Browse Articles

Clinical risk factors for polyneuropathy in patients receiving immune checkpoint inhibitor therapy.

e24174 Background: This study investigates neurological toxicities, particularly polyneuropathy, as immune-related adverse events (irAEs) following immune checkpoint inhibitor (ICI) therapy, aiming to clarify clinical factors associated with polyneuropathy development. Methods: We analyzed participants who received ICIs in the All of Us Controlled Tier v8 dataset from December 2012 to September 2023. Variables included age, sex, race, alcohol consumption, smoking status, comorbid conditions including hypertension and diabetes mellitus, anticancer agents potentially associated with neuropathy, and individual ICI therapies. Associations were initially assessed using chi-square tests, and variables that demonstrated statistically significant associations in univariable analyses were subsequently included in multivariable logistic regression analyses. Results: Among 998 ICI-treated patients, 202 developed polyneuropathy, with an incidence of 20.2%. In unadjusted analyses, polyneuropathy was significantly associated with sex, hypertension, and exposure to platinum- and taxane-based chemotherapy (p < 0.05). In multivariable analyses, female sex (adjusted OR = 1.47, 95% CI 1.05–2.05), hypertension (adjusted OR = 1.62, 95% CI 1.13–2.34), and taxane-based chemotherapy exposure (adjusted OR = 1.71, 95% CI 1.14–2.59) remained independently associated with increased risk of polyneuropathy. Conclusions: Female sex, hypertension, and taxane-based chemotherapy exposure are independent risk factors for polyneuropathy in patients treated with ICIs. These findings highlight the need for proactive risk stratification and vigilant monitoring, particularly in female patients receiving concomitant taxane therapy.

Radical treatment of extraskeletal myxoid chondrosarcoma: A retrospective analysis of long-term outcomes and inflammatory prognostic factors.

e23561 Background: Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare soft tissue sarcoma characterised by recurrent NR4A3 gene rearrangements. Real-world data on survival and prognostic biomarkers is limited. Therefore, we evaluated long-term oncological outcomes and inflammatory prognostic factors in a cohort of patients (pts) treated with curative intent at a national reference centre. Methods: We retrospectively analysed institutional records to identify consecutive pts with histologically confirmed EMC who underwent a curative-intent surgery over the last 25 years. Kaplan–Meier analysis was used to calculate the survival outcomes including overall survival (OS), relapse-free survival (RFS) and distant metastasis-free survival (DMFS). Log-rank test was used to determine the prognostic impact of pre-treatment peripheral blood biomarkers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], systemic immune-inflammation index [SII]). Results: 37 pts were included (median age 57.6 years; range 24.9–80.3; 51.4% female). Low-grade tumours accounted for 67.6%, while 24.3% were high-grade. Surgical resection margins were R0 in 24 (64.9%) pts, and R1/R2 in 11 (29.7%) pts. Metastasis were present at diagnosis in 5 (13.5%). Pre-operative radiotherapy was used in 24 cases, mostly 5 x 5 Gy. For the entire cohort median OS, RFS, and DMFS were 162.76, 46.88, and 58.87 months, respectively. Low values (below median) of PLR, LMR, MLR and SII were reported in pts with prolonged OS (216–276 months), whereas high values were associated with shorter survival curves. Also, high (above median or median) NLR tended to be associated with shorter OS than low NLR. However, statistical significance was not reached. Conclusions: In EMC pts treated with radical intent, long-term survival is favourable, although characterised by substantial recurrence and metastatic risk. Systemic inflammatory indices, derived from routine blood tests, identify prognostically distinct subgroups and may complement established clinicopathological factors. However, further research on a larger group is needed.

Data from a real-world study: Association of CDCP1 expression level with survival outcomes in mCRC patients treated with bevacizumab or cetuximab plus chemotherapy.

3593 Background: CUB domain-containing protein 1 (CDCP1) is a transmembrane protein shown to be over-expressed in colorectal cancer (CRC), with an important role in tumor initiation, growth and metastasis. Through interactions with EGFR, CDCP1 promotes nuclear translocation of the key regulators of Wnt signaling, β-catenin and E-cadherin. High CDCP1 expression has been associated with poor survival outcomes in multiple solid tumors but data in CRC remains limited. We investigated associations between CDCP1 level and survival outcomes in patients with metastatic CRC (mCRC) in the phase III clinical trial CALGB/SWOG 80405 (Alliance). Methods: Data from 433 mCRC patients in the CALGB/SWOG 80405 (Alliance) trial were analyzed. Patients received bevacizumab (n = 226) or cetuximab (n = 207) plus chemotherapy as 1st-line treatment. Tumor RNA was extracted from FFPE samples and processed through the HiSeq 2500 (Illumina) platform. Overall survival (OS) and progression free survival (PFS) curves were evaluated in all treatment subgroups and stratified according to high or low CDCP1 expression. Likelihood ratio tests, hazard ratios (HRs), and 95% confidence intervals (CIs) were calculated using Cox proportional hazards multivariate models, adjusting for age, sex, ECOG performance status, tumor location, number of metastatic sites, KRAS status, consensus molecular subtypes, and treatment arm. Results: Overall, low CDCP1 expression was associated with better OS compared to high expression (HR = 1.38; 95% CI 1.07-1.77; 35.8 vs 25.0 months, p = 0.045). Subgroup analysis re-demonstrated this pattern in males (HR = 1.64; 95% CI 1.64-2.28; 35.9 vs 23.6 months, p = 0.01), patients with MSS tumors (HR = 1.56; 95% CI 1.17-2.08; 36.7 vs 25.1 months, p = 0.0094), and patients treated with cetuximab+FOLFOX (HR = 1.79; 95% CI 1.16-2.77; 40.8 vs 24.0 months, p = 0.03). The effect of CDCP1 expression on PFS was less pronounced. Relative to high expression, low expression was associated with better PFS in males (HR = 1.49; 95% CI 1.10-2.03; 13.1 vs 9.8 months, p = 0.027) and left-sided tumors (HR = 1.50; 95% CI 1.10-2.04; 14.4 vs 10.1 months, p = 0.034). Conclusions: Our findings represent real-world data of the predictive role of CDCP1 in patients with mCRC undergoing anti-EGFR or anti-VEGF treatment. Consistent with studies of other cancers, we show that low CDCP1 expression is predictive of better survival outcomes, with subgroup analysis revealing associations in males, MSS tumors, and left-sided tumors. Among treatment groups, low CDCP1 expression is predictive of better OS in cetuximab+FOLFOX-treated patients, a key finding given CDCP1’s close mechanistic ties to EGFR. Further studies should explore whether these associations are seen in other treatment modalities and whether CDCP1 blockade could represent a viable strategy in patients with high expression.

MC1923: Phase II durvalumab plus lurbinectedin in platinum-resistant relapsed extensive-stage small cell lung cancer after prior chemoimmunotherapy (cohort B).

8094 Background: Patients with extensive-stage small cell lung cancer (ES-SCLC) who progress after platinum-based chemotherapy plus immunotherapy have limited options. Whether adding lurbinectedin while continuing immune checkpoint blockade at relapse improves outcomes is unknown. We report results for the platinum-resistant cohort (progression ≤3 months from last chemotherapy) of MC1923. Methods: MC1923 is a phase II trial using a Simon optimal two-stage design. Patients were assigned to a starting dose of durvalumab 1500 mg IV plus lurbinectedin 3.2 mg/m 2 IV on Day 1 of 21-day cycle. The primary endpoint was the 6-month progression-free survival rate (PFS6). Accrual continued to 22 eligible patients if ≥2/9 achieved PFS6; the regimen would be considered promising if ≥7/22 (32%) were alive and progression-free at 6 months. Secondary endpoints included adverse events (AEs), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-two patients enrolled (02/04/2022–05/21/2025); all were eligible and treated. Median age was 66 years; 32% were male; ECOG performance status was 0 in 9% and 1 in 91%; 96% had prior atezolizumab. Median cycles delivered were 4 (range 1–13). PFS6 was 4/22 (18.2%; 95% CI, 7.5–44.1%), below the prespecified threshold. Median PFS was 3.1 months (95% CI, 1.6–5.3). ORR was 13.6% (3/22; all partial responses; 95% CI, 2.9–34.9%). At data cutoff (12/18/2025), 4 patients were alive; median follow-up was 16.8 months (range 5.5–39.6). Median OS was 7.4 months (95% CI, 4.3–18.6) and 1-year OS was 33.1% (95% CI, 17.6–61.9%). One (1) patient discontinued treatment with durvalumab due to AE. No treatment-related Grade 5 AEs occurred; Grade 3–4 AEs at least possibly related to treatment occurred in 32% (7/22); Grade 4 AEs occurred in 5% (1/22), all hematologic. Most common Grade 3 AEs were decreased neutrophils and white blood cells (each 9%). Conclusions: Durvalumab plus lurbinectedin demonstrated manageable toxicity in platinum-resistant ES-SCLC after chemoimmunotherapy but did not meet the prespecified PFS6 efficacy threshold, supporting the need for alternative strategies in this high-risk population. Clinical trial information: NCT04607954 .

Phase Ib/II clinical study of adebrelimab combined with decitabine, nab-paclitaxel, and gemcitabine as first-line (IL) treatment for metastatic pancreatic cancer (mPC).

4200 Background: Epigenetic enzyme inhibitors may synergize with immunotherapy by modulating antigen presentation and enhancing tumor-related gene expression. Preclinical studies suggest that low-dose decitabine can restore chemosensitivity in chemotherapy-resistant tumors. We conducted the Ib/II study to explore the efficacy and safety of decitabine combined with adebrelimab, nab-paclitaxel, and gemcitabine as 1L treatment for mPC. Methods: Eligible patients (pts) were prior untreated mPC or pts who had experienced disease progression more than six months after the end of postoperative adjuvant therapy. In the phase Ib, enrolled pts received dose escalation of decitabine (10 mg/m²/15 mg/m²,iv,d1-d3,q4w), adebrelimab (1200mg,iv,d1,q3w) , nab-paclitaxel (125 mg/m 2 , iv,d1,d8,d15,q4w), and gemcitabine (1000 mg/m 2 ,iv,d1,d8,d15,q4w) to determine the recommended phase 2 dose (RP2D) in a standard 3+3 design. In the phase II, pts received decitabine at the RP2D, adebrelimab, nab-paclitaxel and gemcitabine combination therapy. Primary endpoints were dose-limiting toxicities, RP2D, and objective response rate (ORR). Secondary endpoints included overall survival, progression free survival, disease control rate (DCR), duration of response, and safety. Results: From April 2024 to February 2025, 28 pts were enrolled and the median age was 62 yrs; 69.2% male, and 80.8% ECOG PS 1. The Ib phase established the RP2D of decitabine as 10 mg/m². Total of 22 pts were included in the efficacy analysis. The median follow-up was 11.9 mo. The ORR was 46% (10PR, 9SD, 3PD) and DCR was 86.4%. Median duration of response (mDoR) was 10.94 months, while the median progression-free survival (mPFS) was 6.47 months. 24 pts were analyzed for safety. The most common TRAEs of any grade were anemia (95.8%), lymphocyte count decreased (79.2%), hypoalbuminemia (75.0%), hyponatremia (75.0%), vomiting (66.7%). Grade ≥3 TRAEs were were anemia (25.0%), white blood cell decreased (20.8%), platelet count decreased (20.8%), lymphocyte count decreased (12.5%), neutrophil count decreased (12.5%). No new safety signals were observed. Conclusions: This study preliminarily demonstrates that the decitabine combination regimen has favorable efficacy and safety in 1L treatment of mPC. Future clinical studies with larger sample sizes are needed to be validated. Clinical trial information: NCT06454448 .

Clinicopathologic characteristics and treatment outcomes of adenoid cystic carcinoma (ACC) by different primary sites.

6121 Background: Although ACC commonly arises in the salivary glands, nearly 40% arise at extra-salivary sites and are often managed as site-specific malignancies rather than as a unified histologic entity. Population-based data suggest that thoracic and head and neck ACC are associated with poorer survival compared with breast ACC; however, the factors underlying these differences remain poorly understood. Methods: We retrospectively identified all patients (pts) with ACC, irrespective of primary site, who were followed at a large cancer center between 2011 and 2024. Collected data included staging at diagnosis, primary site, local treatment (i.e. surgery, radiation), histologic subtype (solid, cribriform or tubular), lymphovascular invasion (LVI), perineural invasion (PNI), margin status (R0, R1), and clinical outcomes including local recurrence-free survival (LRFS), distant metastasis free-survival (DMFS), and overall survival (OS). Primary sites were grouped as major salivary glands (MASG), oral cavity or oropharynx (OCOP), sinonasal region (SINO), breast (BRST), thorax-lung (THLU), lacrimal gland (LCGL), and others (i.e., skin OTHR). Clinicopathologic characteristics were compared using Fisher tests, and associations between primary site and clinical outcomes were evaluated with multivariable Cox models comparing each site versus all others combined adjusted for local treatment type, margins, and solid histology, defined a priori following a causal inference framework. Results: Of 220 pts, 151 (69%) were female, and 199 (90.5%) had localized or locally advanced disease at diagnosis. The most common primary site was OCOP (n=67, 30%), followed by MASG (n=60, 27%), SINO (n=25, 11%), THLU (n=22, 10%), BRST (n=20, 9.1%), LCGL (n=6, 2.7%), and OTHR (n=20, 9.1%). Among 210 pts that received local treatment, 41 (19%) had surgery only, 134 (61%) surgery plus radiation, and 35 (16%) radiation alone. Patients with THLU primary had less up-front surgery (50% vs 76-100%, p<0.001). Among surgical cases, 58% had R1 resections; PNI was present in 48%. BRST pts had lower rates of positive margins (R1 7.7%, p=0.04) and PNI (28% vs 35-83%, p=0.019). Histologic subtype was reported in 108 (49%) pts with 72 (78%) cribriform, 58 (54%) solid, and 49 (45%) tubular. Median LRFS, DMFS, and OS were 103 months [mo] (95%CI 77-141), 87 mo (95%CI 70-131), and 153 mo (95%CI 124-222) respectively. Pts with SINO experience worse LRFS (HR 2.01, p=0.03), DMFS (HR 2.07, p=0.02), and OS (HR 3.51, p<0.001) while MASG had potentially improved DMFS (HR 0.63, p=0.07) and THLU OS (HR 0.31, p=0.07) in adjusted models. Conclusions: Primary site-specific clinical outcomes in ACC are not fully explained by treatment approach or histologic features. These findings suggest biological heterogeneity across ACC by primary site and underscore the need for molecular characterization of site-specific disease drivers.

First results from the OPTIMA phase III randomized non-inferiority trial of test-directed chemotherapy in patients with high clinical risk ER-positive HER2-negative early breast cancer.

500 Background: Tumor gene expression tests are widely used to assist adjuvant chemotherapy decisions for women with early breast cancer (EBC). OPTIMA (Optimal Personalised Treatment of early breast cancer using Multi-parameter Analysis) is an international RCT comparing chemotherapy decisions made with the Prosigna (PAM50) gene expression test with standard treatment in mostly node-positive patients. Methods: Women and men aged >40 recommended to receive chemotherapy for ER+ HER2- EBC with 0-9 involved axillary nodes and T size >30mm if node negative were eligible. Randomization was between standard chemotherapy followed by endocrine therapy (CET) or to a Prosigna test directed chemotherapy decision. Patients with Prosigna ROR score > 60 tumors were assigned CET whilst those with low ROR score (≤60) tumors received endocrine therapy (ET) alone. ET for premenopausal women included ovarian function suppression (OFS) in the absence of chemotherapy-induced ovarian insufficiency. ROR scores were not disclosed, and patients receiving CET were blinded to their randomization. OPTIMA was designed to demonstrate non-inferiority (NI) of 5-year invasive breast cancer free survival (IBCFS) in the test-directed arm with a 3% margin in the per protocol (PP) population using a 5% 1-sided alpha. Control arm testing allowed treatment comparison within the low ROR score population at a 3.5% NI margin. Results: From 16 th Jan 2017 to 12 th Dec 2025 4429 patients were randomized, 2215 to the control arm and 2214 to the test-directed arm of whom 2061 (93%) and 2097 (95%) were included in the respective PP group. Patient characteristics in the PP population were well-balanced; 62% were postmenopausal, 37% premenopausal and 0.8% male. 73% had pN1/pN1sn, 8% had pN0/pN1mi and 19% had pN2 tumors. 68% had low ROR score tumors. With a median follow-up of 3.9 years (interquartile range 2.0-5.9), 280 IBCFS events occurred (141 on control arm; 139 on test directed arm) of which 66% were distant recurrences. The 5-year IBCFS rate in the control arm was 91.5% [95% CI 89.7- 92.9%] and 90.4% [95% CI 88.6- 92.0%] in the test-directed arm, Hazard Ratio (HR) 0.99 [90% CI 0.81- 1.20], NI p = 0.013, thereby meeting the pre-defined NI margin. The corresponding 5-year IBCFS rates for the low ROR score population were 94.9% [95% CI 92.9- 96.4%] and 93.7% [95% CI 91.8- 95.2%] for the two arms respectively, HR 1.06 [90% CI 0.78- 1.46] NI p = 0.0051 again demonstrating non-inferiority. There was no significant outcome heterogeneity between subgroups including for menopausal and nodal status. Conclusions: The OPTIMA trial demonstrates that women and men with ER+ HER2- EBC and ROR score ≤60 tumors can safely avoid chemotherapy. It provides evidence for the utility of test-directed chemotherapy in premenopausal women treated with OFS and patients with high levels of nodal involvement. Clinical trial information: ISRCTN42400492.

Clinical-stage AI-enabled therapeutic assets: An industry-wide analysis of scale, clinical progression, and company characteristics.

11072 Background: Artificial intelligence (AI) is increasingly applied in therapeutic discovery and has driven substantial investment in AI-native biotechnology firms. However, the extent to which AI-enabled assets have progressed into and through clinical development remains incompletely characterized. We performed an industry-wide descriptive analysis of AI-enabled therapeutic assets that have entered interventional clinical trials. Methods: We identified AI-enabled therapeutic assets that entered at least one Phase 1–3 interventional clinical trial through July 1, 2025. Assets were manually curated using industry databases, public disclosures, and trial registries. AI enablement was defined at the asset level and required evidence of AI contribution to discovery or design. Drug-, trial-, and company-level characteristics were summarized using descriptive statistics. Company characteristics were obtained from PitchBook and public sources. Results: A total of 117 AI-enabled therapeutic assets across 63 companies entered interventional clinical trials. Oncology accounted for 69 assets (59.0%), and most assets were small molecules (96/117; 82.1%). As of December 1, 2025, 60 assets (51.3%) had completed Phase 1 and 8 (6.8%) had completed Phase 2. Among assets with reported Phase 1 enrollment (n = 103), the median sample size was 50 participants (IQR, 24–76.5). Approximately 35.9% of assets targeted a novel biological target. At the company level, the median time from founding to Phase 1 entry was 6.5 years (IQR, 4.0–9.2; n = 44). Median total funding was $186.7 million (IQR, $48.1M–$595.0M; n = 57), and median employee count at clinical entry was 73 (IQR, 32–129; n = 35). Median operational intensity was $2.72 million per employee (IQR, $1.71M–$5.83M; n = 47). Conclusions: AI-enabled therapeutic assets are increasingly entering clinical development, particularly in oncology, but most remain early in the clinical pipeline, with few having completed Phase 2. AI-native biotechnology companies that have reached the clinic typically do so within several years of founding with relatively small employee counts and high operational intensity. These findings provide a transparent baseline for evaluating the clinical impact of AI-enabled drug discovery as this cohort matures.

PARP inhibitor and immune checkpoint inhibitor combination therapy in PD-L1-negative tumors: A meta-analysis.

e14568 Background: Poly(ADP-ribose) polymerase inhibitors (PARPis) can enhance antitumor immunity and potentially improve the efficacy of immune checkpoint inhibitors (ICIs) through mechanisms such as PD-L1 upregulation and STING pathway activation, providing a rationale for combining ICIs with PARPis. However, whether PD-L1-negative patients benefit from this combination therapy remains unclear. Methods: We performed a systematic search of PubMed, Embase, Web of Science, Cochrane library, and relevant conference proceedings for clinical trials evaluating PARPi-ICI combination therapy in patients with PD-L1-negative tumors. The pooled objective response rate (ORR), disease control rate (DCR) and 12-month progression-free survival (12-m PFS) were estimated using a random-effect model and were compared with those in PD-L1-positive patients within the same trials. Subgroup analyses were conducted based on BRCA mutation and HRD status, as well as cancer type. Results: Twenty-two clinical trials comprising 1849 patients (718 PD-L1-negative) were included. Among unselected all-comers, the pooled ORR was significantly lower in the PD-L1-negative patients (21% [95% CI: 12-30%]) than in PD-L1-positive patients (36% [95% CI: 26-47%], p = 0.046). BRCA-mutant patients showed high ORR irrespective of PD-L1 status (67% vs. 73%, p = 0.643), and HRD-positive patients showed no significant difference (31% vs. 57%, p = 0.139). By cancer type, breast cancer showed significantly lower ORR in PD-L1-negative patients (24% vs. 46%, p = 0.090), whereas ovarian cancer showed no significant difference (36% vs. 43%, p = 0.578). Non–breast/ovarian cancers had low ORRs overall, although significant difference was observed between PD-L1-negative and PD-L1-positive subpopulations (9% vs. 19%, p = 0.001). The pooled DCR and 12-m PFS rates were numerically but not significantly lower in PD-L1-negative patients compared with PD-L1-positive patients (40% vs. 55%, p = 0.217; and 40% vs. 56%, p = 0.350, respectively). Conclusions: Despite generally lower responses in PD-L1-negative patients, HRD—particularly BRCA-mutant—tumors and PARPi–sensitive cancers like ovarian cancer derived clinically relevant benefit regardless of PD-L1 status, underscoring the dominant role of HRD/BRCA-driven genomic instability and other intrinsic tumor features in determining treatment sensitivity. These results indicate that PD-L1 negativity alone should not preclude patients from receiving this regimen. N PD-L1-negative PD-L1-positive p ORR All-comer 30 21% [12-30%] 36% [26-47%] 0.046 BRCA-mutantHRD-positive 511 67% [45-86%]31% [10-57%] 73% [43-97%]57% [33-80%] 0.6430.139 BreastOvarianNon–breast/ovarian 81411 24% [10-40%]36% [18-56%]9% [5-13%] 46% [29-65%]43% [25-62%]19% [11-27%] 0.090 0.578 0.001 DCR All-comer 12 40% [30-51%] 55% [38-72%] 0.217 12m PFS All-comer 5 40% [22-59%] 56% [33-78%] 0.350

Patient-reported socioeconomic vulnerability and treatment delivery in patients receiving oral anticancer drugs within the Oncoral outpatient care program.

e23272 Background: Socioeconomic vulnerability has been identified as a major determinant of cancer outcomes and treatment adherence, supporting the need for personalised follow-up strategies. While several studies suggest that social deprivation adversely affects treatment delivery, the extent to which structured multidisciplinary outpatient care can mitigate these inequalities remains unclear. We aimed to assess the association between socioeconomic vulnerability and treatment delivery in patients treated with oral anticancer drugs (OADs) within the multidisciplinary ONCORAL care plan, based on personalised community and hospital follow-up by oncologists, pharmacists and nurses. Methods: We conducted an observational real-life study of patients initiating the ONCORAL pathway between October 2021 and April 2024. Socioeconomic vulnerability was assessed using the simplified EPICES score, a validated composite index capturing self-reported social and material deprivation, including financial issues, access to leisure activities and social support. Associations between EPICES score and patient characteristics, cancer type, metastatic status, treatment characteristics, relative dose-intensity (RDI: the ratio of prescribed to the theoretically approved dose), early treatment termination and overall survival were analysed using non-parametric tests. Results: Two hundred and seventy patients were included: M/F sex ratio 0.8; median [range] age, 71 [31-93] years; with solid tumour (62.6%) or haematological malignancy (37.4%). Baseline EPICES scores ranged from 0 to 10 (median = 3), with 32.6% of patients presenting a score ≥ 4, the threshold defining social vulnerability. EPICES score correlated weakly with age (p = 0.002) and was higher in patients with metastatic disease (p = 0.039). EPICES distributions differed between cancer types (p = 0.013). However, mean RDI was 85.2 ± 21.4% at 6 months, and remained above the recommended 80%-85% target range for OAD efficacy throughout follow-up, including in patients aged ≥ 75 years. RDI did not correlate with EPICES score at any time point. Socioeconomic vulnerability was not associated with treatment characteristics, adherence, early treatment termination or overall survival. Conclusions: In this real-life cohort, socioeconomic vulnerability was associated with age, metastatic status and cancer type but not with treatment intensity, treatment delivery or survival. Despite heterogeneity in patients’ social vulnerability and cancers, treatment delivery and intensity were comparable across all patients within the personalised ONCORAL outpatient care pathway, suggesting that multidisciplinary community-hospital follow-up may attenuate the impact of socioeconomic inequalities in treatment delivery.

Study design of OMAHA-015: A phase 2 basket study of steroidogenesis inhibitor opevesostat in participants with selected solid tumors.

TPS3183 Background: Opevesostat (MK-5684; ODM-208), an oral steroidogenesis inhibitor, selectively inhibits CYP11A1, blocking synthesis of all steroid hormones and their precursors, and may suppress steroid-driven tumor growth. The randomized, open-label, phase 2 OMAHA-015 trial (NCT06979596) is designed to evaluate the efficacy and safety of opevesostat compared with standard of care in breast, ovarian, and endometrial cancers. Methods: Cohort A will enroll participants (pts) with locally advanced unresectable or metastatic hormone receptor–positive (estrogen receptor and/or progesterone receptor ≥1% expression)/HER2-negative breast cancer (IHC 0, 1+ or 2+/ISH-) and disease progression on or after ≥1 prior endocrine-based therapy in the metastatic setting. Exclusion criteria include any line of cytotoxic chemotherapy (chemo) or PARP inhibitor in the inoperable or noncurative advanced/metastatic setting and prior treatment with both fulvestrant and exemestane in the metastatic setting. Cohort B will enroll pts with platinum-sensitive, histologically confirmed high-grade epithelial ovarian (including high-grade serous or predominantly serous, high-grade endometrioid, clear cell, or malignant mixed Müllerian tumors [carcinosarcoma]), fallopian tube, or primary peritoneal carcinomas. Pts must have received 4-8 cycles of platinum-based doublet chemo in a third-line setting for ovarian cancer with ≤9 weeks between the last dose of third-line chemo and randomization. Cohort C will enroll pts with histologically confirmed primary advanced or recurrent low-grade endometrioid carcinoma (FIGO grade 1/2, or well/moderately differentiated), with known pMMR status, and wild type p53 expression. Pts must either be treatment naive or have received 1 prior line of platinum-based therapy in the advanced/metastatic or adjuvant/neoadjuvant setting. In cohort A, ~80 pts will be randomized 1:1 to arm 1: opevesostat 5 mg PO twice daily (BID) + daily corticosteroids or arm 2: physician’s decision of fulvestrant 500 mg IM (D1 and D15 of cycle 1 and D1 of each cycle thereafter) or exemestane 25 mg PO daily. Randomization will be stratified by 1 line versus ≥2 lines of prior endocrine therapy. In cohort B, ~90 pts will be randomized 1:1 to arm 3: opevesostat 5 mg PO BID + daily corticosteroids; or arm 4: observation. In cohort C, ~80 pts will be randomized 1:1 to arm 5: opevesostat 5 mg PO BID + daily corticosteroids; or arm 6: physician’s choice of megestrol acetate 80 mg PO BID, alternating megestrol + tamoxifen 20 mg PO BID, or letrozole 2.5 mg PO daily. The primary end point is progression-free survival per RECIST v1.1 assessed by blinded independent central review (BICR). Secondary end points include overall survival, clinical benefit rate (cohort A only), objective response rate, and duration of response per RECIST v1.1 assessed by BICR, and safety. The study is currently enrolling. Clinical trial information: NCT06979596 .

Longitudinal <i>MTAP</i> copy number alteration (CNA) in NSCLC with repeated biopsy samples.

e23348 Background: MTAP homozygous deletion (HomD) is associated with inferior survival outcome and represents an emerging biomarker for PRMT5 and MAT2A inhibitors in non–small cell lung cancer (NSCLC). However, longitudinal transition of MTAP CNA in repeated biopsy samples remains unknown, which may inform patient selection for rebiopsy or potential resistance mechanisms for therapeutics. Methods: We analyzed 30,454 NSCLC patients comprising 36,069 tumor samples from the AACR Project GENIE public v18.0 database. Longitudinal analyses were performed in 2,850 patients with ≥2 sequentially obtained biopsies. CNA was categorized as Intact (No Copy Loss), Heterozygous Loss (HetL, 1-copy loss), and HomD (2-copy loss). Statistical comparisons were performed using contingency analyses, with Fisher’s exact test applied where appropriate. Sensitivity analyses were performed for CNA calling methods. Results: Among patients with ≥2 biopsies, 91.8% (2615), 4.4% (126), and 3.8% (109) were MTAP Intact, HetL, and HomD at baseline, respectively. Among patients with baseline MTAP HetL and Intact, acquired HomD was detected in 4.8% (137) of patients at 2 nd biopsy and more commonly in baseline HetL (13.5% [17/126] vs 4.6% [120/2,615], p &lt; 0.001). Baseline CDKN2A status was associated with a stepwise increase in MTAP HomD acquisition. Among baseline MTAP -intact tumors, rates increased from 3.9% to 7.1% to 13.1% across CDKN2A Intact, HetL, and HomD ( p &lt; 0.001), with a numeric trend among baseline MTAP HetL tumors (0%, 11.9%, 20.8%). Acquisition of MTAP HomD was significantly more frequent in primary-to-metastatic transitions than in metastatic-to-primary pairs (9.1% vs 3.0%, p &lt;0.01). Among tumors with baseline MTAP HetL, MTAP HomD acquisition occurred more frequently in patients with EGFR mutation vs. wildtype (18.2% [10/55] vs 9.9% [7/71]), but not according to KRAS mutation status (0% [0/16] vs 15.5% [17/110]). All major associations were consistent across CNA calling methods. Conclusions: MTAP HomD can be an acquired event in NSCLC patients. Initial MTAP HetL, CDKN2A CNA, and EGFR mutation are predisposed to develop further MTAP copy loss to HomD and may contribute to resistance mechanism and can be prioritized when considering rebiopsy to look for acquired MTAP HomD. Acquired MTAP homozygous deletion at second biopsy. Acquired MTAP HomDel at 2nd Biopsy P value All 137 / 2,741 (5.0%) Baseline MTAP Intact vs. HetL MTAP Intact: 120 / 2,615 (4.6%) MTAP HetL: 17 / 126 (13.5%) &lt; 0.001 Baseline MTAP Intact CDKN2A Intact vs. HetL vs. HomD Intact: 94 / 2,388 (3.9%)HetL: 3 / 42 (7.1%)HomD: 23 / 176 (13.1%) &lt; 0.001 EGFR mutation vs. wildtype EGFR -mut: 55 / 946 (5.8%) EGFR -WT: 65 / 1,765 (3.7%) 0.014 Baseline MTAP HetL CDKN2A Intact vs. HetL vs. HomD Intact: 0 / 1 (0%)HetL: 12 / 101 (11.9%)HomD: 5 / 24 (20.8%) 0.32 EGFR mutation vs. wildtype EGFR -mut: 10 / 55 (18.2%) EGFR -WT: 7 / 71 (9.9%) 0.20

Impact of hematological parameters and timing of immunotherapy administration on outcomes in first-line advanced non–small cell lung cancer: A retrospective real-world study.

e20575 Background: Baseline hematological parameters have emerged as potential prognostic biomarkers in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). In parallel, growing evidence suggests that circadian timing of immunotherapy administration may influence treatment efficacy. However, real-world data evaluating the combined impact of hematological parameters and timing of ICI administration in the first-line setting remain limited. Methods: We performed a retrospective analysis of patients with advanced NSCLC without actionable driver mutations treated at the Vietnam National Cancer Hospital with off-trial first-line platinum-doublet chemotherapy plus pembrolizumab or pembrolizumab monotherapy between June 2018 and June 2025. Baseline hematological parameters, including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were collected prior to treatment initiation. NLR was dichotomized at 3 and PLR at 150. Timing of immunotherapy administration was categorized at the patient level based on predominant infusion timing as morning (before 12:00) or afternoon (after 12:00). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared between groups. Results: A total of 225 patients were included, with a median age of 63 years; 83.1% were male, 84.8% had non-squamous histology, and 33.8% had PD-L1 expression ≥50%. Patients with baseline NLR ≤3 demonstrated significantly longer median OS compared with those with NLR &gt;3 (35.7 vs 19.0 months; p = 0.0058), while no significant difference in median PFS was observed (14.0 vs 11.0 months; p = 0.231). Similarly, patients with PLR ≤150 had superior median OS compared with those with PLR &gt;150 (35.7 vs 20.3 months; p = 0.0162), without a significant impact on PFS ( p = 0.306). Patients with predominant morning immunotherapy administration had numerically longer OS (30.1 vs 22.4 months) and PFS (14.0 vs 10.1 months) compared with those with predominant afternoon administration, although these differences did not reach statistical significance (OS p = 0.1276; PFS p = 0.1113). Conclusions: In this real-world cohort of patients with advanced NSCLC treated with first-line immunotherapy, lower baseline NLR and PLR were significantly associated with improved overall survival. Timing of immunotherapy administration showed a favorable numerical trend for morning infusion but did not reach statistical significance. These findings support the prognostic value of readily available hematological biomarkers and suggest that circadian factors may warrant further investigation in prospective studies.

PD-1 inhibitor plus VEGFR-2 inhibitor and chemotherapy versus chemotherapy alone for locally advanced gastric cancer: A systematic review and meta-analysis.

e16125 Background: Despite multimodality treatment, pathological response rates remain suboptimal in patients with locally advanced gastric cancer (LAGC). Perioperative chemotherapy combined with immune checkpoint inhibition, such as FLOT plus durvalumab, has recently demonstrated clinically meaningful benefit and is emerging as a new standard of care. However, a substantial proportion of patients fail to achieve deep pathological responses. Evidence suggests that anti-angiogenic therapy potentiate the activity of immune checkpoint inhibition and chemotherapy. Several recent studies have evaluated this triplet strategy; however, the magnitude of pathological benefit and safety profile remain incompletely defined. We conducted a pooled analysis to assess efficacy and toxicity of PD-1/PD-L1 inhibitor plus VEGFR-2 inhibitor and chemotherapy compared with chemotherapy alone in LAGC. Methods: A comprehensive search of PubMed, Cochrane library,and clinicaltrials.gov was conducted from inception until December 2025. We pooled aggregate data from three comparative studies, including DRAGON IV and CAP-05, evaluating neoadjuvant/perioperative PD-1/PD-L1 inhibitor + VEGFR-2 inhibitor + chemotherapy versus chemotherapy alone. Primary endpoints were pathological complete response (pCR) and major pathological response (MPR). Selected hematologic and nonhematologic adverse events (AEs) were assessed. Risk ratios (RR) with 95% confidence intervals (CI) were estimated using random-effects models. Results: A total of 590 patients with locally advanced gastric cancer were included, including 286 who received PD-1/PD-L1 inhibitor plus VEGFR-2 inhibitor and chemotherapy and 304 who received chemotherapy alone. Combination therapy significantly improved pathological outcomes compared with chemotherapy alone: pCR (RR 3.45, 95% CI 2.05–5.78) and MPR (RR 1.39, 95% CI 1.15–1.66). For safety, most hematologic toxicities were numerically higher but not statistically significant, including anemia (any grade RR 1.06, 95% CI 0.77–1.45) and leukopenia (any grade RR 1.26, 95% CI 0.87–1.82). Grade ≥3 leukopenia was increased (RR 2.14, 95% CI 1.17–3.90). Any-grade diarrhea occurred more frequently with combination therapy (RR 1.49, 95% CI 1.02–2.16), while grade ≥3 diarrhea was not increased. Grade ≥3 hypertension was significantly higher with triplet therapy (RR 10.78, 95% CI 1.36–85.42). Conclusions: Across included studies, adding PD-1/PD-L1 and VEGFR-2 inhibition to chemotherapy substantially improved pathological response rates in LAGC, supporting a biologically synergistic strategy. Increased risks of grade ≥3 leukopenia and hypertension highlight the importance of careful toxicity monitoring. Larger randomized trials with survival endpoints are warranted to define the long-term benefit–risk balance of this approach.

Temporal shift in task factor influence across the stretch reflex

Mechanical perturbations applied to the arm can elicit reflexive actions. These rapid corrective responses include the stretch reflex, which consists of different components: the short-latency reflex (SLR) and the early and late long-latency reflex (LLR). In this study, we examine how different task factors dynamically influence these reflex components in the context of a specific delayed-reach paradigm. Using multiple linear regression (MLR), we analysed electromyographic (EMG) activity from seven muscles actuating the right arm to examine the effects of mechanical load, preparatory delay, perturbation and target direction, on reflex responses, as well as two-factor interactions. The MLR analysis shows that our delayed-reach tasks engaged shoulder girdle muscles in a task-dependent manner, whereas the biceps and triceps primarily acted as stabilizing muscles, with rapid responses triggered regardless of perturbation direction. Specifically, our analyses show that the earliest corrective response, the SLR, exhibited some task-dependent modulation particularly in muscles of the shoulder girdle, although background (pre-)loading decreased this modulation. The SLR was primarily influenced by the main factors Load and Perturbation , along with the interaction Load × Perturbation . Perturbations aligned with the load direction were associated with increased EMG activity across all examined muscles. While there was a small but significant effect of load during the early LLR, this effect diminished by the late LLR epoch. Task-dependent modulation was most pronounced at the late LLR epoch, suggesting greater top-down modulation of this reflex component. In particular, the late LLR was shaped by the factors Perturbation and Target , as well as the interaction Perturbation × Target . Targets and perturbations in opposite directions resulted in heightened EMG activity, and shoulder muscles exhibited stronger LLR responses for targets located farther along the muscle shortening direction. Our results complement and expand on previous findings concerning stretch reflex modulation and help guide the design of future studies.

Root-applied graphene oxide, nano-Fe3O4, and GO/Fe3O4: Role in mitigating arsenic and cadmium mixed toxicity in ryegrass (Lolium perenne L.)

Systemic induction therapy and the expanding frontier of bladder preservation in MIBC

Design and evaluation of novel microtube-based and fan-assisted evaporative cooling vests in climatic chamber under hot and dry conditions

Structural determinants of ligand response specificity in the mast cell activating GPCR, MRGPRX2

Nilvanstomig (ZG005), an anti-PD-1/TIGIT bispecific antibody, plus bevacizumab vs. sintilimab plus bevacizumab biosimilar as first-line therapy for advanced hepatocellular carcinoma: A randomized, multi-center, phase II trial.

4014 Background: Checkpoint inhibitors combined with anti-angiogenic therapy represents one of the standard first-line therapies for advanced hepatocellular carcinoma (aHCC). Nilvanstomig (ZG005) is a recombinant humanized anti-PD-1/TIGIT bispecific antibody. By blocking both pathways, it can synergistically activate T cells and enhance the anti-tumor activity of NK cells. This study evaluated ZG005 plus bevacizumab vs. sintilimab plus IBI305 (a bevacizumab biosimilar) as first-line therapy for aHCC. Methods: In this randomized, open-label, multicenter, phase 2 trial conducted in China, patients with aHCC who had not previously received systemic treatment were randomly assigned (1:1:1) to receive ZG005 10 mg/kg plus bevacizumab 15 mg/kg (Arm A); ZG005 20 mg/kg plus bevacizumab 15 mg/kg (Arm B); or sintilimab 200 mg plus IBI305 15 mg/kg (Arm C). All treatments were administered intravenously every 3 weeks until disease progression or unacceptable toxicity. Randomization was stratified by baseline AFP level ( &lt; 400 vs. ≥400 ng/mL), macrovascular invasion or extrahepatic metastasis (presence vs. absence). The primary endpoint was IRC-assessed PFS per RECIST v1.1, with key secondary endpoints including PFS per mRECIST, ORR and DCR by both criteria, and OS. Results: As of the data cutoff (Nov 25, 2025), 95 patients were enrolled and received at least one dose of treatment (Arm A, n = 31; Arm B, n = 32; Arm C, n = 32). Baseline characteristics were well-balanced across the treatment arms. For all patients enrolled, the median age was 61 years (range, 37-75), with 85.3% of patients being male. Disease characteristics included BCLC stage B (28.4%) or C (71.6%), Child-Pugh score A5 (83.2%) or A6 (16.8%), baseline AFP ≥400 ng/mL in 45.3% of patients, and HBV positivity in 73.7%. Macrovascular invasion and/or extrahepatic metastasis were present in 71.6% (68/95) of patients. With a median follow-up of about 5 months, the IRC-assessed ORR was 32.3% in Arm A, 37.5% in Arm B, and 25.0% in Arm C per RECIST v1.1; the corresponding ORRs per mRECIST were 54.8%, 50.0%, and 34.4%. The IRC-assessed median PFS per RECIST v1.1 was not reached in Arm A or B, compared with 5.8 months in Arm C (Arm A vs. C: HR 0.40, 95% CI 0.15-1.05; Arm B vs. C: HR 0.28, 95% CI 0.10-0.79). The safety profiles were comparable across the three arms. No grade ≥3 hemorrhagic adverse events were reported in either Arm A or B. Conclusions: The combination of ZG005 and bevacizumab as first-line treatment in patients with aHCC demonstrated an early encouraging efficacy with an acceptable safety profile. Higher response rates and prolonged PFS were observed with the ZG005-based regimens. Longer follow up of the current study and future phase 3 trials are warranted to validate the efficacy and safety of ZG005 in combination with bevacizumab in aHCC. Clinical trial information: NCT06558227 .