RET fusions are rare, and occur in 1%-2% of all non-small cell lung cancer (NSCLC) patients. While neoadjuvant immunotherapy-chemotherapy has demonstrated significant benefit for resectable NSCLC, data remain limited for oncogene-positive NSCLC, particularly for rare alterations like RET fusions. Herein, we present a clinical case of a patient with stage IIIA RET fusion-positive adenocarcinoma who received neoadjuvant nivolumab immunotherapy combined with nab-paclitaxel and carboplatin chemotherapy followed by surgery. The postoperative pathologic results revealed pathological complete response (pCR) and no residual viable tumor cells were observed in lymph nodes. This case validates the clinical activity of immunotherapy-chemotherapy in the neoadjuvant setting, providing a foundation for continued exploration in the treatment of early-stage RET fusion-positive NSCLC.

e20711 Background: Methionine adenosyltransferase 2A (MAT2A) links metabolic reprogramming with epigenetic regulation by producing S-adenosylmethionine (SAM) in the methionine cycle. The regulatory mode of MAT2A in metabolic reprogramming of non-small cell lung cancer (NSCLC) is still unclear. The current efficacy of MAT2A inhibitors is limited, and further exploration is needed to improve their effectiveness. Methods: We systematically characterized the metabolic reprogramming of MAT2A rewiring in NSCLC cell lines treated with siRNA targeting MAT2A or inhibitor AG-270 using proteomics and metabolomics, supplemented by targeted metabolomics, RT qPCR, and ATAC seq, in order to characterize MAT2A-rewired metabolic reprogramming and identify potential combination strategies. Results: Knockout and inhibition of MAT2A significantly disrupt fatty acid biosynthesis, cholesterol metabolism, glycolysis, and transsulfuration pathway. In fatty acid biosynthesis, MAT2A affects the expression of key genes FASN and SCD, as well as the levels of key metabolites palmitic acid (PA) and oleic acid (OA), as exogenous PA reverses the cell growth inhibition caused by AG-270.In cholesterol metabolism, MAT2A regulates biosynthesis and efflux, binding AG-270 to liver X receptor agonists to promote cholesterol efflux and enhance anti-tumor efficacy. In energy metabolism, MAT2A affects glycolysis by regulating HIF1A. GLUT1 inhibitors that inhibit glucose uptake exhibit a synergistic effect when combined with AG-270. In the sulfur conversion pathway, MAT2A transcriptionally regulates the key enzyme CBS involved in cysteine biosynthesis. The combination therapy of AG-270 and inhibitors targeting genes upregulated by AG-270, such as PHGDH and SLC7A11, shows a synergistic effect. The former produces serine through cysteine biosynthesis, while the latter mediates cysteine uptake. Conclusions: Overall, our research findings confirm that MAT2A is a critical regulatory factor in NSCLC metabolism and propose a reasonable combination strategy to enhance the efficacy of MAT2A inhibitors.

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.

3011 Background: SKB500 is an antibody drug conjugate (ADC) composed of an antibody targeting the B7 homolog 3 (B7-H3), which is overexpressed in many types of solid tumors, conjugated to a topoisomerase I inhibitor payload via a cleavable pyrimidine-tripeptide linker. We hereby report initial results of the FIH study (NCT06736327). Methods: This phase 1 study comprised dose-escalation, dose-expansion, and indication-expansion phases to evaluate the safety, tolerability, pharmacokinetics, and efficacy of SKB500. Patients (pts) with unresectable solid tumors refractory to standard treatment will be enrolled and receive SKB500 at doses ranging from 2 to 18 mg/kg every three weeks (Q3W) until disease progression or unacceptable toxicity. The primary efficacy endpoint was objective response rate (ORR) assessed by investigators per RECIST v1.1. Results: As of Dec 23, 2025, 150 pts were treated with SKB500 across all dose levels (2-18 mg/kg). No dose-limiting toxicities (DLT) were observed during dose escalation. Based on preliminary data, the recommended phase 2 dose (RP2D) was established as 12 mg/kg. Among 97 pts treated at 12 mg/kg, the median treatment duration was 6.7 weeks. Treatment-related adverse events (TRAEs) occurred in 70 pts (72.2%), with most frequent (≥20%) being anemia (35.1%), nausea (34.0%), and white blood cell count decreased (24.7%). Grade ≥3 TRAEs occurred in 16 pts (16.5%), with most frequent being anemia, lymphocyte count decreased, pneumonia, and asthenia (each 3.1%). Pneumonitis occurred in 2 pts (2.1%; both grade 1). Both pneumonitis and grade ≥ 3 hematologic toxicities demonstrated low occurrence rates. No TRAEs led to treatment discontinuation or death. Among 55 pts treated at 12 mg/kg who had at least 6 weeks of follow-up (≥2 prior lines: 34.5%; prior platinum: 98.2%; prior IO therapy: 76.4%), the ORR was 54.5% (30/55) and the DCR was 92.7% (51/55). In tumor-specific subgroups, the small cell lung cancer (SCLC) cohort (n = 21) achieved an ORR of 71.4% (15/21) and a DCR of 100% (21/21), while the esophageal squamous cell carcinoma (ESCC) cohort (n = 18) showed an ORR of 55.6% (10/18) and a DCR of 88.9% (16/18). Conclusions: SKB500 demonstrated a manageable safety profile and promising antitumor activity in patients with treatment-refractory advanced solid tumors, with notable efficacy in SCLC and ESCC cohorts, supporting further clinical development. Clinical trial information: NCT06736327 .

Thymine DNA glycosylase (TDG) is a multifaceted protein involved in base-excision repair, DNA demethylation and transcriptional regulation, with key roles in embryonic development and tumorigenesis. However, the mechanisms underlying its role in cancer progression and the therapeutic applications targeting TDG remain largely unknown. Here we demonstrate that targeting TDG induces synthetic lethality in p53-deficient cancers. We developed C-271, a first-in-class, small-molecule inhibitor that covalently binds to TDG, disrupting its DNA-binding capability. C-271 exhibits potent therapeutic efficacy in suppressing p53-deficient tumors. Mechanistically, TDG and p53 redundantly promote the transcription of DHX9, an RNA helicase that resolves double-stranded RNA (dsRNA). TDG inhibition in p53-deficient cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5–MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity. These findings highlight the synthetic lethality between TDG and p53, positioning TDG inhibition as a promising therapeutic strategy for p53-deficient cancers. Thymine DNA glycosylase (TDG) was identified as a synthetic-lethal target in p53-deficient cancers through alterations in double-stranded RNA accumulation. A covalent small-molecule inhibitor of TDG exhibited potent efficacy against p53-deficient tumors.

Targeting immune checkpoints, specifically programmed death 1, has significantly improved clinical outcomes in non-small cell lung cancer. However, only a proportion of patients benefited from immune checkpoint blockades (ICBs) therapy. Thus, identifying novel biomarkers to better select responders to ICBs is critically important in clinical practice. This retrospective study included two cohorts, a discovery cohort (n = 24) and a validation cohort (n = 21) of lung adenocarcinoma (LUAD) patients treated with ICB at Shanghai Pulmonary Hospital between April 2016 and November 2019. Formalin-fixed paraffin-embedded tissue samples were collected for RNA sequencing. Additionally, a TCGA dataset (GSE135222) and a clinical study dataset (POPLAR) were utilized as external validation and test sets, respectively. In the discovery cohort, cilia-associated pathways were significantly enriched in LUAD patients with non-durable benefit. A three-gene cilia-associated signature (TMEM100, DNAH3, and NEFH) was established and effectively predicted resistance to ICB treatment (discovery cohort, Hazard Ratio [HR, 95

Background With the increasing progression of bevacizumab and the urgent need for anti-angiogenic strategies, we aimed to evaluate the efficacy and safety of anlotinib in bevacizumab-pretreated patients with non-squamous non-small cell lung cancer. Methods This was a retrospective real-world study. We enrolled bevacizumab-naïve patients and bevacizumab-pretreated patients from six hospitals during Jan 2018 and May 2024. Progression-free survival (PFS) was the primary outcome. Secondary outcomes included objective response rate (ORR), disease control rate (DCR) and safe outcome. Results A total of 1256 patients were screened, and 746 patients were included in the study. Firstly, we selected patients treated with anlotinib monotherapy. After propensity score matching (PSM), we divided them into beva-pretreated (n = 73) and beva-naïve group (n = 146), and no statistical differences were observed in PFS (6.43 vs. 7.60 months; HR 1.14, p = 0.334). So previous bevacizumab didn't affect the efficiency of anlotinib in non-squamous NSCLC. We further divided the bevacizumab-pretreated patients into three groups according to the post-treatment: anlotinib monotherapy (n = 108), anlotinib combination (n = 345), and other therapies (n = 119). After PSM, the PFS was similar between the anlotinib monotherapy (n = 93) and other treatment group (n = 93) (5.90 vs. 5.23 months; HR 0.96, p = 0.766), whereas the PFS was significantly longer in the anlotinib combination group (n = 297) than other treatment group (n = 99) (6.50 vs 5.23 months; HR 0.82, p = 0.048). Conclusion This study demonstrated that previous bevacizumab didn't affect the efficiency of anlotinib in non-squamous NSCLC. For beva-pretreated patients, combined with anlotinib was effective and well-tolerated. Further studies are warranted to confirm these results and explore the potential advantages of anlotinib.

Abstract Background: ROS1 tyrosine kinase inhibitors (TKIs) are highly effective in ROS1-positive non-small cell lung cancer (NSCLC), but acquired resistance remains a challenge, particularly solvent front (SF) mutations like G2032R and D2033N, and the central beta sheet (Cβ6) mutation L2086F. ANS03 is a next generation type II TKI targeting both ROS1 and TRK, possessing a broad spectrum of acquired drug-resistant mutation coverage. In preclinical studies, ANS03 was more potent than repotrectinib against SF mutations and more potent than repotrectinib or zidesamtinib against L2086F. Method: A phase 1 study (NCT06716138) was designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ANS03 in participants with locally advanced or metastatic solid tumors harboring a ROS1 or NTRK alteration. Dose escalation was determined by Bayesian optimal interval design. Response was assessed by investigators using RECIST V1.1. Results: As of January 6, 2026, the dose escalation study is ongoing. Five dose levels (15mg qd, 30mg qd, 45mg qd, 67.5mg qd and 90mg qd) have been completed. A total of 20 NSCLC patients harboring ROS1/NTRK fusions were enrolled. No dose-limiting toxicities were observed. The most frequently reported treatment related adverse events (TRAE) were low grade, including the elevation of AST/ALT (80%), bilirubin (35%) and LDH (35%). Grade ≥3 TRAE occurred in 25% of patients. Only low grade neurotoxicities (15%) including dizziness, dysgeusia and pain in the limbs occurred. Among 18 efficacy evaluable ROS1 fusion-positive cancers, objective response rates (ORRs) were 38.8% (7/18) for all enrolled patients and 54.5% (6/11) for patients previously received ≥2L systemic therapy and at least 1 prior ROS1 TKI. Of the latter, six patients were pre-treated with 2-4 ROS1 TKIs including lorlatinib, repotrectinib, taletrectinib, and zidesamtinib. Among heavily pretreated patients, one patient posted 5 prior lines of systemic therapy (3 prior TKIs) with an L2086F mutant cancer had a confirmed partial response (PR) with ANS03 at 12 weeks. Two additional patients who received ≥6 prior lines of systemic therapy and ≥4 prior TKIs had a PR at the first tumor assessment and remain on ANS03 therapy. Conclusions: ANS03 had a manageable safety profile with a low incidence of neurotoxicity. In ROS1 fusion-positive NSCLCs, promising preliminary anti-tumor activity was achieved, including against ROS1 L2086F. Citation Format: Alexander Drilon, Jia Yu, Zhiyong He, Yongsheng Wang, Kejing Tang, Tianqing Chu, Shutan Liao, Junjun Zhang, Xinlong Zheng, Jaime Rubio-Perez, Matteo Repetto, Brendan Putz, Shengxiang Ren. A phase I study of the type II ROS1 TRK inhibitor ANS03 in ROS1 fusion-positive lung cancers [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 CT061.

Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality worldwide, highlighting the urgent need for non-invasive strategies for early detection. Here, we present a machine learning-assisted metabolomics approach for the early detection of LUAD. Untargeted metabolomic profiling was performed on 199 serum samples from healthy individuals, patients with lung precancerous lesions, and those with stage I LUAD. An ensemble machine learning workflow was developed to identify metabolite panels capable of discriminating clinical status with high accuracy. We observed progressive metabolic alterations in bile acid, lipid, amino acid, and purine metabolism during LUAD initiation and stepwise progression. Notably, ensemble learning identified a six-metabolite panel, including 12-hydroxydodecanoic acid, hypoxanthine, xanthosine, cholic acid, agmatine, and paraxanthine, for accurate detection of early-stage LUAD, and a distinct four-metabolite panel, comprising 7-α,27-dihydroxycholesterol, 11-undecanedicarboxylic acid, biliverdin, and Prolyl-Valine, for precise differentiation between pre-invasive and invasive lesions. Both panels demonstrated promising diagnostic potential, with performance metrices comparing favorably to established methodologies within the current study cohort. This study delineates the evolutionary trajectory of the serum metabolome associated with early LUAD pathogenesis and provides promising biomarkers for non-invasive early detection.

3032 Background: EGFR and c-Met overexpression are common across various solid tumors. TQB6411 is a novel ADC binding to both EGFR and c-Met with a valency of 1:2 to enhance the affinity to c-Met. Here we report the preliminary results of this first-in-human phase 1 study of TQB6411(NCT07043751). Methods: Patients (pts) with advanced malignant tumor who had failed or were intolerant to standard treatment were eligible. TQB6411 was administered intravenously once every 3 weeks. An accelerated titration design was used for the initial dose level (0.8 mg/kg), followed by a conventional 3+3 dose escalation design for the remaining dose levels. The primary endpoints were dose-limiting toxicity (DLT), recommended phase II dose and safety. Results: As of December 31, 2025, 26 pts were enrolled and received research treatment (median age [range], 60[33–75] years; 46.2% female). The most common diagnosis was non-small cell lung cancer (NSCLC, 21 pts), followed by esophageal cancer (EC, 3 pts) and colorectal cancer (CC, 2 pts). All pts had received at least one previous line of systemic treatment. Dose group assignments were as follows: 1 in 0.8mg/kg, 3 in 2.4mg/kg, 13 in 4mg/kg, 6 in 5.3mg/kg, and 3 in 6.6mg/kg. By the data cutoff date of January 9, 2026, the dose had been escalated to 6.6mg/kg, with no DLT occurring. The median treatment duration was 3 cycles (rang:1-9). In 22 pts who were followed up for at least 21 days, 19 (86.4%) experienced at least 1 treatment-related adverse event (TRAE). The most common TRAEs included asthenia (54.5%), infusion reaction (50.0%, decreasing to 38.9% in the ≥4 mg/kg dose group after prophylaxis modification), myalgia (27.3%), alopecia (22.7%), and neutrophil count decreased (22.7%). No interstitial lung disease occurred. Only 4 cases of grade 3 AEs (two of neutrophil count decreased, one of allergic shock, one of white blood cell count decreased) were observed in 3 pts and were all attributed to TQB6411. No ≥ grade 4 AEs occurred. In the ≥4 mg/kg dose group, 8 pts received at least one imaging assessment, 4 achieved a partial response (PR), giving an objective response rate of 50.0%. The disease control rate was 100%. The details of efficacy results are shown in the table below. Conclusions: In this ongoing phase 1 study. TQB6411 showed an impressive safety profile, with a lower incidence of higher-grade TRAEs (especially lower haematological toxicities), and encouraging efficacy, with tumor responses could be observed even in the relatively lower dose group. Clinical trial information: NCT07043751 . 4mg/kg (N = 6) 5.3mg/kg (N=2) PR, n 3 (NSCLC: 2, EC:1) 1(NSCLC) SD, n 3 (NSCLC) 1 (NSCLC)

8563 Background: Local consolidative therapy (LCT) has been demonstrated to augment the survival benefits of immunotherapy in non-small cell lung cancer (NSCLC) patients with oligo-residual disease (ORD) in the phase2 BOOSTER Trial (ChiCTR2000032479) as previously reported (2024 WCLC OA05.03; Signal Transduction and Targeted Therapy 2025). Here we report updated data with longer follow-up. Methods: This randomized, phase 2 trial enrolled patients with advanced NSCLC who developed oligo-residual disease after anti-PD-1/L1 therapy, defined as partial response or stable disease as the best response with residual tumors confined to a maximum of three organs and five lesions. Participants were randomly assigned (2:1) to receive ablation (thermal ablation or cryoablation) plus immunotherapy or immunotherapy maintenance alone. The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), safety, patterns of disease progression and immunogenic changes after ablation. Results: Among 65 patients enrolled, the full analysis set finally included 42 patients in ablation plus immunotherapy group and 20 patients in immunotherapy maintenance group. In this updated data cutoff (December 2025) compared to the prior data cutoff (March 2024), median duration of follow-up has increased from 17.8 months to 28.9 months. Patients receiving ablation were associated with significantly longer PFS than those without ablation (median 28.1 vs. 12.8 months, p < 0.001, HR = 0.310, 95%CI 0.169–0.596). The median OS was not reached in either group. The 48-months OS rate were 79.0% (95% CI, 59.5–90.0) in ablation group and 67.6% (95% CI, 41.3–84.1) in the without ablation group. Updated subgroup analysis further suggested a trend of superior efficacy of cryoablation (n=13) compared with thermal ablation (n=29), with a median PFS of 37.6 versus 22.4 months, respectively (p=0.028). The safety profile of ablation combining with immunotherapy was similar to previously reported, and most of the adverse events were well managed. Conclusions: With extended follow up, the updated data suggested that the addition of local consolidative ablation confers durable clinical benefit in patients with advanced NSCLC who develop ORD after anti-PD-1/L1 therapy. Cryoablation was associated with potentially superior survival outcomes compared with thermal ablation. Clinical trial information: ChiCTR2000032479.

ABSTRACT Local ablative therapy has emerged as an essential treatment for patients with non‐small cell lung cancer (NSCLC). Whether cryoablation is superior to thermal ablation in the era of immunotherapy and the related mechanism remains undefined. We first observed superior progression‐free survival with cryoablation compared with thermal ablation in patients with oligoresidual disease after immunotherapy. Single‐cell RNA sequencing of human peripheral blood monocyte cells and mouse tumors showed that cryoablation combined with anti‐PD‐1 expanded more CXCL10+ macrophages than thermal ablation combination. CXCR3 blockade and inhibition of T cells egressing from draining lymph nodes abolished the systemic anti‐tumor efficacy. Mechanistically, tumor DNA released by cryoablation was taken up by macrophages, activating the cGAS–STING signaling pathway, increasing the pool of CXCL10+ macrophages and CXCL10 secretion. Our study demonstrated that CXCL10+ macrophages and the CXCR3+ T cells were critical mediators of the systemic anti‐tumor immunity induced by cryoablation in advanced NSCLC.

BACKGROUND:SHR-A2102 is a new antibody-drug conjugate consisting of a fully human nectin-4-directed monoclonal antibody bound to a topoisomerase I inhibitor payload via a cleavable linker. We did a phase 1 trial to evaluate the safety, preliminary activity, and pharmacokinetics of SHR-A2102 in advanced solid tumours. METHODS:This multicentre, single-arm, phase 1 trial was done at 39 hospitals in China and included dose-escalation (Bayesian Optimal Interval design), pharmacokinetic-expansion, and efficacy-expansion stages. Eligible patients were aged at least 18 years, had unresectable, locally advanced or metastatic solid tumours that had progressed after, were intolerant to, or had no available standard therapy, and had an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients received SHR-A2102 intravenously at doses of 2-10 mg/kg once every 3 weeks. The primary endpoints were safety, dose-limiting toxicity, maximum tolerated dose, and recommended phase 2 dose. All patients who received at least one dose of SHR-A2102 were included in the safety and activity analyses. This trial is registered at ClinicalTrials.gov (NCT05701709) and is ongoing. FINDINGS:Between April 17, 2023 and Feb 20, 2025, 395 patients (median age 59 years [IQR 53-66]; 239 [61%] male and 156 [39%] female; 395 [100%] Chinese) were enrolled and treated across study stages, including 197 with non-small cell lung cancer, 32 with hormone receptor-positive, HER2-negative breast cancer, 36 with triple-negative breast cancer, 77 with oesophageal squamous cell carcinoma, 26 with head-and-neck squamous-cell carcinoma, and 27 with other solid tumours. As of data cutoff (June 20, 2025), the median follow-up was 7·2 months (IQR 4·7-9·7). Based on data from the dose-escalation stage, 6 mg/kg (n=10) and 8 mg/kg (n=11) were selected for pharmacokinetic expansion. During dose escalation, one dose-limiting toxicity was reported at 10 mg/kg (grade 4 decreased platelet count); maximum tolerated dose was not reached. Grade 3-4 treatment-related adverse events were reported in 212 (54%) of 395 patients, with the most common being decreased neutrophil count (118 [30%]), decreased white-blood-cell count (75 [19%]), and anaemia (69 [17%]). Treatment-related serious adverse events were reported in 98 (25%) patients with the most common being pneumonia (21 [5%]). Treatment-related deaths occurred in two (<1%) patients (pulmonary embolism and pneumonia). INTERPRETATION:SHR-A2102 demonstrated a safety profile consistent with its topoisomerase I inhibitor payload and showed promising activity in patients with various advanced solid tumours who had previously received anti-cancer treatment. A range of active dose was identified in various tumour types. Several trials are ongoing to evaluate SHR-A2102, either as monotherapy or in combination, in advanced solid tumours. FUNDING:Jiangsu Hengrui Pharmaceuticals.

As an emerging biomarker, tumor mutational burden (TMB) has attracted increasing attention from clinicians in predicting the efficacy of tumor immunotherapy. Currently, TMB is detected primarily by whole-exome sequencing or targeted panel sequencing on high-throughput sequencing platforms. However, the lack of uniformity in detection methods, threshold settings, and reporting formats, as well as the significant differences in TMB values among different cancer types, have hindered the standardized application of this biomarker in clinical practice. This consensus focuses on the definition, standardization of detection, clinical significance, and limitations of TMB, and provides consensus recommendations for the clinical application of TMB in real-world practice in China. This consensus is aimed at helping clinicians and laboratory personnel understand the clinical significance and testing standards of TMB, promoting more accurate interpretation of test results, and improving patient care.

Background: Following the 2021 first International Consensus on Severe Lung Cancer, global attention to patients with PS 2-4 has grown significantly. Recent advances in novel therapies, interventional techniques, and supportive care, along with emerging real world data, have expanded treatment opportunities for this population. To incorporate these advances, we have updated the consensus. Methods: A multidisciplinary panel comprising experts from oncology, radiation oncology, thoracic surgery, radiology, interventional medicine, respiratory medicine, critical care medicine, and nursing. After being presented with a comprehensive review of the current evidence pertaining to severe lung cancer and thorough discussions, the panel reached a consensus on 11 recommendations, each with over 70% expert agreement. Results: The 11 consensus points focused on definition and causes (n=2), assessment and general strategies (n=4), and specific treatment modalities (n=5) were updated or newly developed. This updated consensus emphasizes dynamic and precise detection, robust life support, flexible application of novel therapies, and MDT guided treatment adjustment based on PS dynamics. Early rehabilitation and comprehensive supportive care are integral to disease management. Conclusions: This consensus updates the definition, diagnostic evaluation, and treatment strategies, providing a practical framework for clinicians based on current evidence and multidisciplinary expert consensus. Prospective trials focusing specifically on patients with severe lung cancer are urgently needed.

8521 Background: The central nervous system (CNS), particularly after progression on third-generation EGFR TKIs, represents a common yet challenging scenario. While recent trials establish amivantamab-lazertinib for EGFR-mutant NSCLC, their real-world applicability is limited by patient complexity and access barriers, highlighting an urgent need for flexible, real-world solutions. Methods: To evaluate the intracranial efficacy of amivantamab, used as monotherapy or in combination, we conducted a multi-center, retrospective study of patients with EGFR-mutated NSCLC and brain parenchymal metastases (BM) and/or leptomeningeal metastases (LM) treated with amivantamab monotherapy or combination based on routine clinical practice. The cohort included two key populations: heavily pretreated patients with sensitizing exon19del/L858R mutations after progression on third-generation EGFR TKIs, and treatment-limited patients with atypical mutations. Efficacy endpoints included intracranial progression-free survival (PFS) and intracranial objective response rate (ORR) by RANO-BM and/or RANO-LM. Exploratory endpoints included symptom improvement, and longitudinal cerebrospinal fluid (CSF) biomarker dynamics. Results: Thirty-one patients from seven centers were included (BM, n=13; BM+LM, n=18). Most (25/31, 80.6%) harbored EGFR sensitizing mutations and had progressed on third-generation EGFR TKIs; six (19.4%) carried atypical EGFR mutations. Over half (17/31, 54.8%) had received ≥4 prior lines. Amivantamab monotherapy was received in 10/31 patients (32.3%). Median intracranial PFS was 10.3 months (95% CI, 4.5-16.1). Among 24 evaluable patients, intracranial ORR was 25.0% (n=6), and disease control rate was 91.7% (n=22). CNS-related symptoms improved in 26/31 (83.9%). CSF analyses showed decreased pressure and CEA, reduced EGFR amplification, and clearance of EGFR C797S. Conclusions: In real-world settings, amivantamab-based regimens demonstrate promising intracranial efficacy in EGFR-mutated NSCLC patients with refractory brain or leptomeningeal metastases. These findings support the use of amivantamab as a viable therapeutic strategy in this challenging population and suggest that CSF biomarkers can serve as a valuable tool for monitoring treatment response.