PURPOSE:Antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) could be a promising strategy for HER2-expressing gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJ) and colorectal cancer (CRC). We conducted a phase I trial to assess trastuzumab rezetecan, a novel HER2-targeted ADC, in HER2-expressing advanced GC/GEJ and CRC. METHODS:Patients with HER2-expressing advanced GC/GEJ and CRC whose disease progressed on and/or had no available/applicable standard treatment were enrolled. Patients were intravenously given trastuzumab rezetecan at 3.2, 4.8, 6.4, and 8.0 mg/kg (once every 3 weeks) in an i3+3 dose-escalation scheme, followed by pharmacokinetics expansion at selected doses and then clinical expansion. The primary end points were dose-limiting toxicity (DLT) and safety. RESULTS:Between March 30, 2021, and August 1, 2023, 100 patients were enrolled (57 with GC/GEJ and 43 with CRC). One DLT occurred in the 8.0 mg/kg dose cohort. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 66 (66.0%) patients. Only 5 (5.0%) patients discontinued treatment because of TRAEs. In HER2-positive GC/GEJ (n = 40), trastuzumab rezetecan achieved an objective response rate (ORR) of 45.0%, a median progression-free survival (PFS) of 9.0 months (95% CI, 7.0 to 11.3), and a median overall survival (OS) of 16.3 months (95% CI, 12.4 to not reached [NR]). In GC/GEJ with HER2 immunohistochemical 2+ and in situ hybridization-negative (n = 12), trastuzumab rezetecan had an ORR of 25.0%, a median PFS of 12.2 months (95% CI, 2.8 to 14.0), and an immature median OS. In HER2-positive CRC (n = 37), trastuzumab rezetecan had an ORR of 40.5%, a median PFS of 9.5 months (95% CI, 7.3 to 11.2), and a median OS of 22.7 months (95% CI, 17.5 to NR). CONCLUSION:Trastuzumab rezetecan showed tolerable safety and preliminary efficacy in HER2-expressing advanced GC/GEJ and CRC.

BackgroundIgG4-SC typically requires long-term corticosteroid therapy. We report a distinctive case of a 65-year-old woman with biopsy-supported IgG4-SC that closely mimicked malignancy.Case summaryThe patient presented with 10 kg weight loss and CA19–9 of 315 U/mL. She achieved sustained clinical and biochemical remission after repeated endoscopic mechanical decompression alone, with no recurrent obstructive cholestasis during long-term clinical and biochemical follow-up. However, serum IgG4 remained elevated at long-term reassessment, and complete immunologic remission could not be assumed.ConclusionThis case raises the possibility of an “obstruction-dominant” presentation of IgG4-SC and suggests that intensive endoscopic biliary decompression may serve as a temporary or, in selected cases, sustained steroid-sparing strategy in carefully selected high-risk patients, without challenging the current role of corticosteroids as standard first-line therapy.

4626 Background: SHR-1501, an IL-15 agonist fusion protein composing of a humanized antibody Fc region fused with IL-15 and IL-15Rα sushi domain, demonstrated promising efficacy, well tolerance, and acceptable safety in alone or in combination with BCG in patients with BCG-naive and BCG-unresponsive high-risk NMIBC ( ASCO 2025 ). Here, we report the updated results of this phase 1/2 study (NCT05410730). Methods: In the dose-escalation phase 1a and 1b parts, SHR-1501 monotherapy (200, 400, and 600 μg) or SHR-1501 (600 μg) in combination with BCG (120 mg) was administered to patients with high-risk NMIBC. In the phase 2 part, patients with BCG-naive NMIBC (cohort A), BCG-unresponsive NMIBC carcinoma in situ (CIS; cohort B), and BCG-unresponsive high-grade Ta/T1 NMIBC without CIS (cohort C) were enrolled to receive SHR-1501 (600 μg) plus BCG (120 mg). During the induction phase, all patients received weekly intravesical study treatment for 6 weeks. In the maintenance phase, instillations were administered weekly for three weeks at months 3, 6, 12, 18, and 24 following the initial induction dose. Primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase 2 dose in phase 1a and 1b parts; and was complete response (CR) rate for cohort B and 12-mo disease-free survival (DFS) rate for cohorts A and C in phase 2 part. Results: As of Oct 31, 2025, 112 patients were enrolled (n=8 in phase 1a; n=6 in phase 1b; n=30, 25, and 43 in cohorts A, B, and C in phase 2). The median follow-up duration was 23.0 months (range 3.5-25.6) in patients with BCG-naive NMIBC, 6.5 months (range 2.6-21.2) in patients with BCG-unresponsive NMIBC CIS, and 13.5 months (range 2.5-23.1) in patients with BCG-unresponsive high-grade Ta/T1 NMIBC without CIS. In cohort B, the overall CR rate was 80.0% (20/25), the median DFS was 12.0 months (95% CI 6.0-NR). The 12-mo DFS rate was 90.3% (95% CI, 72.8-96.8) in patients with BCG-naive NMIBC and 62.7% (95% CI, 44.9-76.1) in patients with BCG-unresponsive high-grade Ta/T1 NMIBC without CIS. The 18-mo DFS rates were 90.3% (95% CI, 72.8-96.8) and 58.2% (95% CI, 39.6-72.9), respectively. Treatment-related adverse events (TRAEs) and grade 3 TRAEs occurred in 90 (86.5%) and 19 (18.3%) of 104 patients with SHR-1501 + BCG. The most common TRAEs were urinary tract infection (62.5%) and pollakiuria (35.6%). No TRAEs led to death. Conclusions: This updated analysis confirms the promising efficacy and manageable safety profile of SHR-1501 monotherapy or in combination with BCG in BCG-naive and BCG-unresponsive high-risk NMIBC patients. Two randomized, controlled phase 3 trials are underway in both BCG-unresponsive and BCG-naïve, high-risk NMIBC populations, with the recommended dose of 600 μg SHR-1501 plus BCG. Clinical trial information: NCT05410730 .

3112 Background: ADT plus NHA have been approved for PC of different stages. However, patients (pts) inevitably develop drug resistance, and AR mutations are a common cause of this resistance. HRS-5041 is a novel, oral, highly effective AR degrader that specifically targets the AR wild type (AR WT) and clinically relevant AR LBD mutants. We conducted a phase 1 trial to assess HRS-5041 in NHA-resistant mCRPC. Methods: Pts with mCRPC who had progressed on ≥1 NHA and ≥1 taxane chemo (unless refused or not indicated to chemo) were eligible. Pts orally received HRS-5041 at 30–540 mg QD or 240–300 mg BID during dose-escalation (DE), followed by dose or indication expansion at 180–360 mg QD or 240-300 mg BID. 240 mg BID and 360 mg QD were selected for dose optimization. The primary endpoints were DLT, MTD, and RP2D. Results: As of Dec. 12, 2025, 156 pts were enrolled, including 77 with AR-LBD mutation and 79 with AR-LBD WT. During DE, no DLT occurred. MTD was not reached. TRAEs were reported in 133 (85.3%) pts; the most common were anemia (38.5%), decreased appetite (25.6%), and diarrhea (24.4%). Grade ≥3 TRAEs and serious TRAEs occurred in 20 (12.8%) and 4 (2.6%) pts. No TRAEs led to death. Among all evaluable pts, rate of PSA reduction ≥50% was 0 for 1 pt at 30 mg QD, 0 for 4 pts at 90 mg QD, 17.4% for 23 pts at 180 mg QD, 32.1% for 53 pts at 360 mg QD, 40.0% for 5 pts at 540 mg QD, 35.7% for 56 pts at 240 mg BID, and 11.1% for 9 pts at 300 mg BID. Data by AR-LBD status for expanded doses are shown in table. Both 360mg QD and 240mg BID groups showed excellent PSA response rates and rPFSs, regardless of AR-LBD status. Among pts with AR-LBD mutations, the 240 mg BID group showed a superior rate of PSA reduction ≥50% and a higher 8-month rPFS rate than the 360 mg QD group. Notably, 2 patients in the 240 mg BID group achieved CR, including 1 with liver metastases. Conclusions: HRS-5041 showed tolerable safety and promising antitumor activity in pretreated mCRPC. A phase 3 study is currently underway in mCRPC pts with AR-LBD mutation, with a recommended dose of 240mg BID. Clinical trial information: NCT05942001 . Efficacy outcomes. Dose 180 mg QD 180 mg QD 360 mg QD 360 mg QD 240 mg BID 240 mg BID AR-LBD status AR-LBD mutation AR-LBD WT AR-LBD mutation AR-LBD WT AR-LBD mutation AR-LBD WT PSA reduction ≥30% * 5 (50.0) 1 (7.7) 15 (48.4) 8 (36.4) 17 (54.8) 7 (28.0) PSA reduction ≥50% * 3 (30.0) 1 (7.7) 10 (32.3) 7 (31.8) 15 (48.4) 5 (20.0) rPFS, mo † NR (2.2–NR) 5.8 (2.1–8.6) 11.0 (5.5–NR) 13.8 (8.2–NR) 11.0 (8.2–NR) NR (3.5–NR) 8-month rPFS rate † 53.3 (17.7–79.6) 32.6 (5.8–64.3) 58.1 (35.6–75.2) 82.9 (55.7–94.2) 85.3 (60.2–95.1) 71.2 (46.4–86.0) ORR # 2 (66.7) 0 0 0 3 (42.9) 1 (11.1) Data are n (%) or median (95% CI). * Assessed in pts who had at least one post-baseline PSA assessment or who discontinued treatment due to death/clinical progression without post-baseline PSA assessment; N was 10, 13, 31, 22, 31, and 25. † Assessed in full analysis set; N was 10, 14, 32, 23, 33, and 25. # Assessed in pts with baseline target lesions; N was 3, 4, 10, 5, 7, and 9.

Purpose:The outcomes of different antidiarrheal strategies in HER2-positive breast cancer patients treated with pyrotinib plus trastuzumab and docetaxel are unknown. Materials and Methods:97 eligible patients received pyrotinib once daily from Cycle 1 Day 7 onwards, combined with intravenous trastuzumab and docetaxel on Day 1 of each 21-day cycle. In the 400PYR cohort, patients were treated with 400 mg pyrotinib, without mandatory antidiarrheal prophylaxis. In the 320PYR+Pro-L and 400PYR+Pro-L cohorts, patients were given 320 or 400 mg pyrotinib and loperamide prophylaxis. In the 320PYR cohort, patients were treated with 320 mg pyrotinib, without mandatory antidiarrheal prophylaxis. In the PYR-DE+Pro-L cohort, patients were treated with escalating pyrotinib doses and loperamide prophylaxis. Results:The incidence of grade 3 diarrhea in cohorts with loperamide prophylaxis was lower than in the 400PYR cohort. In the 3 cohorts with loperamide prophylaxis, the dose escalation cohort had the lowest incidence of grade 3 diarrhea. The incidence of grade 3 diarrhea in 320PYR cohort was similar to the 3 cohorts with prophylactic antidiarrheal loperamide. No event of grade 4 or 5 diarrhea was reported. Conclusion:Loperamide prophylaxis and pyrotinib dose escalation were associated with lower observed rates of grade 3 diarrhea in patients receiving pyrotinib plus trastuzumab and docetaxel. The lower rate observed in the 320PYR cohort should be interpreted cautiously and may reflect improved clinical management rather than a reproducible protocolized intervention.

5047 Background: The development and progression of prostate cancer are regulated by steroid hormones. HSK46575 Tablet is a novel oral small-molecule inhibitor of cytochrome P450 11A1 (CYP11A1), which can block the production of all downstream steroid hormones and their precursors, thereby reducing the activation of the androgen receptor (AR) signaling pathway and inhibiting tumor progression. Herein, we report the safety and efficacy of HSK46575 in patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: This multicenter, open - label Phase I clinical trial had two parts: Phase Ia (dose escalation and expansion) and Phase Ib (dose optimization). Eligible patients were mCRPC patients who failed at least one NHA treatment and either failed, were intolerant to, or refused at least one line of chemotherapy. Phase Ia's dose escalation used a "3 + 3" design to explore four doses (3 mg, 10 mg, 30 mg, 60 mg), and dose expansion was done at 30 mg due to good safety and preliminary efficacy.The primary endpoints were safety and the recommended Phase II dose (RP2D). Results: As of November 4, 2025, 27 subjects were enrolled, with a median follow-up of 3.7 months and a median age of 68 years (range: 51-82 years). Among them, 15 (55.6%) had AR ligand -binding domain (AR-LBD) mutations, and 12 (44.4%) had received taxane-based chemotherapy before. No dose-limiting toxicities were observed in any dose group. Treatment-related adverse events (TRAEs) occurred in 18 subjects (66.7%), most of which were Grade 1-2. The most common TRAEs were alanine aminotransferase elevation (18.5%), sinus bradycardia (11.1%), and nausea (11.1%).No adverse events leading to permanent treatment discontinuation or death were observed. Prostate-specific antigen (PSA) assessment was available for 26 subjects, with PSA response rates confirmed after at least 3 weeks. The PSA 30 and PSA 50 response rates were 42.3% and 34.6% in the total population, 71.4% and 57.1% in AR-LBD mutant subjects (n = 14), and 75% and 58.3% in the 30 mg dose group with AR-LBD mutations (n = 12). The PSA 50 response rate was 12.5% (1/8) in the 30 mg dose group with AR-LBD wild-type. Fourteen subjects were eligible for soft tissue assessment, 8 of whom had AR-LBD mutations. One partial response (PR) was seen during treatment in an AR-LBD mutant patient in the 30 mg dose group, leading to an objective response rate (ORR) of 14.3% in this population. . The radiographic progression-free survival (rPFS) has not been reached. The 6-month rPFS rates were 67.5% in the total population and 76.2% in the AR - LBD mutation population. Conclusions: HSK46575 shows a manageable safety profile and preliminary antitumor activity, especially in the population with AR - LBD mutations. These findings support further exploration in the mCRPC population. Clinical trial information: NCT07007910 .

GZR18 is a long-acting glucagon-like peptide-1 receptor agonist that is under development for the treatment of type 2 diabetes mellitus (T2DM). In this randomized, double-blind, placebo-controlled phase 1b/2a trial in Chinese adults with T2DM, the safety and efficacy of once-weekly GZR18 are evaluated using different dose-titration regimens in two separate parts: Part A (0.5-4 mg over 26 weeks) and Part B (1.5-13 mg over 23 weeks). Overall, 72 participants are enrolled, of whom 62 complete the trial. GZR18 significantly reduces glycated hemoglobin (HbA1c) in both parts (Part A: -1.32% for GZR18 versus 0.86% for placebo; Part B: -1.81% for GZR18 versus 0.12% for placebo). Improvements in body weight and other metabolic parameters are also observed. GZR18 is safe and well tolerated, with mostly mild-to-moderate gastrointestinal adverse events; no severe hypoglycemia or treatment-related serious adverse events occurred. These findings support further development of GZR18 in larger, longer-term trials. The trial is registered at ClinicalTrials.gov (NCT06256523).

1123 Background: TROP2 and HER3 are frequently overexpressed in most of solid tumors. JSKN016 is a first-in-class bispecific ADC targeting TROP2/HER3, site specifically conjugated to topoisomerase I inhibitor via a cleavable linker (DAR4). Glycan conjugation provides high stability and minimizes off-target toxicity. Methods: JSKN016-101 (NCT06592417) is a first-in-human, dose-escalation and expansion study in China, enrolling patients with advanced solid tumors to receive JSKN016 monotherapy. This analysis focused on the HER2-negative BC cohort. Results: As of December 22, 2025, JSKN016 was escalated to 8 mg/kg IV Q3W without reaching the maximum tolerated dose. A total of 82 HER2- BC pts were enrolled: 50 TNBC and 32 HR+/HER2- BC, treated at 4 mg/kg (n=14), 6 mg/kg (recommended phase II dose [RP2D]; n=65), and 8 mg/kg (n=3). Overall, 98.8% (81/82) had stage IV disease including 13.4% (11/82) with brain metastases. Median age was 50 (TNBC) and 52y (HR+/HER2- BC); ECOG PS 1 was reported in 78.7% and 76.7%, respectively. All TNBC pts had prior taxane-based chemotherapy, 28.0% had received ≥3 prior systemic regimens. All HR+/HER2- BC pts had progressed after ≥1 endocrine therapy with CDK4/6 inhibition and ≥1 chemotherapy. Among 47 efficacy-evaluable TNBC pts, objective response rate (ORR) was 61.7% (by INV and IRC). At RP2D (n=31), ORR was 64.5% (INV) and 61.3% (IRC), with disease control rates (DCR) of 83.9% and 90.3%. The median PFS was 7.9 months (95%CI: 5.5, NE) by IRC and 7.6 months (95%CI: 4.1, NE) by INV. Among 30 efficacy-evaluable HR+/HER2- BC pts, ORR was 50.0% (INV) and 53.3% (IRC); at RP2D (n=29), ORR was 51.7% (INV) and 55.2% (IRC), with DCR of both 100%. The median PFS was 11.1 months (8.3, NE) by IRC and was not yet mature by INV. With a median follow-up of 8 months, grade 3 or above TRAEs occurred in 25.6% (21/82) pts, with no G4 or 5 events reported. The most common G3 TRAEs were neutrophil count decreased (6.1%), amylase increased (4.9%), white blood cell count decreased (4.9%), stomatitis (3.7%), asthenia (2.4%), lymphopenia (2.4%). The incidence of TRAEs was 9.8%. Only one TRAE (G3 conjunctivitis) led to treatment discontinuation. No interstitial lung disease (ILD) was reported. Conclusions: JSKN016 demonstrated robust antitumor activity with good safety profile in pts with HER2-negative BC. The results support further development of JSKN016 as monotherapy or in combination. Clinical trial information: NCT06592417 . Efficacy of JSKN016 in HER2-BC at 6 mg/kg Q3W. TNBC (N=31) HR+/HER2- BC (N=29) Assessed by INV IRC INV IRC uORR, % (95% CI) 64.5 (45.4, 80.8) 61.3 (42.2, 78.2) 51.7 (32.5, 70.6) 55.2 (35.7, 73.6) DCR, % (95% CI) 83.9 (66.3, 94.5) 90.3 (74.2, 98.0) 100 (88.1, 100) 100 (88.1, 100) mPFS, mos (95% CI) 7.6 (4.1, NE) 7.9 (5.5, NE) NR 11.1 (8.3, NE) 6-months PFS rate, % 57.7 (38.5, 72.9) 68.4 (47.9, 82.2) 74.0 (53.0, 86.7) 84.5 (63.8, 93.9)

Previous preclinical studies suggested that Shexiang Tongxin Dropping Pill (STDP) would be effective for coronary slow flow phenomenon (CSFP), but its clinical efficacy and safety remain uncertain. A multicenter, randomized, controlled phase IV trial was implemented to enroll 200 participants diagnosed with angina and CSFP between July 2016 and August 2020 to examine the drug's effectiveness and safety. The analysis revealed that corrected TIMI frame count (CTFC) values in left anterior descending (LAD) and left circumflex (LCX) arteries in STDP group could be decreased, respectively (both p < 0.01), whereas no significant changes were seen with placebo; between group differences were significant for both LAD (p = 0.008) and LCX (p = 0.044). Furthermore, STDP was well tolerated. Taken together, the results demonstrated STDP could significantly improve coronary blood flow and maintain an excellent safety profile, making it a favorable option in clinic for angina patients with CSFP. Trial registration: The trial was registered in Chinese Clinical Trial Registry (ID: ChiCTR-IPR-16008950).

2527 Background: QLS31905 is a Claudin18.2/CD3 bispecific antibody. Here we report the updated data of a phase 1 study of QLS31905. Methods: This multicenter phase 1 trial (NCT05278832) recruited patients (pts) with advanced solid tumors who had progressive disease or were intolerable to or inapplicable of standard therapy. In dose-escalation stage adopting accelerated titration and interval 3+3 design, pts regardless of Claudin18.2 status were administered QLS31905 via intravenous infusion in 11 sequential single doses (0.5, 1.5, 5, 15, 45, 100, 200, 350, 500, 800, 1200 μg/kg qw or q2w) with priming dose from 350 μg/kg. In dose-expansion stage, Claudin18.2-positive (≥1% tumor cells) pts were recruited. The primary endpoint was dose limiting toxicities (DLT) and maximum tolerated dose (MTD) in dose-escalation stage, and was objective response rate (ORR) in dose-expansion stage. Results: As of Jul 26, 2024, 31 pts were included from 0.5 μg/kg qw to 1200 μg/kg q2w in dose-escalation stage, and 48 pts were included in five cohorts (100~200 μg/kg qw and 350~800 μg/kg q2w) in dose-expansion stage. The 1200 μg/kg q2w cohort is ongoing. There were 43 (54.4%) pts with gastric or gastroesophageal junction (G/GEJ) cancer and 26 (32.9%) with pancreatic adenocarcinoma (PAC). Over half of (61.8%) pts had received ≥2 lines of prior treatment. No DLT occurred. MTD was not reached. Treatment-related adverse events (TRAEs) occurred in 79 (100%) pts, of whom 34 (43.04%) were ≥grade 3. The most common ≥grade 3 TRAEs (≥3%) were lymphocyte count decreased (21.5%), γ-glutamyl transferase increased (3.8%), neutrophil count decreased (3.8%), cytokine release syndrome (CRS [3.8%]), and anemia (3.8%). CRS occurred in 17 (21.52%) pts including two pts with grade 3 and one with grade 4, and all recovered. Two pts (2.53%) discontinued treatment due to TRAEs of abdominal pain and CRS, respectively. No TRAE leading to death occurred. In 33 Claudin18.2-positive pts in 350~1200 μg/kg q2w cohorts, six pts (three with G/GEJ cancer and three with PAC) had partial response. ORR was 18.18% (95% confidence interval [CI]: 6.98%, 35.46%), disease control rate (DCR) was 87.88% (95% CI: 71.80%, 96.60%), median progression-free survival (PFS) was 4.21 months (95% CI: 2.99, 5.55), and median overall survival (OS) was 9.53 months (95% CI: 7.69, not evaluable). Among the Claudin18.2-positive pts in 350~1200 μg/kg q2w cohorts, ORR, DCR, median PFS, median OS was 15.79%, 89.47%, 4.40 months, 9.20 months in 19 pts with G/GEJ cancer, and was 25.00%, 91.67%, 3.94 months, not reached in 12 pts with PAC, respectively. QLS31905 exposure was generally linear with the administered dosage. There was no tendency of accumulation after multiple administrations. Conclusions: QLS31905 was safe and tolerable, and showed encouraging efficacy in Claudin18.2-positive pts with gastrointestinal tumors. QLS31905 is worthy of further exploration in combined therapy in phase 2 trials. Clinical trial information: NCT05278832 .

Endothelial dysfunction is one of the earliest processes in diabetes and a major contributor to diabetic vascular complications, which often exhibit limited response to glucose-lowering therapies. We identified up-regulated S-nitrosoglutathione reductase (GSNOR) as a critical factor associated with diabetic vascular complications by unbiased proteomics. Elevated GSNOR expression was observed in the endothelium of patients with type 2 diabetes and in streptozotocin (STZ)-induced type 1 diabetes mice as well as in db/db type 2 diabetes mouse models. Genetic ablation of endothelial Gsnor promoted angiogenesis, maintained vascular permeability, and improved vasodilation in type 1 diabetes mice induced by STZ. GSNOR deficiency protected against high glucose-induced endothelial dysfunction in vitro, as evidenced by rescued tube formation, enhanced spheroid sprouting, maintained barrier integrity, and reduced permeability. Mechanistically, GSNOR orchestrated endothelial dysfunction independently of its enzymatic activity by binding the transcription factor ETS-related gene (ERG) and triggered its nuclear export through chromosome region maintenance 1. We synthesized NYY-001, an oral agent, that selectively blocks the GSNOR-ERG interaction. The direct targeting of NYY-001 to GSNOR was determined by resolving the crystal structure of their complex using cryo-electron microscopy. NYY-001 treatment enhanced postischemic neovascularization and restored vascular permeability in the peripheral vasculature in STZ-induced type 1 diabetes and db/db type 2 diabetes mouse models. These findings reveal a mechanistic role for the GSNOR-ERG complex in diabetic vascular complications and highlight NYY-001 as a promising therapeutic candidate.

Pancreatic ductal adenocarcinoma (PDAC) depends a lot on how it uses glutamine to grow quickly and stay alive. Oncogenic drivers such as KRAS, c-Myc, and HIF-1α increase how much glutamine gets taken up and broken down. Meanwhile, the bacteria in the gut and tumor itself also affect how much glutamine is available throughout the body and near the tumor. This impacts both how the tumor grows and how the immune system can detect and respond to it. Multiple strategies have emerged to disrupt this dependence: glutamine antagonists (DON and its prodrugs DRP-104, JHU-083), small-molecule glutaminase inhibitors (CB-839), antibody-drug conjugates targeting the ASCT2 transporter, and combination regimens pairing glutamine blockade with immune checkpoint inhibitors. Nanoparticle formulations-including pH-sensitive and PEGylated liposomes co-delivering DON and gemcitabine-enable targeted delivery and reduce off-target toxicity. Single-agent treatments do not work so well because the cells can adapt. They boost enzymes such as asparagine synthetase and increase how they burn fatty acids to make up for the lack of glutamine. To overcome these escape routes, future interventions must concurrently target compensatory pathways and integrate biomarker-driven patient selection. Combining glutamine-targeted agents with inhibitors of asparagine synthesis or lipid oxidation, guided by multi-omics profiling, promises a more durable therapeutic benefit and lays the groundwork for personalized treatment of PDAC.

In this ongoing phase 1b study (NCT04930432) of the MET/EGFR bispecific antibody MCLA-129 in patients (pts) with advanced NSCLC, we aimed to gain a deeper insight into the relationship between MCLA-129 and efficacy in the MET amplification (METamp) or protein overexpression (OE) population. Eligible pts (≥18 years; ECOG PS 0-1; confirmed metastatic or unresectable NSCLC; and positive EGFR or MET alterations) received MCLA-129 (1500 mg biweekly) intravenously. MET OE was defined as IHC 2+/3+ and METamp was defined based on the gene copy number (GCN). Using a wide range of GCN cut-offs, we aimed to explore its relationship with efficacy outcomes.Results: At data cut-off (March 31, 2024), in 24 NSCLC pts, 6 with MET IHC 2+/3+ and 18 with METamp were evaluable for efficacy. Four out 6 pts with MET IHC 2+/3+ (median No. of previous lines: 1 [0-1]) achieved confirmed PRs (ORR: 66.7% [95% CI 22.3-95.7]), and all these 4 pts harbored concurrent mutations (3 METex14 skipping and 1 EGFR exon20ins). The median DOR and PFS were not reached. Eight out of 18 pts with METamp achieved confirmed PRs (median No. of previous lines: 2 [1-7]) (ORR: 44.4% [95% CI 21.5-69.2]; DOR: NR [2.8-NR]; PFS: 4.8 months [2.7-9.6]). Of 7 pts with METamp (METamp was detected prior to systemic antitumor therapy), 4 pts achieved confirmed PRs, with an ORR of 57.1% (95% CI 18.4-90.1), and all these 4 pts harbored concurrent mutations (2 EGFR exon20ins, 1 METex14 skipping and 1 L861Q). Among 9 pts that progressed on 3rd-generation EGFR-TKIs, 3 pts achieved confirmed PRs. Pts with different cut-offs of MET showed a differentiated ORR (Table). MCLA-129 showed clinically meaningful antitumor activity in advanced NSCLC with MET OE or METamp, particularly in pts with concurrent mutations. High GCN seemed to be associated with better efficacy in MET-amplified advanced NSCLC, suggesting its predictive properties. Jie Wang, Jia Zhong, Yu Yao, Di Wu, Xiujuan Qu, Guojun Zhang, Haibo Zhang, Yu Cao, Zhuang Yu, Kai Chen, Maoqiong Jiang, Zhihua Li, Jianlin Long, Xiubao Ren, Huijuan Wang, Zhehai Wang, Lin Wu, Bolin Chen, Aimin Zang, Haie Chen, Lin Ma, Kan Liu, Peiqi Li, Lieming Ding. Correlation between MET amplification/overexpression status and response to MCLA-129 in advanced non-small-cell lung cancer (NSCLC): biomarker results from a phase 1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5921.

In order to ensure food safety, controlling foodborne pathogen contamination is of utmost importance. Growing apprehensions regarding the safety of synthetic antimicrobials, due to their adverse health effects, have prompted a search for alternative options. Plant natural products (PNPs) with antimicrobial activity are being explored as a viable alternative. Among the various antimicrobial natural products studied, plant essential oils, plant flavonoids, plant polyphenols, plant polysaccharides, and plant antimicrobial peptides have been identified as potential candidates. PNPs demonstrate a diverse array of antimicrobial mechanisms, encompassing cell wall and membrane damage, interference with genetic replication, disruption of energy metabolism, and induction of oxidative stress at the single-cell level, as well as inhibition of biofilm formation and quorum sensing at the population level. Certain PNPs have been harnessed as natural antimicrobial agents for the food preservation. The utilization of encapsulation technology proves to be an effective strategy in protecting PNPs, thereby ensuring good antimicrobial efficacy, enhanced dispersibility, and controlled release within food products. The utilization of nanoemulsions, nanoliposomes, edible packaging, electrospun nanofibers, and microcapsules formed by encapsulation has enriched the ways in which PNPs can be applied in food preservation. Although PNPs have great potential in food preservation, their widespread application in the food industry is currently constrained by factors such as production costs, safety concerns, and legal considerations. Chemical synthesis and biosynthesis pathways offer viable strategies for reducing the cost of producing PNPs, and ongoing efforts to assess safety and improve regulatory frameworks are likely to facilitate the broader adoption of PNPs in food preservation practices. This article provides an overview of the main types of PNPs with antimicrobial activity and their properties, focusing on their mechanisms of action. Additionally, it summarizes the use of PNPs in food preservation and discusses the characteristics and applications of different encapsulation technologies. Lastly, the paper briefly analyzes current limitations and proposes potential future trends for this field.

ABSTRACT To investigate if a newly developed tadalafil oral soluble film (OSF) was bioequivalent to the approved tadalafil tablets, a clinical study was conducted in healthy Chinese male volunteers under fasting conditions. In this study, 36 volunteers were randomized into three groups and received one tadalafil tablet, one tadalafil OSF with water, or one OSF without water in each period. The dosages were all 10 mg. Blood samples were collected and centrifuged. Plasma concentrations of tadalafil were determined by liquid chromatography tandem mass spectrometry. Pharmacokinetic (PK) parameters including maximum plasma concentration (Cmax), area under the concentration versus time curve (AUC) from dosing to the last sampling time (AUC0–t), AUC from administration to infinity (AUC0–∞), time to Cmax, half‐life and terminal elimination rate constant were calculated. Primary PK parameters including Cmax, AUC0–t, and AUC0–∞ were logarithmically transformed and an analysis of variance was applied to determine the bioequivalence between the reference and test formulation, as well as bioequivalence between tadalafil OSF administered with or without water. Safety was assessed by adverse events (AEs), serious adverse events (SAEs) and results of laboratory tests and examinations. The 90% confidence intervals of geometric mean ratios of primary PK parameters were all within the bioequivalence range of 80.00%–125.00%. AEs were mild or moderate and no SAEs were reported. Under fasting conditions, the test OSF formulation was bioequivalent to the reference tablets, and the test OSF administered with water was bioequivalent to that without water. All investigational formulations were well tolerated in the study. Trial Registration: chinadrugtrials.org.cn (CTR20181044).

Dirozalkib is a novel anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with an intended indication for ALK-positive advanced non-small cell lung cancer (NSCLC). Given that the solubility of Dirozalkib is pH-dependent, this study was conducted to evaluate the effect of the acid-reducing agent, esomeprazole magnesium (EMZ-Mg) enteric-coated tablets, on the pharmacokinetics of Dirozalkib. In this open-label, single center, two-treatment, single-sequence clinical trial, 24 healthy adults were enrolled. Participants received a single oral dose of 500 mg Dirozalkib on Day 1 and 16. Oral EMZ-Mg enteric-coated tablet (40 mg) were administered once daily from Days 11 to 16. Blood samples were collected, and plasma concentrations of Dirozalkib and its primary metabolite XZP-5089 were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic parameters were derived via noncompartmental analysis, and safety was assessed throughout the study. All 24 participants completed both treatment periods. Coadministration with EMZ-Mg enteric-coated tablet resulted in a reduction of the geometric mean maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to the last measurable concentration (AUC0 − t), and area under the curve from time zero to infinity (AUC0−∞) of Dirozalkib by about 27.0 https://clinicaltrials.gov (NCT05586568).

JS107 is a monomethyl auristatin E conjugated, CLDN18.2 specific ADC. JS107 exhibited potent anti-tumor activities in preclinical studies with a tolerable safety profile. Here we report the safety and efficacy results of JS107 monotherapy or in combination for pts with advanced solid tumors from the first-in-human phase 1 trial (NCT05502393). In Part A of the study, pts with advanced solid tumors refractory to standard therapies were treated with JS107 at 0.15-3.5 mg/kg Q3W during dose escalation and CLDN18.2+ pts were treated with JS107 at 2.0 and 3.0 mg/kg Q3W during dose expansion. In Part B of the study, pts with CLDN18.2+, HER2-negative, previously untreated, advanced gastric or gastroesophageal junction cancer (GC/GEJ) were treated with JS107 combined with toripalimab (240 mg Q3W) and XELOX (capecitabine and oxaliplatin), in dose escalation (JS107 at 2.0-3.0 mg/kg Q3W) and expansion (JS107 at 2.0 mg/kg Q3W) phases. The primary endpoint was safety. Secondary endpoints included efficacy and pharmacokinetics (PK). As of January 7, 2025, 63 pts were enrolled in Part A (22 in dose escalation and 41 in dose expansion) and 27 enrolled in Part B (9 in dose escalation and 18 in dose expansion). The maximum tolerated dose was not reached for JS107 monotherapy and was 2.5 mg/kg for combination treatment. Grade 3 and above treatment-related adverse events (TRAEs) occurred in 47.6% pts in Part A and 40.7% pts in Part B. The most frequent grade 3 and above TRAE was neutropenia (22.2%) in Part A and thrombocytopenia (18.5%) in Part B. Among pts with CLDN18.2-high (defined as ≥20% of tumor cells with ≥2+ staining intensity) GC/GEJ who received JS107 monotherapy at 2.0-3.0 mg/kg (n=24), the objective response rate (ORR) was 34.8% (8/23, 95%CI 16.4-57.3) and median progression-free survival was 4.11 months (95%CI 3.15-9.63). Among efficacy evaluable pts with CLDN18.2-high GC/GEJ in Part B (n=14), the ORR was 78.6% (11/14, 95%CI 49.2-95.3). A positive association between CLDN18.2 expression level and efficacy was observed in Part A and Part B. PK analysis showed a dose-dependent ADC and total antibody exposure at doses of 0.15-3.5 mg/kg. JS107 elimination half-life was 4.41-6.96 days at doses of 2.0-3.5 mg/kg, with no obvious accumulation observed after multiple dosing. JS107 monotherapy or in combination with toripalimab and XELOX showed promising efficacy in pts with CLDN18.2-high advanced GC/GEJ with a manageable safety profile. The clinical benefit of CLDN18.2 ADC combination treatment was thus demonstrated for the first time. Further clinical development of JS107 in CLDN18.2+ advanced solid tumors is warranted. Rui-Hua Xu, Dan-Yun Ruan, Rong-Bo Lin, Jian-Zhen Shan, Peng Nie, Ying-Hua Ji, Jing Wang, Yu Cao, Fu-Nan Liu, Jie-Er Ying, Li Liu, Tao Zhang, Hui-Ting Xu, Yan-Qiao Zhang, Wen-Can Song, Jin Xia, Wen-Feng Li, Zhi-Ye Zhang, Jian Shi, Ming-Xia Wang, Long Wu, Yan-Yan Lu, Xiao Zhang, Yan-Yan Hu, Yong-Dong Zhang. Phase I dose-escalation and expansion study of JS107, a claudin 18.2 (CLDN18.2)-targeting antibody-drug conjugate (ADC), as monotherapy or in combination for patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT010.