Hepatocellular carcinoma (HCC) remains one of the most lethal malignancies worldwide. Tumor-associated endothelial cells (TECs) play crucial roles in HCC progression, yet their molecular characteristics and functional contributions remain poorly understood. We performed comprehensive single-cell RNA sequencing and spatial transcriptomic analysis on 49 samples comprising 145,692 high-quality single cells. Spatial transcriptomic data from 12 samples encompassing normal liver tissue, tumor boundary regions, and HCC tissue yielded 49,091 spatial spots. Endothelial cell subpopulations were identified and functionally characterized through in vitro experiments using human umbilical vein endothelial cells (HUVECs) and in vivo validation using endothelial cell-specific knockout mice. Clinical validation was performed using tissue microarrays from 90 paired HCC samples and an immunotherapy-treated advanced HCC cohort. We identified 6 distinct endothelial cell subpopulations, with S100A16+ TECs significantly enriched in HCC tissues. The S100A16+ TECs signature correlated with shorter overall survival and disease-free survival. Functional analyses demonstrated that S100A16 overexpression promoted endothelial cell proliferation, migration, and tube formation capacity. RNA sequencing identified CCL20 and TGF-β2 as key downstream effectors. Co-culture experiments and multiplex immunofluorescence analysis demonstrated that S100A16+ TECs promote regulatory T cell (Treg) differentiation. Endothelial-specific S100A16 knockout significantly reduced tumor angiogenesis, Tregs infiltration, and HCC growth in mice. Clinical validation revealed that high S100A16+ TECs abundance correlated with vascular invasion, immunotherapy resistance, and shorter progression-free survival. Our study identifies S100A16+ TECs as a distinct endothelial subpopulation that drives HCC progression through coordinated promotion of pathological angiogenesis and immunosuppression, representing a potential therapeutic target and biomarker for immunotherapy response prediction in HCC.

Importance Perioperative immunotherapy has improved clinical outcomes for patients with early-stage non–small cell lung cancer (NSCLC). The influence of immune checkpoint inhibitor in combination with chemotherapy on surgical outcomes remains to be explored. Objective To evaluate perioperative toripalimab in combination with chemotherapy on surgical outcomes. Design, Setting, and Participants This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (Neotorch study) enrolled patients with resectable stage III NSCLC and took place at 50 centers in China. Patients who had histologically confirmed resectable stage IIIA or IIIB NSCLC were eligible. These data were analyzed from July 2024 to March 2026. Interventions Patients were randomized (1:1) to receive toripalimab (240 mg) plus platinum-based chemotherapy or placebo plus platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by maintenance with toripalimab or placebo alone for 13 cycles. Main Outcomes and Measures Surgical outcomes, including perioperative complications, tumor downstaging, and lymph node downstaging, and their association with event-free survival (EFS), were studied in this post hoc analysis. Results Among 404 patients enrolled, 314 patients (median [SD] age 60 [6.82] years; 90% of patients were male and 10% were female) underwent surgery (166 in toripalimab group and 148 in placebo group). Percentage of patients canceling surgery (17.8% vs 26.7%; P = .03) was significantly lower in the toripalimab group. Proportions of minimally invasive surgery, R0 resection, and lobectomy were slightly higher in the toripalimab group. Surgical complications were similar between the 2 groups. Rates of postsurgery tumor (80.7% vs 50.7%; P < .001) and lymph node downstaging (67.5% vs 48.6%; P = .001) were both significantly higher with toripalimab than placebo. With a median follow-up of 18.3 months, a better EFS was noticed in the toripalimab group. Tumor and lymph node downstaging in the toripalimab group were both associated with better EFS than nondownstaging (median EFS, not estimable [NE] vs 17.5 months; P = .004 and NE vs 19.2 months; P = .001, respectively), and were also associated with even better EFS than tumor and lymph node downstaging in the placebo group (median EFS, NE vs 22.0 months; P = .002 and NE vs NE; P = .009, respectively). Conclusions and Relevance In this study, perioperative toripalimab plus chemotherapy showed comparable perioperative outcomes, as with chemotherapy alone without new safety signals, and could help improve survival through effective tumor downstaging in patients with resectable stage III NSCLC. Trial Registration ClinicalTrials. gov Identifier: NCT04158440

Collective cell migration (CCM) is a pivotal driver of tumor progression and metastasis in non-small cell lung cancer (NSCLC), yet its upstream regulatory mechanisms remain poorly understood. Here, we investigated the functional role and molecular mechanism of MTAP deficiency in modulating CCM in NSCLC. Clinical sample analysis revealed that NSCLC patients with MTAP deficiency exhibited significantly shorter overall survival. Using a three‑dimensional culture system, we verified that MTAP deficiency had little effect on cell proliferation, but markedly promoted CCM by inducing cytoskeletal rearrangement of leader cells within tumor clusters. Mechanistically, MTAP deletion leads to intracellular MTA accumulation, which suppresses PRMT5 activity and reduces global protein symmetric dimethylarginine (sDMA) modification. Decreased sDMA further enhances USF2 phosphorylation and nuclear translocation, facilitates USF2 binding to the WNT3A promoter, and concurrently reduces DNA CpG methylation of the WNT3A promoter, thereby synergistically activating WNT3A transcription. Upregulated WNT3A strengthens intercellular crosstalk between leader and follower cells, elevates adhesion among follower cells, and drives cytoskeletal remodeling in leader cells, ultimately accelerating CCM progression. Pharmacologically, the WNT3A specific inhibitor C59 effectively blocked CCM formation and mitigated collective metastasis in MTAP‑deficient NSCLC. In summary, our results define a novel MTAP-PRMT5-sDMA-WNT3A regulatory axis that controls CCM and malignant progression of NSCLC. Targeting WNT3A represents a promising therapeutic strategy for the clinical treatment of MTAP‑deficient NSCLC.

Introduction: At the first interim analysis of the phase 3 ADRIATIC trial, durvalumab consolidation significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo in patients with limited-stage SCLC (LS-SCLC) without progression after concurrent chemoradiotherapy (cCRT). We report a prespecified subgroup analysis of patients enrolled in China. Methods: Patients with stage I to III LS-SCLC were randomized to durvalumab, durvalumab plus tremelimumab (arm remained blinded), or placebo for up to 24 months. The dual primary end points were OS and PFS by blinded independent central review for durvalumab versus placebo. Results: Of the global population, 95 of 530 patients (17.9%) were randomized in China; 49 of 264 versus 46 of 266 received durvalumab versus placebo. For prior cCRT, 69.4% versus 69.6% of the China subgroup received cisplatin-etoposide, and 53.1% versus 69.6% had once-daily radiotherapy; post-cCRT, 55.1% versus 67.4% received prophylactic cranial irradiation. The hazard ratio for OS (durvalumab versus placebo; median follow-up 35.5 mo) was 0.71 (95% confidence interval: 0.37–1.37). Median OS was not reached in either arm (36-mo OS: 63.7% versus 55.4%). The hazard ratio for PFS (median follow-up 27.7 mo) was 0.67 (95% confidence interval: 0.39–1.14); median PFS was 22.9 versus 14.3 months (24-mo PFS: 45.8% versus 37.6%). With durvalumab versus placebo, 16.3% versus 17.4% of patients had maximum grade 3 or 4 adverse events (AEs), 42.9% versus 21.7% had serious AEs, and 10.2% versus 13.0% discontinued treatment due to AEs; 55.1% versus 63.0% had pneumonitis/radiation pneumonitis (grade 3 or 4: 4.1% versus 4.3%). Conclusion: Consolidation durvalumab demonstrated a favorable benefit to risk profile in patients with LS-SCLC without progression after cCRT who were enrolled in China.

Importance:Perioperative immunotherapy has improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). The influence of immune checkpoint inhibitor in combination with chemotherapy on surgical outcomes remains to be explored. Objective:To evaluate perioperative toripalimab in combination with chemotherapy on surgical outcomes. Design, Setting, and Participants:This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (Neotorch study) enrolled patients with resectable stage III NSCLC and took place at 50 centers in China. Patients who had histologically confirmed resectable stage IIIA or IIIB NSCLC were eligible. These data were analyzed from July 2024 to March 2026. Interventions:Patients were randomized (1:1) to receive toripalimab (240 mg) plus platinum-based chemotherapy or placebo plus platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by maintenance with toripalimab or placebo alone for 13 cycles. Main Outcomes and Measures:Surgical outcomes, including perioperative complications, tumor downstaging, and lymph node downstaging, and their association with event-free survival (EFS), were studied in this post hoc analysis. Results:Among 404 patients enrolled, 314 patients (median [SD] age 60 [6.82] years; 90% of patients were male and 10% were female) underwent surgery (166 in toripalimab group and 148 in placebo group). Percentage of patients canceling surgery (17.8% vs 26.7%; P = .03) was significantly lower in the toripalimab group. Proportions of minimally invasive surgery, R0 resection, and lobectomy were slightly higher in the toripalimab group. Surgical complications were similar between the 2 groups. Rates of postsurgery tumor (80.7% vs 50.7%; P < .001) and lymph node downstaging (67.5% vs 48.6%; P = .001) were both significantly higher with toripalimab than placebo. With a median follow-up of 18.3 months, a better EFS was noticed in the toripalimab group. Tumor and lymph node downstaging in the toripalimab group were both associated with better EFS than nondownstaging (median EFS, not estimable [NE] vs 17.5 months; P = .004 and NE vs 19.2 months; P = .001, respectively), and were also associated with even better EFS than tumor and lymph node downstaging in the placebo group (median EFS, NE vs 22.0 months; P = .002 and NE vs NE; P = .009, respectively). Conclusions and Relevance:In this study, perioperative toripalimab plus chemotherapy showed comparable perioperative outcomes, as with chemotherapy alone without new safety signals, and could help improve survival through effective tumor downstaging in patients with resectable stage III NSCLC. Trial Registration:ClinicalTrials. gov Identifier: NCT04158440.

4126 Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits poor prognosis largely due to early lymph node metastasis, yet the cellular and molecular mechanisms governing lymphatic dissemination remain incompletely understood. Methods: We integrated multi-omics approaches including single-cell RNA sequencing (scRNA-seq) of 19 PDAC samples, spatial transcriptomics of 6 specimens, bulk RNA sequencing of 174 cases, and multiplex immunofluorescence of 166 clinical samples stratified by lymph node metastasis status. Cell-cell communication analysis, trajectory inference, and functional validation were performed to elucidate pro-metastatic mechanisms. Results: Single-cell profiling of 145,283 cells revealed substantial cellular heterogeneity, with fibroblasts and pericytes serving as dominant signaling hubs within the tumor microenvironment. Lymph node metastasis-positive (pLNM) tumors exhibited enhanced stromal-epithelial crosstalk mediated by PTN and ANGPT pathways. We identified invasive epithelial subpopulations (Epi_MUC5AC_CD24 and Epi_NEAT1_MALAT1) significantly enriched in pLNM samples, characterized by activation of EMT and invasion-related programs. Critically, high-resolution subclustering uncovered a CXCL12-expressing pericyte subset (PCs_CXCL12) preferentially expanded in metastatic tumors. Multiplex immunofluorescence validation in 166 specimens demonstrated that CXCL12+ pericyte infiltration correlated with perineural invasion, lymph node metastasis, advanced TNM stage, and inferior survival outcomes. Multivariate analysis established CXCL12+ pericyte score as an independent prognostic factor for both disease-free and overall survival. Mechanistically, we identified MYC as the master transcriptional regulator driving CXCL12 secretion in pericytes. Functional studies revealed that MYC-driven pericyte-derived CXCL12 promoted PDAC cell proliferation, invasion, and EMT. Spatial transcriptomics demonstrated co-localization of MYC, CXCL12, and its receptor CXCR4 in perineural pericyte niches. Orthotopic xenograft models confirmed that pericyte-specific Myc depletion significantly reduced tumor growth, CXCL12+ pericyte density, and tumor-associated lymphangiogenesis. Conclusions: This study establishes the pericyte MYC-CXCL12 axis as a critical driver of PDAC lymphatic metastasis through promotion of tumor cell invasion, EMT, and lymphangiogenesis. CXCL12+ pericytes represent a novel prognostic biomarker and potential therapeutic target for preventing lymph node metastasis in PDAC patients.

e15569 Background: For patients with metastatic colorectal cancer (mCRC) who progress after first-line oxaliplatin-based therapy, irinotecan-based regimens represent a standard second-line option. Liposomal irinotecan, designed to exploit the enhanced permeability and retention (EPR) effect, may improve tumor targeting while reducing systemic toxicity. This study evaluated the efficacy and safety of liposomal irinotecan combined with 5-FU/LV and bevacizumab as second-line treatment for mCRC. Methods: This was a multicenter, single-arm phase II study conducted across multiple institutions in China. Eligible patients were aged 18-75 years with histologically confirmed unresectable mCRC, progressive disease after first-line oxaliplatin-based therapy. Patients received liposomal irinotecan (70 mg/m²) + 5-FU (2400 mg/m²) + LV (400 mg/m²) + bevacizumab (5 mg/kg) on Day 1, every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between December 2023 and September 2025, 172 patients were enrolled and included in the full analysis set. At data cutoff, 60 patients remained on treatment and 112 had completed treatment. Median age was 60 years (range: 18-75), 57.6% were male, and 39.0% had rectal primary tumors. Among 111 efficacy-evaluable patients, the ORR was 18.0% (95% CI: 11.4–26.4%) and the DCR was 82.9% (95% CI: 74.6–89.4%). After a median follow-up of 4.7 months (range: 0.03-19.0), the median PFS was 7.8 months (95% CI: 5.54-9.96), and median OS was not reached. Subgroup analyses revealed longer PFS in patients with baseline CEA < 5 ng/L (9.3 vs. 6.5 months, p = 0.037) and in those who had not received bevacizumab in the first-line setting (9.6 vs. 6.1 months, p = 0.015). Treatment-related adverse events (TRAEs) occurred in 90.1% of patients, with grade ≥3 TRAEs in 43.6%. The most common grade ≥3 TRAEs were neutropenia (21.5%), leukopenia (13.4%), and diarrhea (8.7%). Serious adverse events (SAEs) occurred in 6.4% of patients, with no new safety signals identified. Conclusions: Liposomal irinotecan combined with 5-FU/LV and bevacizumab showed promising antitumor activity and a manageable safety profile as second-line therapy for mCRC. These results support this regimen as a valuable therapeutic option for patients progressing after oxaliplatin-based first-line treatment. Clinical trial information: NCT06184698 .

Jie Zhang,1– 3 Xiaojia Wang,4 Huiting Xu,5 Aimin Zang,6 Jun Zhao,7 Jinping Chen,8 Ruiwen Lei,9 Zhen Zhang,10 Chunfang Hao,1– 3 Yunpeng Liu,11 Rongwei Zhou,12 Lijia He,13 Tao Sun,14 Quchang Ouyang,15 Sheng Chen,16 Jingqiao Xu,16 Wei Zhou,17 Yehui Shi,1– 3 Zhongsheng Tong1– 31Department of Breast Oncology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, People’s Republic of China; 2Tianjin’s Clinical Research Center for Cancer, Tianjin, People’s Republic of China; 3Key Laboratory of Breast Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University, Ministry of Education, Tianjin, People’s Republic of China; 4Department of Breast Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China; 5Department of Medical Oncology, Hubei Cancer Hospital, Wuhan, Hubei, People’s Republic of China; 6Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding, Hebei, People’s Republic of China; 7Department of Medical Oncology, Changzhi People’s Hospital, Changzhi, Shanxi, People’s Republic of China; 8Department of Oncology, The People’s Hospital of Yichun City, Yichun, Jiangxi, People’s Republic of China; 9Department of Breast, Thyroid, Head and Neck, Yuebei People’s Hospital, Shaoguan, Guangdong, People’s Republic of China; 10Department of Medical Oncology, Nanyang First People’s Hospital, Nanyang, Henan, People’s Republic of China; 11Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China; 12Department of Oncology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 13Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 14Department of Breast Oncology, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, People’s Republic of China; 15Department of Breast Oncology, Hunan Cancer Hospital, Changsha, Hunan, People’s Republic of China; 16Medical Affairs Department, Hubei Biomedical Industry and Technology Research Institute Co., Ltd, Wuhan, Hubei, People’s Republic of China; 17Clinical Research Department, Hubei Biomedical Industry and Technology Research Institute Co., Ltd, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Yehui Shi, Email shiyehui@tjmuch.com Zhongsheng Tong, Email tongzhongsheng@tjmuch.comObjective: HWH340 is a novel, orally administered poly(ADP-ribose) polymerase inhibitor (PARPi) developed for the treatment of solid tumors with homologous recombination repair (HRR) deficiency. It features a distinct chemical structure that has shown high selectivity and favorable PARP inhibitory and anti-tumor activities in preclinical studies. In this study, we evaluated the safety, tolerability, pharmacokinetics, and clinical profiles of HWH340 tablets in patients with advanced solid tumors to determine the recommended Phase 2 dose (RP2D).Methods: This Phase 1, open-label, multicenter study (25 centers across China) consisted of three stages: dose-escalation (n=21; 3+3 design; 20– 520 mg single doses), multiple-dose escalation (n=14; 3+3 design; 100/140/200/260 mg BID), and dose-expansion (n=42; 140/200 mg BID; 28-day cycles). The dose-expansion study enrolled two cohorts: 50% of patients with germline/systemic BRCA1/2 mutations and 50% of patients with non-BRCA1/2 HRR gene mutations.Results: No dose-limiting toxicities were detected, and the maximum tolerated dose was not reached. The most common treatment-related severe adverse events of grades ≥ 3 were neutropenia (14.3%), anemia (14.3%), vomiting (11.9%), leukopenia (9.5%), thrombocytopenia (4.8%), and elevated γ-glutamyl transferase (4.8%). Among the 41 patients in the dose-expansion study with evaluable preliminary anti-tumor activity, the objective response rate (ORR) was 19.5%, and the disease control rate (DCR) was 56.1%, with a median duration of response of 4.68 months. Patients with BRCA1/2 mutations in the 200 mg group showed better outcomes, achieving an ORR of 41.7% and a DCR of 75.0%. Breast cancer patients with BRCA1/2 mutations in the 200 mg cohort achieved an ORR of 50%.Conclusion: HWH340 was well-tolerated and demonstrated promising preliminary anti-tumor activity in cancer patients with HRR-mutated advanced solid tumors. An integrated assessment of safety, preliminary efficacy, and pharmacokinetic profiles established 200 mg BID as the RP2D, balancing anti-tumor activity with acceptable tolerability. Given the small sample size and patient heterogeneity, these preliminary efficacy data need further confirmation by subsequent studies with larger sample sizes.Additional Resources: This study is registered with ClinicalTrials.gov, NCT03415659.Keywords: HWH340, Poly(ADP-ribose) polymerase inhibitor, Phase 1 clinical trial, homologous recombination repair, BRCA1/2 mutations, solid tumors, safety profile

271 Background: Immune checkpoint inhibitors (PD-1/PD-L1) combined with chemotherapy have become the standard first-line treatment for ES-SCLC, but long-term benefit remains limited. Anti-angiogenic therapy with immunotherapy has shown promising activity and may offer synergistic antitumor effects. This study reports the preliminary results of the CLOG2402-ADAPT trial evaluating adebrelimab (a PD-L1 inhibitor) plus apatinib (a VEGFR-2 tyrosine kinase inhibitor) as maintenance therapy. Methods: Patients with ES-SCLC who had not progressed after 4–6 cycles of 1L induction therapy with adebrelimab plus platinum–etoposide were eligible to enter the maintenance phase. These patients received maintenance adebrelimab（1200 mg, IV, q3w） plus apatinib (250 mg, po, qd) until progression, toxicity, or withdrawal. The primary endpoint was progression-free survival (PFS), defined as the time from initiation of maintenance therapy to the first documented disease progression. Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), time to second progression (PFS2). Results: As of February, 2026, 19 patients entered maintenance phase with a median follow-up of 7.4 months (range 3.4–15.6). Median age was 65 years (49–77); Male and female patients accounted for 58% and 42%. 58% had a current or previous smoking history. Liver metastases were present in 16% and brain metastases in 20%. The median duration of induction therapy was 4.0 months (range, 2.3–6.2). Most patients (85%) achieved a partial response to induction therapy. During the maintenance phase, 17 patients underwent at least one tumor response assessment. The ORR was 12%, with a DCR of 71% (comprising 2 PR, 10 SD, and 2 PD). Median PFS was 4.37 months during the maintenance phase, while the the median PFS from the first dose was 8.43 months. OS remain immature. Treatment-related adverse events (TRAEs) occurred in 86.7% of patients, with grade 3 TRAEs in 13.3% (elevated lipase; interstitial pneumonitis). No treatment-related deaths occurred. Conclusions: Adebrelimab plus apatinib showed clinically meaningful antitumor activity and acceptable tolerability as 1L maintenance therapy in patients with ES-SCLC following induction with adebrelimab plus chemotherapy. Clinical trial information: NCT06480864 .

With the ongoing evolution and mutation of SARS-CoV-2, current antiviral therapies face notable limitations, including emerging resistance mutations, inadequate immunomodulation, and suboptimal organ protection. This situation highlights the urgent need for novel therapeutic strategies. In this study, we evaluated the combined effects of Carrimycin (CAM) and Azvudine (FNC) in SARS-CoV-2-infected rhesus macaques (RMs), focusing on their antiviral activity, lung protection, and immunoinflammatory modulation roles. RMs were intratracheally challenged with SARS-CoV-2 and treated orally for 7 days with CAM (9 mg/kg), FNC (0.07 mg/kg), or their combination. Viral load, lung pathology, immune responses, and gut microbiota were analyzed. Both CAM and FNC monotherapies significantly inhibited SARS-CoV-2 replication, while their combination produced additive antiviral effects, reducing viral loads in throat swabs and lung tissue without significant side effects. Chest imaging and histopathological examination of lung tissues showed reduced ground-glass opacities and a mitigation of focal interstitial pneumonia with monotherapy, while the combination treatment demonstrated superior efficacy. Transcriptomic and immunofluorescence analyses of the lung indicated enhanced immunomodulation with combination therapy, including suppressed neutrophil degranulation, increased CD19⁺ B and CD3⁺ T cells, decreased CD68⁺ macrophages, and downregulation of pro-inflammatory and apoptotic markers, suggesting improved adaptive immunity and lung protection. Furthermore, CAM, but not FNC, increased beneficial short-chain fatty acid-producing gut bacteria and decreased harmful pathogens associated with COVID-19 progression. The combination of CAM and FNC showed superior efficacy in suppressing viral replication, alleviating lung injury, and correcting immune and inflammatory dysregulation, with CAM alone providing additional gut microbiota benefits. This combination represents a promising therapeutic strategy against COVID-19 and its complications.

Gastric cancer (GC) remains a formidable public health challenge in China, characterized by a high incidence and mortality rate. A significant proportion of patients are diagnosed with advanced or metastatic disease, where traditional chemotherapy has historically offered limited survival benefits. However, driven by a deeper molecular understanding of GC heterogeneity, the paradigm of GC treatment is undergoing a revolutionary shift from a "one size fits all" approach toward precision medicine. The identification of predictive biomarkers, such as human epidermal growth factor receptor 2 (HER2/ERBB2; MIM: 164870) expression, microsatellite instability-high (MSI-H) status, PD-L1 (CD274; MIM: 605402) expression, and Claudin 18.2 (CLDN18; MIM: 609210) overexpression, has established biomarker-guided strategies as the unequivocal future direction for managing advanced GC. In particular, the emergence of immune checkpoint inhibitors (ICIs) and agents targeting Claudin 18.2 has revolutionized the landscape of first-line (1L) treatment for GC. China has achieved accelerated breakthroughs in gastric cancer drug research and development, leading to more innovative therapies and improved diagnostic/treatment regimens, providing patients with more abundant and effective treatment options and significantly improving the landscape of diagnosis and treatment. Nevertheless, integrating complex biomarkers and novel agents into practice poses challenges, including inconsistencies in biomarker testing and the need for nuanced treatment regimen selection. Without standardized guidelines, inconsistent application may lead to suboptimal patient outcomes and inefficient use of healthcare resources. This expert consensus has been jointly formulated with the aim of further enhancing and standardizing the biomarker testing and precision medicine of 1L therapy for advanced GC.

Abstract Malignant tumors are major diseases that seriously threaten human health, and the unmet clinical demand for treatments in the field of oncology has been persistently large. The research and development of new antineoplastic drugs has become a powerful means to address this demand. The purpose of this guideline is to provide a systematic overview and summary of clinical research on antineoplastic drugs in terms of study format, trial staging, mechanism of action, ethical review, trial process, patient needs, and the evaluation of efficacy and adverse events. It provides practical suggestions and references to aid the fundamental role of clinical research on antineoplastic drugs, i.e., to address clinical needs and maximize patient benefits.

424 Background: This study evaluated the strategy of dose-dense chemotherapy plus a PD-1 inhibitor with selective organ-preservation in patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients with locally advanced or metastatic (confined to the supraclavicular lymph nodes) ESCC were enrolled to receive treatment with a PD-1 inhibitor plus albumin bound-paclitaxel, cisplatin and 5-FU every two weeks. After six cycles of treatment, patients with clinical complete response (cCR) confirmed by computed tomography (CT), endoscopy and biopsy underwent an organ-preserving strategy with continuation of immunochemotherapy. The primary endpoint was cCR rate in the intention-to-treat population. A post hoc analysis was also conducted in patients with advanced ESCC who had a best response of CR after immunochemotherapy from three prospective studies we previously reported. Consecutive patients who had not received esophagectomy prior to immunochemotherapy, and had durable CR as confirmed by imaging, endoscopy with or without biopsy were identified to provide supporting evidence for the organ-preserving strategy. Results: A total of twenty patients were enrolled. At data cut-off (September 12, 2024), eight patients fulfilled the criteria of cCR (40%), while six patients actually adopted the organ-preserving strategy. 75% of the patients experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly neutropenia and leukopenia. All TRAEs were managed with appropriate medical care. In the post hoc analysis, out of 71 patients who had a best response of CR to immunochemotherapy in three previous trials, sixteen consecutive patients who had not received esophagectomy before immunochemotherapy, and remained CR assessed with CT at data cut-off were identified. Although endoscopy was not mandatory during follow-up, twelve patients underwent endoscopic exams, and none of them had suspected tumor with endoscopic visualization. Biopsies were taken for eight patients, and were all negative for tumor. The median follow-up for these twelve patients reached 42.7 months, suggesting a long-term disease-free survival after immunochemotherapy. Conclusions: Dose-dense nab-paclitaxel, cisplatin and 5-FU combined with a PD-1 inhibitor showed encouraging cCR rate and manageable safety, making organ-preservation a possible subsequent approach in patients with advanced ESCC. Clinical trial information: ChiCTR2300072992.

Importance:Patients with extensive-stage small cell lung cancer (ES-SCLC) have poor prognoses and unmet medical needs. Objective:To evaluate the efficacy and safety of toripalimab plus etoposide and platinum-based chemotherapy (EP) vs placebo plus EP as a first-line treatment for patients with ES-SCLC. Design, Setting, and Participants:This multicenter, double-blind, placebo-controlled phase 3 randomized clinical trial (EXTENTORCH study) enrolled patients from September 26, 2019, to May 20, 2021, and was conducted at 49 sites in China. Eligible patients had histologically or cytologically confirmed ES-SCLC without previous systemic antitumor therapy for ES-SCLC. Data were analyzed between May 6, 2023, and June 1, 2024. Interventions:Patients were randomized (1:1) to receive toripalimab, 240 mg, or placebo plus EP every 3 weeks for up to 4 to 6 cycles, followed by maintenance with toripalimab or placebo until disease progression, intolerable toxic effects, or up to 2 years of treatment. Main Outcomes and Measures:The primary end points were investigator-assessed progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing results identified correlative biomarkers for clinical efficacy. Results:Among 595 screened patients, 442 eligible patients were randomized (median [range] age, 63 [30-77] years; 366 [82.8%] male); 223 patients were randomized to toripalimab plus EP, and 219 to placebo plus EP. By April 20, 2023, the median (range) survival follow-up was 13.7 (0.0-42.7) months. Compared with placebo, toripalimab improved investigator-assessed PFS (hazard ratio [HR], 0.67 [95% CI, 0.54-0.82]; P < .001), and significantly reduced the risk of death (HR, 0.80 [95% CI, 0.65-0.98]; P = .03). The median OS was 14.6 (95% CI, 12.9-16.6) months in the toripalimab group vs 13.3 (95% CI, 11.8-14.4) months in the placebo group. Whole-exome sequencing results from 300 patients identified low intratumor heterogeneity, HLA-A11+ HLA-B62- haplotype, wild-type KMT2D and COL4A4, or sequence variations in CTNNA2 or SCN4A correlated with favorable PFS and OS in the toripalimab group. No new safety signals were observed. Grade 3 or higher treatment-emergent adverse event incidence was similar between the toripalimab and placebo safety set groups (199 of 222 patients [89.6%] vs 193 of 216 patients [89.4%], respectively). Conclusions and Relevance:In this phase 3 randomized clinical trial, adding toripalimab to first-line chemotherapy demonstrated significant improvements in PFS and OS for patients with ES-SCLC. The treatment exhibited an acceptable safety profile, supporting this combination regimen as a new treatment option for patients with ES-SCLC. Trial Registration:ClinicalTrials.gov Identifier: NCT04012606.

Cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) represents a first-line therapeutic standard for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Despite this established approach, cetuximab β (CMAB009), as a modified antibody of cetuximab, prospectively selected for dual RAS/BRAF wild-type patients, has not yet been validated in the Chinese mCRC patients through phase 3 trial. In this study (ClinicalTrials.gov identifier: NCT03206151), patients with RAS/BRAF wild-type mCRC who were not suitable for radical resection were randomly assigned in a 1:1 ratio to receive cetuximab β plus FOLFIRI or FOLFIRI alone. The primary endpoint was blinded independent review committee-assessed progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), surgery rate for metastasis and R0 resection rate, and safety. From January 4, 2018 to September 2, 2021, a total of 505 eligible patients were enrolled and received study treatment; the median follow-up duration was 8.7 months (95% confidence interval [CI], 7.77 to 9.29) and 5.9 months (95% CI, 5.63 to 6.65) in cetuximab β plus FOLFIRI group and FOLFIRI group, respectively. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI demonstrated statistically significant improvements in median PFS (13.1 vs. 9.6 months, hazard ratio [HR], 0.639; 95% CI, 0.468 to 0.872; P = 0.004), median OS (28.3 vs. 23.1 months, HR, 0.729; 95% CI, 0.551 to 0.965; P = 0.024), and ORR (69.1% vs. 42.3%, odds ratio, 3.090; 95% CI, 2.280 to 4.189; P < 0.001). Cetuximab β plus FOLFIRI exhibited manageable toxicity without novel safety signals. This study demonstrated that cetuximab β plus FOLFIRI provided significant clinical benefits as a first-line treatment for patients with RAS/BRAF wild-type mCRC. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI therapy led to prolonged median PFS and OS while maintaining a manageable safety profile, offering a new treatment option for this patient population.

BACKGROUND:GEMSTONE-302 was a phase 3 trial in patients with treatment-naive metastatic squamous or non-squamous non-small-cell lung cancer (NSCLC), showed significant improvement in progression-free survival and overall survival with sugemalimab, a PD-L1 inhibitor, plus chemotherapy versus placebo plus chemotherapy. We report the 4-year outcomes from this study. METHODS:This randomised, double-blind, phase 3 trial was conducted across 35 hospitals and academic research centres in China. Eligible patients were aged 18-75 years; had treatment-naive, histologically or cytologically confirmed stage IV NSCLC, irrespective of PD-L1 expression levels; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomised (2:1) by investigators using an interactive web response or voice response system via permuted blocks (block sizes of three or six, randomised within each stratum). Patients received histology-specific platinum-based chemotherapy combined with either sugemalimab (1200 mg; sugemalimab group) or placebo (placebo group) for up to four cycles, followed by for up to 35 cycles of maintenance therapy with sugemalimab alone for patients with squamous NSCLC and sugemalimab plus pemetrexed for patients with non-squamous NSCLC in the sugemalimab group, or placebo for patients with squamous NSCLC and placebo plus pemetrexed for patients with non-squamous NSCLC in the placebo group, administered intravenously. Treatment beyond 35 cycles was permitted at the investigator's discretion. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Here, we report post-hoc 4-year efficacy and safety outcomes from GEMSTONE-302. This study is registered with ClinicalTrials.gov (NCT03789604) and concluded on May 15, 2023, with all patients discontinued. FINDINGS:Between December 13, 2018, and May 15, 2020, 846 patients were assessed for eligibility. 479 patients were randomly assigned into the sugemalimab group (n=320) and placebo group (n=159). 254 (79%) patients were men and 66 (21%) were women in the sugemalimab group and 129 (81%) were men and 30 (19%) were women in the placebo group. All patients were Asian. As of the data cutoff on May 15, 2023, median follow-up durations were 43·5 months (IQR 41·2-46·9) in the sugemalimab group and 43·0 months (40·7-44·8) in the placebo group; median treatment durations were 7·2 months (4·2-18·8) with sugemalimab and 4·6 months (2·8-6·9) with placebo. Median progression-free survival was 9·0 months (95% CI 7·4-10·9) in the sugemalimab group versus 4·9 months (4·8-5·2) in the placebo group (hazard ratio [HR] 0·49 [95% CI 0·39-0·60]). Median overall survival was 25·2 months (20·1-30·2) in the sugemalimab group versus 16·9 months (12·8-20·7) in the placebo group (HR 0·68 [0·54-0·85]). The 4-year overall survival rates were 32·1% (95% CI 26·7-37·6) in the sugemalimab group versus 17·3% (11·1-24·7) in the placebo group. The most common grade 3-4 treatment related adverse events were decreased neutrophil count (105 [33%] with sugemalimab vs 52 [33%] with placebo), decreased white blood cell count (48 [15%] vs 27 [17%]), anaemia (44 [14%] vs 18 [11%]), and decreased platelet count (35 [11%] vs 15 [9%]). Treatment-related serious adverse events occurred in 82 (26%) patients with sugemalimab and 31 (20%) with placebo. No additional treatment-related deaths occurred since the previous overall survival interim analysis. No new safety signals were identified. INTERPRETATION:Sugemalimab with chemotherapy showed a superior long-term overall survival benefit compared with placebo with chemotherapy, as a first-line treatment for patients with NSCLC with no known sensitising EGFR, ALK, ROS1, or RET genomic alterations. These results underscore the efficacy of sugemalimab plus platinum-based chemotherapy as a standard first-line treatment option for both squamous and non-squamous metastatic NSCLC while maintaining a manageable safety profile. FUNDING:CStone Pharmaceuticals. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

In hepatocellular carcinoma (HCC), lenvatinib is a key first-line treatment that significantly improves survival in some patients with advanced stage. However, lenvatinib resistance presents a major clinical challenge. This study aims to identify key molecular factors driving lenvatinib resistance in HCC and propose intervention strategies to overcome this resistance, thereby enhancing therapeutic efficacy. A genome-wide CRISPR-Cas9 activation screen identified METTL8 as a crucial gene associated with lenvatinib resistance. Validation through in vitro and in vivo assays confirmed METTL8’s role in mediating lenvatinib resistance. Higher METTL8 expression was observed in lenvatinib-resistant HCC cells compared to parental cells. Immunohistochemical staining of tissue sections from HCC patients revealed a negative correlation between high METTL8 expression and lenvatinib sensitivity. To inhibit the function of METTL8 that mediate lenvatinib resistance, we conducted a screening using a natural compound library, virtual drug screening identified Rabdosiin as a potential METTL8 inhibitor, subsequent experiments demonstrated that Rabdosiin could effectively overcome METTL8-mediated lenvatinib resistance. In conclusion, this research highlights METTL8 as a novel target for mitigating lenvatinib resistance, proposing that targeting METTL8 could restore lenvatinib sensitivity in HCC, and underscores its value as a biomarker for lenvatinib application in clinical settings.

ImportanceGastric cancer, including gastroesophageal junction cancer, is one of the most commonly diagnosed cancers worldwide, with high mortality. Sugemalimab is a fully human anti–programmed death-ligand 1 (PD-L1) antibody. The combination of sugemalimab and chemotherapy showed promising antitumor activity and safety in a phase 1b study among patients with treatment-naive, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. This combination was further evaluated in the GEMSTONE-303 phase 3 trial.ObjectiveTo evaluate the efficacy of sugemalimab in combination with capecitabine and oxaliplatin (CAPOX) compared with placebo plus CAPOX as first-line treatment for patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 combined positive score (CPS) of 5 or greater.Design, Setting, and ParticipantsGEMSTONE 303 is a phase 3, randomized, double-blind, placebo-controlled study conducted at 54 sites in China that enrolled patients from April 9, 2019, through December 29, 2021, with follow-up to July 9, 2023. A total of 479 eligible patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS of 5 or greater who did not receive any prior systemic therapy were randomized.InterventionPatients received sugemalimab (1200 mg intravenously) (n = 241) or placebo (n = 238) every 3 weeks for up to 24 months, plus CAPOX every 3 weeks for up to 6 cycles.Main outcomes and MeasuresPrimary outcomes were overall survival and investigator-assessed progression-free survival.ResultsBaseline characteristics were well balanced between the 2 groups. Most patients were male (71.4% in sugemalimab group, 74.8% in placebo group). Median follow-up was 25.1 months in the sugemalimab group and 26.3 months in the placebo group. The sugemalimab group demonstrated significant improvements in overall survival (median, 15.6 months [95% CI, 13.3-17.8] vs 12.6 months [95% CI, 10.6-14.1]; hazard ratio, 0.75 [95% CI, 0.61-0.92]; P = .006) and progression-free survival (median, 7.6 months [95% CI, 6.4-7.9] vs 6.1 months [95% CI, 5.1-6.4]; hazard ratio, 0.66 [95% CI, 0.54-0.81]; P < .001). Grade 3 or higher treatment-related adverse events occurred in 53.9% of patients in the sugemalimab group and 50.6% in the placebo group.Conclusions and RelevanceSugemalimab plus chemotherapy significantly prolonged overall survival and progression-free survival with a manageable safety profile in previously untreated patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma.Trial RegistrationClinicalTrials.gov Identifier: NCT03802591

e14589 Background: Pucotenlimab, an anti-PD-1 antibody, demonstrated robust antitumor activity in patients (pts) with MSI-H/dMMR, based on findings from the phase II study 1 . Here, we present the long-term survival results and updated safety profile. Methods: Eligible pts were aged ≥18 years with histologically/cytologically confirmed advanced MSI-H/dMMR solid tumors, who had failed at least 1 line of standard systemic therapy. MSI-H/ dMMR status was assessed in a central lab. Pts received pucotenlimab 200 mg Q3W until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was the Independent Review Committee (IRC) evaluated ORR per RECIST1.1, the secondary endpoints included DoR, PFS, OS, and safety. The tumor response data was collected until 36 months for each subject. Results: 100 pts were enrolled from Oct 2018 to Dec 2020, the most common cancer types were colorectal cancer (CRC, N=71GC, N=10; EC, N=7; Other, N=12). By the cut-off date (Sep 19, 2024), median follow-up period was 43.8m (range: 0.3, 61.7). The updated ORR by IRC was 50.0% (95%CI: 39.8, 60.2, CR=12%). The mPFS was 33.8m (95%CI: 7.1, NR), while the 36-m rates were 49.7% (95%CI: 39.2, 59.3). The mDoR was not reached, 36-m DoR rate was 81.1% (95%CI: 66.7, 89.7). The mOS was 55.9 m (95%CI: 55.9, NR), with the 60-m OS rate 46.3% (95%CI: 19.1, 69.9). Pts in the CRC cohort had optimizing clinical benefits, with an ORR by IRC of 57.7% (95%CI: 46.8, 70.7), a 36-m PFS rate of 52.5% (95%CI: 39.9, 63.7), and a longer mOS was 55.9 m (95%CI: 55.9, NR). The 60-m OS rate was 44.3% (95%CI: 10.7, 74.3). The common treatment-related adverse events (TRAEs) of any grade included AST increased (28.0%), ALT increased (26.0%), and anemia (24.0%). TRAEs ≥ Grade 3 were reported in 24 pts (24.0%). No new safety signals were identified in this analysis, and patients had good tolerance to long-term treatment. Conclusions: Pucotenlimab as ≥2L therapy for advanced MSI-H/dMMR solid tumors demonstrates durable OS and PFS benefit. The updated, long-term follow-up data confirmed durable clinical benefit of pucotenlimab in this patient population, especially for CRC pts. References:1. Zhang B, et al. Cell Rep Med. 2023;4(12):101301. Clinical trial information: NCT03704246 .