ObjectiveTo evaluate the cost-effectiveness by comparing four treatment strategies for ROS1-positive non-small cell lung cancer (NSCLC): first-line taletrectinib prior to chemotherapy, second-line taletrectinib following chemotherapy, second-line taletrectinib after crizotinib, and chemotherapy alone.MethodsA partitioned survival model was constructed to analyze the clinical outcomes and healthcare expenditures associated with the four treatment strategies. Costs and utility values were obtained from reputable literature sources and publicly available cost databases. Cost-effectiveness was evaluated under different taletrectinib cost scenarios to determine the impact of taletrectinib pricing on the four treatment strategies.ResultsAll three taletrectinib-containing treatment strategies exceeded the established U.S. willingness-to-pay (WTP) threshold of $150,000 per QALY, indicating they were not cost-effective. Among the evaluated strategies, first-line taletrectinib administered prior to chemotherapy provided the largest gain in quality-adjusted life years (QALYs), adding 4.61372 QALYs. However, this came at a substantial additional cost of $1,263,183.95, resulting in an incremental cost-effectiveness ratio (ICER) of $273,789 per QALY compared to chemotherapy alone. The second-line use of taletrectinib following crizotinib provided a more favorable cost-effectiveness profile. It yielded an additional 2.03260 QALYs at an additional cost of $441,371.10, leading to an ICER of $217,146 per QALY compared to chemotherapy. While all three strategies demonstrated ICERs above the WTP threshold, the second-line approach following crizotinib offered the most favorable, though still not cost-effective, cost-effectiveness compared to the other options. Conversely, second-line taletrectinib administered following chemotherapy exhibited the poorest cost-effectiveness, with an ICER of $587,663 per QALY. Furthermore, the sensitivity analysis highlighted that the cost of taletrectinib was the primary driver of the ICER’s unfavorable results.ConclusionBased on current pricing, none of the taletrectinib-containing treatment strategies were found to be cost-effective for patients with ROS1-positive NSCLC compared to chemotherapy alone, as their ICERs exceeded the established WTP threshold. Nevertheless, considering the individual patient’s priorities, a personalized approach to treatment decisions can be adopted. For patients prioritizing the maximization of QALYs and with the necessary financial resources, first-line taletrectinib prior to chemotherapy may be a preferred option. Conversely, for those with limited financial capacity or in contexts prioritizing cost-containment, second-line taletrectinib after crizotinib could be more suitable.

Background:Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder with high morbidity and mortality, yet non-invasive diagnostic biomarkers remain scarce. Circulating microRNAs (miRNAs) have emerged as promising biomarkers for various diseases, but their role in Group 2 PH (due to left heart disease) is poorly understood. Methods:We performed high-throughput miRNA sequencing on plasma samples from 10 healthy controls (C group), 10 patients with coronary heart disease (CHD group), and 10 patients with coronary heart disease complicated by PH (PH group). Differential miRNA expression was analyzed, and candidate miRNAs were validated by RT-qPCR. Correlations with pulmonary artery pressure parameters (Tricuspid regurgitation maximum velocity (TRVmax) and systolic pulmonary artery pressure (SPAP) were assessed, and bioinformatic analyses were conducted to predict target genes and functional pathways. Results:We identified 575 differentially expressed miRNAs across the three groups. Eleven miRNAs were significantly dysregulated in PH patients compared to CHD and C groups. Among these, five miRNAs (mmu-miR-452-3p_1ss20GA, hsa-miR-10a-3p_R-1, hsa-miR-21-5p, hsa-miR-1287-5p_R + 1, and bta-mir-1246-p5_1ss18AG) showed strong positive correlations with TRVmax and SPAP. Receiver operating characteristic (ROC) curve analyses revealed high diagnostic accuracy. Functional enrichment analysis indicated involvement in key signaling pathways such as p53, PPAR, TGF-β, JAK-STAT, and MAPK. Conclusion:Our study identifies a panel of circulating miRNAs as potential non-invasive biomarkers for diagnosing Group 2 PH and provides insights into their roles in PH pathogenesis, offering new avenues for therapeutic intervention.

8525 Background: SHR-1826 is a novel ADC comprising a humanized IgG2 monoclonal antibody targeting c-MET, conjugated via a cleavable peptide-based linker to a topoisomerase I inhibitor payload. We conducted a multi-center, first-in-human, phase 1 trial of SHR-1826 in patients with advanced solid tumors. Here we report updated results, with a focus on patients with EGFR -mutated ( EGFRmut ) lung adenocarcinoma (LUAD). Methods: The study consisted of dose-escalation (i3+3 design), dose-expansion and efficacy-expansion phases. Patients with advanced solid tumors harboring MET alterations, who had failed standard therapy or had no available standard treatment options, were enrolled and received SHR-1826 intravenously at 2.2–6.0 mg/kg Q3W. In patients with EGFRmut LUAD, 4.0 and 5.0 mg/kg Q3W were evaluated during dose and efficacy expansion. Results: As of Dec. 3, 2025, 195 patients with lung (n=126), colorectal (n=40), gastric (n=22), liver (n=5), or pancreatic (n=2) cancer were treated. Median age was 59.0 yrs; 89.7% had ECOG performance status 1. Among 36 patients with EGFRmut LUAD, median number of prior lines of therapy was 2 (range 1–9); 97.2% had previously received EGFR-TKI (3 rd generation, 88.9%) and 75.0% received platinum-based chemotherapy. As of data cutoff, median follow-up was 14.4 months. Efficacy in EGFRmut LUAD across doses is shown in Table 1. Overall, the confirmed objective response rate (ORR) was 41.7% (95% CI 25.5–59.2) and median duration of response (DoR) was 14.1 months (95% CI 5.6–not reached [NR]). Median progression-free survival (PFS) was 9.8 mo (95% CI 5.8–15.4). Median overall survival (OS) was not reached; 12-month OS rate was 67.4% (95% CI 48.9–80.5). In all 195 patients, grade ≥3 treatment-related adverse events (TRAEs) were reported in 129 patients (66.2%), with all occurring in ≥5% being hematological toxicities. Interstitial lung disease occurred in 4 (3.1%; grade ≥3, n=2 [1.6%]) patients. TRAEs led to treatment discontinuation in 8 (4.1%) patients. No treatment-related deaths were reported. Conclusions: SHR-1826 demonstrated encouraging activity with manageable safety in heavily pretreated patients with MET-altered EGFRmut LUAD. Multiple trials are ongoing to assess SHR-1826 combined with other anti-tumor therapies in NSCLC. Clinical trial information: NCT06094556 . Efficacy outcomes in EGFRmut LUAD. 4.0 mg/kg (n=16) 5.0 mg/g (n=18) All patients (n=36) Confirmed ORR (n/N; 95% CI), % 31.3 (5/16; 11.0–58.7) 50.0 (9/18; 26.0–74.0) 41.7 (15/36; 25.5–59.2) DCR (n/N; 95% CI), % 87.5 (14/16; 61.7–98.4) 100.0 (18/18; 81.5–100.0) 94.4 (34/36; 81.3–99.3) Median DoR (95% CI), mo NR (8.6–NR) 9.7 (4.2–NR) 14.1 (5.6–NR) Median PFS (95% CI), mo 12.4 (2.6–NR) 8.4 (4.5–15.4) 9.8 (5.8–15.4) 12-mo OS (95% CI), % 67.0 (37.9–84.7) 69.1 (40.7–85.9) 67.4 (48.9–80.5) Data are based on the full analysis set. DCR, disease control rate.

Objective: This study assessed the causal link between lipid traits influenced by lipid-lowering drug targets like HMGCR and PCSK9 and gastric cancer risk. Methods We employed Mendelian randomization with genetic instruments based on genome-wide association study data LDL-C as exposure and gastric cancer as outcome. Analytical approaches included inverse variance weighting as primary method alongside MR-Egger weighted median and mode methods. Sensitivity analyses evaluated result robustness. Results Inverse variance weighting analysis showed HMGCR inhibitor treatment was associated with higher gastric cancer risk OR 1.532 95% CI 1.109-2.118 P 0.010. PCSK9 inhibition similarly elevated risk OR 1.466 95% CI 1.098-1.957 P 0.009. Sensitivity analyses detected no heterogeneity P greater than 0.05. Conclusion In conclusion LDL-C causally affects gastric cancer development. HMGCR and PCSK9 inhibitors appear to raise gastric carcinogenesis risk.

8506 Background: Pembrolizumab has been the standard first-line treatment for PD-L1 positive advanced NSCLC. Sac-TMT, a TROP2-directed antibody-drug conjugate with a unique bifunctional linker, and PD-1/L1 inhibitors demonstrate complementary mechanisms that enhance antitumor activity in the first-line treatment of NSCLC ( Hong et al., Nat Med, 2025 ). Here, we report the results from the planned interim analysis for PFS in this phase 3 OptiTROP-Lung05 study (NCT06448312). Methods: Eligible patients (pts) had treatment-naïve, locally advanced or metastatic NSCLC without EGFR/ ALK alterations and positive PD-L1 expression (defined as TPS ≥1%, 22C3 assay). Pts were stratified by PD-L1 (TPS 1-49% vs ≥ 50%), histology (squamous vs non-squamous) and ECOG (0 vs 1) and then randomized (1:1) to receive sac-TMT 4 mg/kg Q2W plus P 400 mg Q6W or P 400 mg Q6W. The primary endpoint was PFS per RECIST 1.1 assessed by blinded independent central review (BICR), and the key secondary endpoint was OS. Results: A total of 413 pts (median age 65 yrs; 84.5% ECOG 1; 40.0% squamous; 40.0% PD-L1 TPS ≥ 50%) were randomized to receive sac-TMT + P (n = 208) or P (n = 205). As of Sep 29, 2025, the median follow-up was 10.5 months. PFS by BICR was significantly longer in the sac-TMT + P group than the P group (median, not reached vs 5.7 months; HR, 0.35; 95% CI, 0.26-0.47; p < 0.0001). The data for OS were not mature, and a favorable trend was observed in the sac-TMT + P group (HR, 0.55; 95% CI, 0.36-0.85). The BICR-assessed ORR was 70.2% in the sac-TMT + P group versus 42.0% in the P group. In the pre-specified PD-L1 subgroups, the HRs for PFS in pts with TPS 1-49% and TPS ≥ 50% were 0.28 (95% CI, 0.19-0.41) and 0.47 (95% CI, 0.29-0.77). In the pre-specified histology subgroups, the HRs for PFS in pts with non-squamous and squamous were 0.28 (95% CI, 0.18-0.43) and 0.44 (95% CI, 0.29-0.66). Grade ≥ 3 TEAEs were 55.3% in the sac-TMT + P group and 31.4% in the P group. Most common grade ≥3 TEAEs of special interest for sac-TMT were neutrophil count decreased (17.3%), anemia (9.1%), and stomatitis (5.3%). TEAEs led to discontinuation of sac-TMT/ pembrolizumab in 3.8%/5.3% of pts in the sac-TMT + P group while discontinuation of pembrolizumab occurred in 4.9% of pts in the P group. Conclusions: To our knowledge, this is the first phase 3 study to demonstrate the significant PFS benefit of an antibody-drug conjugate plus pembrolizumab in the first-line treatment of PD-L1 positive advanced NSCLC compared to pembrolizumab. The safety profile of sac-TMT + P was generally manageable and consistent with the safety profile of the components. No new safety signals were seen. These results from phase 3 OptiTROP-Lung05 study support sac-TMT + P as a potential new treatment option for this population. Clinical trial information: NCT06448312 .

BackgroundFirst-line immunotherapy combined with chemotherapy for extensive-stage small-cell lung cancer (ES-SCLC) has been consistently recommended by clinical guidelines, but the improvement in overall survival remains limited. There is an urgent need to identify reliable predictive biomarkers for immunotherapy to select patients who would benefit most. Serum ferritin (SF) is a key regulator in ferroptosis and plays a significant role in immunotherapy of lung cancer. Therefore, we hypothesized that the change rate of serum ferritin (ΔSF) during immunotherapy, combined with inflammation-related indicators, could serve as a useful predictive marker for treatment response in ES-SCLC patients.MethodsWe comprehensively reviewed the medical records of 550 ES-SCLC patients, divided into an experimental group (425 patients receiving immune checkpoint inhibitors (ICIs) plus chemotherapy) and a control group (125 patients receiving chemotherapy alone). The study analyzed the correlation between pre-immunotherapy SF levels and molecular subtypes, clinical stage, tumor location, and programmed death-ligand 1 (PD-L1) expression in ES-SCLC patients; the correlation of SF levels and ΔSF with objective response rate (ORR); the correlation of ΔSF combined with a multidimensional inflammation model—including neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), and C-reactive protein (CRP)—with ORR; and survival analysis for these parameters.ResultsPatients with lower SF levels before immunotherapy had a higher ORR (χ² = 4.837, P = 0.035) and longer progression-free survival (PFS) (median 6.9 vs. 4.1 months). Patients with a high ΔSF during immunotherapy showed a higher ORR (χ² = 6.475, P = 0.019). Patients with high ΔSF combined with low NLR and LDH levels before immunotherapy were more likely to achieve a higher ORR (P < 0.001). After integration, patients with low SF levels and high ΔSF before immunotherapy had the best PFS, whereas those with high SF levels and low ΔSF before immunotherapy had the worst PFS (median 8.9 vs. 4.5 months). Within the high ΔSF group, patients with lower NLR had longer PFS than those with higher NLR (median 9.8 vs. 5.2 months); similarly, patients with lower LDH levels had longer PFS than those with higher LDH levels (median 9.2 vs. 5.6 months). Multivariate analysis identified SF levels before immunotherapy (HR = 1.58, P = 0.026) and ΔSF during immunotherapy (HR = 0.52, P = 0.002) as independent prognostic factors. SCLC clinical stage (HR = 0.56, P = 0.037) and molecular subtype (SCLC-A: HR = 1.67, P = 0.003; SCLC-N: HR = 1.51, P = 0.012; SCLC-P: HR = 0.73, P = 0.004; SCLC-Y: HR = 0.64, P = 0.003) were also independent prognostic factors. However, NLR and LDH levels alone were not independent prognostic factors and required combined assessment with ΔSF.ConclusionOur study suggests that the serum ferritin change rate combined with the NLR and LDH inflammation model can serve as a biomarker for predicting the efficacy and survival outcomes of immunotherapy in ES-SCLC.

Background The circadian gene hepatic leukemia factor (HLF), a proline and acidic amino acid-rich basic leucine zipper (PAR bZIP) transcription factor, is under-explored in terms of its prognostic and immunotherapeutic roles across various cancers. Methods Utilizing databases like UCSC Xena, TIMER2.0, and TCGA, this study assessed HLF's expression variability across numerous cancer forms. The research further assessed the survival outcomes, clinical attributes, and genetic alterations associated with HLF. Additionally, the impact of HLF on immunotherapy outcomes was analyzed through methodologies such as Gene Set Enrichment Analysis, evaluation of the tumor microenvironment, and immune cell infiltration studies. Results Findings indicate a notable reduction in HLF's transcription and protein levels in most cancers, highlighting its prognostic relevance for patient survival in specific cancers like CESC, HNSC, KIRC, KIRP, LGG, LUAD, MESO, PAAD, and READ. Furthermore, in certain cancers, a significant correlation between HLF expression and tumor mutation burden (TMB), microsatellite instability (MSI), and clinical features was observed. Gene Set Enrichment Analysis revealed significant links between HLF and immune-related pathways. The study also confirmed a strong association between HLF expression and the infiltration of immune cells, as well as its correlation with chemotherapy resistance-related genes, genes related to immune microenvironment reprogramming, and genes related to carbohydrate metabolism. The biological function of HLF was verified in common lung cancer cell lines. Knockdown of HLF enhanced the proliferation and migration abilities of tumor cells, while overexpression inhibited these abilities. Conclusions This comprehensive investigation underscores the potential of HLF as a valuable prognostic and immunotherapeutic biomarker in pan-cancer, offering novel insights and evidence for enhancing cancer treatment strategies.

The full text of this preprint has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.

Although immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 have revolutionized lung adenocarcinoma (LUAD) therapy, resistance and low response rates persist. Cytoplasmic phospholipase A2α (cPLA2α), a key enzyme in inflammatory pathways, promotes tumor progression, yet its immunomodulatory role in LUAD is unclear. Here, cPLA2α overexpression is found in LUAD tissues, correlating with poor prognosis. cPLA2α knockdown inhibits lung cancer cell proliferation, migration in vitro, and tumor growth in immunodeficient mice, but efficacy diminishes in immunocompetent models due to STAT3-mediated PD-L1 upregulation. In syngeneic models, cPLA2α silencing promotes CD8+ T cell and M1 macrophage infiltration and reduces immunosuppressive neutrophils and M2 macrophages. Strikingly, cPLA2α knockdown with anti-PD-1 synergistically suppresses tumor growth, where granzyme B+ cytotoxic CD8+ T cells amplifies. Our findings unveils cPLA2α's dual role in LUAD: promoting tumorigenesis and orchestrating immune evasion via STAT3-PD-L1 signaling. Targeting cPLA2α may overcome PD-1 blockade resistance, particularly benefiting patients with high cPLA2α and low baseline PD-L1. This study highlights cPLA2α as a promising therapeutic target to enhance ICI efficacy and reshape LUAD immunotherapy strategies.

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) often exhibits limited clinical response to targeted therapies, such as Cetuximab. Identifying key drivers of tumor progression and elucidating the factors that modulate therapeutic sensitivity are essential for improving clinical outcomes. In this study, we aimed to investigate the role of CAV2 in HNSCC proliferation and its impact on Cetuximab sensitivity. Methods: Prognosis-associated genes in HNSCC were screened using the The Cancer Genome Atlas (TCGA) database. The functional role of Caveolin-2 (CAV2) in cell proliferation and apoptosis was assessed via Cell Counting Kit-8 (CCK-8), colony formation, and flow cytometry assays. Mechanistic insights were obtained through co-immunoprecipitation, ubiquitination assays, and proteomic analysis. The impact of CAV2 on Cetuximab sensitivity was evaluated both in vitro and in a xenograft mouse model. Results: Clinical analysis of 43 pairs of HNSCC tumor and adjacent normal tissues revealed that elevated CAV2 expression was significantly associated with poor prognosis in HNSCC patients (95%CI: 1.197-1.7518, p = 1.33 × 10-13). In vitro, knockdown of CAV2 suppressed cell proliferation and significantly increased apoptosis rates (from 5.1% to 10.8%, p = 0.004). Mechanistically, CAV2 interacted with the PACT protein and disrupted the PACT-PKR axis via the ubiquitin-proteasome pathway. Notably, CAV2 deficiency synergized with Cetuximab treatment, reducing the the half maximal inhibitory concentration (IC50) value by 6-fold compared with control cells and suppressing tumor growth by 48.41% in xenograft models compared to Cetuximab monotherapy (p < 0.0001). Conclusions: In conclusion, these findings establish CAV2 as a critical regulator of HNSCC progression and Cetuximab sensitivity via post-translational modulation of the PACT-PKR axis. Targeting the CAV2/PACT/PKR axis may therefore represent a promising therapeutic strategy to potentiate the efficacy of EGFR-targeted therapy in patients with HNSCC.

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) frequently exhibits resistance to targeted therapies, including cetuximab. Identifying key drivers of tumor progression and elucidating the mechanisms underlying therapeutic resistance are essential for improving clinical outcomes. This study aimed to investigate the role of Caveolin-2 (CAV2) in HNSCC proliferation and cetuximab resistance. Methods: Prognosis-associated genes in HNSCC were screened using the TCGA database. The functional role of CAV2 in cell proliferation and apoptosis was assessed via CCK-8, colony formation, and flow cytometry assays. Mechanistic insights were obtained through co-immunoprecipitation, ubiquitination assays, and proteomic analysis. The impact of CAV2 on cetuximab sensitivity was evaluated both in vitro and in a xenograft mouse model. Results: CAV2 emerged as a top prognostic candidate. Knockdown of CAV2 significantly suppressed HNSCC cell proliferation and induced apoptosis. Mechanistically, CAV2 interacted with and stabilized the PACT protein, thereby inhibiting PKR activation via the ubiquitin–proteasome pathway. Notably, CAV2 deficiency markedly enhanced the sensitivity of HNSCC cells and tumor xenografts to cetuximab treatment. Conclusions: These findings establish CAV2 as a critical driver of HNSCC progression and cetuximab resistance through post-translational regulation of the PACT–PKR axis. Targeting CAV2 may therefore represent a promising strategy to potentiate the efficacy of EGFR-targeted therapy in HNSCC.

Lung adenocarcinoma (LUAD) shows marked heterogeneity, limiting the effectiveness of traditional classifications. We integrated bulk transcriptomic data from TCGA and multicenter cohorts with spatial transcriptomics for in situ validation. Analysis of glucocorticoid (GC) and mitophagy pathways identified 127 core genes, enabling a novel molecular subtyping and survival risk model that predicted prognosis and correlated with immune infiltration. High mobility group AT-hook 1 (HMGA1) emerged as a key regulator of tumor metabolism, immune evasion, and therapy resistance. Spatial transcriptomics with RCTD-based deconvolution showed a tumor-enriched and heterogeneous HMGA1 expression pattern and a positive spatial association with epithelial cell proportion in tumor sections. Single-cell RNA-seq analysis further resolved HMGA1 enrichment to tumor epithelial cells, and CIBERSORTx projection linked the HMGA1-high tumor epithelial cell state to poor prognosis and increased proliferation. Functional assays showed that high HMGA1 expression conferred sensitivity to metabolic inhibitors but resistance to proteasome inhibitors, while HMGA1 knockout suppressed tumor growth and enhanced anti-PD-1 efficacy. By integrating bulk modeling with spatial validation, this study establishes a GC-mitophagy-based classification and highlights HMGA1 as a promising biomarker for prognostic stratification and personalized immunotherapy in LUAD.

BACKGROUND:Sacituzumab tirumotecan (sac-TMT), a trophoblast cell-surface antigen 2-targeting antibody-drug conjugate, combined with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, has shown promising antitumour activity as first-line therapy for non-small-cell lung cancer (NSCLC) in early-phase studies. Our aim was to evaluate the efficacy and safety of sac-TMT plus pembrolizumab as first-line treatment for patients with PD-L1-positive advanced NSCLC without targetable genomic alterations. METHODS:In this randomised, open-label, phase 3 trial (OptiTROP-Lung05) conducted across 68 hospitals in China, eligible patients had locally advanced or metastatic NSCLC without targetable genomic alterations and a PD-L1 tumour proportion score (TPS) of 1% or greater. Patients were randomly assigned (1:1) to receive sac-TMT (4 mg/kg on days 1, 15, and 29) plus pembrolizumab (400 mg fixed dose on day 1), or pembrolizumab alone, administered intravenously every 6 weeks. The primary endpoint was progression-free survival, as assessed by blinded independent central review in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT06448312). Recruitment is complete, with the trial ongoing and the final analysis to be reported later. FINDINGS:Between June 7, 2024, and March 27, 2025, 741 patients were screened and 413 eligible patients were randomly assigned to receive sac-TMT plus pembrolizumab (n=208) or pembrolizumab alone (n=205). At the prespecified interim analysis, conducted after a median follow-up of 10·5 months (IQR 8·7-12·5), median progression-free survival was significantly longer with sac-TMT plus pembrolizumab than with pembrolizumab alone (not reached vs 5·7 months; stratified hazard ratio [HR] 0·35 [95% CI 0·26-0·47]; p<0·0001). The progression-free survival benefit was broadly consistent across subgroups, including patients with PD-L1 TPS of 1-49% (HR 0·28 [95% CI 0·19-0·41]) and those with PD-L1 TPS of 50% or greater (HR 0·47 [0·29-0·77]). Grade 3 or higher treatment-emergent adverse events occurred in 115 (55%) of 208 patients in the sac-TMT plus pembrolizumab group and 64 (31%) of 204 patients in the pembrolizumab group. INTERPRETATION:Among patients with PD-L1-positive advanced NSCLC without targetable genomic alterations, first-line treatment with sac-TMT plus pembrolizumab significantly prolonged progression-free survival compared with pembrolizumab alone. Therefore, sac-TMT plus pembrolizumab has the potential to redefine first-line treatment for patients with PD-L1-positive advanced NSCLC without targetable genomic alterations. FUNDING:Sichuan Kelun-Biotech Biopharmaceutical.

8617 Background: Acquired resistance to first-generation selective RET inhibitors (SRIs) remains a significant clinical challenge in the treatment of RET fusion-positive NSCLC. APS03118 is a next-generation, highly selective RET inhibitor also with additional potent inhibitory activity against YES1, a SRC family kinases. This Phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of APS03118 treatment in patients with advanced RET fusion-positive NSCLC. Methods: This multicenter Phase I trial enrolled 108 patients, including 85 patients with NSCLC harboring RET aberrations. In the dose escalation stage (Ia), APS03118 was administered orally at doses ranging from 40 mg once daily to 120 mg twice daily (BID) 28 days a cycle in 29 patients with solid tumors. In the expansion stage (Ib), 79 patients received 80 mg BID and 100 mg BID, including 66 patients of NSCLC with RET fusions. Efficacy was assessed per RECIST v1.1 every 2 cycles (4 weeks/cycle). Safety was evaluated according to CTCAE v5. Molecular profiling was performed using next-generation sequencing on blood and, when available, tumor tissue. This report focuses mainly on the NSCLC cohorts, including treatment-naïve and previously treated patients with 1-4 lines of therapy, including six different SRIs, (e.g., pralsetinib and selpercatinib). Results: Out of 85 NSCLC patients (Ia+Ib), the Objective Response Rate (ORR) was 80% (confirmed) in 20 (20/22) evaluable treatment-naïve patients. The median Progression-Free Survival (mPFS) is not reached, with 10 patients up to or over the 16 cycles at the data cutoff date. In 22 (22/25) evaluable patients with prior systemic therapy not including the SRIs, the ORR was 55%. There were 38 patients in the cohort of prior SRIs treatment failure. Among 22 (22/26) evaluable patients without known bypass pathway mutations, ORR was 23% with 14 patients’ PFS up to or over 6 cycles and 10 patients up to or over 8 cycles (data cutoff date). Promising anti-tumor action was observed in the two patients with G810S and G810C mutations, who experienced tumor shrinkage of up to 50%. Grade ≥3 TRAEs occurred in 50.9% of patients. The most common AEs were creatine phosphokinase, AST and ALT elevation, which were reversible and mostly observed within cycle 1-3 and rarely after cycle 5. Dose reductions in 22.2%, and permanent discontinuation in 4.6%. Overall, APS03118 demonstrated a manageable and predictable safety profile. Conclusions: APS03118 shows highly promising clinical activity in both treatment-naïve and SRI failed NSCLC patients harboring RET fusions. Its survival benefit may result from potent inhibition of RET and YES1. The safety profile is manageable, characterized primarily by reversible enzyme elevations. Further development in NSCLC patients harboring RET fusion is warranted. Clinical trial information: NCT05653869 .

Background: The SMARCA4 gene encodes the BRG1 protein, a key component of the switch (SWI)/ sucrose nonfermenting (SNF) chromatin remodeling complex, and its loss has been implicated in the pathogenesis of various tumors. SMARCA4-deficient undifferentiated thoracic tumor (SMARCA4-UT) is a rare, rapidly progressive, and highly aggressive subtype that is associated with a poor prognosis, with subcutaneous metastasis being one of its uncommon distant-spread phenotypes. The tumor microenvironment (TME) of SMARCA4-UT is closely associated with tumor metastasis and immunotherapeutic response, but the expression profiles of key immune and stromal markers in subcutaneous metastatic lesions have not been clarified. Case Description: A 49-year-old male patient with a history of heavy smoking experienced an insidious onset of symptoms, including a painful left lower-limb mass, dyspnea, chest tightness, and hoarseness. Diagnosis of SMARCA4-UT was confirmed by genetic testing of cancer and immunohistochemistry. The patient received four cycles of tislelizumab combined with albumin-bound paclitaxel and carboplatin, followed by four cycles of tislelizumab monotherapy maintenance. Multiplex immunofluorescence (mIF) staining was performed on the subcutaneous metastatic lesion tissue of the left lower limb to detect the expression patterns of six target molecules [CD20, CD56, CD8, programmed cell death protein 1 (PD-1), CD68, and pan-CK], with ZEN software (Zeiss) being used for qualitative and quantitative analysis. The patient's general condition improved significantly after treatment; dyspnea, chest tightness, and left lower-limb pain were resolved; and the best therapeutic response was partial response. mIF staining revealed varying intensities of positive signals for all six target markers in the subcutaneous metastatic lesion: CD56, PD-1, and pan-CK exhibited high expression, while CD8, CD68, and CD20 exhibited low expression. Conclusions: SMARCA4-UT has an insidious onset and a diversity of metastatic sites, which can easily result in misdiagnosis, and genetic testing of cancer and immunostaining for SMARCA4 are crucial for achieving an accurate diagnosis. The distinct marker expression profile in subcutaneous metastatic lesions (high CD56, PD-1, and pan-CK expression with low CD8, CD68, and CD20 expression) reflects the unique TME of SMARCA4-UT, which may be related to its metastatic potential and immunotherapeutic response. Chemotherapy combined with immunotherapy shows promising efficacy in the treatment of SMARCA4-UT, and the mIF-based marker profile may provide a potential basis for optimizing individualized treatment strategies.

Introduction The emergence of acquired resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) presents a significant barrier to effective treatment in lung adenocarcinoma. This study investigates the antitumor efficacy of FN-1501 and its potential synergistic interaction with Almonertinib (Alm) to combat this resistance.Methods The impact of FN-1501 on lung adenocarcinoma and its synergistic effects with Almonertinib (Alm) were assessed through flow cytometry, Western blot analysis, CCK-8 assays, and clonogenic formation assays. Additionally, transcriptome analysis and network pharmacology were employed to elucidate the functional mechanisms by which FN-1501 may reverse EGFR-TKI acquired resistance.Results FN-1501 demonstrated the ability to inhibit cell proliferation, induce apoptosis, and arrest the cell cycle. The combination of Alm and FN-1501 restored sensitivity in resistant cell lines. Mechanistic investigations indicated that this combination triggered ferroptosis via the FOXO1-mediated upregulation of NCOA4. In vivo experiments showed that the Alm+FN-1501 combination significantly inhibited tumor growth compared to either treatment alone.Discussion These results provide compelling evidence that targeting ferroptosis pathways could be a viable approach to overcoming resistance to EGFR-TKIs. The FOXO1/NCOA4 axis emerges as a critical component in this process, enhancing our understanding of the mechanisms underlying resistance. While these findings are promising, further research is needed to evaluate toxicity, pharmacokinetics, and the applicability of this strategy in a broader context of resistance. Identifying predictive biomarkers could help refine patient selection for this treatment approach.Conclusion FN-1501 exhibits significant antitumor activity and, when combined with Alm, effectively reverses EGFR-TKI resistance by inducing ferroptosis, highlighting its potential for clinical application.

Abstract Background: The EGFR C797S mutation is a major resistance mechanism following third-generation EGFR tyrosine kinase inhibitors (TKIs) treatment in EGFR-mutant NSCLC, with no clinically validated and accessible target therapies. HS-10504 is a novel, potent, and highly selective fourth-generation EGFR TKI designed to target tumors with EGFR sensitizing mutations and C797S with or without T790M. Here we report the initial results of HS-10504 from a first-in-human phase 1 study. Methods: This single-arm, open-label, multicenter phase 1 study (NCT06461156; 26 centers in China) enrolled patients (pts) with locally advanced/metastatic NSCLC harboring EGFR sensitizing mutations, who failed prior EGFR TKI treatment. The escalation phase evaluated oral doses from 50 mg to 500 mg once daily (QD). The study's primary objectives were to evaluate safety, tolerability, and preliminary efficacy. Results: As of December 25, 2025, 82 pts had been enrolled and dosed. No dose-limiting toxicities were observed during the dose-escalation phase (n=20), and the maximum tolerated dose was not reached at doses up to 500 mg QD. In the dose expansion phase, 300 mg and 400 mg QD were further investigated, and 400 mg showed more promising clinical benefit. Among pts treated at the 400 mg QD dose level (n=35), selected as the recommended phase 2 dose (RP2D), all pts had stage IV adenocarcinoma with EGFR C797S mutation (median age 61 years, range: 35-78; 71.4% female). Twenty-five pts (71.4%) had received ≥2 prior lines of anti-tumor therapy, and all pts had previously received at least one third-generation EGFR TKI. Overall, HS-10504 demonstrated a favorable and manageable safety profile, with most treatment-emergent adverse events (TEAEs) being Grade 1-2. Grade ≥3 TEAEs occurred in 74.3% (26/35) of patients and were primarily laboratory abnormalities, including decreased lymphocyte count (31.4%) and anemia (14.3%), which were clinically manageable. TEAEs leading to permanent treatment discontinuation occurred in 2.9% (1/35), with no fatal TEAEs reported. At the RP2D of 400 mg QD (n=34, efficacy-evaluable set), encouraging antitumor activity was observed. The partial response was observed in 17 (50%) pts and stable disease in 14 (41.2%) pts. The confirmed objective response rate was 47.1% (95% CI: 29.8-64.9), and the disease control rate was 91.2% (95% CI: 76.3-98.1). Most pts remained on treatment as of the data cut-off date. Conclusions: HS-10504 demonstrated a manageable safety profile and encouraging antitumor activity in patients with advanced cancer harboring EGFR C797S resistance mutations, supporting further development of HS-10504 at the selected RP2D and its continued evaluation as a potential oral targeted therapy for EGFR C797S mutation-mediated resistance. Citation Format: Zhanhong Xie, Qiming Wang, Lin Wu, Jun Ge, Jianchun Duan, Juan Li, Yalei Zhang, Yan Yu, Jian Fang, Peng Chen, Zhangzhou Huang, Wei Zheng, Qing Bi, Haibo Zhang, Wenfeng Li, Ai Wang, Lu Chen, Xiaoqing Zhang, Jianxing He. The safety, tolerability, and efficacy of HS-10504 in patients with EGFR mutation-positive locally advanced or metastatic NSCLC: Initial results from a first-in-human phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT302.

8520 Background: Patients with EGFR-mutant NSCLC whose disease progresses on or after 3 rd generation EGFR TKI treatment often acquire resistance mutations, among which EGFR C797X is one of the most frequently reported. DZD6008 is a 4 th generation EGFR TKI, designed to target classical EGFR sensitizing mutations (L858R/19del), as well as resistant double (T790M and L858R/19del) and triple mutations (C797X, T790M and L858R/19del), with preclinical data showing high selectivity over wild-type EGFR and other kinases and full blood-brain-barrier (BBB) penetration. Here we report results in pretreated NSCLC patients with EGFR C797X mutations (C797X+) from phase 1/2 studies. Methods: TIAN-SHAN1 (NCT06905197) and TIAN-SHAN2 (NCT06813365; CTR20241790) are ongoing, multicenter phase 1/2 studies evaluating the safety, tolerability, and anti-tumor activity of DZD6008 in EGFR-mutant NSCLC patients, conducted in the US/Australia and China, respectively. The efficacy endpoints include objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) by investigator per RECIST v1.1, and safety endpoints include treatment-related adverse events (TRAEs) per CTCAE 5.0. Results: As of December 19, 2025, a total of 24 patients with confirmed C797X+ NSCLC were treated with once daily (QD) oral DZD6008 (20 mg, n=1; 40 mg, n=13; 60 mg, n=10), and had at least 1 post-baseline tumor assessment. The median age was 66.5 years, 58.3% were female, 91.7% were Asian, 58.3% had ECOG PS of 1. All patients had metastatic disease upon study entry and received median 2 (range 1 - 6) lines of prior therapies. Across all dose levels, tumor shrinkage was observed in 75% of patients, with an ORR of 41.7%. Intracranial anti-tumor activity was observed in patients with baseline brain metastasis. The doses of 40 mg and 60 mg QD were defined as the recommended phase 2 doses (RP2Ds). The ORRs were 23.1% and 60.0% at these two dose levels, respectively. The median DoR and median PFS were not reached for either dose. The 9-month PFS rates were 54.5% and 64.8%, respectively. DZD6008 was well tolerated at the doses evaluated, with no dose limiting toxicities observed. The majority of TRAEs were grade 1 or 2. The TRAEs with grade ≥3 included lymphocyte count decreased (8.3%), anemia, malaise, fatigue and amylase increased (all 4.2%). There were no Grade 5 TRAEs. Conclusions: DZD6008 demonstrated promising and durable anti-tumor activity in patients with EGFR C797X+ NSCLC with a manageable safety profile, supporting its potential use as a later line treatment option after 3 rd generation EGFR TKI failure. The updated data will be presented at the meeting. Clinical trial information: NCT06905197 , NCT06813365 .

KRAS G12D mutations occur in approximately 2–4% of patients with non-small cell lung cancer (NSCLC). GFH375, a compound that targets both “ON” (GTP-bound) and “OFF” (GDP-bound) states of the KRAS G12D proteins, was evaluated in a phase 1/2 study among patients with advanced solid tumors harboring KRAS G12D mutations. The objectives were to evaluate safety and tolerability, characterize pharmacokinetics, and evaluate preliminary efficacy. A total of 86 patients with KRAS G12D -mutant advanced solid tumors, including 28 with advanced NSCLC, were treated with the single agent GFH375 administered orally once or twice daily. Overall, GFH375 was well tolerated and had a manageable safety profile. Treatment-related adverse events occurred in 97.7% of the patients: 37.2% experienced grade ≥3 adverse events, and 1 patient (1.2%) experienced a grade 5 adverse event. Encouraging antitumor activity was demonstrated in patients with previously treated NSCLC, with objective response rates of 57.7% (90% CI: 39.8–74.2) at all dose levels and 68.8% (90% CI: 45.2–86.8) at 600 mg once daily; the 6-month progression-free survival rates were 60.4% (90% CI: 46.2–78.8) and 77.4% (90% CI: 60.6–98.9), respectively. Co-occurring alterations were analyzed with circulating tumor DNA (ctDNA) collected at baseline and at the end of treatment. The study is ongoing (ClinicalTrials.gov identifier: NCT06500676).

Background Acquired resistance limits the durability of programmed cell death protein-1 (PD-1) blockade in lung adenocarcinoma, yet the tumor-intrinsic programs and immune circuits that drive acquired resistance relapse remain poorly defined. The purpose of this study was to identify tumor-intrinsic mediators of acquired resistance and determine how they remodel antitumor immunity.Methods An orthotopic bioluminescence-tracked Lewis lung carcinoma (LLC1) lung adenocarcinoma model was established in immunocompetent mice treated with anti-PD-1. Tumor-intrinsic regulators were identified by an in vivo genome-wide CRISPR loss-of-function screen and validated using inducible tetracycline-off knockdown. Prostaglandin E2 (PGE2) signaling was interrogated through tumor-cell Ptgs2 knockdown/deletion, 16,16-dimethyl PGE2 administration, selective EP2/EP4 antagonists, and celecoxib treatment. Natural killer (NK)-cell function was analyzed by flow cytometry, immunofluorescence, RNA sequencing, cAMP measurement, calcium flux assays, mouse and human NK-cell co-culture cytotoxicity assays, and NK-cell adoptive transfer. Celecoxib was used to evaluate the therapeutic potential of pharmacologic PGE2 blockade in vivo. Public immunotherapy datasets were analyzed to assess the clinical relevance of PTGS2.Results The orthotopic LLC1 model captured key features of heterogeneous anti-PD-1 responses, including relapse after initial regression. The CRISPR screen identified Ptgs2 as a key driver of acquired resistance. Tumor-derived PGE2 progressively increased in resistant tumors, and its genetic silencing overcame resistance by restoring NK-cell infiltration and function. Mechanistically, PGE2 signaled through EP2/EP4 receptors to elevate cAMP and induce CREM, thereby suppressing NK-cell cytotoxicity and cytokine production. This axis was validated in human NK cells. Pharmacologic inhibition of cyclooxygenase-2 with celecoxib reversed acquired resistance, an effect abrogated by NK-cell depletion.Conclusions Tumor-derived PGE2 is an important contributor to acquired resistance to PD-1 blockade in lung adenocarcinoma. Therapeutic disruption of the EP2/EP4–cAMP–CREM axis restores NK-cell function and overcomes acquired resistance.