BACKGROUND:Previous studies on extensive-stage small cell lung cancer (ES-SCLC) have primarily focused on serum tumor markers (STM) measurements at a single time point, overlooking the prognostic value of sequential STM monitoring. METHODS:We conducted a retrospective cohort study of 253 patients with ES-SCLC and applied latent class growth mixed modeling to define trajectory groups for neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), and cytokeratin 19 fragment (CYFRA21-1). RESULTS:Overall survival (OS) and adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) for mortality in the persistent-rising vs. low-stable groups were 1.19 (0.73 - 1.95), 1.58 (1.07 - 2.33), and 2.34 (1.11 - 4.92) for NSE, CEA, and CYFRA21-1, respectively. Persistent elevations of CEA (p = 0.021) and CYFRA21-1 (p = 0.026) were independent OS prognostic factors. For progression-free survival (PFS), adjusted HRs (95% CIs) were 2.27 (1.38 - 3.74), 1.22 (0.83 - 1.80), and 0.99 (0.48 - 2.05) for NSE, CEA, and CYFRA21-1, respectively, with NSE (p < 0.001) independently predicting PFS. Combined subgroups (three-low, one-high, and two-high) demonstrated significant OS and PFS stratification (p < 0.001). CONCLUSION:Dynamic monitoring of NSE, CEA, and CYFRA21-1 provides a valuable approach for prognostic prediction in patients with ES-SCLC.

ABSTRACT Efferocytosis—the phagocytic clearance of apoptotic cells (ACs)—is essential for maintaining tissue homeostasis, immune tolerance, and inflammation resolution. Beyond classic receptor‐mediated recognition, this process drives phagocyte metabolic reprogramming to actively facilitate tissue repair. Consequently, defective efferocytosis serves as a core pathogenic mechanism across major human diseases. This review outlines the molecular and metabolic foundations of efferocytosis and defines four universal hallmarks of its dysfunction: senescence‐driven impairment, unresolved inflammation, loss of immune tolerance, and fibrotic tissue repair. Subsequent sections explore how these defects manifest in cardiovascular, autoimmune, and neurodegenerative conditions, as well as cancer. Because efferocytosis exhibits a dual pathophysiological nature, therapeutic interventions must be highly disease‐specific. Enhancing apoptotic clearance can effectively resolve chronic inflammatory and fibrotic conditions. Conversely, because tumors hijack these same pathways to build immunosuppressive microenvironments, inhibiting efferocytosis remains a critical strategy in oncology. The synthesis of these divergent roles informs a “context‐dependent directionality” framework to guide the clinical translation of efferocytosis‐targeted precision therapies.

3115 Background: Protein arginine methyltransferase 5 (PRMT5) methylates multiple protein substrates with a variety of biological functions known to be dysregulated in cancer. CTS3497 is an orally available, brain-penetrable, MTA (methylthioadenosine) -cooperative PRMT5 inhibitor that preferentially targets the MTA-bound PRMT5 in MTAP (MTA phosphorylase) -deficient tumors and potently inhibits tumor growth in various preclinical models. Here we present clinical data from an ongoing Phase I/II study of CTS3497 in solid tumors (NCT06971523). Methods: Eligible pts with homozygous MTAP deletion (by next generation sequencing), or MTAP protein loss (by immunohistochemistry [IHC]) and advanced solid tumors in the dose-escalation stage received 50, 200, 300, 400 mg BID of CTS3497 orally, while pts in the dose-expansion stage were treated with 200, 300 or 400 mg BID until disease progression or intolerable toxicity. Efficacy, safety, PK, PD and biomarker profiles were evaluated. Results: As of 22 Jan 2026, 41 patients received ≥1 dose of CTS3497 treatment. No DLT was observed, and MTD was not reached; CTS3497 was well-tolerated. Most common (≥20%) treatment-related adverse events (TRAEs) were anemia (34%), white blood cell count decreased (32%), platelet count decreased (27%) and neutrophil count decreased (22%). The most common Grade ≥3 TRAE (occurring in ≥5% of patients) was platelet count decreased. No central nervous system (CNS) effects were reported. Among 21 centrally-confirmed MTAP-deficient, efficacy-evaluable patients, including 9 gastrointestinal (GI) cancers (ampullary cancer, biliary tract carcinoma, esophageal squamous cell carcinoma, gastric cancer and pancreatic ductal adenocarcinoma), 5 non-small cell lung cancer (NSCLC), 1 urothelial carcinoma and 6 rare cancers, the objective response rate (ORR) was 43%, and the disease control rate (DCR) was 91%. In GI cancers, the ORR and DCR were 56% and 89%. In NSCLC, the ORR and DCR were 60% and 80%. The exposures (Cmax, AUC0-24h) of CTS3497 increased in a linear, dose-proportional manner. The pharmacodynamic (PD) marker, plasma symmetric dimethylarginine (SDMA) level, showed a significant decrease. Conclusions: CTS3497 demonstrated a favorable safety profile and promising efficacy in heavily pretreated pts with MTAP-deficient advanced solid tumors, including GI cancers, NSCLC. Clinical trial information: NCT06971523 .

4133 Background: Subsequent treatment options for advanced cholangiocarcinoma (CCA) after failure of chemotherapy and FGFR inhibitors (FGFRi) are limited. Tinengotinib (TT-00420), a novel FGFRi, potently inhibited FGFR2 fusion/rearrangement and acquired resistant/FGFR2 kinase domain mutations. The FIRST-08 study is an open-label, multicenter Phase II study in Chinese patients (pts) with advanced/metastatic CCA (NCT06057571). Methods: Eligible pts with advanced/metastatic CCA harboring FGFR2 fusion or arrangement, who had failed prior chemotherapy and one FGFRi, received tinengotinib 10 mg orally once daily in 21-day cycles. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included progression free survival (PFS), disease control rate (DCR), duration of response (DoR), overall survival (OS), safety, PK and quality of life (QOL) per EORTC QLQ-C30. Results: As of June 27, 2025, 50 pts were enrolled (median age 56.5 years; 52.0% male; ECOG of 1: 44.0%). Median follow-up was 8.5 months. Forty percent had ≥ 3 prior systemic regimens, 66.0% had prior immunotherapy, and 42.0% had received other targeted therapies beyond FGFRi. The ORR by BICR was 28.0% (95%CI, 17.5~41.7) with 14 confirmed partial responses, and median DoR was 7.9 (5.6~ -) months. The disease control rate (DCR) was 82.0%. The median PFS was 5.7 (4.3~8.3) months. The median OS had not reached, with the 18 months survival rate 66.9% (47.3~80.6). Common Gr3/4 TRAEs (≥15%) included hypertension (42.0%), palmar-plantar erythrodysesthesia syndrome (16.0%), No Gr 5 TRAE was observed. 41 out of 50 pts had biomarker ctDNA samples collected at baseline, 82.9% pts had FGFR2 fusion and 48.8% had FGFR2 mutation (SNV). 28 pts had biomarker ctDNA samples collected at both baseline and C3D1. A significant decrease in maximum variant allele frequencies (MaxVAF) from baseline to C3D1 by a median relative VAF reduction of 83.7% (p<0.0001), indicating strong molecular response to tinengotinib. Conclusions: Tinengotinib demonstrated durable clinical anti-tumor activity and a manageable safety profile in heavily pretreated CCA pts with FGFR2 fusion/rearrangement following prior chemotherapy and FGFRi therapy. Clinical trial information: NCT06057571 . Efficacy outcomes by BICR and investigator. BICR Investigator ORR, % (95%CI) 28.0 (17.5~41.7) 20.0 (11.2~33.0) DCR, % (95%CI) 82.0 (69.2~90.2) 78.0 (64.8~87.3) mPFS, months (95%CI) 5.7 (4.3~8.3) 6.9 (4.3~8.5) mDoR, months (95%CI) 7.9 (5.6~ -) 6.6 (2.4~ -)

Tumor-associated macrophages (TAMs) reshape the tumor immune microenvironment and promote tumor progression, yet the underlying mechanisms remain largely unclear. Through integration of single-cell RNA (scRNA) sequencing datasets from esophageal squamous cell carcinoma (ESCC), we identified a distinct protumoral macrophage population with elevated expression of phospholipase D3 (PLD3). Multiomics investigations revealed that high infiltration of these PLD3-high macrophages was associated with poor clinical outcomes in ESCC patients. Mechanistically, tumor cells secreted cholesterol to modulate the microenvironment. Upon the uptake by TAMs, cholesterol triggered the nuclear translocation of transcription factor EB (TFEB), which directly bound to the PLD3 promoter region and activated its transcription. The overexpressed PLD3 localized to lysosomes, enzymatically degrading single-stranded nucleic acids, thereby suppressing the activation of the toll-like receptor 9 (TLR9) pathway. This cascade ultimately impaired effector T cell function and sustained an immunosuppressive tumor microenvironment (TME). Notably, therapeutic intervention using ODN2216-siPLD3 in murine models enhanced CD8 T cell infiltration and significantly inhibited tumor growth. Our findings highlight PLD3-high macrophages as a promising diagnostic biomarker and a therapeutic target for ESCC, paving the way for potential clinical translation.

4011 Background: MET amplification is a poor prognosis for survival in patients (pts) with gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJa). Currently no approved targeted therapy is available for MET-amplified GC/GEJa. Savolitinib is a potent and highly selective oral MET-TKI. Here we reported the primary analysis results from a pivotal phase 2 trial investigating savolitinib in MET-amplified GC/GEJa, conducted with registration intent (NCT04923932). Methods: Eligible pts had locally advanced or metastatic GC/GEJa with MET amplification (gene copy number ≥10 by FISH) and had failed ≥2 lines of prior standard therapy. Pts received savolitinib 200 mg (BW < 50 kg) or 300 mg (BW ≥50 kg) BID. The primary endpoint was ORR assessed by an Independent Review Committee (IRC) per RECIST 1.1, with a pre-specified efficacy threshold defined as the lower limit of the 95% CI of ORR exceeding 15%. Secondary endpoints mainly included DCR, DoR, TTR, PFS, OS and safety. An exploratory OS analysis was conducted in pts with MET-amplified GC/GEJa, who had previously received first-line, second-line, or later-line standard therapies, but were ineligible for study enrollment and did not receive the study drug. Plasma samples were also collected at baseline and end of treatment (EOT) for comprehensive genomic profiling using a 671-gene sequencing panel (Benrui GCP, OrigiMed). Results: As of Oct 8, 2025, 65 eligible pts were enrolled and received savolitinib. Baseline characteristics were: median age of 57.4 years, ECOG PS of 0 (13.8%) or 1 (86.2%), primary tumor sites of GC (84.6%) or GEJa (15.4%), and baseline ctDNA MET-positive rate of 64.6% (42 pts). Per the IRC assessment, ORR was 32.3% (95%CI: 21.2%, 45.1%), which exceeded the pre-specified efficacy threshold; in baseline ctDNA MET-positive pts (42 pts), IRC-assessed ORR was 45.2% (95%CI: 29.8%, 61.3%). IRC-assessed secondary efficacy endpoints were: DCR of 63.1%; mTTR of 1.4 months; mDoR of 9.7 months; and mPFS 4.0 of months. mOS was 6.9 months in the 65 treated pts, versus 4.8 months in 139 pts who received alternative treatments rather than the study drug in the exploratory OS analysis. Savolitinib-related TEAEs of Grade ≥3 occurred in 23 pts (35.4%). Exploratory ctDNA biomarker analysis showed that pts (N = 14) harboring baseline alterations in FGFR2, EGFR, PIK3CA, BRAF, or KRAS had lower ORR (14.3%, 2/14) and shorter mPFS (1.4 months). Additionally, in pts (N = 26) who provided PD/EOT samples, 12 pts developed alterations in these genes that were identified as putative acquired resistance mechanisms, and 4 pts had acquired MET mutations. Conclusions: Savolitinib showed clinical efficacy and a tolerable safety profile in pts with MET-amplified GC/GEJa who had received ≥2 lines of prior therapy, supporting it to be a future treatment option for this genetically defined population. Clinical trial information: NCT04923932 .

Purpose EMB-01 is a novel EGFR × c-MET bispecific antibody. The phase Ib/II study (NCT05176665) presents the safety and antitumor activity of EMB-01 in patients predominantly with heavily pretreated metastatic colorectal cancer (mCRC). Patients and methods EMB-01 was administered at 1600 mg intravenously weekly. Primary endpoints were safety and tolerability in phase Ib, and antitumor activity in phase II. Secondary endpoints included cross-phase validation of antitumor activity and safety. Exploratory endpoints included biomarker analysis. Results Fifty-two patients were enrolled (phase Ib, n=27; phase II, n=25). All patients (100%) experienced at least one treatment-emergent adverse event (TEAE), and 98.1% experienced treatment-related adverse events (TRAEs). Grade ≥ 3 TRAEs occurred in 63.5% of patients, with rash (25.0%) and dermatitis acneiform (17.3%) most frequently. Among the 48 mCRC patients, the confirmed objective response rate (cORR) was 12.5% (95% confidence interval [CI], 4.7 to 25.2%), with a median duration of response (DOR) of 32.0 weeks (95% CI, 16.0 to not estimable). All responses were observed in a favorable mCRC subgroup with evaluable response (left-sided, RAS/RAF wild-type, naïve to fruquintinib/regorafenib/trifluridine-tipiracil [TAS-102]; n=29). In this subgroup, the unconfirmed ORR (uORR) and the cORR were 24.1% (95% CI, 10.3 to 43.5%) and 20.7% (95% CI, 8.0 to 39.7%), respectively. Median progression-free survival (mPFS) was 19.0 weeks (95% CI, 12.3 to 24.1 weeks). Conclusions EMB-01 demonstrated a manageable safety profile and promising antitumor activity in heavily pretreated mCRC, particularly in the RAS/RAF wild-type, left-sided mCRC subgroup naïve to late‑line therapies, warranting further clinical development.

The immunosuppressive tumor microenvironment (TME) remains a major therapeutic challenge in oncology. This immunosuppression arises through two synergistic mechanisms: impaired cytotoxic function of T cells and NK cells, and differentiation of immune cells into immunosuppressive subtypes. Metabolic reprogramming, particularly the Warburg effect (aerobic glycolysis in tumor cells), plays a pivotal role in shaping this immunosuppressive TME. While lactate was traditionally viewed as a metabolic byproduct, emerging evidence reveals its profound immunomodulatory functions. As the end-product of glycolysis, lactate actively reshapes immune cell behavior to foster immunosuppression. This review systematically examines: (1) the bidirectional lactate-mediated crosstalk between tumor and immune cells that drives immunosuppression, and (2) current therapeutic strategies targeting lactate metabolism. By elucidating these mechanisms, we aim to advance lactate-targeting approaches for TME reprogramming and improved cancer immunotherapy outcomes.

Vasculogenic mimicry (VM), a novel endothelial-independent blood perfusion pathway, is linked to advanced stage and poor prognosis in esophageal squamous cell carcinoma (ESCC). In this study, by integrating single-cell RNA sequencing and transcriptomic data and employing a machine learning framework incorporating 117 algorithmic combinations, we constructed a robust 4-VM-related gene prognostic model for ESCC. Consensus clustering further stratified patients into two subtypes. The high-risk subtype (C2) was characterized by unfavorable prognosis, activated stroma, enrichment of M2 macrophages, and multidrug resistance. As the core regulatory hub of this model, SAP18 was markedly upregulated in ESCC tissues and showed positive correlations with aggressive clinicopathological features. Mechanistically, SAP18 binds to PIK3CB, activating the AKT/mTOR signaling cascade and upregulating HIF-1α, thereby conferring VM-forming capability to epithelial-derived tumor cells. Both in vitro and in vivo experiments confirmed that knockdown of SAP18 significantly suppressed malignant phenotypes in ESCC. Pharmacological intervention using the highly selective AKT inhibitor MK-2206 effectively abolished VM network formation and profoundly inhibited tumor growth. Our integrated multi-omics and functional analyses decipher the molecular architecture of VM in ESCC, nominating SAP18 as a precise prognostic biomarker and therapeutic target, and providing a foundation for individualized VM-targeted strategies in ESCC management.

Abstract Background: Aberrant activation of FGFR signaling is implicated in tumorigenesis across multiple cancer types. Lavengratinib, the first-in-class selective FGFR2/3 inhibitor, showed encouraging efficacy and a favorable safety profile as monotherapy in pts with FGFR2/3 alterations in a phase 1 study (NCT05244551). We used next-generation sequencing (NGS) of ctDNA to define the molecular mechanism of acquired resistance to lavengratinib. Method: Pts with FGFR2/3 activating alterations who had progressed on or declined standard therapy, and who had no prior FGFR inhibitor treatment, were treated with lavengratinib. Pts with both baseline and post-progression ctDNA samples were included in the study. Sequential ctDNA profiling (Onco Sonar, Genetron) was performed to compare genomic alterations at baseline and at disease progression. Result: Seventeen pts with paired baseline and post-progression ctDNA samples were analyzed in this study, containing individuals with cholangiocarcinoma (CCA), gastric cancer (GC), non-small-cell lung cancer (NSCLC), cervical cancer and urothelial carcinoma. All the pts initially achieved an objective response or stable disease before developing progression. Seven pts acquired one or more secondary mutations in the kinase domain of FGFR2 or FGFR3. In FGFR2-altered pts, 15 residues in FGFR2 kinase domain were found mutated at the time of resistance to lavengratinib. The molecular brake residue N549 was the most frequently affected site. Additional recurrent mutations involved L617, the molecular brake residue E565 and the gatekeeper residue V564, particularly in FGFR2-amplified GC and CCA with FGFR2 fusion. These putative cases of FGFR2 acquired resistance in GC were consistently polyclonal, a pattern also commonly observed in CCA. In one cervical cancer pt with FGFR3 S249C, an emergent FGFR3 M528I was detected at progression. In contrast, FGFR2-altered NSCLC was prone to develop acquired alterations in genes involved in RTK/RAS pathways other than FGFR2, suggesting the resistance mainly driven by bypass mechanisms in this indication. Moreover, ATM, a key gene in the DNA damage response (DDR) network, exhibited the highest incidence of off-target emergent mutations across tumor types. Conclusion: This study revealed diverse genomic mechanisms imparting acquired resistance to the selective FGFR2/3 Inhibitor lavengratinib, including secondary FGFR2/3 kinase domain mutations as well as off-target alterations in RTK/RAS and DDR pathways. In GC and CCA, polyclonal FGFR2 acquired mutations represent a convergent, on-target resistance mechanism to FGFR inhibition. These findings provide molecular insights into resistance mechanisms and guide the combination and sequential therapy strategies to overcome resistance in FGFR2/3 driven advanced solid tumors. Citation Format: Yue Wang, Chunyu Zhou, Liyun Zhao, Chaoze Cheng, Zhixuan Zhu, Zishuo Wang, Peng Zhang, Jing Zhang, Hua Zou, Jing Ji, Hongping Yu, Ji Zhu, Yan Zhao, Dewei Li, Yongsheng Li, Wei Li, Yanru Qin, Shujun Yang, Nannan Zhang. Circulating tumor DNA (ctDNA)-based profiling of acquired resistance to the fibroblast growth factor receptor (FGFR)2/3 inhibitor lavengratinib(ABSK061) in patient(pt)s with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5319.

e16399 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with limited therapeutic options in advanced stages. Building upon the foundational evidence from the PAN-HEROIC-1 trial which demonstrated the clinical benefits of irinotecan liposome (II) and supported its approval for unresectable locally advanced or metastatic PDAC in China, this study aimed to evaluate the real-world safety and effectiveness of irinotecan liposome (II)-based combination regimens in patients with PDAC. Methods: This multicenter, prospective, real-world study included patients with pathologically or radiologically confirmed PDAC who were considered eligible by investigators for irinotecan liposome (II)-based combination regimens incorporating chemotherapy, chemoradiation, radiotherapy, immunotherapy, or targeted therapy. Patients were assigned to three cohorts according to treatment stage at enrollment: perioperative, first-line, and later-line treatment. Observational data were collected including adverse events, baseline characteristics, therapeutic regimens, and tumor response. The primary endpoint was treatment-emergent adverse events (TEAEs); secondary endpoints included overall survival (OS) and real-world progression-free survival (rwPFS), real-world time to progression (rwTTP), real-world objective response rate (rwORR), real-world disease control rate (rwDCR), real-world disease-free survival (rwDFS) and real-world duration of treatment (rwDOT). Results: As of August 30, 2025, a total of 236 patients were enrolled (perioperative, n = 23; first-line, n = 98; later-line, n = 115). The median age was 62.0 years (range, 33.0–83.0), with males and females accounting for 57.2% and 42.8%, respectively. Tumors were located in pancreatic head (25.4%), pancreatic body (11.4%), pancreatic tail (11.4%) and other pancreatic sites (51.7%). The most frequent metastasis site was the liver (39.0%). Baseline CA19-9 ≥37 U/mL was observed in 81.8% of patients. Any-grade TEAEs occurred in 36.9% of patients, with the most common being anemia (7.2%), nausea (6.8%), diarrhea (6.8%) and leukopenia (5.1%); grade ≥3 TEAEs occurred in 7.2% of patients. Median rwPFS was not reached in any cohort; the 6-month rwPFS rates were 83.3%, 66.4%, and 41.1% for the perioperative, first-line, and later-line cohorts, respectively. The median OS was not reached in any of the three cohorts. Conclusions: This real-world study revealed that the combination regimen based on irinotecan liposome (II) showed a manageable safety profile and encouraging effectiveness signals. Follow-up and patient enrollment are ongoing.

8639 Background: Oncogenic RET gene fusions represent a clinically validated molecular driver occurring in approximately 1–2% of all NSCLC cases, establishing a critical need for targeted therapeutic strategies. Soxataltinib is a novel, orally bioavailable, and highly selective small-molecule inhibitor of RET kinase. Its anti-tumor potency and safety have been previously reported in a phase I/II study. Here we confirmed its clinical value in a pivotal phase III study. Methods: This multicenter, single-arm Phase III clinical trial was designed to evaluate the efficacy and safety of Soxataltinib in patients with RET fusion–positive NSCLC who were previously untreated for advanced disease. The primary endpoint was the confirmed Objective Response Rate (ORR), as determined by Blinded Independent Central Review (BICR) per RECIST v1.1. The secondary endpoints included investigator-assessed ORR, Disease Control Rate (DCR), Duration of Response (DOR), Progression-Free Survival (PFS), Overall Survival (OS), and safety. Results: At the data cutoff (April 10, 2025), the Per-Protocol Population (PPP) comprised 95 patients, 61 of whom were Key efficacy population (KEP) for statistical hypothesis. Soxataltinib demonstrated profound anti-tumor efficacy. The primary endpoint was met. The BICR-confirmed ORR was 90.0% (95%CI: 79.5, 96.2) for KEP and 87.4% (95%CI: 79.0, 93.3) for PPP. The overall DCR was 96.7% (95%CI: 88.5, 99.6) for KEP and 93.7% (95%CI: 86.8, 97.6) for PPP. The median PFS and DOR had not yet been reached, with an estimated 15-month PFS rate of 68.9% (95%CI: 54.3, 79.7) and 65.0% (95%CI: 51.5, 75.6) and 12-month DOR rate of 73.8% (95%CI: 58.2, 84.4) and 69.1% (95%CI: 53.8, 80.1), respectively for KEP and PPP. The OS data remained immature. The safety analysis population comprised 96 patients who received at least one dose of Soxataltinib. The most common Grade ≥3 treatment-emergent adverse events (TEAEs) were hypertension (22.9%), diarrhea (16.7%), Aspartate aminotransferase increased (6.3%), Alanine aminotransferase increased (5.2%), and hyponatraemia (5.2%). These events were predominantly manageable. None of the patients permanently discontinued treatment due to a treatment-related adverse event. No patient died due to TEAE that was definitely related, probably related, or possibly related to Soxataltinib. Conclusions: The primary analysis of this Phase III trial confirmed Soxataltinib as a highly effective and well-tolerated therapeutic agent for patients with RET fusion–positive NSCLC in the first-line setting. This observed high response rates and durable disease control benefit underscored its potential as a best-in-class RET inhibitor. The adverse event profile was predictable and manageable, supporting its feasibility for long-term administration. Clinical trial information: NCT06031558 .

118 Background: Left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) is sensitive to anti-EGFR containing regimens, however, the impact of clinicopathological features on treatment outcomes in this subgroup remains unclear. This analysis aimed to identify factors associated with EMB-01 response. Methods: In this exploratory baseline characteristics/response subgroup analysis, all patients with left-sided, RAS/BRAF wild-type mCRC and no prior fruquintinib/regorafenib/TAS-102 (favorable group) were selected from a Phase 1/2 study (NCT05176665). Baseline variables—including metastatic status, prior therapies, time from diagnosis, and genomic alterations identified via ctDNA- were collected at screening. Response was assessed by investigators per RECIST v1.1 every 6 weeks. Retrospective correlations between these factors and treatment outcomes were evaluated. Results: As of Jun 9, 2025, 29 response-evaluable mCRC patients with favorable features were included in the analysis. Median prior lines were 3, and ORR was 24.1%. Among them, 22 patients aged <65 years had a higher ORR than older patients (27.3% vs. 14.3%). Patients with single metastatic site (n=7) had slightly higher ORR than those with multiple sites (28.6% vs 22.7%). ORRs were comparable for patients with (n=17) or without (n=12) liver metastases (23.5% vs 25.0%), but modestly higher for those with lung metastases (n=18) than without (27.8% vs 18.2%). No responses occurred among the four patients with peritoneal metastases. Baseline lymph node metastatic patients (n=16) yielded an ORR of 25%. Regarding treatment history, prior anti-EGFR therapy (n=18) was associated with a slightly lower ORR compared to anti-EGFR-naïve patients (22.2% vs 27.3%). Patients diagnosed within 24 months (n=7) or with metastatic disease within 18 months (n=7) had higher ORRs (42.9% and 57.1%, respectively) than their counterparts (18.2% and 13.6%). Patients with ≤2 detected baseline genomic alterations (n=14) showed higher ORR (28.6% vs 20%), DCR (92.9% vs 73.3%) and longer median PFS (24.1 weeks vs 15 weeks). Conclusions: EMB-01 demonstrated a promising efficacy signal in left-sided, RAS/BRAF wild-type mCRC patients naive to 3 rd line SOC. In addition to typical prognostic factors, such as younger age, fewer metastatic sites and shorter intervals from initial or metastatic diagnosis, fewer baseline genomic alterations via ctDNA may be a novel positive indicator for EMB-01 efficacy, while liver/lung metastases appear less impactful as adverse prognostic factors. In summary, these findings warrant further evaluation of EMB-01 in late-line mCRC. Clinical trial information: NCT05176665 .

IntroductionLiver metastases are associated with dismal prognosis in solid tumors. This retrospective study evaluated the efficacy and safety of anlotinib in patients with solid tumors and liver metastases in the real-world setting.MethodsPatient data from 5 centers in China were reviewed, and patients treated with anlotinib-based therapy were included in a single group. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). Secondary outcomes included hepatic ORR (hORR), hepatic PFS (hPFS), overall survival (OS), duration of response (DOR), and safety.ResultsBetween January 2020 and February 2023, 475 patients were included. Median PFS was 5.80 months (95% confidence interval [CI]: 5.27-6.60). The ORR and hORR were 17.89% and 18.74%, with a median DOR of 8.63 months (95% CI: 6.57 to not reached [NR]) and 8.80 months (95% CI: 7.51-NR), respectively. Median hPFS and OS were 6.03 months (95% CI: 5.33-6.60) and 9.53 months (95% CI: 8.40-NR), respectively. Similar median PFS, hPFS, and OS were observed across different tumor types. Patients with body mass index (BMI) <18.5 kg/m2 had significantly shorter median PFS and hPFS than those with BMI of 18.5-23.9 kg/m2 and ≥24.0 kg/m2. The incidence of any-grade adverse events was 19.58%, with the most common being hematological toxicities (14.11%). Grade ≥3 adverse events occurred in 1.68% of the patients. DiscussionThese findings suggest the clinical benefits of anlotinib for the treatment of solid tumors with liver metastases, with a manageable safety profile.

3030 Background: BL-M05D1 is a novel Claudin18.2-directed ADC with a potent topoisomerase I inhibitor Ed-04. Results for safety and efficacy data from a phase I study on BL-M05D1 in patients (pts) with locally advanced or metastatic (LA/M) Claudin18.2-expressing solid tumors are presented. Methods: Pts who had LA/M solid tumors enrolled in dose escalation and dose expansion phase, and treated with BL-M05D1 at 0.66, 2.0, 3.0, 4.0 or 5.0mg/kg on Day 1 every 3 weeks (D1 Q3W). Gastric cancer/gastroesophageal junction cancer (GC/GEJ), biliary tract cancer (BTC), and pancreatic cancer (PanC) patients with Claudin18.2-expressing enrolled in dose expansion phase were treated at 2.0, 3.0 or 4.0mg/kg D1 Q3W. Results: As of Nov 30, 2025, a total of 245 pts were enrolled (87 GC/GEJ, 53 BTC, 104 PanC) and 1 other). The most frequent grade≥3 TRAEs were all hematological, including thrombocytopenia (33.9%), neutropenia (32.7%), leukopenia (31.8%) and anemia (14.3%); non-hematologic TRAEs were relatively low. One pt at 5.0mg/kg group experienced grade 3 febrile neutropenia as a DLT. No treatment-related deaths or ILD were reported. In PanC, BL-M05D1 has demonstrated a promising efficacy with an ORR of 35.7% and mPFS of 5.6 mo at 4.0mg/kg in CLDN18.2-positive pts; in the second line pts, ORR was 50.0% with a mPFS of 5.7 mo. Furthermore, BL-M05D1 has shown promising efficacies in CLDN18.2-positive GC and BTC with an ORR of 39.2% and 37.9%, and mPFS of 5.4 mo and 5.9 mo, respectively, at 4.0mg/kg. Efficacy results are summarized below. Conclusions: BL-M05D1 has demonstrated a promising antitumor activity with a tolerable safety profile in pts with pretreated Claudin18.2-positive PanC, GC, and BTC. 4.0mg/kg D1 Q3W was chosen as RP2D. The data support further development of BL-M05D1 in Claudin18.2-positive PanC, GC, and BTC. Phase III studies are in preparation. Clinical trial information: NCT06349811 . PanC-Total * PanC CLDN 18.2 + # 4.0 mg/kg PanC CLDN 18.2 + # 1 Prior Chemo in 4.0mg/kg GC-Total * GC CLDN 18.2 + # 4.0 mg/kg GC CLDN 18.2 + # 1 Prior Chemo in 4.0 mg/kg BTC-Total * BTC CLDN 18.2 + # 4.0 mg/kg BTC CLDN 18.2 + # 1 Prior Chemo in 4.0 mg/kg N = 81 N = 28 N = 16 N = 79 N = 51 N = 29 N = 40 N = 29 N = 20 Median prior LoT (range) 2 (1-4) 2 (1- 3) / 2 (1-4) 1 (1-3) / 1 (1-3) 1 (1-3) / ORR, % (95% CI) 17.3 (9.8-27.3) 35.7 (18.6-55.9) 50.0 (24.7-75.3) 35.4 (25.0-47.0) 39.2 (25.8-53.9) 44.8 (26.4-64.3) 37.5 (22.7-54.2) 37.9 (20.7-57.7) 45.0 (23.1-68.5) DCR, % (95% CI) 74.1 (63.1-83.2) 89.3 (71.8-97.7) 100 (79.4-100) 88.6 (79.5-94.7) 88.2 (76.1-95.6) 86.2 (68.3-96.1) 92.5 (79.6-98.4) 93.1 (77.2-99.2) 90.0 (68.3-98.8) mFU for PFS (mo) 2.8 5.5 4.2 4.4 4.4 4.3 2.8 2.7 2.7 mPFS (mo) 4.0 5.6 5.7 4.4 5.4 7.7 6.9 5.9 5.9 * Efficacy analysis included all pts who received at least one dose of BL-M05D1 and with at least one post baseline scan. # PanC CLDN 18.2 +: IHC 2+/3+ ≥ 50%; GC CLDN 18.2 +: IHC 2+/3+ ≥ 40%; BTC CLDN 18.2 +: IHC1+/2+/3+≥30%.

2557 Background: Claudin18.2 (CLDN18.2) has emerged as a new target for the treatment of gastric cancer in the first-line (1L) setting with the approval of zolbetuximab. This long-term analysis reports the extended efficacy and safety of satri-cel (autologous CLDN18.2-specific CAR T cells) as sequential therapy after 1L treatment in patients with advanced gastric/gastroesophageal junction (G/GEJ) cancer, after the results of all cohorts published in 2024 (Qi C, et al. Nat Med. 2024;30(8):2224-2234. NCT03874897). Methods: This trial is an open-label, multi-cohort, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. Cohort 3 in dose-expansion stage enrolled patients with advance G/GEJ cancer and were given satri-cel as sequential treatment after 1L therapy. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. Results: As of October 18, 2025, 5 patients with CLDN18.2-positive G/GEJ cancer received satri-cel infusion(s) of 250×106 cells, sequentially after 1L therapy. Each patient received a total of one (n=1), two (n=1), and three doses (n=3) of satri-cel. Patients had received a median of 5 cycles (range, 4-11) of 1L chemotherapy before satri-cel infusion, with 1 (20%) treated with PD-1 inhibitor. Notably, only 1 patient achieved PR after first-line therapy. Three patients (60%) were Lauren diffuse type and 1 (20%) with mixed type, 4 (80%) had signet ring cell carcinoma, and 4 (80%) had peritoneal metastases. Median follow-up from initial 1L therapy was 54.6 months (reverse KM, 95% CI: 51.1, NE). Among 4 patients with target lesions, confirmatory objective response rate was 100%, and median duration of response was not reached. One has maintained SD for 20.9 months and 2 received surgical resection after satri-cel therapy. Median progression-free survival and median overall survival since 1L therapy was 20.9 months (95% CI: 10.8, NE) and 22.1 months (95% CI: 10.8, NE), respectively. Two were still alive as of cutoff date, with a follow-up of 58.1 months and 51.1 months. Safety was manageable. No grade 3 or higher cytokine release syndrome (grade 1: n=1, 20%; grade 2: n=4, 80%), any grade immune effector cell-associated neurotoxicity syndrome, or treatment-related deaths occurred. Despite common hematologic toxicities, no severe infections (grade ≥3) or febrile neutropenia were reported. Conclusions: With an extended follow-up exceeding 4.5 years, satri-cel as first-line sequential treatment continues to demonstrate durable survival benefit with a manageable safety profile in patients with advanced G/GEJ cancer, supporting its highly promising potential in earlier lines of therapy. Clinical trial information: NCT03874897 .

MET proto-oncogene amplification (METamp) is associated with poor prognosis in gastric or gastroesophageal junction (G/GEJ) cancer. Currently, effective targeted therapies for G/GEJ cancer harboring METamp remain unavailable, and clinical evidence supporting the use of MET inhibitors in this disease population is limited. Here we report the results of a phase 2 study of savolitinib, an oral MET inhibitor, in patients with METamp G/GEJ cancer. This open-label, multicenter, phase 2 trial in China comprised an exploratory phase and a pivotal phase. Patients with METamp (gene copy number ≥10 for pivotal phase), locally advanced or metastatic G/GEJ cancer that had progressed following ≥1 (≥2 for pivotal phase) prior lines of systemic therapy received savolitinib orally. The primary endpoint was objective response rate (ORR) by independent review committee in the pivotal phase. In total, 110 patients were enrolled and received savolitinib, including 45 in the exploratory phase and 65 in the pivotal phase. Independent review committee-assessed ORR was 32.3% (95% confidence interval 21.2-45.1%) in the pivotal phase, which met the predefined efficacy threshold (lower limit of 95% confidence interval of ORR ≥15%). Among all patients enrolled (n = 110), grade ≥3 treatment-related adverse events were reported in 38 patients (34.5%); one (0.9%) treatment-related death occurred. Savolitinib monotherapy showed encouraging antitumor activities and a tolerable safety profile in heavily treated, later-line METamp G/GEJ cancers, supporting further investigation in randomized controlled trials. ClinicalTrials.gov identifier: NCT04923932 .

367 Background: Recently, PD-1 blockades combined with dual chemotherapy regimens in first-line setting exhibited encouraging efficacy for patients with ESCC. However, the safety profile of conventional dual chemotherapy remained unsatisfactory. Therefore, PD-1 blockades combined with anti-angiogenic tyrosine kinase inhibitors (TKIs) and single chemotherapy regimen might offer a promising strategy. Anlotinib, a novel multitarget TKI primarily targeting VEGFR1-3, demonstrated promising therapeutic activity as first-line combination therapy or second-line monotherapy for ESCC patients in China clinically. Therefore, this study was designed to explore the efficacy and safety of anlotinib combined with penpulimab (PD-1 blockade) and nab-paclitaxel as first-line therapy in advanced ESCC. Methods: Patients with previously untreated metastatic or locally advanced ESCC were recruited and treated with anlotinib (12mg, po, d1~14, q3w) and penpulimab (200mg, iv, d1, q3w) plus nab-paclitaxel (220mg/m 2 , iv, d1, q3w) until disease progression or unacceptable toxicity. The tumor response was assessed according to RECIST 1.1 using CT scans every two cycles. Adverse events were recorded by severity in accordance with the NCI CTC AE Version 5.0. The predefined sample size was 30. Primary endpoint was PFS and secondary endpoints included safety, ORR, DCR and OS. Results: From Jul 2022 to Sep 2024, a total of 30 patients were enrolled, with 29 patients who had received first tumor response were included in this analysis. The best overall response indicated that there were 1 CR (3.4%), 23 PR (79.3%), 2 SD (6.9%) and 3 NE (10.3%). Therefore, the preliminary ORR was 82.8% (95%CI: 64.2%-94.2%), DCR was 89.7% (95%CI: 72.6%-97.8%). The primary median PFS of the 29 patients was 10.84 months (95%CI: 7.57-14.11). Additionally, safety profile exhibited that the regimen was tolerable. The most common treatment-emergent adverse events among the 29 patients with the incidence >20% were anemia (62%), leukopenia (31%), peripheral neurotoxicity (28%) and rash (21%). Common grade ≥3 treatment-emergent adverse events were leukopenia (7%), glutamic-pyruvic transaminase was elevated (3%), glutamic oxalacetic transaminase increased (3%), hypertension (3%), diarrhea (3%) and rash (3%). Conclusions: The combination of anlotinib plus penpulimab and nab-paclitaxel as first-line therapy for advanced ESCC demonstrated promising efficacy and manageable safety profile. And the conclusions needed to be confirmed in subsequent trials. Clinical trial information: ChiCTR2400089133 .

4054 Background: While PD-1 inhibitors plus chemotherapy have become standard first-line therapy for advanced HER2-negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma, patients with low PD-L1 expression (Combined Positive Score (CPS)＜5) derive limited benefit. Anti-angiogenic agents can modulate the tumor immune microenvironment and synergize with immune checkpoint inhibitors. Anlotinib, a multi-targeted tyrosine kinase inhibitor approved in China, offers a promising combination strategy. This study evaluates the efficacy and safety of benmelstobart (a PD-L1 inhibitor) combined with anlotinib and SOX (S-1 plus oxaliplatin) as first-line therapy in patients with advanced G/GEJ adenocarcinoma and low PD-L1 expression. Methods: Patients with HER2-negative, unresectable, locally advanced, or metastatic G/GEJ adenocarcinomas and PD-L1 CPS＜ 5, who had not received prior systemic therapy were included. They received benmelstobart (1200mg, iv, d1, q3w) combined with anlotinib (10mg, po, d1~14, q3w), oxaliplatin (130mg/m 2 , d1, iv, q3w) and S-1 (40mg, po, bid, d1~14, q3w) for 6 cycles as initial therapy. Maintenance therapy with benmelstobart (1200mg, iv, d1, q3w) plus anlotinib (10mg, po, d1~14, q3w) followed for non-progressive disease until PD or unacceptable toxicity occurred. Tumor responses were evaluated by RECIST 1.1 criteria. The target sample size was 37, with ORR as the primary endpoint, and safety, DCR, DoR, PFS, and 1-year OS rate as secondary endpoints. Results: From June 2023 to June 2025, 37 patients were enrolled. At the data cut-off date (December, 2025), the best overall response indicated that there were 31 PR (83.8%) and 6 SD (16.2%). Therefore, the preliminary ORR was 83.8% (95%CI: 68-93.8), DCR was 100% (95%CI: 90.5-100). The preliminary prognostic result exhibited that the median PFS of the 37 patients was 11.3 months (95%CI: 8.07-14.53). The 1-year OS rate was 91.33% (95%CI: 75.46–97.12). Safety was manageable, common TRAEs＞20% included platelet count decreased (54.1%), white blood cell decreased (32.4%), anemia (24.3%). Conclusions: The combination of benmelstobart, anlotinib, and SOX demonstrated promising efficacy with a manageable safety profile as first-line therapy for advanced G/GEJ adenocarcinoma with low PD-L1 expression. These findings warrant validation in larger cohorts. Clinical trial information: NCT06939452 .

2639 Background: LB1410 is a recombinant humanized anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&L Bio Co., Ltd, Shanghai, China for patients (pts) resistant/refractory (R/R) to anti-PD-(L)1 therapies. Pre-clinical studies revealed superior T cell and DC activity and in vivo antitumor efficacy compared to the combined use of TIM-3 and PD-1 monoclonal antibodies. This ongoing open-label phase I trial evaluates LB1410 monotherapy in pts with advanced solid tumors. Methods: Eligible pts were ≥18 yrs old with ECOG PS 0-1. Dose ranged from 0.001 to 20 mg/kg IV Q2W or 2000 mg/kg IV Q3W in an accelerated titration or a traditional 3+3 design. The RPIID of 20 mg/kg was used for efficacy expansion in pts with advanced clear cell renal cell carcinoma (ccRCC), cervical cancer (CC) and hepatocellular carcinoma (HCC). The primary objective was safety, including dose-limiting toxicities (DLTs); secondary objectives included efficacy, pharmacokinetics (PK) and immunogenicity. Results: As of Jan 4, 2026, 94 pts were enrolled: median age 59 yrs (31-73 yrs); 64.9% male; 84.0% ECOG PS 1. Tumor types included NSCLC (26.6%), CRC (21.3%, all non-MSI-H), CC (14.9%), ccRCC (11.7%), HCC (9.6%) and others (16.0%). 77 pts (81.9%) had received ≥ 2 prior lines of therapy. 98.6% non-CRC pts (73/74) were R/R to anti-PD-(L)1 therapies. 72 pts (76.6%) experienced TRAEs. The most common TRAEs (≥ 10%) included anemia (25.5%), proteinuria (11.7%), elevated ALT (11.7%), elevated AST (11.7%) and elevated lactate dehydrogenase (10.6%). Only 10 pts (10.6%) experienced Grade 3-4 TRAEs, most frequently hypertension (4.3%) and hypokalemia (2.1%). Only 1 hypertension and 1 elevated GGT in 1 pt were Grade 4. Serious TRAEs occurred in 3 pts (3.2%). No DLTs were observed. Among pts with available on-treatment scans, the overall ORR per RECIST 1.1 was 7.1% (6/85) with 5 confirmed PRs and 1 confirmed CR; the DCR was 48.2% (41/85). Notably, among CC pts previously treated with anti-PD-(L)1 therapies, there were 4 confirmed PRs and 1 confirmed CR: ORR 38.5% (5/13); DCR 69.2% (9/13); mPFS 7.5 months. 5 pts with CR/PR/SD remained on treatment (max. 16 treatment cycles; max. follow-up 14.4 months). The CR patient had received 5 prior lines of therapy, including PD-1/CTLA-4 BsAb. In anti-PD-1-resistant ccRCC, LB1410 monotherapy had an ORR of 11.1% (1/9) and a DCR of 77.8% (7/9). Conclusions: LB1410 showed an excellent safety profile and promising antitumor efficacy in pts with immune-oncology (IO)-R/R CC. Further studies of LB1410 as monotherapy and in combination with lenvatinib in pts with IO-R/R CC are ongoing. Clinical trial information: NCT05357651 .