Browse Articles
Discover research articles across all indexed journals
Association of CT-based deep learning–derived consensus molecular subtypes with survival outcomes in locally advanced colon cancer: A secondary analysis of the phase III OPTICAL trial.
3639 Background: The Consensus Molecular Subtypes (CMS) provide a robust framework for the biological stratification of colorectal cancer (CRC), but their clinical use is limited by the cost and complexity of transcriptomic profiling. We evaluated the prognostic and predictive utility of a non-invasive, CT-based deep learning model for CMS classification (CT-CMS) in patients with locally advanced colon cancer (LACC) enrolled in the OPTICAL trial. Methods: Patients from the OPTICAL trial with available baseline venous-phase contrast-enhanced CT images were included. A previously validated deep learning model was applied to predict CMS subtypes (CMS1-4). The association between CT-CMS and survival outcomes, including disease-free survival (DFS) and overall survival (OS), was assessed using multivariable Cox proportional hazards regression models adjusted for age, sex, TNM stage, and tumor location. Results: The study included 394 patients, with 189 patients in the neoadjuvant chemotherapy (NAC) group and 205 in the upfront surgery group. The median follow-up was 48.0 months. The distribution of CT-CMS subtypes was as follows: CMS1 (n=64, 16.2%), CMS2 (n=135, 34.5%), CMS3 (n=69, 17.5%), and CMS4 (n=126, 32.0%). In the total population, CMS3 showed the most favorable outcomes, with a 3-year OS rate of 96.1% (95% CI, 90.9%-100.0%) and a 3-year DFS rate of 87.9% (95% CI, 80.3%-96.2%). Multivariable analysis confirmed that CMS3 was independently associated with superior prognosis compared to CMS1 (adjusted hazard ratio [aHR] = 0.39, 95% CI 0.17-0.92, p = 0.030). In the NAC group, CMS was a significant independent prognostic factor for DFS (p = 0.044), with CMS3 (p = 0.027) and CMS2 (p = 0.046) showing significant improvement over CMS1. Notably, patients with CMS2 tumors exhibited significant survival benefits from neoadjuvant chemotherapy compared with upfront surgery, with improved OS (aHR = 0.08, 95% CI 0.01-0.62, p = 0.016, log-rank p = 0.002) and DFS (aHR = 0.45, 95% CI 0.20-0.99, p = 0.047). Conclusions: CT-based CMS3 was associated with favorable prognosis, while CMS2 identified patients were most likely to benefit from neoadjuvant chemotherapy. These findings support the clinical utility of CT-CMS as a non-invasive, pre-treatment tool for molecular stratification in LACC. All 3-year DFS rate HR (95% CI) P CMS1 76.4% (66.2%-88.2%) Reference - CMS2 79.8% (73.1%-87.1%) 0.67 (0.36-1.27) 0.219 CMS3 87.9% (80.3%-96.2%) 0.39 (0.17-0.92) 0.030 CMS4 78.2% (71.3%-85.8%) 0.89 (0.49-1.64) 0.715 NAC vs surgery (reference) * CMS1 70.3% vs 81.4% 1.20 (0.45-3.15) 0.717 CMS2 86.5% vs 72.8% 0.45 (0.20-0.99) 0.047 CMS3 90.2% vs 85.2% 0.36 (0.08-1.60) 0.180 CMS4 78.2% vs 78.3% 1.04 (0.50-2.17) 0.915 * For treatment comparisons, 3-year DFS rates are presented as NAC versus surgery.
MAGMA: Multi-arm glioblastoma Australasia phase 3 trial.
2004 Background: MAGMA (ACTRN12620000048987; COGNO cooperative trials group) is a prospective, open-label, partial factorial randomized platform trial with optional randomization, aiming to improve treatments for glioblastoma (GBM). Two initial hypotheses were tested: Question 1 (Q1), ‘early’ daily temozolomide (TMZ) as soon as possible postop, pre-radiotherapy (RT); and Question 2 (Q2), ‘extended’ adjuvant TMZ beyond 6 cycles. Prior phase 2 studies suggest longer survival with early TMZ and inconsistent outcomes with extended adjuvant TMZ. MAGMA used baseline randomization with molecular stratification aiming for robust randomized evidence. Methods: Participants (pts) with newly diagnosed GBM (CNS WHO 2016) could be randomized to each question, stratified by extent of resection and IDH status (Q1 and Q2) and MGMT methylation (Q2 only). For Q1, pts were randomized to daily TMZ (75 mg/m 2 ) initiated as soon as possible after surgery followed by standard RT-TMZ (either 15 or 30 fractions), or RT-TMZ alone. For Q2, pts were randomized prior to adjuvant TMZ, to stop after 6 cycles or continue until progression. Primary outcome was overall survival (OS) from initial surgery. Secondary outcomes included progression-free survival (PFS), time to next treatment, OS from each randomization, clinically significant toxicity and health-related quality of life. Results: From September 2020 to July 2023, 347 pts consented across 28 Australian sites including 6 regional sites. Median follow-up was 40 months; final data cutoff was 31 July 2025. Mean age was 60 years (range 21-85), 60% were male, 92% IDH-wildtype, 42% MGMT-methylated, 56% had gross total resection and 13% biopsy-only. For Q1 (n=259), pts randomized to early TMZ (n=131) started TMZ at median 21 days post-surgery with mean exposure 13 days. Concurrent TMZ exposure, time to starting RT (median 34 vs 33 days), RT completion and toxicity (G3+ 34% vs 31%) were similar between arms. Median OS (months; 95% CI) was 16 (14-20) with early TMZ vs 20 (17-22) for control, HR 1.18 (0.89-1.56), p=0.24. Median PFS was 8 (7-9) vs 9 (7-12), HR 1.15 (0.88-1.52), p=0.31. For Q2 (n=291), among pts randomized to extended adjuvant TMZ (n=146), only 42% remained progression-free through 6 cycles and received more than 6 adjuvant TMZ cycles. Toxicity was similar between arms (G3+ 34% vs 31%). Median OS was 20 months (17-22) with extended adjuvant TMZ vs 18 (15-20) for control, HR 0.82 (0.63-1.06), p=0.13; after multivariable analysis, HR 0.73 (0.56-0.95). Median PFS was 9 (8-9) vs 9 (7-10), HR 0.88 (0.69-1.13), p=0.32. Conclusions: Early TMZ does not improve OS in pts with newly diagnosed GBM. Extended adjuvant TMZ beyond 6 cycles was safe, with insufficient evidence of improved OS in the primary analysis, although moderate effects remain plausible. Notably, many pts had progression before completing 6 cycles. Collaboration enables large-scale, pragmatic cancer trials across diverse healthcare settings in Australia. Clinical trial information: ACTRN12620000048987.
NRG-GY036: A phase III trial of one vs. two years of maintenance olaparib, with or without bevacizumab, in patients with <i>BRCA1/2</i> -mutated or homologous recombination deficient (HRD+) ovarian cancer following response to first line platinum-based chemotherapy.
TPS5634 Background: The profound progression-free survival (PFS) benefit shown in the SOLO-1 and PAOLA-1 randomized clinical trials set the standard of 2 years of PARP inhibitor (PARPi) maintenance with olaparib, with or without bevacizumab, in patients with BRCA1/2 -mutated and homologous recombination deficient (HRD+) ovarian carcinoma after response to frontline platinum-based chemotherapy, and this was approved by the FDA in December 2018. However, newer studies have elucidated the long-term toxicity risk of prolonged PARPi use, specifically treatment-related myeloid neoplasms (TMN), along with detrimental effects on subsequent platinum-based chemotherapy and overall survival. Given this, we seek to test de-escalation of PARPi maintenance therapy, evaluating if 1 year is non-inferior to 2 years, using a pragmatic and streamlined study design. Methods: NRG GY036 is a phase III, randomized, non-inferiority study of 1 versus 2 years of olaparib maintenance, with our without bevacizumab, in those with BRCA1/2 -associated and HRD+ ovarian cancer, after response to frontline platinum-based chemotherapy (NCT06580314). Key eligibility criteria include a deleterious BRCA1/2 mutation, germline or somatic, or HRD+ tumor using any CLIA-certified test. Patients must have undergone cytoreductive surgery and had a clinical response after a minimum of 4 cycles of platinum-based chemotherapy. The primary endpoint is investigator assessed PFS using RECIST v1.1 criteria for 1 vs. 2 years in a modified intention to treat (mITT) population, where time at risk starts 360 days after randomization to account for the time where both arms receive the same treatment. Secondary endpoints include overall survival (OS), PFS2, PFS in the ITT and as-treated populations, and toxicity including rates of TMN. The statistical design is based on a hazard ratio non-inferiority margin of 1.36 (1-sided alpha 0.05, power 0.9). The null hypothesis will be rejected if HR <1.15, giving 90% certainty that the true median PFS loss is not more than 10 months based on historical controls from SOLO1 and the HRD+ subgroup of PAOLA-1. We anticipate enrolling 880 patients to have at least 735 patients in the mITT population. This IND-exempt study pragmatically mimics real-world clinical practice by using commercially available drug, implementing broad eligibility criteria, allowing physician’s choice bevacizumab, and incorporating individual physician and institution’s standard practices. It also employs a streamlined approach with minimal data collection forms and abbreviated adverse event reporting. NRG GY036 was activated on 1/16/2025. The first patient enrolled on 3/12/2025. As of 1/16/2026, there are 676 participating sites and 152/880 (17%) patients enrolled. Clinical trial information: NCT06580314 .
Clinical outcomes in phase 1 study of EBC-129, a first-in-class, anti–N256-glycosylated CEACAM5 and CEACAM6 antibody-drug conjugate (ADC), in patients with gastroesophageal adenocarcinomas.
3033 Background: Gastro-oesophageal adenocarcinoma (GEA) is an aggressive malignancy with limited treatment options. EBC-129 is a first in class MMAE-linked ADC against both, N256-glycosylated CEACAM5 and 6. Previously reported dose escalation data identified 1.8 and 2.2 mg/kg Q3W as the RP2Ds. Here we report pooled safety and efficacy data of GEA patients enrolled in dose escalation (DEs) and expansion (DEx) cohorts of the Phase 1 study (NCT05701527). Methods: This study consisted of DEs and DEx cohorts. Previously treated patients with histologically confirmed, locally advanced or metastatic GEA with centrally confirmed immunohistochemistry (IHC) positivity at ≥20% at 2 + and/or 3 + on archival samples were enrolled. Objectives were to evaluate safety, efficacy, PK of EBC-129, administered every 3 weeks. Results: A total of 21 GEA patients were enrolled (4 in DEs and 17 in DEx). Pre-screening data shows that 57% and 77% are positive in IHC at cut-offs of ≥20% at 2/3 + and ≥1% at 3 + , respectively. Patients received 1.2 (n=1), 1.8 (n=9), 2.0 (n=1) or 2.2 (n=10) mg/kg EBC-129 Q3W. 81% were male; mean age 59.0 years; median 3 (range 1-9) lines of previous treatments with 62% prior taxane treated. At data cut-off (9 th Jan 2026), 3 patients are continuing treatment, 12 patients had radiological progression, 3 had clinical progression, and 3 patients withdrew from treatment. Among the 17 evaluable patients, the ORR, DCR and median PFS are outlined in the table below. ORR of 50% was seen in patients with an IHC ≥50%. 65% of patients had any tumour shrinkage overall. Infusion related reactions (IRRs) were seen in 43% of patients most being Grade 1/2 and resolved or reduced with premedication; except for 1 patient who had Grade 3 IRR. The other ≥3 Grade TRAEs (CTCAE v5) included neutropenia (52.4%), anaemia (14.3%), WBC count decreased (9.5%), diarrhoea (9.5%); and amylase increase, vomiting, anorexia, nausea in 1 patient each (4.8%). 4 patients (19.0%) experienced peripheral neuropathy (3 grade 1, 1 grade 2). Other than the 1 patient with Grade 3 IRR, no other drug-related discontinuations occurred in this cohort. Higher antigen expression levels correlated with better response. Conclusions: EBC-129 shows promising clinical activity in heavily treated GEA patients with a manageable tolerability profile. Further evaluation in 2L GEA is planned. Clinical trial information: NCT05701527 . Efficacy results from EBC-129-01, GEA cohort. Dose IHC status * ORR^ DCR mPFS (wks) 1.8 mg/kg ≥20% (n=7) 28.5% 85.7% 18.1 1.8 mg/kg ≥50% (n=4) 50% 100% 29.2 2.2 mg/kg ≥20% (n=8) 25.0% 75.0% 10.1 2.2 mg/kg ≥50% (n=5) 40% 80% 9.3 Overall (All doses) ≥20% (n=17) # 29.4% 82.4% 17.86 Overall (All doses) ≥50% (n=10) # 50% 90% 21.4 *Centrally confirmed IHC positivity at 2 + and/or 3 + on archival samples were enrolled; ^Includes one patient with unconfirmed response; #1 patient each at 1.2 mg/kg and 2.0 mg/kg.
Outcomes of malignant peripheral nerve sheath tumors in neurofibromatosis type 1 and sporadic patients: A 25-year experience from a sarcoma referral center.
11570 Background: Malignant peripheral nerve sheath tumors (MPNST) are rare, aggressive soft-tissue sarcomas frequently associated with neurofibromatosis type 1 (NF1). Prospective trials are scarce, and prognostic factors and treatment effects remain incompletely defined. Methods: We conducted a retrospective observational cohort study of 200 patients (215 tumor episodes) with histologically confirmed MPNST treated at a national sarcoma referral center between 2000 and 2025. Overall survival (OS) and progression-free survival (PFS) were estimated via Kaplan–Meier methods. Multivariable Cox models with multiple imputation (MICE, m=40) were adjusted for clinical factors. Restricted mean survival time (RMST) at 5 years quantified absolute survival differences. Interaction analyses assessed heterogeneity of radiotherapy (RT) effects. Results: Median age was 40 years; 51.5% of patients had NF1. Median OS and PFS were 74.6 and 9.1 months, respectively. NF1-associated MPNST had significantly shorter OS (28.5 vs 141.0m; p=0.012), with a 5-year RMST reduction of 8.5 months (95% CI -15.0 to -2.3; p=0.01). In the multivariable Cox model with multiple imputation, advanced stage (HR 2.28; 95% CI 1.68–3.09; p<0.001), higher FNCLCC grade (HR 1.95; 95% CI 1.39–2.75; p<0.001), NF1 status (HR 1.67; 95% CI 1.11–2.51; p=0.014), central tumor location (HR 1.63; 95% CI 1.02–2.60; p=0.041), and increasing age (HR 1.04 per year; 95% CI 1.02–1.05; p<0.001) were independently associated with inferior OS, whereas female sex was strongly protective (HR 0.43; 95% CI 0.29–0.66; p<0.001). Major biopsy-surgery histologic discordance occurred in 21.6% of cases, and diagnostic delays > 60 days in 28.4%. A significant interaction was observed between RT and surgical margins (p_int=0.028): RT markedly improved OS in R1/R2 resections (HR 0.31, 95% CI 0.16–0.61) and in locally advanced disease, but not after R0 resection. In NF1 patients, imaging-detected tumors had better surgical margins and lower risk of synchronous metastasis despite similar tumor size. Conclusions: MPNST outcomes remain poor, particularly in NF1. Radiotherapy confers a clear survival benefit in high-risk surgical contexts. Optimizing diagnostic pathways, especially in NF1 patients, may improve outcomes. Survival Predictors (Multivariable OS) Hazard Ratio (95% CI) p-value Stage 2.28 (1.68–3.09) <0.001 FNCLCC Grade 1.95 (1.39–2.75) <0.001 NF1-associated 1.67 (1.11–2.51) 0.014 Central Location 1.63 (1.02–2.60) 0.041 Female Sex 0.43 (0.29–0.66) <0.001 RT Benefit in R1/R2 Resection 0.31 (0.16–0.61) 0.001
3D Structural Revelations of Neoadjuvant Hormonal Therapy Treatment in High Risk Localized Prostate Cancer by Light-Sheet Imaging.
e17124 Background: Neoadjuvant hormonal therapy for high-risk (Gleason score ≥ 8), high volume localized prostate cancer produces heterogeneous architectural changes that are difficult to assess on 2D histology. We assessed whether three-dimensional (3D) light-sheet imaging may add additional qualitative information for assessing Minimal Residual Disease (MRD) after neoadjuvant treatment. Methods: Ten patients of the neoadjuvant GUNS clinical trial (NCT04812366) receiving 24 weeks of doublet hormonal therapy (LHRHa + APA) contributed paired pre-treatment biopsies (n = 10) and post-treatment radical prostatectomy (RP) tissue (n = 10). FFPE tissues were cleared using a modified iDISCO protocol and stained with an H&E fluorescent analogue (To-Pro-3 for nuclei, eosin for stroma). Stained and cleared tissues were imaged on the Aurora 3Di light-sheet microscope and reviewed in 3D and 2D by a genitourinary pathologist. Qualitative features recorded included tumor volume, cellular and acinar connectivity, stromal remodeling, and degenerative changes. Results: High-volume carcinoma in biopsies frequently corresponded to highly connected residual carcinoma in RP specimens (cases 007, 021, 030, 046, 047). Several cases demonstrated reduced tumor volume with 3D structure still being highly connected (056, 070), while others showed predominantly isolated single cells with minimal connectivity (033, 034) only detectable in 3D. Similar to cellular connectivity, structural connectivity of tumor acini was visible as an interconnected angulated tubular system in 3D while appearing as discreet cavities in 2D imaging . One RP specimen (061) showed no residual carcinoma in 3D or 2D. 3D analysis highlighted infiltrative projections, acinar connectivity and reconstruction, stromal expansion, hyalinization, and heterogeneous degeneration after neoadjuvant treatment that were underestimated or not visible in 2D histology. Correlation with 2D confirmed residual tumor and added additional details on nuclear morphology. Conclusions: 3D light-sheet microscopy revealed treatment-related structural patterns as well as residual tumor architecture and volume that were not captured by 2D histology alone. Persistent lesion connectivity, architectural fragmentation, and stromal changes were readily identified in 3D. These findings suggest the use of 3D pathology could inform post-neoadjuvant response classification in prostate cancer once future work validate quantitative metrics and correlate structural features with clinical outcomes.
Tumor infiltrating lymphocytes (LM103 infusion) in solid tumors: A phase I trial evaluating clinical and immunological anti-tumor activity.
2537 Background: Tumor-infiltrating lymphocyte (TIL) therapy has shown clinical promise in melanoma, but its applicability across diverse solid tumors in Asian patients remains unclear, and exploring molecular targets to improve anti-tumor responses of TIL are needed. Methods: In the phase I investigator-initiated trial, we evaluated the safety, feasibility, and preliminary efficacy of autologous TIL therapy in twelve patients with advanced melanoma, cervical, lung, or head and neck cancers. Twelve patients who failed with standard treatments were successfully enrolled in the trail from August 2022 to December 2024. The patients received a lymphodepletion therapy which consisted of cyclophosphamide (30mg/kg) for 2 days, followed by fludarabine (25mg/m 2 ) for 5 days, approximately 24 hours before receiving the intravenous autologous TILs infusion, and then received high doses of IL-2 for 6-12 days with the purpose of maintaining T cell survival and proliferation. After a 28 days safety observation, tumor assessment according to RECIST 1.1 was conducted every 6 weeks until 6 months followed by every 12 weeks long-term follow-up. T cell receptor (TCR) sequencing was performed to explore TIL persistence in vivo after TIL infusion. Differential genes were identified via Bulk-RNA sequencing on TILs of responders and non-responders. Target gene knocking out of TIL using CRISPR/Cas9 technology was performed to enhance its anti-tumor function. Results: The most common adverse observed events were fever, anemia, nausea, hypertension, and hyponatremia. The objective response rate (ORR) was 33.3% (4/12), including one complete response (CR) and three partial responses (PR), and the disease control rate (DCR) reached 75% (9/12). Infused TILs persisted in peripheral blood and induced reversed peripheral CD4+T and CD8+T percentages. T cell receptor (TCR) sequencing revealed dynamic clonal remodeling in responders. Transcriptomic profiling of infused TILs identified ASS1 and CEP20 as genes negatively associated with therapeutic activity. CRISPR/Cas9-mediated knockout of these targets enhanced TIL memory phenotypes, cytokine production, and tumor cytotoxicity in vitro and in vivo . Conclusions: Autologous TIL monotherapy is feasible and safe. This study reveals effective TIL therapy in diverse solid tumors of Asian patients and potent anti-tumor activity of genetically enhanced ASS1 KO and CEP20 KO TILs, which offer mechanistic insights that may guide optimization of TIL therapy for broader clinical application. Trial registration number: NCT05366478. Clinical trial information: NCT05366478 .
Impact of food access and poverty on somatic genomic profiles and clinical outcomes in metastatic breast cancer.
1015 Background: Patients living in food deserts or experiencing food insecurity have higher cancer mortality rates. While neighborhood poverty correlates with more aggressive tumor biology, including higher OncotypeDX scores and rates of TP53 mutations, the associations among food access, somatic genomic profiles, and clinical outcomes in metastatic breast cancer (MBC) remain understudied. Methods: This multi-institutional retrospective cohort study included patients with MBC and circulating tumor DNA (ctDNA) testing through the Guardant360 assay from Washington University in St. Louis (N = 651), Massachusetts General Hospital (N = 349), Weill Cornell Medicine (N = 187), and Northwestern University (N = 86). Patient census tracts were linked with the USDA Food Access Research Atlas, which provides data on census-level food access throughout the United States. Deidentified data were shared across sites. We categorized patients by: Food access: Low access (LA) if ≥33% of the census tract lived > 1 mile (urban) or > 10 miles (rural) from a food store Income and food access: Low-income and low access (LILA) if the census tract was both LA and poverty rate was ≥20% We assessed descriptive differences and determined associations between LA/LILA and ctDNA profiles using multivariate analysis adjusted for race, stage, and subtype. Results: Of the 851 patients with census tract data, 46.8% lived in LA and 8.0% lived in LILA areas. Although White patients were more likely to live farther from food stores than Black patients (48.9% vs 34.4%, p = 0.003), Black patients were significantly more likely to live in LILA areas (19.2% vs 6.1%, p = < 0.001). On multivariate analysis, patients in the overall cohort living in LA areas were more likely to have RTK/RAS pathway mutations (Odds ratio [OR] 2.05, 95% confidence interval [CI] 1.36-3.09, p = 0.001), confirmed in the hormone receptor positive, HER2 negative (HR+/HER2-) cohort (OR 2.18, 95% CI 1.34-3.55, p = 0.002). Patients in the overall cohort living in LILA areas were more likely to have CCNE1 copy number variants [cnv] (OR 2.81, 95% CI 1.18-6.73, p = 0.02). Patients in LA areas had significantly shorter overall survival (OS) after first ctDNA test (24 months [mos] vs 31 mos, p = 0.01). In HR+/HER2- MBC, Black patients in LA areas had the shortest OS (11 mos) compared to those in high access areas (38 mos) and White patients in either setting (27-33 mos, p = 0.02). Conclusions: Patients with MBC living in food deserts appear to have distinct ctDNA profiles, including higher rates of RTK/RAS pathway mutations, which drive tumor growth, and CCNE1 cnv, associated with poor prognosis. We also found a significant survival disadvantage associated with living in LA areas, particularly among Black patients. These findings demonstrate the necessity of considering the intersection of tumor biology and social determinants of health in understanding and treating MBC.
Phase 1 dose escalation study of CD34 selected CD19 directed CAR T with metabolic programming in relapsed/refractory B-cell lymphoma.
2544 Background: CD19 CAR T cell therapy (CAR-19) has been a breakthrough for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-cell NHL). However, both relapse and toxicity remain major challenges. We utilized novel programming conditions aimed at enhancing the function and persistence of our CAR T products by improving metabolic fitness, via promotion of a hybrid Th1/Th17 phenotype. Additionally, CD34 selection was employed, via CD34 tag, to yield a more purified product and reduce potential toxicity. Methods: This single institution IRB approved phase 1B trial (NCT 05702853) evaluated a novel CD28 co-stimulated CAR-19 product, with metabolic programming and CD34 selection (CD19-CAR-CD34t hybrid T cells). Eligible patients had R/R B-cell NHL and were enrolled at dose level (DL) 1, 2, or 3 (1x10 6 , 1.5x10 6 , 2x10 6 CAR T cells/kg with max dose of 2.0x10 8 ). Dose escalation (Desc) used a model-assisted keyboard design. Dose-limiting toxicity (DLT) evaluation occurred in the first 28 days following infusion per CTCAE v5.0, with CRS and ICANS assessed per ASTCT criteria. The primary objectives were to evaluate safety and determine recommended dose for expansion. Results: Desc completed enrollment with 15 patients across dose levels DL1-3, DL2-3, DL3-9. NHL subtypes included DLBCL (8), mantle cell (4), follicular (2), and marginal zone lymphoma (1). Patients received a median of two prior systemic therapies (range 1-5), and 11 (73%) received bridging therapy. All patients underwent successful leukapheresis, manufacturing, CAR T infusion, and completion of the 28-day DLT evaluation. Common AEs included neutropenia (100%), fatigue (53%), and nausea (47%). One DL3 patient experienced a DLT (grade 4 lung infection). CRS was noted in 9 patients (60%; (grade 1: 7 pts; grade 2: 2 pts), with no grade 3+ events. No ICANS was observed. Six patients (40%) received tocilizumab (toci) and two (13%) received corticosteroids for CRS management with cumulative administration of 8 doses of toci (mean 0.5 doses/patient) and 20 mg of dexamethasone (mean 1.3 mg/patient) for entire cohort. With 11.1-month median follow-up, ORR/CR rates were 73%/67% (1-year PFS 0.67; 95% CI 0.47-0.95). All 10 patients with CR remained relapse-free as of 1/1/26; 2 deaths occurred due to lymphoma progression. The median percentage of CD34 CAR T cells at infusion was 67%. Median total T-cell doses were 165.1 (DL1), 262.8 (DL2), and 236.2 (DL3) x 10 6 . Data on persistence/expansion of Desc cohort are forthcoming. Conclusions: CD19-CAR-CD34t hybrid T cells showed promising efficacy and durability, with no relapses among patients with CR. There were no occurrences of either ICANS or grade 3+ CRS and limited CRS intervention needed. This is a promising toxicity profile for a CD28 co-stimulated CAR-19, likely owing to a more purified product via CD34 selection. DL3 was chosen for dose expansion and currently ongoing. Clinical trial information: NCT05702853 .
Phase II study of NC410 and FOLFIRINOX in combination with nivolumab with or without ipilimumab in patients with treatment-naive metastatic pancreatic cancer.
TPS4260 Background: Pancreatic adenocarcinoma (PDAC) is now the third leading cause of cancer-related death in the United States (1). Median overall survival for patients with metastatic PDAC is 11.1 months with first-line FOLFIRINOX chemotherapy (2) and more effective treatments are needed. A major resistance mechanism to immunotherapy in PDAC is the desmoplastic stroma (3). Collagen physically hinders T cell infiltration and suppresses immune cells in the tumor microenvironment (TME) through the Leukocyte Associated Immunoglobulin-like Receptor-1 (LAIR-1) (4). Both collagen and the complement protein C1q, overexpressed in the PDAC TME, are primary ligands for the inhibitory LAIR-1 receptor on myeloid and lymphoid cells, and binding results in immune cell downregulation (5-7). LAIR-2, primarily made by CD4+ T cells, is a competitive inhibitor of LAIR-1 that reverses the immunosuppressive effect (8). NC410 is a dimeric fusion protein of LAIR-2 with human IgG1 Fc that remodels collagen, reduces tumor growth, enhances T cell tumor infiltration, and overcomes neutrophil-mediated T cell suppression in preclinical studies (7,9,10). NC410 binds the collagen-rich PDAC TME with high avidity when compared across tumor types (7). Our group contributed to the recent phase Ib/II study demonstrating clinical activity of NC410 with pembrolizumab in patients with advanced colorectal and ovarian cancer (NCT05572684). Based on these promising results, our study combines NC410 and immunotherapy with FOLFIRINOX in the first-line setting to assess safety and clinical efficacy in patients with metastatic PDAC. Methods: This is a single-center, open-label, two-arm phase II study evaluating safety and efficacy of NC410 and FOLFIRINOX in combination with nivolumab with or without ipilimumab in patients with untreated metastatic PDAC. The two arms enroll sequentially. In Cycle 1, NC410 and FOLFIRINOX are given with nivolumab (Arm 1, n =10) or nivolumab + ipilimumab (Arm 2, n = 10). In Cycle 2 and beyond, patients in both arms receive NC410 and FOLFIRINOX every 2 weeks and can continue to receive treatment per investigator discretion. On study scans are obtained every 8 weeks. Eligible patients have untreated metastatic PDAC, measurable disease per RECIST 1.1, and are willing to undergo tumor biopsy at baseline and on treatment. Primary endpoint is safety. Secondary endpoints are disease control rate, objective response rate, progression free survival, and overall survival. Correlative studies will profile circulating neutrophils and markers of immune activation in paired whole blood and tumor biopsy samples at baseline and on-treatment at Cycle 4. Enrollment began in August 2025 and is ongoing. 10 of planned 20 patients have been enrolled; awaiting 8-week primary safety endpoint evaluation in Arm 1. Trial information: NCT06941857. References upon request. Clinical trial information: NCT06941857 .
AI-based opportunistic risk model to predict pancreatic cancer risk using pre-diagnostic contrast-enhanced CT scans.
e16470 Background: Pancreatic cancer (PC) remains a leading cause of cancer-related mortality. While surgical resection offers the best chance for survival, patients are often diagnosed late, at an inoperable stage. Consequently, identifying high-risk individuals for surveillance is critical for improved survival. While recent efforts have utilized electronic health records for early risk-stratification, the predictive value of CT scans within an opportunistic screening framework remains under-explored. We hypothesized that (a) radiomic features capturing structural changes, and (b) quantification of steatosis (fat) capturing obesity and metabolic dysfunction from across different pancreatic subregions (head, body, tail), may be able to reliably predict likelihood of PC risk, up to 3-months before disease manifestation. Methods: We curated a dataset on n = 190 studies from the University of Wisconsin Hospital containing longitudinal pre-diagnostic CT scans with IV contrast (67 patients who developed PC within a timeframe of 36-months, 123 healthy patients). Scans were reorientated, reshaped, HU’s clipped to [-200,300], and normalized. Pancreas and subregion segmentations were generated via PanSegNet. Radiomic features (intensity, laws, gradient, haralick, CoLIAGe, shape) as well as fat (ie. steatosis) features from different subregions (head, body, tail) were computed per scan. Highly correlated and low variant features were removed before further pruning via elastic net. Following cross-validation within a random forest model with 70% for training, 15% for validation, and 15% for testing, a binary classification was performed for forecasting malignancy in 3-12 months, 24-36 months, and 3-36 months. Results: A combination of 20 features including law textural features, perimeter, convexity, volume, and voxel-wise counts of fat within the pancreas and its subregions along with fat distribution discrepancies between different regions resulted in AUROCs of 76.2% ± 9.1% for 3-12 months, 77.9% ± 11.7% for 24-36 months, and 69.3% ± 9.1% for 3–36 months on the test set. These results suggest that there may be a relationship between pancreas dysfunction and the spatial distribution of pancreas fat and pancreas morphology. Conclusions: Radiomics and fat features from opportunistic CT scans may be complimentary to existing risk-stratification approaches in flagging patients at risk for PC. A large multi-institutional validation is warranted.
Final analysis of daratumumab, carfilzomib, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma.
7517 Background: Frontline therapy for patients with multiple myeloma (MM) has mainly consisted of a proteasome inhibitor and an immunomodulatory imide drug (IMiD). Anti-CD38 monoclonal antibodies are fast becoming incorporated into frontline regimens, but many patients experiencing relapse today remain naïve to this drug class. While quadruplet therapies have become a standard-of-care in the newly diagnosed setting, they have not been well studied in patients with relapsed/refractory MM (RRMM). Here, we report the final analysis of a phase 2 Multiple Myeloma Research Consortium study of daratumumab combined with carfilzomib, pomalidomide, and dexamethasone in RRMM (NCT01665794). Methods: Eligible patients had documented MM with 1-3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug. Prior exposure to a CD38-directed monoclonal antibody was exclusionary. Dose and frequency were described previously. The primary endpoint was the rate of near complete response (nCR) after 4 cycles of DaraKPd; secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: A total of 28 patients were treated with DaraKPd. Patients had received a median of 1 prior line of therapy (range 1-3), including 24 (85.7%) with prior autologous stem cell transplant, and 82% that were refractory to lenalidomide. The study reached the statistical threshold for efficacy (nCR of 39%; 95% CI 22-59%), and the study was stopped early as a result. At a median follow-up of 70.2 months, the median progression-free survival (mPFS) was 38.3 months (95 % CI 18.4 mo-not reached [NR]) and median OS (mOS) was not reached. The 36-month PFS and OS were 54% (95% CI 35-70%) and 75% (95% CI 57-87%), respectively. High-risk cytogenetics, as defined by the presence of t(4;14), t(14;16), t(14;20), deletion 17p, and 1q gain or amplification, were present in 18 (64%) patients. The mPFS in the high risk group was 42.8 mo (18.4-NR) and mOS was not reached. For patients with standard-risk cytogenetics, neither the mPFS nor mOS were reached. Of the 26 patients evaluable for MRD negativity by flow cytometry (limit of detection 10 -5 ), 17 (65%) achieved MRD-negativity and 11 (42%) had sustained MRD negativity for ≥1 year. Among patients with MRD-negativity as best response, mPFS was 69.4 mo (18.9-NR) compared to 14.0 mo (1.2-NR) in patients with MRD positivity (p = 0.002). There were no new safety signals or treatment-related deaths. Conclusions: With nearly 6 years of follow-up, DaraKPd in lenalidomide-exposed and anti-CD38 monoclonal antibody-naïve RRMM showed deep and durable responses, with a mPFS of 38.3 months and 36-month OS of 75%. These long-term follow-up data support DaraKPd as a safe and effective treatment in patients with RRMM. Clinical trial information: NCT01665794 .
Comparison of anthracycline-containing and anthracycline-free neoadjuvant regimens in HER2-positive breast cancer.
e13021 Background: Concurrent anti-HER2 therapies and chemotherapy improve response rates (43%-55% in prior studies). However, combined cardiotoxicity with anthracyclines has prompted the use of anthracycline-free regimens. This study compares the efficacy and safety of anthracycline-containing versus anthracycline-free (TCHP) neoadjuvant chemotherapy in HER2-positive early-stage breast cancer. Methods: This multicenter retrospective study analyzed HER2-positive breast cancer patients (2015–2025) treated with neoadjuvant anti-HER2 therapy and surgery. Clinicopathological, treatment, and outcome data were reviewed. Associations between regimens and pathological complete response (pCR; no residual invasive tumor in breast/axilla) and event-free survival (EFS; time to progression, recurrence, or death) were evaluated. Results: Of 358 patients (mean age 50), most had invasive ductal carcinoma, T2 tumors (74%), and N1 disease (60.9%). Common regimens were AC+DPT (35.2%) and TCHP (30.7%); 95.5% completed treatment. pCR rates were comparable between AC+DPT and TCHP (p = 0.360) but significantly lower with other regimens (OR 0.35, 95% CI 0.17–0.73; p = 0.005). HER2 3+ status and N3 involvement (HR 8.43, p = 0.038) predicted worse EFS; ER/PR status had no impact. Febrile neutropenia occurred in 8.2% (TCHP) vs. 1.6% (AC+DPT). No grade 3–4 cardiac toxicity occurred (Table 1). Conclusions: TCHP showed comparable efficacy to anthracycline-containing regimens with similar cardiac safety but higher hematological toxicity. Anthracycline-free regimens may be preferred for patients with cardiac risks. Advanced lymph node involvement remains a poor prognostic factor. Results of univariate and multivariate analyses of parameters affecting event-free survival. Univariate analysis Multivariate analysis Variables P value HR 95% CI P value HR 95% CI Grade Grade 1* 0.81 Grade 2 0.58 0.67 0.15-2.83 Grade 3 0.52 0.6 0.13-2.80 ER % (linear) 0.02 0.99 0.98-0.99 0.083 0.994 0.986-1.001 PR % (linear) 0.63 0.99 0.99-1.00 HER-2 status (+2*/+3) 0.02 9.03 1.24-65.3 0.038 8.436 1.12-63.43 Pathological subtype İDC* 0.65 İLC 0.97 0.00 0.00-6.43 Others 0.63 0.61 0.08-4.49 NOS 0.23 0.53 0.19-1.49 Treatment protocol ddAC + DPT* 0.016 TCHP 0.13 0.32 0.07-1.43 Other 0.017 2.4 1.17-5.18 ddAC+ taxan +herceptin 0.41 1.32 0.66-2.64 T stage T1* 0.04 T2 0.48 0.75 0.34-1.64 T3 0.18 1.97 0.71-5.46 T4 0.2 2.17 0.65-7.25 N stage N0* 0 0.11 N1 0.12 4.8 0.65-35.3 0.078 6.11 0.81-45.63 N2 0.1 5.4 0.69-42.3 0.163 4.38 0.54-34.97 N3 0.004 20.4 2.65-157.4 0.010 15.33 1.90-123.78
Safety and efficacy of BAL0891 as monotherapy and in combination with paclitaxel: Results from a phase I study in advanced solid tumors.
e15160 Background: BAL0891 is a first-in-class dual threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) inhibitor designed to disrupt the spindle assembly checkpoint (SAC), resulting in aberrant mitosis and tumor cell death. We report interim safety, PK/PD, and preliminary antitumor activity from the ongoing first-in-human (FIH) phase I TTK-CS-101 study evaluating BAL0891 as monotherapy (Substudy 1) and in combination with paclitaxel (Substudy 3) in patients with advanced solid tumors. Methods: Patients (pts) with advanced/metastatic solid tumors refractory to or intolerant of standard therapy were enrolled. In this ongoing, multicenter, open-label FIH phase I study, pts received escalating BAL0891 as monotherapy in Substudy 1 Regimen A (RA; D1/D8 Q3W) or Regimen C (RC; D1/D15 Q4W), or in Substudy 3 (BAL0891 D1/D15 plus paclitaxel 60 mg/m² D1/D8/D15 Q4W). The primary objectives were to assess safety/tolerability and to determine MTD/RP2D. Results: As of December 31, 2025, 61 pts received ≥1 dose across 9 dose levels (5–280 mg): Substudy 1 RA n = 42 (24 escalation, 18 backfill), Substudy 1 RC n = 9, and Substudy 3 n = 10. DLTs (neutropenia, febrile neutropenia, anemia) occurred at 160 mg (RA), 240 mg (RA/RC), and 280 mg (RC); no DLTs were reported in Substudy 3 to date. The Substudy 1 RA MTD was 240 mg, and RP2D was 160 mg. Most pts (88%) had ≥2 prior metastatic treatment lines. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 38 pts (62.3%); the most common TRAEs were neutropenia (n = 41), fatigue (G1/2; n = 17), and leukopenia (n = 15). PK in Substudy 1 RA showed predictable exposure with minimal inter-occasion variability. Thirty-nine pts were efficacy-evaluable (≥1 post-baseline assessment). Dose escalation is ongoing, and updated results will be presented. Conclusions: BAL0891 demonstrated a tolerable safety profile and consistent systemic exposure in heavily pretreated pts. These interim data support continued clinical evaluation of BAL0891 as monotherapy and in combination with paclitaxel. Clinical trial information: NCT05768932 . Best overall response and clinical outcomes. Substudy 1 (D1/D8 Q3W) Substudy 1 (D1/D15 Q4W) Substudy 3 (Paclitaxel Combination) N 23 8 8 Median prior treatment lines (range) 3 (1–5) 3 (1–6) 2 (1–5) Best overall response CR 0 1 0 PR 0 1 3 SD 16 4 4 PD 7 3 1 DCR, % (95% CI) 70 (47–87) 63 (25–92) 88 (47–100) CBR, % (95% CI) 52 (31–73) 25 (3–65) 63 (25–92) ORR, % (95% CI) 0.00 (0.00–15) 25 (7–53) 38 (9–76)
A phase II trial of neoadjuvant zanzalintinib (ZANZA) plus nivolumab (NIVO) in patients with locally advanced and/or surgically challenging clear cell renal cell carcinoma (EXPLORE-RCC).
TPS4629 Background: Immunotherapy doublet combinations (+/- vascular endothelial growth factor receptor-tyrosine kinase inhibitor [VEGFR-TKI]) are established for front-line treatment of metastatic, clear cell renal cell carcinoma (ccRCC). However, their role in the perioperative setting for locoregional ccRCC remains to be defined. We designed the EXPLORE-RCC trial to evaluate neoadjuvant ZANZA (novel, next generation VEGFR-TKI with short half-life) plus NIVO (PD-1 inhibitor) in patients with locally advanced ccRCC, where the combination has the potential to shrink the primary tumor, increase resectability, and/or allow a partial nephrectomy or minimally invasive approach. Methods: In this multisite, phase 2, open-label, single-arm trial coordinated by the Hoosier Cancer Research Network, subjects will receive ZANZA 60mg orally once daily plus NIVO intravenously per standard of care (SOC) dosing for 12 weeks (w), followed by restaging scans and an adaptive approach: (1) subjects who are deemed operable will undergo resection (Cohort A); (2) subjects who remain inoperable can receive up to 48w total of ZANZA plus NIVO (Cohort B1) with the option to undergo resection when deemed operable; or (3) subjects who have disease progression will stop protocol mandated therapy and receive subsequent SOC treatment (Cohort B2). The main inclusion criteria include age ≥ 18 years, ECOG Performance Status of 0-1, histologically confirmed ccRCC, and locally advanced (cT3/4, N0-1, with or without tumor thrombus) disease and/or deemed surgically challenging per surgeon discretion. Non-measurable metastasis per RECIST 1.1 criteria, including soft tissue metastasis with longest diameter <10mm or distant lymph nodes <15 mm in short axis are allowed. Main exclusion criteria are non-clear cell histology, measurable metastatic disease per RECIST 1.1 criteria, and prior systemic treatment for ccRCC. The primary endpoint is overall response rate (ORR) after 12w of therapy. This single arm trial is powered to detect an improvement in ORR from a historical rate of 30% to 45%, with 80% power and a 0.05 one-sided type I error. Estimating 10% drop out, 69 subjects will be enrolled. Key secondary/exploratory endpoints include efficacy outcomes (conversion to operable, disease free survival, overall survival, pathologic response), safety, surgery-related complications (including Clavien-Dindo), and biomarker correlatives. The trial is actively enrolling (ClinicalTrials.gov NCT06794229) at UT Southwestern and opening at Ohio State, Fox Chase Cancer Center, Virginia Commonwealth, Northwestern University, and Washington University in St Louis. Clinical trial information: NCT06794229 .
A retrospective study of donafenib with or without TACE as postoperative adjuvant therapy for hepatocellular carcinoma (HCC) patients at high risk of recurrence after radical resection.
e16258 Background: Although hepatectomy offers a potential cure for HCC, postoperative recurrence remains high and adversely impacts long-term survival. Currently, no standard adjuvant therapy has been established for patients at high risk of recurrence. This study evaluated the efficacy and safety of adjuvant donafenib with or without transarterial chemoembolization (TACE) in this population. Methods: We retrospectively analyzed clinicopathological data from HCC patients with high recurrence risk after radical resection at Nantong Third People’s Hospital, between March 2023 and November 2025. High risk was defined as meeting at least two of the following criteria: tumor diameter > 5 cm; multiple tumors; microvascular invasion (MVI) positive; Edmondson–Steiner grade Ⅲ–Ⅳ; postoperative alpha-fetoprotein (AFP) at the first month ≥10 μg/L; or postoperative des-gamma-carboxy prothrombin (DCP) at the first month > 32 mAU/mL. Patients received adjuvant donafenib alone or combined with one session of TACE; the TACE procedure was performed within the first postoperative month. Recurrence-free survival (RFS), overall survival (OS), and safety (assessed per CTCAE v5.0) were analyzed. Results: At data cutoff (December 2025), 37 patients were included with a median age of 64.4 years (SD: 9.0), most were male (73.0%), and had HBV infection (89.2%). All patients with Child-Pugh A liver function and ECOG PS 0. High-risk features included: tumor > 5 cm (29.7%), multiple lesions (37.8%), MVI-positive (73.0%), Edmondson-Steiner grade Ⅲ (89.2%), postoperative AFP≥10 μg/L (18.9%), and postoperative DCP > 32 mAU/mL (32.4%). Treatment distribution included donafenib monotherapy (n = 19) and donafenib plus TACE (n = 18). For the overall population, median RFS and OS were not reached, and the 1-year RFS rate was 76.4% (95% CI: 59.8–97.8%); the 2-year RFS rate was 67.9% (95% CI: 48.5–95.2%). Subgroup analyses were performed based on treatment, biomarker levels, and pathological features. The 1-year RFS was 81.2% for donafenib alone and 73.3% for donafenib plus TACE. According to postoperative AFP levels, the 1-year RFS was 57.1% in patients with AFP≥10 μg/L and 81.3% in those with AFP < 10 μg/L. By MVI status, the rate was 100.0% in MVI-negative patients and 71.1% in MVI-positive patients. According to Edmondson–Steiner grade, the 1-year RFS was 100.0% for grade Ⅱ and 74.9% for grade Ⅲ. Treatment-related adverse events (TRAEs) occurred in 7 patients (18.9%), all grade 1–2; no grade ≥3 TRAEs were observed. Conclusions: In this retrospective analysis, adjuvant donafenib with or without TACE demonstrated promising recurrence-free survival with a favorable safety profile in HCC patients at high risk of recurrence after radical resection. These results support further investigation in prospective studies.
Impact of <i>NPM1</i> co-mutation on post-transplant outcomes in MRG-mutated AML.
6562 Background: Myelodysplasia-related gene (MRG) mutations are classified as adverse risk per ELN 2022, and allogeneic cell transplantation (allo-HCT) is recommended. However, it remains unclear whether post-transplant outcomes in MRG-mutated AML are inferior compared with other ELN-defined higher-risk AML without MRG mutations, and whether the presence of a favorable co-mutation NPM1 modifies prognosis after transplantation. Methods: We conducted a retrospective study of adult patients with AML who underwent allo-HCT at our institution between January 2015 and January 2025. MRG mutations defined per ELN. Patients were categorized into four molecular groups: MRG-mutated/NPM1 wild-type (MRG^mutNPM1^wt), MRG-mutated/NPM1-mutated (MRG^mutNPM1^mut), MRG–wild-type/NPM1-mutated (MRG^wtNPM1^mut), and MRG–wild-type/NPM1 wild-type (MRG^wtNPM1^wt).Overall survival (OS) and RFS were calculated using the Kaplan–Meier. Adjusted OS and RFS were estimated using propensity score matching accounting for age, sex, remission status at transplant (CR1 vs others), and conditioning intensity. Results: A total of 146 patients with complete molecular and cytogenetic data were included. Forty-two percent were MRG^wtNPM1^wt, 16% were MRG^wtNPM1^mut, 23% were MRG^mutNPM1^mut, and 19% were MRG^mutNPM1^wt. Cytogenetic risk distribution was 11% favorable, 71% intermediate, and 18% adverse. Among patients with favorable cytogenetics, 86% were either MRG^wtNPM1^wt or MRG^mutNPM1^mut, and none had MRG^mutNPM1^wt disease. In contrast, among patients with adverse cytogenetics, 17% had MRG^mutNPM1^wt, 23% had MRG^mutNPM1^mut, and 45% had MRG^wtNPM1^wt disease (p = 0.07).There was no significant difference in OS across molecular subgroups, with median OS of 70 months (95% CI 40–NR) for MRG^wtNPM1^mut, 101 months (95% CI 20–NR) for MRG^mutNPM1^mut, 69 months (95% CI 27–NR) for MRG^mutNPM1^wt, and 94 months (95% CI 59–NR) for MRG^wtNPM1^wt (p = 0.5). However, patients with MRG^mutNPM1^wt demonstrated a trend toward inferior RFS, with a median RFS of 17 months (95% CI 13–NR), compared with RFS not reached in the MRG^wtNPM1^mut, MRG^mutNPM1^mut, and MRG^wtNPM1^wt groups (p = 0.1). These findings remained consistent after propensity score adjustment. Conclusions: Our findings suggest that the presence of an NPM1 mutation may mitigate post-transplant relapse risk in patients with MRG-mutated AML. In contrast, patients with MRG-mutated/NPM1 wild-type disease appear to have inferior relapse-free survival after allo-HCT compared with other ELN-defined adverse-risk AML subgroups. These results indicate biologic heterogeneity within adverse-risk AML and highlight the need for refined post-transplant risk stratification and relapse-prevention strategies in MRG-mutated/NPM1 wild-type AML.
Multiple myeloma in the United States and India: An international, collaborative study comparing patient characteristics and treatment patterns.
e19506 Background: Multiple myeloma (MM) is one of the most common hematological malignancies globally, and has an array of treatments available, including targeted and CAR-T therapies. In this retrospective real-world data study, we investigated treatment patterns in patients with MM in the US and India using hospital chargemaster data and electronical medical records from the Premier Healthcare Database and Mango Sciences’ Healthcare Database, respectively. Methods: Patients newly diagnosed with MM (ICD-10-CM C90.0x) between 01/01/2022 and 09/30/2023 were followed for ≥ 1 year through 09/30/2024. Patient characteristics and MM-related drug treatments were described separately for patients in the United States and India. Proportions were compared using Pearson’s Chi-squared test. MM-related drug treatments included 24 individual drugs and 10 drug classes. A study protocol was developed prior to the implementation of this study. Patients with missing data were removed from the study. Results: Among patients diagnosed with MM in the US (N = 77,901) and India (N = 2,268), patients in the US (vs. India) were older (67% vs. 42% were 65+ years old), less likely to be male (55% vs. 63%), and more likely to have health insurance (99% vs. 36%). In addition, 39% and 74% received MM-related drug treatment, respectively. Among patients receiving MM-related drug treatment in the US (N = 30,242) and India (N = 1,672), the most common therapies were corticosteroids (91% and 63%) and proteasome inhibitors (31% and 85%, respectively), and patients in the US (vs. India) were more likely to receive more recently launched therapies, such as daratumumab (18% vs. 8%), bispecific agents (1.3% vs. 0.1%), and CAR-T therapy (2.4% vs. 0%). P-values < 0.001. Conclusions: US and Indian MM cohorts show strong alignment in core treatment patterns – corticosteroids are nearly universally used, and proteasome inhibitors are widely adopted – providing real-world evidence of consistent frontline care. Despite demographic and access differences, both settings rely heavily on established regimens, underscoring shared approaches in multiple myeloma management.
Niraparib and dostarlimab in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) treated with (chemo)radiotherapy (CRT): Results from the phase IB-II TTCC-2022-01 RADIAN trial.
6096 Background: Treatment intensification with antiPD-(L)1 agents given concurrently to definitive CRT in LA-HNSCC have failed to improve survival. Beyond radiation sensitization, PARP inhibition is predicted to trigger immune responses via STING pathway activation and synergize with anti-PD-(L)1 agents. TTCC-2022-01 RADIAN Trial evaluates niraparib and dostarlimab in LA-HNSCC patients (pts) treated with CRT (cohort A) or RT alone (Cohort B-cisplatin ineligible) (Oliva M et al ASCO 2024). Results of cohort A are presented. Methods: Investigator-initiated, non-randomized phase 1b/II study of niraparib and dostarlimab in LA-HNSCC pts candidates for definitive CRT or RT alone conducted in 7 Spanish sites. In cohort A, pts received 500 mg dostarlimab intravenously on week (w)-3 prior to RT and 200-300 mg/day niraparib from w-2 until 48h before start of CRT (70Gy/35 fractions plus cisplatin 100mg/m 2 w1,4 and 7). Maintenance dostarlimab (500 mg/3w) plus daily niraparib started 4w post-CRT for up to 14 cycles. Eligibility criteria: newly-diagnosed stage III-IVA-IVB HPV-negative oro-hipopharyngeal or laryngeal SCC and stage III HPV-related oropharyngeal, ECOG 0-1, centrally-confirmed PD-L1 CPS≥1, and with no cisplatin/dostarlimab/niraparib contraindications. Primary endpoint was 1-year disease-free survival (1y-DFS). Secondary objectives include safety; overall response rate (ORR) and ctDNA dynamics. 17 pts per cohort were planned. Experimental treatment was expected to increase 1y-DFS up to 75.9 % vs 65% historical control. Results: From Dec 23 to Jun 25, 17 pts were enrolled: median age 65 y (41-68); 71% male; 88% smokers; larynx/hypopharynx/oropharynx (HPV-related)= 53/6/41% (43%); stage III/IVA/IVB=29/53/18%. All pts completed dostarlimab and niraparib pre-CRT with no serious or Grade(G) 3-4 treatment-related adverse events (TRAEs); 15/17 completed CRT: 2 pts died during this phase (1 G5 febrile neutropenia cisplatin-niraparib-related; 1 unknown cause); 14/17 pts started maintenance: 2 completed, 7 ongoing and 5 (36%) discontinued due to TRAEs. The most common grade ≥3 TRAEs were neutropenia (71%), lymphopenia and dysphagia (29% each). Niraparib dose reductions/interruptions occurred in 12 (71%) pts. Most common TRAEs leading to dostarlimab+niraparib maintenance discontinuation were immune-mediated pneumonitis (18%) and respiratory tract edema (12%). ORR was 100% (14 complete+1 partial response) in 15 evaluable pts. With a median follow-up of 8.5 months (95% CI: 8.3-11.1), 15/17 were alive with no disease recurrence or progression. Intention-to-treat 1y-DFS was 88% (95% CI:74.1-100). Conclusions: Dostarlimab and niraparib with CRT showed promising efficacy results in this preliminary analysis. Maintenance post-CRT was poorly tolerated leading to high rate of discontinuation. Clinical trial information: NCT05784012 .
Alrizomadlin (APG-115) alone or in combination with lisaftoclax (APG-2575) for the treatment of pediatric patients with relapsed/metastatic rhabdomyosarcoma (RMS) or other soft-tissue sarcomas (STSs).
10012 Background: Pediatric tumors rarely harbor TP53 mutations but often overexpress antiapoptotic BCL-2 family proteins (BCL-2, BCL-XL, MCL-1), making MDM2 and BCL-2 inhibitors attractive therapeutic approaches. Preclinical data have shown that dual targeting these proteins results in synthetic lethality, which may overcome chemoresistance in pediatric patients with STSs. The study evaluated the safety and preliminary efficacy of alrizomadlin alone or combined with lisaftoclax in heavily pretreated relapsed/metastatic pediatric RMS, neuroblastoma (NB) and other STSs. Methods: This Chinese multicenter trial (NCT05701306; APG115XC103) assessed alrizomadlin (± lisaftoclax) in children with heavily pretreated relapsed/metastatic RMS, Ewing sarcoma (EWS), NB, or other STSs; Lansky or Karnofsky PS ≥ 50; and no CNS metastases. Alrizomadlin alone was administered orally at 30, 60, or 90 mg/m 2 QOD (2 weeks on, 1 week off). When combined with lisaftoclax (250, 375, or 500 mg/m 2 oral QD), alrizomadlin dose was 90 mg/m 2 QOD in 21-day cycles until progression or toxicity. The primary endpoints were safety and RP2D for the combination. ORR was assessed per INRC for NB or RECIST v1.1 for other solid tumors. Results: As of January 16, 2025, 16 pediatric patients received alrizomadlin monotherapy at 30 (n = 5), 60 (n = 4), or 90 mg/m 2 (n = 7). No DLT was observed; the recommended dose was 90 mg/m 2 when combined with lisaftoclax. Most common TRAEs were gastrointestinal and hematologic. Grade ≥ 3 TRAEs included thrombocytopenia (42.9%) and neutropenia (28.6%). One patient (14.3%) experienced treatment-related SAEs (thrombocytopenia, febrile neutropenia, and leukopenia). No treatment-related discontinuation or death occurred. In the combination arm, 18 patients were treated with alrizomadlin (90 mg/m 2 ) combined with lisaftoclax at 250 (n = 13) or 375 mg/m 2 (n = 5). No DLT was observed. Most common TRAEs were gastrointestinal and hematologic. Grade ≥ 3 TRAEs included thrombocytopenia (38.9%), neutropenia (33.3%), leukopenia (27.8%), and anemia (27.8%). One (5.6%) treatment-related SAE of thrombocytopenia was reported. No treatment-related discontinuation or death occurred. In monotherapy, 1 patient with refractory RMS achieved CR; 2 patients with STSs maintained stable disease. In the combination arm, 10 patients were evaluable for response, showing 1 CR (EWS), 1 PR among 4 patients with RMS, and 1 PR among 3 patients with NB. ORR (CR + PR) was 30% and DCR 80%. Conclusions: Alrizomadlin alone or in combination with lisaftoclax showed a manageable safety profile, with preliminary antitumor activity in heavily pretreated R/R RMS, EWS, and NB. The potential mechanisms, safety, and efficacy of alrizomadlin combined with lisaftoclax for pediatric RMS and other STSs warrant further investigation. Clinical trial information: NCT05701306 .