Abnormal DNA hypermethylation mediated by DNA methyltransferases (DNMT) is a nearly universal hallmark of human cancers. However, while DNA methyltransferase inhibitors (DNMTi) such as decitabine and azacitidine are effective in treating myelodysplatic syndrome/leukemia, they have had limited utility for the majority of other cancers. Through a chemical library screen, we identify that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, and multiple of its analogs, significantly augment the epigenetic and anti-cancer effects of decitabine in vitro and in vivo. These effects are attributable to inhibition of DCTPP1-mediated cleavage of 5-aza-deoxycytidine triphosphate, the convergent activated metabolite of nucleoside DNMTi, leading to enhanced drug incorporation into genomic DNA, increased DNMT degradation, enhanced DNA demethylation and associated transcriptional reprogramming. We show that high DCTPP1 expression mediates cell-intrinsic resistance to nucleoside DNMTi, and that triptolide and its analogs could overcome this resistance. These findings nominate combining DNMTi with triptolide or its analogs as a rational cancer therapeutic strategy. Abnormal DNA hypermethylation is common in cancer, but DNA methyltransferase inhibitors show limited activity in many tumors. Here, the authors employ a chemical library screen to identify triptolide as an active agent that enhances these drugs by blocking DCTPP1, increasing drug incorporation into DNA, promoting demethylation and epigenetic reprogramming, and improving anti-cancer effects.

e20546 Background: Non-small cell lung cancer (NSCLC) is one of the world's deadliest cancers, including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) . Osseous metastasis (OM) is common metastatic event and represents one of the direst consequences of NSCLC, portending a grim prognosis. Therefore, it’s vital to explore and improve the understanding of the etiology and pathogenesis of OM in NSCLC. Anatomizing tumor microenvironment (TME) can provide new insights into the mechanisms of osseous metastases. And the TME distinctions of advanced NSCLC with or without OM at the single-cell protein level have not been fully explored. Methods: We collected 32 tissues biopsy samples and clinical characteristics from advanced NSCLC patients with or without OM. 32 tissues were divided in to 4 groups (n = 8, each group): LUAD-NC, LUAD-OM, LUSC-NC and LUSC-OM. Then, we used imaging mass cytometry (IMC) to explore the spatial proteomic features and the factors influencing the therapeutic effect. Results: A total of 193,246 cells with spatial information revealed by IMC depicted the differences in the TME. Compared to LUSC-NC, CAFs and LYVE1 + epithelial cells showed higher abundance in LUSC-OM, while CD8 + T cells, CX3CR1 + CD4 + T cells, CX3CR1 + M1 like macrophage and E-cad - Ki67 + proliferating epithelial cells showed lower abundance. Among all CAFs, mCAFs, vCAFs, tCAFs and LYVE1 + CAFs were higher infiltration in LUSC-OM. Compared to LUAD-NC, B cells, memory CD4 + T cells, TCF1 + CD4 + T cells, memory CD8 + T cells and EMT epithelial cells showed higher abundance in LUAD-OM, while CAFs showed lower abundance. In our study, 4 LUSC-OM , 4 LUSC-NC, 2 LUAD-OM and 1 LUAD-NC received the immunotherapy plus chemotherapy treatment. The efficacy assessment of LUSC-OM is 3 SD, 1 PD, while 4 PR in LUSC-NC and 3 PR in LUAD. The main reasons for treatment failure in LUSC-OM were the low abundance of PD-L1 + , HLA-DR + and E-cad + Ki67 + proliferating epithelial cells. In patients with effective treatment, the main positive factor influencing drug efficacy was the low abundance of CX3CR1 + CD8 + T cells. Moreover, the low abundance CD8 + TRM and Treg in preoperative TME were the high-risk factors for 1-year postoperative recurrence in LUSC-NC. Conclusions: This study determines the spatial multi-omics profiling of TME components at a single-cell resolution in NSCLC with OM. The TME in LUSC-OM presents an oligoimmune state, in which CAFs and LYVE1 + epithelial cells are high risk factors for OM. And the TME in LUAD-OM presents an immune-enrichment state with EMT epithelial cells paling important role in OM. Moreover, the complex TME affect the treatment efficacy and postoperative recurrence. In a word, the comprehensive analysis may contribute to the early identification of OM in NSCLC and the development of therapeutic options.

Concomitant anti-programmed cell death protein 1 (anti-PD-1) therapy and denosumab treatment can improve clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastasis. However, limited data are available among Chinese patients in real-world clinical practice, and the effect of this treatment combination on bone metastases has not been adequately studied. This single-centre, retrospective study analysed NSCLC patients with bone metastases who received first-line anti-PD1-therapy and concomitant denosumab treatment between March 2021 and June 2022. Clinical outcomes were described and bone lesion response was evaluated using a novel, exploratory quantitative method based on single photon emission computed tomography/computed tomography scans. Among 66 included patients, the median overall survival was 21.5 months (95

Background In the global phase 3 randomized LEAP-006 study (NCT03829319), addition of lenvatinib to pembrolizumab plus chemotherapy did not significantly improve efficacy outcomes in metastatic nonsquamous non-small–cell lung cancer (NSCLC). We present findings from an extension study of LEAP-006 (NCT04716933) including participants from China. Methods Adults (≥18 years) from mainland China with untreated metastatic nonsquamous NSCLC without targetable genetic alterations were randomized 1:1 to lenvatinib 8mg once daily or placebo, plus pembrolizumab 200mg plus cisplatin or carboplatin plus pemetrexed for 4 cycles, followed by lenvatinib or placebo plus pembrolizumab plus pemetrexed for ≤35 cycles. PFS and OS were dual primary endpoints. No alpha was assigned to these analyses. Results Of 201 enrolled participants from China, 101 received lenvatinib plus pembrolizumab and chemotherapy (lenvatinib arm) and 100 to placebo plus pembrolizumab and chemotherapy (placebo arm). Median follow-up was 32.7 months (data cutoff August 11, 2023). Median PFS (95% CI) was 15.3 (12.2‒19.6) and 9.2 (8.2‒12.5) in the lenvatinib and placebo arms, respectively (HR, 0.68; 95% CI, 0.48‒0.97); median OS (95% CI) was 26.6 (22.2‒35.0) months and 22.0 (16.6‒24.8) months (HR, 0.78; 95% CI, 0.54‒1.12). Grade ≥3 treatment-related adverse events occurred in 83.2% and 62.0% of participants in the lenvatinib and placebo arms, respectively; treatment-related AEs that led to death were reported in 7.9% and 3.0% of participants. Conclusions In the China extension of LEAP-006, addition of lenvatinib to pembrolizumab plus chemotherapy was associated with numerical improvements in PFS and OS with manageable safety in previously untreated metastatic nonsquamous NSCLC.

Abstract Background: Second-line options for non-small-cell lung cancer (NSCLC) without actionable genomic alterations (AGAs) remain limited and new therapies are urgently needed. Risvutatug rezetecan (Ris-Rez, also known as HS-20093 or GSK5764227) is a promising B7-H3 targeted antibody-drug conjugate with a payload of topoisomerase 1 inhibitor (TOP1i), and the antitumor activity as a monotherapy in NSCLC has been demonstrated in the first-in-human phase 1 study (NCT05276609). This study (NCT06332170) aims to further explore the therapeutic potential of Ris-Rez combinations in solid tumors. Method: This open label phase 1 study enrolled adult patients with advanced solid tumor into 5 cohorts, comprising of dose escalation and dose expansion phase. In cohort 1a, eligible patients received intravenous Ris-Rez at initial dose of 8.0 mg/kg and adebrelimab at dose of 20 mg/kg every 3 weeks. The preliminary results of efficacy and safety from a subgroup of cohort 1a, involving pretreated patients with non-squamous (nsq) NSCLC without AGAs, are reported here. Results: As of October 20, 2025, 40 patients with nsq-NSCLC without AGAs were enrolled and received ≥1 dose of treatment, with a median age of 64.0 years (range: 39, 73) and median follow-up time of 8.7 months (range: 0.7, 11.5). All patients received ≥1 line of systemic anti-tumor therapies: platinum-based chemotherapy (100%), immunotherapy (75.0%) and antiangiogenic therapy (45.0%). Of 34 efficacy-evaluable patients, the confirmed objective response rate (cORR) was 47.1% (95% CI: 29.8, 64.9) and disease control rate was 94.1% (95%CI: 80.3, 99.3). The 9-month duration of response rate was 90.0% (95% CI: 47.3, 98.5) and median progression-free survival (mPFS) was 11.2 (95% CI: 11.2, not reached [NR]) months. Similar efficacy results were observed in patients who had previously received chemotherapy and immunotherapy but were naive to TOP1i, with a cORR of 52.2%. Antitumor activity was observed across PD-L1 subgroups: cORR in patients with tumor proportion score (TPS) <1 was 33.3%, with mPFS of 11.2 (95% CI: 4.2, NR) months; and 62.5% in patients with TPS≥1, with an immature mPFS. Treatment emergent adverse events (TEAEs) leading to dose reduction and discontinuation occurred in 20.0% and 7.5% of patients. No TEAEs led to death. Grade ≥3 TEAEs reported in ≥20% patients were white blood cell count decreased (30%), lymphocyte count decreased (30%), neutrophil count decreased (30%) and anaemia (25%). Conclusion: Based on the efficacy of Ris-Rez monotherapy, the combination with adebrelimab showed a trend toward improved efficacy in previously treated patients with nsq-NSCLC without AGAs and no new safety signals were observed. Citation Format: Hua Zhong, Haifeng Liu, Wei Zheng, Linlin Wang, Baogang Liu, Fangling Ning, Yongzhong Luo, Qiming Wang, Weiliang Zhu, Jianying Zhou, Qingwei Zhao, Ruoyu Wang, Xiang Li, Juan Li, Runbo Zhong, Yizhou Jin, Xiangru Mao, Jing Wang, Qingyuan Liu, Xiaoqing Zhang. Combination of risvutatug rezetecan and adebrelimab in previously treated advanced nsq-NSCLC without actionable genomic alterations: Results from ARTEMIS-101, a 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 CT038.

Purpose:Approximately 38% of Chinese patients with non-small cell lung cancer (NSCLC) exhibit a mutation in the epidermal growth factor receptor (EGFR) gene. Afatinib, which targets the EGFR, is approved for first-line treatment in advanced EGFR mutation-positive NSCLC worldwide. The aim of this prospective, observational and non-interventional real-world study was to examine the effectiveness and safety of first line afatinib in Chinese patients, newly diagnosed with EGFR mutation-positive NSCLC. Patients and Methods:Patients were enrolled at 10 sites in China from May 2020 to December 2021 and followed-up from May 2020 to December 2023. Adult patients (aged ≥18 years) were treated with oral afatinib 30 mg or 40 mg once daily. The primary outcome was time on treatment (TOT). Secondary outcomes were overall survival (OS), overall response rate (ORR) and safety. Results:A total of 72 patients were enrolled and treated with afatinib. Most were male (54.2%), Chinese (98.6%), never smokers (63.9%), and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (98.6%) and patients had a mean (SD) age of 62.2 (9.6) years. Median TOT overall was 14.4 months and was prolonged in younger (aged <65 years) vs older (aged ≥65 years) age groups, common vs uncommon baseline EGFR mutations, and higher afatinib starting dose (40 mg vs 30 mg). Median OS was not reached; the median follow-up time of the study was 25.1 months. ORR was 62.7% overall and was higher in common vs uncommon baseline EGFR mutations, higher afatinib starting dose, and with vs without brain metastases. The two most common treatment-emergent adverse events were diarrhea and rash. No new safety concerns were found. Conclusion:This study provides real-world evidence of the effectiveness and safety of afatinib as first-line therapy for Chinese patients with EGFR mutation-positive advanced NSCLC.

Lung cancer is a highly aggressive malignancy associated with a high global mortality rate. Immunotherapy, particularly anti‑programmed cell death protein 1 (PD‑1) therapy, has offered new hope for patients; however, therapeutic resistance remains a major obstacle to clinical success. In the present study, single‑cell RNA sequencing was utilized to investigate the molecular characteristics of lung cancer and to elucidate the mechanisms underlying resistance to anti‑PD‑1 immunotherapy. Cancer‑associated fibroblasts (CAFs) were identified as key contributors to immune resistance. Functional assays, including CCK‑8, EdU, TUNEL and Transwell experiments, demonstrated that CAFs regulated the expression of lipocalin 2 (LCN2) in lung cancer cells, and elevated LCN2 levels were found to promote resistance to immunotherapy, as well as to enhance cellular proliferation and invasion. The effects of LCN2 on tumor growth, invasion, immune infiltration and ferroptosis were further validated by molecular and histological analyses. The results showed that silencing LCN2 induced ferroptosis in lung cancer cells, resulting in increased sensitivity to anti‑PD‑1 therapy, suppressed tumor growth and reduced invasiveness. These findings highlight the critical role of the CAF‑LCN2 axis in mediating resistance to anti‑PD‑1 immunotherapy and suggest that targeting this pathway may represent a promising strategy to enhance treatment efficacy in lung cancer.

BACKGROUND:Neutrophilic asthma is one of the main types of severe asthma. Our previous studies demonstrated that neutrophil extracellular traps (NETs) contribute to its pathological process. However, the underlying mechanisms remains unclear. This study aimed to investigate the potential mechanisms of NETs in neutrophilic asthma. METHODS:Clinical samples were collected from patients with neutrophilic asthma and healthy controls. A neutrophil-dominant asthmatic murine model was established using ovalbumin (OVA), Freund's complete adjuvant (CFA) and lipopolysaccharide (LPS). Airway inflammation and remodeling were assessed by pathological staining. The expression of EMT markers and Hedgehog (Hh)/Gli1 pathway markers were measured by Western blot, qPCR, and immunofluorescence. RESULTS:We found that the expression of dsDNA, one of the skeleton components of NETs, was significantly higher in the peripheral plasma of patients with neutrophilic asthma than that of healthy controls, and neutrophils in neutrophilic asthma patients were more likely to induce the production of NETs. We further demonstrated that NETs induced EMT in airway epithelial cells. Both in vivo and in vitro, we confirmed that reducing NETs formation or enhancing NETs degradation reversed EMT process, attenuated airway hyperresponsiveness (AHR) and alleviated airway inflammation in neutrophil-dominant asthmatic mouse model. We also found that the Hh/Gli1 pathway was activated during this process, and inhibition of the Hh/Gli1 pathway also reversed the EMT process of airway epithelium. Similarly, AHR and airway inflammation in neutrophil-dominant asthmatic mice were reduced. CONCLUSIONS:We confirmed that NETs promote EMT in airway epithelium via activation the Hh/Gli1 signaling pathway, thus playing an important role in the pathogenesis of neutrophilic asthma. Targeting NETs or the Hh/Gli1 pathway may provide a promising therapeutic strategy for the treatment of severe neutrophilic asthma.

Background Pembrolizumab plus chemotherapy prolonged overall survival (OS) and progression-free survival (PFS) versus placebo plus chemotherapy with manageable toxicity among participants with metastatic squamous non‒small-cell lung cancer (mNSCLC) enrolled in China in KEYNOTE-407 global (NCT02775435) and China extension (NCT03875092) studies. We report outcomes after ⁓5 years of follow-up from KEYNOTE-407 China. Methods Eligible participants from China with previously untreated squamous mNSCLC were randomized 1:1 to pembrolizumab 200 mg or placebo plus carboplatin and paclitaxel/nab-paclitaxel every 3 weeks for 4 cycles, followed by pembrolizumab/placebo for ≤35 total cycles. Primary endpoints were OS and PFS per RECIST v1.1 by blinded independent central review. Results Among 125 participants (pembrolizumab plus chemotherapy, n=65; placebo plus chemotherapy, n=60), median follow-up was 56.5 (range, 53.5‒69.3) months at database cutoff (February 10, 2023). Median (95% CI) OS was 29.6 (18.2‒50.4) months for pembrolizumab and 12.7 (9.4‒17.3) for placebo; OS hazard ratio (HR) was 0.43 (95% CI, 0.29‒0.65). Median (95% CI) PFS was 8.3 (6.2‒10.5) months versus 4.2 (4.0‒5.4), and HR was 0.35 (95% CI, 0.24‒0.52). Grade 3‒5 treatment-related adverse events occurred in 81.5% and 81.7% of participants, respectively. Among 20 participants who completed 35 cycles of pembrolizumab, objective response rate was 90.0%; 3-year OS rate after completion of 35 cycles (∼5 years after randomization) was 79.4%. Conclusion After 4.7 years of follow-up, first-line pembrolizumab plus chemotherapy maintained clinically meaningful improvements in OS and PFS versus chemotherapy alone in squamous mNSCLC regardless of PD-L1 expression, supporting this regimen as a standard-of-care for Chinese patients with squamous mNSCLC.

INTRODUCTION:Deulorlatinib (TGRX-326), a potent third-generation anaplastic lymphoma kinase (ALK) inhibitor, has reported promising activity and a favorable safety profile in ALK-positive NSCLC in a phase 1 trial. Here, we report the primary results of the pivotal phase 2 trial (NCT05955391) evaluating deulorlatinib in patients with ALK-positive NSCLC in whom second-generation ALK inhibitors had failed. METHODS:This single-arm, phase 2 trial was conducted at 36 centers in China. Eligible patients received deulorlatinib 60 mg once daily. The primary end point was objective response rate (ORR) assessed by an independent review committee (IRC). Key secondary end points included disease control rate, progression-free survival (PFS), duration of response, overall survival, intracranial efficacy, and safety. Exploratory biomarker analyses were performed using cell-free DNA. RESULTS:The efficacy and safety analysis sets comprised 158 and 163 patients, respectively. The primary end point was met with an IRC-assessed ORR of 43.7% (95% confidence interval [CI], 35.8-51.8). The IRC-assessed median PFS was 11.1 months (95% CI, 8.3-13.7). Among patients with measurable central nervous system (CNS) metastases (n = 43), the intracranial ORR was 55.8% (95% CI, 39.9-70.9). In patients harboring the G1202R mutation (n = 8), robust activity was observed (ORR: 62.5%; disease control rate: 100%; median PFS: 11.0 months). The investigator-assessed results were consistent with the IRC-assessed findings. Treatment-related adverse events occurred in 96.3% of patients (47.2% grade ≥3). Nevertheless, dose modifications were infrequent (interruption, 13.5%; reduction, 11.0%; permanent discontinuation, 0.6%). The incidence of CNS-related treatment-related adverse events was 12.9%, with no patients interrupting or discontinuing treatment owing to CNS toxicity. CONCLUSIONS:Deulorlatinib indicated encouraging antitumor activity in patients with advanced ALK-positive NSCLC after failure of second-generation ALK inhibitors, including those with the G1202R mutation. Given its favorable safety profile, deulorlatinib represents a promising new option for this population.

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.

Objective: Osimertinib has demonstrated superior efficacy as a first-line treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) in clinical trials. This study was aimed at providing real-world evidence of osimertinib treatment in Chinese populations. Methods: This prospective, multicenter, non-interventional study was conducted from July 27, 2020, to April 27, 2022. Treatment-naïve adults (≥18 years of age) with locally advanced or metastatic EGFR-mutated NSCLC scheduled to receive first-line osimertinib were included. Of 507 patients screened, 481 were eligible in the full analysis set. The primary endpoint was time to treatment discontinuation (TTD). Secondary endpoints included real-world progression-free survival (rwPFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Among 481 patients (median age 64.1 years; 62.2% women), the median follow-up was 31.3 months. The mTTD was 24.6 months (95% CI, 22.4–26.7), the median rwPFS was 19.4 months (95% CI, 16.2–20.4), and the mOS was 41.0 months [95% CI, 39.7 to not reached (NR)]. The mOS was 43.1 months (95% CI, 39.7 to NR) in FLAURA-eligible patients vs. 33.5 months (95% CI, 26.8 to NR) in FLAURA-ineligible patients. The mOS was 29.3 months (95% CI: 25.4 to NR) in patients with co-mutations vs. NR (95% CI: 32.9 to NR) in the cohort with EGFR-only mutations. Adverse events occurred in 71.7% of patients, and grade ≥3 events occurred in 11.4%. The safety profiles were similar between FLAURA-eligible and ineligible patients. Conclusions: First-line osimertinib demonstrated robust effectiveness and manageable safety in real-world Chinese patients with EGFR-mutated advanced NSCLC, including those ineligible for clinical trials. Patients with co-mutations showed diminished clinical benefit, thus suggesting a potential need for intensified treatment strategies in this population.

Molecular residual disease (MRD), detected through circulating tumor DNA, has emerged as a promising biomarker for surveillance in patients with early-stage non-small cell lung cancer (NSCLC) following curative-intent resection. Here we report the MRD analysis from the phase 3 EVIDENCE trial, which includes patients with stage II-IIIA resected EGFR-mutated NSCLC who have received either adjuvant icotinib or chemotherapy. A total of 1,352 plasma samples from 175 patients are analyzed using the MinerVa Prime assay, a personalized tumor-informed MRD platform. At the landmark timepoint, MinerVa Prime detects MRD positivity in 35.8% (38/106) of patients with stage III disease and 14.7% (10/68) of patients with stage II disease, with a longitudinal positivity rate of 47.4%. MRD-positive status is significantly correlated with inferior disease-free survival (DFS), both at landmark (hazard ratio [HR]: 4.44, P < 0.001) and during longitudinal monitoring (HR: 7.82, P < 0.001). Icotinib confers DFS benefits over chemotherapy in both MRD subgroups, enhancing MRD clearance in MRD-positive patients while reducing molecular recurrence in landmark MRD-negative patients. Longitudinal MRD shows a 91.3% negative predictive value, with a median lead time of 169 days prior to clinical recurrence. Among serial monitoring timepoints, MRD status at 24 weeks post-randomization demonstrates the highest prognostic value.

Abstract Background: Dysregulation of MET gene could serve as oncogenic driver in NSCLC. The efficacy of MET inhibitor monotherapy was limited in EGFR wild-type NSCLC patients(pts) with MET alterations. Pre-clinical study demonstrated that MET inhibitor combined with immunotherapy may synergistically enhance anti-tumor activity. SOUND study aims to explore the efficacy and safety of savolitinib plus durvalumab in EGFR wild-type advanced NSCLC pts with MET alterations. Methods: Pts who did not receive immunotherapy previously were enrolled into MET Ex14m cohort (Cohort 1) or MET Overexpression/AMP cohort (Cohort 2) according to MET alteration status determined by NGS, FISH or immunohistochemistry and received savolitinib (600mg [body weight≥50kg] / 400mg [body weight < 50kg], once daily) in combination with durvalumab (1,500 mg once every four weeks). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), 12-month overall survival (OS) rate, and safety. Here, we report the interim analysis results. Results: At data cutoff (January 17, 2025), forty-seven pts were enrolled and received at least one dose of study treatment, with 24 in Cohort 1(C1) and 23 in Cohort 2(C2), respectively. For C1, 83.3% pts had adenocarcinoma, 16.7% had brain metastases, 37.5% had PD-L1 ≥ 50% and 87.5% were treated in first line. For C2, 56.5% had adenocarcinoma, 34.8% had brain metastases, 56.5% had PD-L1 ≥ 50% and 87.0% were treated in first line. Median follow-up was 15.4 months(m) in C1 and 13.2 m in C2. The median PFS was not reached (maturity of 33.3%) in C1 and 5.5 m (95% CI, 3.2-9.2, maturity of 78.3%) months in C2. The confirmed ORR per investigator in C1 and C2 were 45.8% (95% CI, 25.6-67.2%) and 52.2% (95% CI, 30.6-73.2%), respectively. 12-month OS rate for C1 and C2 were 82.0% and 60.1%, respectively. Any grade treatment-related adverse events (TRAEs) were observed in 44 (93.6%) pts. The most common TRAEs were peripheral oedema (38.3%), anemia (38.3%), hypoalbuminemia (34%), aspartate aminotransferase increased (34%) and alanine aminotransferase (ALT) increased (31.9%). Grade 3 and above TRAEs were reported in 14 (58.3%) pts in C1 and 12 (52.2%) pts in C2. The most common grade 3 and above TRAE were hepatic function abnormal (14.9%), drug-induced liver injury (12.8%) and ALT (10.6%) increased. Conclusions: Savolitinib plus durvalumab showed promising clinical anti-tumor activity in pts with advanced EGFR wild-type NSCLC with MET alterations, especially in pts with MET ex14m. Close and frequent(i.e. weekly) monitoring of liver function should be conducted in pts receiving this combination. Prospective studies with larger sample sizes are needed to further evaluate the efficacy and safety of this combination in EGFR wild-type NSCLC pts with MET alterations. Clinical trial information: NCT05374603 Citation Format: Yong-Feng Yu, Xiao-Ying Huang, Qian Chu, An-Wen Liu, Li Zhuang, Xiao-Rong Dong, Hong-Cheng Wu, Jian-Ying Zhou, Shun-Dong Cang, Yan Wang, Yi Hu, Zhen-Zhou Yang, Meng-di Wu, Xiao-yuan Wang, Shun Lu. Savolitinib combined with Durvalumab in EGFR wild-type advanced NSCLC patients with MET alterations (SOUND): A multicenter, open-label, Phase II trial [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 CT247.

8638 Background: Treatment options are limited for anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) patients (pts) who have developed resistance to second-generation ALK inhibitors. Deulorlatinib is a highly potent third-generation ALK inhibitor. The Previous phase 1 study (NCT05441956) found that deulorlatinib had a high overall and intracranial response rate in pts who had progressed on second-generation inhibitors, with encouraging activity against the G1202R mutation and favorable tolerability. Methods: This is a multicenter, open-label pivotal phase 2 study. Pts with locally advanced or metastatic ALK+ NSCLC who had progressed on second-generation inhibitors received deulorlatinib 60 mg orally once daily. The primary endpoint was objective response rate (ORR) per RECIST v1.1 by independent review committee (IRC). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The ORR in patients harboring the G1202R mutation was also assessed. Results: Between Jan 18, 2023 and Dec 29, 2023, a total of 163 patients were enrolled and 158 were evaluable for efficacy. Of these pts, the median age was 53.5 years old, 53.2% were female, 95.6% had adenocarcinoma, and 56.2% had baseline brain metastasis; 56.3% of these pts had progressed on alectinib. As of December 16, 2025, the median follow-up was 28.7 months and 44 pts were still on deulorlatinib. The IRC assessed confirmed ORR was 43.7% (95%CI 35.8, 51.8). The median DoR and PFS was 20.7 months (95%CI 15.4, NR) and 13.8 months (95%CI 8.3, 16.5), respectively; median OS was not reached. Of the 43 pts with measurable baseline CNS lesions, confirmed ORR was 55.8% (95%CI 39.9, 70.9). In pts with the G1202R mutation, the ORR was 62.5% (95%CI 24.5, 91.5). Treatment-related adverse events (TRAEs) were reported in 96.3% of pts. The most common TRAEs were hypercholesterolaemia (77.9%), hypertriglyceridaemia (71.2%), and weight gain (52.8%). Grade ≥3 TRAEs were reported in 51.5% of pts. Of note, only 1.2% of pts had Grade ≥3 CNS TRAEs. Conclusions: Deulorlatinib produced robust and durable responses in locally advanced or metastatic ALK+ NSCLC pts with progression on second-generation inhibitors, including those with the G1202R mutation, with low incidence of Grade ≥3 CNS TRAEs. Although across trials comparisons must be interpreted cautiously, deulorlatinib might have a better safety profile than lorlatinib. Altogether these findings suggest that deulorlatinib has a favourable risk benefit ratio and support its further development, particularly in the first-line setting. Clinical trial information: NCT05955391 .

Background:Savolitinib, a potent MET inhibitor, showed promising efficacy and tolerable safety in a Phase 3b confirmatory trial for the treatment of Chinese patients with non-small cell lung cancer (NSCLC) harbouring MET exon 14 (METex14)-skipping mutations. Herein, we report the final trial results. Methods:This multicentre, open-label, non-randomised, confirmatory Phase 3b study at 48 Chinese hospitals used a single-arm design. Eligible patients received savolitinib 400 mg (body weight <50 kg) or 600 mg (body weight ≥50 kg). Previously treated and treatment-naïve cohorts had a once-daily dosing frequency. The primary endpoint was objective response rate (ORR) assessed by an Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumours v1·1 criteria. The trial is registered with ClinicalTrials.gov, NCT04923945, and has been completed. Findings:From Aug 31, 2021, to Nov 30, 2024, 166 patients were enrolled. In previously treated patients (N = 79), median follow-up was 25·1 months; IRC-assessed ORR, 42% (95% confidence interval [CI] 31%-53%); IRC-assessed median PFS, 13·7 months (95% CI 8·3-17·9), and median OS, 25·3 months (95% CI 20·5-30·5). Among treatment-naïve patients (N = 87), with a median follow-up of 34·5 months, ORR was 62% (95% CI 51%-72%); PFS, 13·7 months (95% CI 8·5-16·6); and OS, 28·3 months (95% CI 17·5-not estimated). Grade ≥3 treatment-related adverse events occurred in 62% of patients and were manageable. Interpretation:Savolitinib demonstrated robust and durable efficacy in patients with METex14-mutated, locally advanced NSCLC with manageable safety, supporting savolitinib as a treatment option in this disease setting. Funding:HUTCHMED, AstraZeneca.

BACKGROUND:First-line amivantamab plus carboplatin-pemetrexed demonstrated efficacy and an acceptable safety profile in the PAPILLON trial (NCT04538664) in patients with advanced non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 20 insertions; we report the efficacy and safety results of the Chinese mainland subgroup population from the PAPILLON study. METHODS:PAPILLON was a randomized, open-label, multicenter, phase 3 study comparing amivantamab plus carboplatin-pemetrexed therapy with standard of care carboplatin-pemetrexed, in patients with treatment-naïve, locally advanced, or metastatic non-small-cell lung cancer characterized by EGFR exon 20 insertion mutations. Between March 2021 and October 2022, 87 treatment-naïve patients were randomized in China (amivantamab plus carboplatin-pemetrexed, 39; carboplatin-pemetrexed, 48). The primary endpoint was progression-free survival as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors v1.1. Comparison between treatment groups was conducted using a stratified log-rank test, with hazard ratios estimated from a stratified Cox proportional hazards model. RESULTS:Progression-free survival was longer in the amivantamab plus carboplatin-pemetrexed group than in the carboplatin-pemetrexed group (median, 12.3 months, 95% confidence interval [CI], 7.0 months to not evaluable vs. 6.7 months, 95% CI, 4.2-8.6 months; hazard ratio, 0.47; 95% CI, 0.26-0.85; nominal P = 0.0109). The 18-month progression-free survival rate was 33% with amivantamab plus carboplatin-pemetrexed and 12% with carboplatin-pemetrexed. The objective response rate was 71.8% (95% CI, 55.1-85.0%) with amivantamab plus carboplatin-pemetrexed and 48.9% (34.1-63.9%) with carboplatin-pemetrexed (odds ratio, 2.46; 95% CI, 1.01-5.98; nominal P = 0.0478). Median progression-free survival after first subsequent therapy was not evaluable for amivantamab plus carboplatin-pemetrexed and 18.8 months for carboplatin-pemetrexed (hazard ratio, 0.32; 95% CI, 0.11-0.88; nominal P = 0.0212). Interim overall survival analysis suggests about 42% improved chance of survival with amivantamab plus carboplatin-pemetrexed vs. carboplatin-pemetrexed. The most common adverse events with amivantamab plus carboplatin-pemetrexed were neutropenia, anemia, leukopenia, and rash. No new safety signals were observed. No patients discontinued amivantamab due to related adverse events. CONCLUSION:Results from the PAPILLON Chinese mainland population were consistent with the overall population and support the use of amivantamab plus carboplatin-pemetrexed in first-line treatment of Chinese patients with EGFR exon 20 insertion-mutated non-small cell lung cancer. TRIAL REGISTRATION:https://clinicaltrials.gov/; registration number, NCT04538664.

This prospective observational study investigated the efficacy of pembrolizumab administered as first-line therapy and the survival outcomes of continuing or combining it with other agents after disease progression in patients with stage IV non-small cell lung cancer (NSCLC). A total of 63 patients who experienced disease progression following pembrolizumab-based first-line treatment between February 2019 and July 2024 were prospectively enrolled. Patients were randomized into two cohorts based on treatment strategy: a treated beyond progression (TBP) group (n = 39) to receive continued pembrolizumab monotherapy or pembrolizumab-based combination regimens after disease progression, and a non-TBP (NTBP) group (n = 24), which discontinued pembrolizumab upon progression. The primary endpoint was overall survival (OS), and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). The median PFS during first-line therapy (mPFS1) was 6.97 months. In the TBP group, the median PFS from first-line initiation to progression after second-line therapy (mPFS2) was 17.6 months, with an ORR of 20.5% and a DCR of 74.4%. OS in the TBP group was significantly longer than that in NTBP group (29.4 vs. 12.4 months, P < 0.001). Multivariate Cox regression analysis identified continued pembrolizumab use and favorable ECOG performance status as independent predictors of prolonged OS. These findings suggest that continued pembrolizumab use or combination therapy after disease progression significantly enhances survival benefits in advanced NSCLC, underscoring the importance of individualized treatment strategies based on clinical characteristics and treatment response.

Background:Immune checkpoint inhibitors (ICIs) have significant advantages in treating lung cancer due to their low toxicity and high efficacy. However, adverse events, especially ICI-related pneumonitis (CIP), may restrict their applicability. CIP not only impairs patients' lung function but also carries a 35% mortality rate, thereby restricting ICIs rechallenge. As information is limited on the efficacy and safety of ICIs rechallenge, these issues were assessed in the present study. Methods:The data on 2673 patients who underwent ICI therapy at the First Affiliated Hospital of Zhejiang University between 2019 and 2023 were reviewed, identifying 106 patients with CIP who were allocated to rechallenge, non-discontinuation, and permanent discontinuation groups. Baseline information was collected, including sex, age, staging, pathological type, medication details, and underlying diseases, along with treatment status post-CIP occurrence, re-challenge of ICIs, and data on disease progression and mortality. The clinical studies examined the efficacy of treatments by assessing progression-free survival (PFS) and overall survival (OS) as key indicators. Results:No significant difference in CIP onset time was observed between grades 1-2 and 3-4 (P = 0.99), CIP was found to occur most frequently 5.17 months after treatment initiation (95%CI 4.61-5.72). The likelihood of CIP recurrence or progression while continuing ICI treatment was 50% (15/30). Patients who resumed ICI treatment and did not cease taking the medication showed markedly improved outcomes relative to those who permanently discontinued treatment, with a 6-month longer mPFS (13.67 vs. 7.90 months, P<0.001) and a twofold increase in mOS (33.77 vs. 13.23 months, P=0.002). Conclusions:The outcomes of patients with CIP were found to be contingent upon rechallenge or continuation of ICIs. Contrary to the belief that an earlier restart is always better, decisions to reinitiate ICIs should be based on the improvement of symptoms and radiographic findings.