesTEC-1 trial. Daratumumab, an anti-CD38 monoclonal antibody, is a cornerstone of modern myeloma treatment. The phase 3 MajesTEC-3 trial evaluated teclistamab plus daratumumab versus daratumumab-based regimens, including daratumumab with pomalidomide and dexamethasone (DPd) or with bortezomib and dexamethasone (DVd) in patients with RRMM. While teclistamab-based combinations have demonstrated strong clinical efficacy, their economic value relative to standard daratumumab-based regimens remains uncertain. Methods: We extracted event-free survival (EFS) and overall survival (OS) data from published Kaplan–Meier curves and reconstructed individual patient data using a validated algorithm (IPDfromKM). A Markov model was developed to compare lifetime costs and health outcomes between treatment strategies. Model inputs were obtained from the Centers for Medicare &amp; Medicaid Services, the Medicare Physician Fee Schedule, and published literature. Health state utilities, adverse event rates, treatment discontinuation probabilities, and toxicity costs were derived from the MajesTEC-3 trial and peer-reviewed sources. Analyses were conducted from a U.S. third-party payer perspective, with costs reported in 2025 U.S. dollars. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) with a $150,000/QALY willingness-to-pay (WTP) threshold, and robustness was examined through one-way and probabilistic sensitivity analyses. Results: Gompertz and lognormal distributions were selected based on Akaike Information Criterion to extrapolate EFS and OS for the teclistamab–daratumumab and DPd/DVd arms, respectively. Using a Markov model, teclistamab plus daratumumab yielded an incremental gain of 1.16 QALYs compared with DPd/DVd, at an additional cost of $95,376, resulting in an ICER of $82,074 per QALY, well below the WTP threshold. Probabilistic sensitivity analysis showed that 88.9% of simulations favored teclistamab plus daratumumab at the $150,000/QALY threshold. Treatment discontinuation rates and the cost of daratumumab in the DVd regimen were the primary drivers of ICER estimates. Conclusions: From a U.S. payer perspective, teclistamab plus daratumumab is cost-effective compared with DPd or DVd in patients with RRMM, supporting its broader adoption in clinical settings. Base-case model. Strategy Cost, USD Incremental cost, USD Effectiveness, QALY Incremental effectiveness, QALY ICER, USD/QALY Teclistamab-Daratumumab 445,405 95,376 16.72 1.16 82,074 DPd or DVd 350,029 15.55

Risk factors for mortality in prostatic abscess: Insights into patient characteristics and drainage practices

Prostatic abscess, which is an uncommon urinary tract disease, can lead to mortality if not properly treated. This retrospective study aimed to identify risk factors associated with mortality in patients with prostatic abscess, with the goal of providing insights to improve clinical outcomes. The study was conducted on patients diagnosed with prostatic abscess and hospitalized between January 2007 and December 2021. The diagnosis was confirmed through imaging. Out of 822 hospitalized patients with acute prostatitis or prostatic abscess, 102 had prostatic abscess (12.4%). The mean age was 68.8 years old, and overall mortality was 8.8%. Drainage was performed in 15.7% cases. There was no significant difference in abscess size, prostate volume, or percentage of abscess formation at other sites between survivors and non-survivors. Age and use of alpha blockers were identified factors related to death, and older age remained significantly related to mortality (OR=1.07) in multivariate analysis. Factors associated with drainage or transurethral resection of the prostate were analyzed. Abscess size (OR=1.70), cystostomy (OR=4.56), prostate volume (OR=1.01) and the presence of abscess in other organs (OR=3.89) were associated with drainage, whereas abscess size (OR=1.58), cystostomy (OR=5.13), and liver cirrhosis (OR=5.67) were associated with transurethral resection of prostate. There were no differences between the drainage and non-drainage groups after propensity score matching for age, BMI, and abscess size. In our study, advanced age was the primary factor associated with mortality in patients with prostate abscess. Other factors, including drainage and abscess size, were not significantly associated with mortality; however, these findings may be influenced by confounding factors and the limited number of mortality events, warranting further investigation.

Microneedle-delivered hybrid carbon–lanthanide nanotheranostic platform for precision localized therapy of early-stage melanoma

Assembling a True “Olympic Gel” From over 16 000 Combinatorial DNA Rings (Adv. Mater. 34/2026)

4D‐Printed Sandwich‐Structured Metamaterial Intestinal Stents for Palliative Tumor Therapy

ABSTRACT Intestinal obstruction is a common complication caused by colorectal cancer, and the implantation of stents has become an indispensable palliative treatment strategy for non‐surgical eligible patients. However, the lack of sustained anti‐tumor efficacy and wear caused by configuration or deformation discrepancies has led to the recurrence of stenosis, posing a significant challenge in clinical treatment. Here, we reported an intestine‐specific, application‐driven 4D‐printed sandwich‐structured metamaterial intestinal stent platform, achieving the triple goals of sustained anti‐tumor effects, customized configuration and performance, and rapid relief of intestinal obstruction. Specifically, the platform comprised an outer Janus layer designed for synergistic photothermal‐and‐drug anti‐tumor effects, an intermediate layer of biomimetic gradient metamaterials for structural support and coordinated deformation, and a hydrophobic inner layer to mitigate the risk of restenosis. Overall, this study presented a multifunctional intestinal stent built upon a scalable design paradigm, offering an innovative and clinically translatable therapeutic strategy for personalized colorectal cancer management.

Computational modeling of Monte Carlo–enhanced PINNs for fractional order differential models with memory effects

Sustained β-catenin activation via GSK3 inhibition promotes direct fibroblast-to-cardiomyocyte reprogramming

Neoadjuvant chemokine modulation of the tumor microenvironment (TME) in resectable metastatic colorectal cancer: Results from a phase I study.

2606 Background: Our preclinical studies using ex vivo explant cultures of resected metastatic colorectal cancer (CRC) tissues and in vivo mouse models showed that the combination of interferon alpha (IFNα) with toll-like receptor-3 (TLR-3) ligands and inhibitors of prostaglandin synthesis selectively induces effector T cell-attracting chemokines (CXCL9, CXCL10, CXCL11, and CCL5) in tumor microenvironments (TME), but not in adjacent healthy tissues, allowing for their systemic application to modulate TME. The chemokine-modulating (CKM) regimen, consisting of IFNα, rintatolimod (a selective TLR3 agonist), and celecoxib (a COX-2 inhibitor), also suppresses CCL22, a Treg-attracting chemokine in the TME. Based on these preclinical data, we hypothesized that a systemic CKM regimen would be safe and effective in modulating the TME of metastatic CRC. Methods: Nine chemotherapy-naïve patients with metastatic or recurrent CRC confined to the abdomen/pelvis and expected to have a complete resection received increasing doses of IFNa2b in a Phase I study to establish a recommended phase II dose of CKM for efficacy studies. The adaptive dose-escalation evaluated IFNα2b at 5, 10, and 20 million units (MU)/m2/day IV (Monday–Friday for 1 week pre-surgery), in combination with fixed doses of rintatolimod (200 mg IV; Monday–Friday) and celecoxib (200 mg orally twice daily; Monday–Friday). Results: No dose-limiting toxicities were observed, and 20 MU/m² of IFNα2b was identified as the recommended Phase II dose. All treated patients underwent R0 resection, as planned. Common treatment-related adverse events were flu-like symptoms (chills, fever, fatigue) and transient laboratory abnormalities (anemia, leukopenia), mostly grade 1–2. Two patients (13%) developed grade 3–4 neutropenia, which resolved without sequelae. There were no unexpected perioperative complications attributable to the regimen. Preliminary analysis of resected tumor tissues showed evidence of immune modulation in CKM-treated patients: increased ratios of CD8+ CTLs to FoxP3+ Tregs, with concomitant elevation of the effector chemokines (CCL5 and CXCL10), along with reduced expression of the Treg-recruiting chemokine CCL22, compared to 77 patients undergoing upfront tumor resections. Conclusions: Neoadjuvant CKM regimen is safe and feasible in resectable metastatic CRC and is associated with improved ratios of CD8+ CTLs to FoxP3+ Tregs in the TME. Further studies combining CKM with immune checkpoint inhibitors and/or chemotherapy are warranted to evaluate the impact of preoperative TME modulation on long-term oncologic outcomes in CRC. Clinical trial information: NCT01545141 .

A novel rapid Th9/Tc9-polarized CAR-T manufacturing platform to enable metabolic fitness and superior antitumor potency in solid tumors.

e14501 Background: The efficacy of CAR-T therapy in solid tumors is hindered by poor T-cell fitness and rapid exhaustion within the tumor microenvironment (TME). IL-9-secreting Th9/Tc9 subsets possess superior adaptability and persistence compared to canonical Th1/Tc1 cells. We present ToughCAR, a rapid manufacturing platform generating Th9/Tc9-polarized CAR-T cells with enhanced metabolic fitness and antitumor potency. Methods: A head-to-head comparison was performed between CEACAM5-specific C-CAR (conventional) and ToughCAR generated from healthy donors and patients. Assessments included flow cytometric, cytotoxicity, and cytokine assays. Metabolic fitness and exhaustion resistance were evaluated via repeat antigen stimulation under hypoxia, with transcriptional profiling (bulk RNA-seq) at pre-stimulation, Round 1, and Round 3. In vivo efficacy and pharmacokinetics were investigated in NCG mice bearing N87 xenografts treated with C-CAR or ToughCAR at escalating doses (0.5–2×10⁶ cells). Results: The 7-day ToughCAR process achieved Th9/Tc9 polarization. Phenotypically, ToughCAR enriched stem-like memory subsets (Tscm: 91.6% vs 77.1%, p = 0.0206) and minimized differentiation (CD197-: 0.6% vs 18.9%, p = 0.005). Functionally, ToughCAR exhibited 4–7-fold higher secretion of IL-2 and TNF-α, while maintaining comparable IFN-γ levels and cytotoxicity relative to C-CAR. Under repeat stimulation, ToughCAR exhibited &gt; 20-fold greater proliferation. RNA-seq revealed metabolic rewiring in ToughCAR cells, characterized by upregulated oxidative phosphorylation and glycolysis pathways, enabling sustained fitness. In vivo, ToughCAR displayed superior dose-dependent expansion (Table). At 1×10⁶ cells, ToughCAR achieved ≈10-fold higher Cmax (p = 0.0021) and ≈8-fold higher AUC 0-56 (p = 0.0012) compared to C-CAR. Notably, superior expansion and persistence were maintained even at the lowest dose (0.5×10⁶). This robust expansion translated into complete tumor regression at doses1×10⁶, with cured mice rejecting secondary tumor rechallenge. Conclusions: ToughCAR establishes a novel manufacturing paradigm by generating metabolically plastic, exhaustion-resistant Th9/Tc9 cells. By overcoming exhaustion and ensuring robust expansion, ToughCAR addresses critical barriers in solid tumor therapy. Crucially, this superior potency translates into clinical benefit, supported by a promising 57% objective response rate (ORR) in patients with heavily pre-treated colorectal cancer in our ongoing first-in-human study. Pharmacokinetics of CAR-T cells in xenograft model (n=5 per group). Dose Level (Cells) Group Mean AUC 0-56d (copies × days) Mean Cmax (copies/μg) 0.5 × 10⁶ C-CAR 3.08 × 10⁴ 1.86 × 10³ ToughCAR 3.85 × 10⁵ 1.45 × 10⁴ 1 × 10⁶ C-CAR 5.73 × 10⁵ 2.99 × 10⁴ ToughCAR 4.38 × 10⁶ 2.85 × 10⁵ 2 × 10⁶ C-CAR 9.47 × 10⁵ 5.71 × 10⁴ ToughCAR 7.34 × 10⁶ 3.70 × 10⁵

KEYMAKER-U01J: Calderasib plus pembrolizumab with or without cetuximab as first-line treatment for advanced or metastatic nonsquamous non–small-cell lung cancer (NSCLC) with <i>KRAS</i> G12C mutations.

TPS8679 Background: The anti–PD-1 pembrolizumab (pembro) + chemotherapy (chemo) is a standard of care first-line therapy for metastatic NSCLC with no EGFR or ALK alterations. Despite these advances, here remains an unmet need for patients with tumors that have certain mutations, including those in the KRAS gene. KRAS mutations are associated with poor OS in NSCLC. Calderasib (MK-1084), a next-generation, selective KRAS G12C-GDP covalent inhibitor, has previously demonstrated preliminary antitumor activity in combination with pembro ± chemo in KRAS G12C–mutant metastatic NSCLC in the phase 1 KANDLELIT-001 study. The anti-EGFR cetuximab has shown promising efficacy in combination therapies in NSCLC with KRAS G12C mutations. The phase 2 KEYMAKER-U01J study (NCT07252739) is evaluating the addition of investigational agents to pembro in advanced or metastatic nonsquamous NSCLC with KRAS G12C mutations; the treatment arms presented here include pembro + calderasib ± cetuximab. Methods: This phase 2, randomized, open-label study is enrolling participants (pts) aged ≥18 years with previously untreated histologically or cytologically confirmed stage IIIB, IIIC, or IV (M1a, M1b, or M1c) nonsquamous NSCLC (AJCC v9), with a KRAS G12C mutation that is ineligible for curative resection or chemoradiation. Pts must also have measurable disease per RECIST v1.1, an ECOG PS of 0 or 1, and provide a tumor sample for biomarker analysis. Following a safety lead-in of ~10 pts in arm 3, 1:1:1 randomization of ~120 pts will occur. In arm 1 (control arm), pts will receive up to 18 cycles of pembro 400 mg Q6W intravenously (IV) plus carboplatin AUC 5 mg/mL/min up to 2 cycles and pemetrexed 500 mg/m 2 Q3W until discontinuation criteria are met. Pts in arm 2 (reference arm) will receive up to 18 cycles of pembro 400 mg IV Q6W plus calderasib orally until discontinuation criteria are met. Pts in arm 3 will receive up to 18 cycles of pembro 400 mg IV Q6W plus calderasib with cetuximab 500 mg/m 2 IV Q2W until discontinuation criteria are met. Discontinuation criteria include unacceptable AEs, PD, occurrence/progression of another malignancy, or pt/physician withdrawal. Randomization will be stratified by PD-L1 tumor proportion score (&lt; 50% vs ≥50%). Dual primary endpoints are safety (dose-limiting toxicities, AEs, and AEs leading to study discontinuations) and objective response (CR or PR) per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints are duration of response and PFS per RECIST v1.1 by BICR, OS, and pharmacokinetic characterization. On-study tumor imaging will occur Q6W until week 24, Q9W until week 51, then Q12W, or more frequently if clinically indicated. AEs will be graded per NCI CTCAE v5.0. Enrollment began in December 2025, with 80–105 sites scheduled to enroll globally. Clinical trial information: NCT07252739 .

Hetrombopag plus caffeic acid tablets for the treatment of chemotherapy-induced thrombocytopenia in solid tumors: A single-center, open-label, phase II trial.

12130 Background: Chemotherapy-induced thrombocytopenia (CIT) frequently complicates cancer therapy, resulting in treatment delays, dose reductions, and premature discontinuation. However, no widely approved therapies are currently available to address this clinical gap. This phase II trial was designed to evaluate the efficacy and safety of the thrombopoietin receptor agonist hetrombopag combined with caffeic acid tablets in this patient population. Methods: This is a single-arm, single-center, prospective phase II trial (ChiCTR2400086043) designed to enroll patients with malignancies experiencing thrombocytopenia (platelet count ≤ 75 ×10⁹/L) during anti-cancer therapy. Eligible participants received hetrombopag 5 mg once daily (QD) plus caffeic acid tablets 0.3 g three times daily (TID) for 14 consecutive days. The primary endpoint is the proportion of patients achieving a platelet count ≥100×10⁹/L after treatment; secondary endpoints included time to first response (platelet count ≥100×10⁹/L), proportion of patients with platelet recovery to ≥ 75×10⁹/L, and safety profile of the regimen. Results: A total of 65 patients were enrolled between 24 June 2024 and 25 December 2025.The median age of enrolled patients was 60.0 years, and 70.8% of patients had a baseline platelet count of ≥50×10⁹/L. The most common tumor types were colorectal cancer (23.1%) and gastric cancer (13.8%). The majority (41.5%) received oxaliplatin-based chemotherapy, 26.2% received immunotherapy plus chemotherapy, and 18.5% received targeted therapy plus chemotherapy. After treatment with hetrombopag plus caffeic acid tablets, 84.6% (55/65) of patients achieved platelet counts ≥100×10⁹/L and 87.7% (57/65) achieved ≥75×10⁹/L. The median durations from the first dose of hetrombopag plus caffeic acid tablets platelet response ≥100×10⁹/L was 7 days (range:5–9). Adverse drug reactions were reported in 17 patients; no drug-related adverse events of grade ≥3 occurred. Conclusions: Hetrombopag plus caffeic acid tablets confer outstanding therapeutic efficacy in CIT while maintaining a well-tolerated safety profile. This oral regimen fulfills an unmet clinical need and provides a practical, non-invasive therapeutic option for CIT management. Clinical trial information: ChiCTR2400086043.

Total tumor burden: An automated estimate of scan-level volumetric lung tumor burden from routine CT.

e15012 Background: In clinical trials, tumor burden and treatment response are routinely estimated by applying RECIST 1.1 criteria to CT scans. Although operationally practical, this framework depends on manual selection and linear measurement of a limited number of lesions, making treatment assessment sensitive to lesion choice and introducing operator variability. Baseline disease burden and response categorization influence trial interpretation, so there is a need for scalable approaches that estimate scan-level lung tumor burden from routine CT and are compatible with established trial workflows and standards. Methods: We applied a machine learning workflow to routine CT thorax imaging to support lesion-level segmentation of malignant lung lesions. The study used a retrospective multi-institutional lung CT dataset where lesions were annotated by two expert radiologists using predefined consensus criteria to serve as reference standards for model training and evaluation. Segmentation of malignant lesions was performed using a 2D U-Net architecture and the scan-level lung tumor burden was computed as the aggregate volume of segmented malignant lesions. Results: Performance was evaluated on an independent test set by comparing model segmentations with expert reference annotations. DICE similarity stratified by lesion size was the primary segmentation endpoint, supported by targeted error analysis for common failure modes. Scan-level lung tumor burden was calculated as the sum of malignant lesion volumes and compared with RECIST-derived linear measurements (sum of target lesion diameters). Analyses quantified concordance and rank-order differences in disease extent across patients, with focused evaluation in multifocal lung disease where target-based sampling is expected to be most sensitive to lesion selection. Conclusions: This work established the feasibility and evaluation framework for a modular workflow to estimate scan-level lung tumor burden from routine CT using lesion segmentation and malignancy characterization. Tumor burden estimation in clinically relevant settings such as multifocal lung disease indicates that this approach could serve as a complementary descriptor alongside RECIST for baseline characterization and exploratory trial analyses. Subsequent phases will incorporate lesion detection, longitudinal tracking, and outcome-linked validation to support stepwise progression toward volumetric response assessment.

Dinutuximab beta in combination with chemotherapy in patients with refractory or relapsed neuroblastoma: A national prospective study (2020/ABM/01/00055).

10037 Background: The ChIm-NB-PL phase IIa trial (EudraCT: 2021-003832-96) evaluated the safety and efficacy of dinutuximab beta (DB) combined with chemotherapy (Cht) in children with relapsed or refractory high-risk neuroblastoma (RR-HRNB), a population with limited therapeutic options and poor prognosis. Methods: Twenty-eight patients aged 1–18 years with RR-HRNB received DB combined with temozolomide/irinotecan (TemIri) or with N5/N6 chemotherapy of the German Pediatric Oncology and Hematology Group (GPOH) protocol. DB was administered as a 5-day continuous infusion (10 mg/m²/day) every 21 days, concurrently with TemIri or sequentially after GPOH. Treatment allocation and number of cycles were individualized based on prior therapy, disease dynamics, metastatic burden, and toxicity. Responses were assessed after 3 and 5–7 cycles. The primary endpoint was safety and best response (complete or partial response); secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: Between 2021 and 2025, 28 patients were enrolled (25% female). Median follow-up was 28.4 months. Median age was 40.9 months at diagnosis and 51.0 months at study entry. Eleven patients had refractory disease (Group 1), while 17 had relapsed or progressive disease (Group 2; 12 early and 5 late relapses). MYCN amplification was present in 9 patients, and 12 had involvement of more than one metastatic compartment. In Group 1, best response rate (BRR) was 91.7%, end-of-treatment response rate 75.0%, and metastatic complete response 58.3%; 1-year PFS was 0.67 ± 0.13. In Group 2, BRR was 87.5% (CR 56.3%, PR 31.3%), with higher BRR in late versus early relapse (100% vs 80%); 1-year PFS was 0.81 ± 0.09. Overall, 71.4% of patients were alive at last follow-up; 1-year PFS and OS were 0.75 ± 0.08 and 0.82 ± 0.07, respectively. Grade ≥3 non-hematologic toxicities occurred 42 times with TemIri and 35 times with GPOH (CTCAE v4.0). Neurotoxicity, pain, capillary leak syndrome, and cytokine release syndrome were comparable between regimens and consistent with DB monotherapy. Conclusions: DB combined with TemIri or GPOH chemotherapy demonstrates high antitumor activity with acceptable and manageable toxicity in children with RR-HRNB. Response-adapted sequencing and individualized chemotherapy selection may improve disease control, including metastatic responses, in this high-risk population. Clinical trial information: 2021-003832-96.

Trastuzumab deruxtecan (T-DXd) + durvalumab (D) in patients (pts) with previously untreated HER2+ unresectable/metastatic breast cancer (mBC): Final analysis from DESTINY-Breast07.

1012 Background: T-DXd is approved for adult pts with HER2+ mBC who received a prior anti-HER2–based regimen, or as 1L therapy when given in combination with pertuzumab (P). DESTINY-Breast07 (NCT04538742) is a Phase 1b/2, open-label, platform study exploring the safety, tolerability, and antitumor activity of T-DXd ± other anticancer agents in HER2+ mBC. 1L T-DXd ± P recently showed encouraging clinical activity and safety profiles consistent with previous reports. D, an anti-PD-L1 antibody, has shown efficacy in combination with T-DXd in HER2-low, hormone receptor (HR)–negative mBC. As part of the DESTINY-Breast07 final analysis, here we report the dose-expansion phase for T-DXd + D as a 1L treatment in HER2+ mBC. Methods: Pts had locally assessed HER2+ (IHC 3+ or IHC 2+/ISH+) mBC. A disease-free interval of ≥12 months (mo) from (neo)adjuvant therapy was required; no prior therapy for mBC was allowed. Pts were stratified by HR (positive vs negative), disease (recurrent vs de novo), and PD-L1 status (positive vs negative; positive defined as ≥1% IHC). Pts received T-DXd 5.4 mg/kg IV, in combination with D 1120 mg IV, every 3 weeks. Primary endpoints were safety and tolerability; secondary endpoints included confirmed ORR (cORR), duration of response (DOR) and progression-free survival (PFS) per RECIST 1.1 by investigator, time to progression on subsequent therapy or death (PFS2) by investigator, and overall survival (OS). Results: At data cutoff (DCO) (January 31, 2025), 64 pts were randomized to the T-DXd + D module, and 63 received treatment. Median follow up was 30.1 mo; median total treatment duration was 26.7 mo for T-DXd and 24.6 mo for D. Efficacy results are given in the Table. The most common adverse events (AEs) were nausea (79.4%), vomiting (46.0%), neutropenia (46.0% by grouped term [GT]), anemia (44.4% by GT), and fatigue (38.1%). Grade ≥3 AEs occurred in 58.7% (n=37/63) and serious AEs in 30.2% (n=19/63) of pts. There were two deaths due to AEs (3.2%): one pt with neutropenia and septic shock and one pt with sepsis. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis events occurred in 11 (17.5%; Grade 1, n=1; Grade 2, n=8; Grade 3, n=2) pts. Additional data by subgroups (stratification factors and biomarkers) will be presented. Conclusions: Encouraging clinical activity was seen for T-DXd + D as a 1L treatment for HER2+ mBC. Safety profiles were consistent with the known profiles for each therapy, with no fatal ILD events. These promising results provide a rationale for further investigation of this treatment combination. Clinical trial information: NCT04538742 . T-DXd + D (n=64) cORR (80% CI), % 82.8 (75.2, 88.8) mDOR* (Q1–Q3), mo 36.1 (23.3, NE) mPFS* (80% CI), mo 37.7 (35.1, NE) PFS rate at 24 mo (80% CI), % 75.5 (67.2, 82.0) mOS (80% CI), mo NE (NE, NE) mPFS2 (80% CI), mo NE (NE, NE) *Most pts were censored at DCO; m, median; NE, not evaluable; Q, quartile.

First-in-human phase I/II study of MRG006A, a first-in-class Glypican-3 (GPC3)–targeted antibody-drug conjugate (ADC), in patients (pts) with advanced hepatocellular carcinoma (HCC).

3028 Background: Pts with advanced HCC face limited treatment options beyond immunotherapy and anti-angiogenic agents. GPC3, a surface antigen overexpressed in HCC and associated with poor prognosis, represents a promising therapeutic target due to its tumor-specific expression. MRG006A, a potential first-in-class GPC3-targeted ADC, demonstrated potent pre-clinical anti-tumor activity. Here we report the preliminary safety and efficacy of MRG006A in advanced HCC with intermediate/high GPC3 expression from a phase I/II trial. Methods: MRG006A-001 (NCT07093970) is an ongoing first-in-human, open-label, multi-center phase I/II study. The phase I study comprises dose escalation (Ia) and dose optimization/expansion (Ib) stages. The dose-escalation employed an accelerated titration plus 3+3 design. Eligible pts who had failed standard treatment received MRG006A intravenously at 1.6-6.4 mg/kg every three weeks (Q3W). GPC3 expression was only required for dose expansion cohorts. The primary endpoints were safety and tolerability. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), clinical benefit rate (CBR), etc. Results: As of Dec 19, 2025, the maximum administered dose was established as 6.4 mg/kg Q3W, with ≥ G3 treatment-related adverse event (TRAE) of platelet count decreased reported in all six pts at this dose level and dose-limiting toxicity (G4 platelet count decreased) observed in one patient. During dose escalation, tumor response was observed at 3.2 mg/kg and 4.8 mg/kg. Accordingly, dose optimization in phase Ib proceeded with three levels (3.2, 4.0, and 4.8 mg/kg Q3W). Twenty-six HCC pts with intermediate or high GPC3 expression were enrolled across three cohorts; 61.5% had BCLC stage C disease; median 2 (range 1-4) prior lines of therapy, and 25 (96.2%) had received immune checkpoint inhibitors and anti-angiogenic agents. Among 25 efficacy evaluable pts, ORR, DCR and CBR were 23.1%, 68.0% and 32.0%, respectively. In pts with high GPC3 expression (n=12), ORR, DCR and CBR increased to 33.3%, 75.0% and 50.0%, respectively; median PFS and DOR were 7.0 and 4.2 months (median follow-up 5.7 months). Most pts (24 [92.3%]) experienced TRAE of any Grade. TRAEs of ≥ G3 were reported in 11 (42.3%) pts . The most common TRAEs were platelet count decreased (88.5%), blood bilirubin increased (50.0%), AST increased (46.2%), white blood cell count decreased (38.5%), and nausea (30.8%). No treatment-related permanent discontinuations or deaths occurred. Conclusions: MRG006A demonstrated manageable safety and promising anti-tumor activity in heavily pretreated pts with GPC3-expressing advanced HCC. Our findings support the therapeutic potential of GPC3-directed ADC and merits further clinical investigations. Clinical trial information: NCT07093970 .