BACKGROUND:PD-1 and PD-L1 inhibitors have been shown to synergise with anti-angiogenic agents in non-small-cell lung cancer (NSCLC). We aimed to compare benmelstobart plus anlotinib with pembrolizumab in patients with previously untreated, driver gene-negative, PD-L1-positive, advanced NSCLC. METHODS:The blinded, randomised, controlled, phase 3 CAMPASS trial was conducted in 79 centres across China. Patients aged 18-75 years with stage IIIB-IV squamous or non-squamous NSCLC, no previous systemic treatment for advanced, recurrent or metastatic diseases, a PD-L1 tumour proportion score of 1% or greater, a life expectancy of 3 months or longer, at least one measurable lesion, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to receive intravenous benmelstobart (1200 mg once on day 1) plus oral anlotinib (12 mg daily on days 1-14) or intravenous pembrolizumab (200 mg once on day 1) plus placebo every 3 weeks. Randomisation was done centrally and stratified by tumour histology, PD-L1 tumour proportion score, and brain metastases. Treatment allocation was open label for investigators and masked to patients and statisticians. The primary endpoint was progression-free survival as assessed by a blinded independent review committee per Response Evalutation Criteria in Solid Tumours version 1.1 in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all randomly assigned patients who received at least dose of study drug. Results reported here are from a preplanned final analysis for progression-free survival. This ongoing study is closed to recruitment and is registered with ClinicalTrials.gov, NCT04964479. FINDINGS:Between Aug 6, 2021, and Dec 14, 2022, 531 patients were randomly assigned (354 to the benmelstobart plus anlotinib group and 177 to the pembrolizumab plus placebo group). 449 (85%) patients were male, 82 (15%) were female, and 493 (93%) were of Han ethnicity. Two patients in the benmelstobart plus anlotinib group and one patients in the pembrolizumab plus placebo group were untreated and therefore excluded from the safety population. After a median follow-up of 11·4 months (95% CI 9·4-13·1) for the benmelstobart plus anlotinib group and 10·6 months (9·0-13·0) for the pembrolizumab plus placebo group, median progression-free survival was 11·0 months (9·2-12·6) and 7·1 months (5·8-9·5), respectively (hazard ratio [HR] 0·70 [95% CI 0·54-0·90]; log-rank p=0·0057). Grade 3 or worse treatment-related adverse events occurred in 206 (59%) of 352 patients in the benmelstobart plus anlotinib group and 51 (29%) of 176 patients in the pembrolizumab plus placebo group, and the most frequent one was hypertension (90 [26%] vs five [3%]). Serious treatment-related adverse events occurred in 89 (25%) patients in the benmelstobart plus anlotinib group and 37 (21%) patients in the pembrolizumab plus placebo group, the most common of which were haemoptysis (nine [3%] vs none) and immune-mediated pulmonary diseases (eight [2%] vs five [3%]). Five (1%) treatment-related deaths occurred in the benmelstobart plus anlotinib group (two due to haemoptysis and one each due to immune-mediated pulmonary disease, disease progression, and infection pneumonia) and four (2%) occurred in the pembrolizumab plus placebo group (one each due to respiratory failure, pulmonary inflammation, disease progression, and myocardial injury). INTERPRETATION:Benmelstobart plus anlotinib showed longer progression-free survival than pembrolizumab plus placebo and no unexpected safety signals were reported, suggesting benmelstobart plus anlotinib as a potential first-line option in driver gene-negative, PD-L1-positive, advanced NSCLC. Longer term follow-up is needed to establish effects on overall survival. FUNDING:Chia Tai Tianqing Pharmaceutical Group.

Importance:Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies. Objective:To provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population. Design, Setting, and Participants:Randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025. Interventions:Patients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy. Main Outcomes and Measures:This final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee). Results:The 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively. Conclusions and Relevance:Ivonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy. Trial Registration:ClinicalTrials.gov Identifier: NCT05184712.

QuestionDoes adding ivonescimab to chemotherapy improve overall survival in patients with epidermal growth factor receptor (EGFR) gene variant non-small cell lung cancer after disease progression with EGFR tyrosine kinase inhibitor (TKI) therapy?FindingsIn this phase 3, randomized, double-blind trial, ivonescimab plus chemotherapy significantly improved overall survival (median, 16.8 vs 14.1 months) and the 30-month survival rate (29.1% vs 18.4%) compared with chemotherapy alone.MeaningThis regimen provides an effective post-EGFR-TKI treatment option, with a statistically significant survival benefit, a modest absolute improvement in median overall survival, and a more pronounced separation in long-term survival rate. ImportancePatients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies.ObjectiveTo provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population.Design, Setting, and ParticipantsRandomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025.InterventionsPatients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy.Main Outcomes and MeasuresThis final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee).ResultsThe 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively.Conclusions and RelevanceIvonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy.Trial RegistrationClinicalTrials.gov Identifier: NCT05184712 This randomized trial assesses the effect of ivonescimab added to chemotherapy on overall survival among patients with EGFR-variant non-small cell lung cancer (NSCLC) who had disease progression with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy.

While elevated levels of the deubiquitinating enzyme BRCC3 have been documented in a range of cancers, its capacity to influence immune checkpoint expression or enable tumor immune evasion in non-small cell lung cancer (NSCLC) remains uncharacterized. BRCC3 expression and clinical relevance were assessed using TIMER2, UALCAN, and Kaplan-Meier Plotter databases, and validated in NSCLC tissues and cell lines. Functional impacts were evaluated through proliferation, migration, invasion, and syngeneic tumor models. CD8+ T cell cytotoxicity and cytokine secretion were measured in co-culture systems. Protein interactions and ubiquitination of PD-L1/B7-H3 were analyzed by co-immunoprecipitation and western blot. Rescue experiments with PD-L1 or B7-H3 overexpression were performed. BRCC3 upregulation correlated with advanced NSCLC, nodal spread, and worse survival. BRCC3 knockdown suppressed malignant phenotypes and tumor growth, and shifted the immune response toward a proinflammatory phenotype, accompanied by enhanced CD8 + T cell killing. Mechanistically, BRCC3 directly interacted with PD-L1 and B7-H3, enhancing their protein levels via deubiquitination. Overexpression of either PD-L1 or B7-H3 partially restored tumor growth and attenuated T cell activation induced by BRCC3 silencing. BRCC3 drives immune escape in NSCLC by deubiquitination-mediated upregulation of PD-L1 and B7-H3, thereby dampening anti-tumor immunity. Targeting BRCC3 may represent a potential therapeutic strategy to overcome resistance to current immunotherapies.

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

Extensive-stage small cell lung cancer (ES-SCLC) is a highly aggressive disease characterized by rapid progression and development of extensive metastases. Standard chemotherapy-based regimens for ES-SCLC often lead to myelosuppression, compromising medication compliance and prognosis. Trilaciclib is a CDK4/6 inhibitor, approved by NMPA in 2022 to decrease the incidence of chemotherapy-induced myelosuppression (CIM) in adult with ES-SCLC. This study aims to evaluate the efficacy and safety of preventive use of trilaciclib prior chemotherapy in Chinese ES-SCLC population under real-world settings. ES-SCLC patients suitable for combined treatment of trilaciclib and chemotherapy were enrolled in this study. Eligible participant received 240 mg/m2 of trilaciclib IV 4 h prior chemotherapy. The primary endpoint was the incidence rate of severe neutropenia (SN). The secondary endpoints included the occurrence of grade 3/4 hematologic adverse events (HAEs), administration rate of G-CSF and ESA, safety, and anti-tumor efficacy of chemotherapy. A total of 201 ES-SCLC patients receiving at least one dose of trilaciclib combined with chemotherapy were included from 60 centers in China during March 10 2023 to August 10 2024, with median age of 65 (58, 71). Metastases occurred in 90.0% of the subjects at baseline, in which brain metastases accounted for 16%. 92.5% of the patients adopted platinum plus etoposide (E/P) regimen. The mean number of completed chemo-cycle was 3.0 (1.4). In Cycle 1, 1 case (0.6%) of SN occurred in patient receiving second-line (2L) treatment with E/P therapy. Grade 3/4 HAEs were reported in 5.4% of the patients in Cycle 1, including neutropenia (3.6%), anemia (1.2%) and thrombocytopenia (1.8%). During the whole treating period, a total of 5 cases (2.6%) of SN occurred, 4 of which received 2L treatment with E/P, while the remaining one received first-line cis-platinum therapy. 17.5% participants experienced grade 3/4 HAEs during the study, in which neutropenia, anemia and thrombocytopenia accounted for 8.2%, 9.3% and 3.1%, respectively. G-CSF and ESA were used in 2.6% and 1.0% of the patients. As for safety, grade ≥3 AEs were reported in 20.9% of the participants. No AEs-related treatment discontinuation happened. No serious AEs and death occurred. Among 48 patients included into tumor response analysis, the best response to chemotherapy was CR (8.3%), PR (43.8%), SD (39.6%) and PD (8.3%). The objective response rate (ORR) and disease control rate (DCR) reached 52.1% and 91.7%, respectively. Prophylactic administration of trilaciclib (240 mg/m2) prior chemotherapy exhibits superior myeloprotective effect and were well-tolerated in Chinese ES-SCLC population, providing evidence for clinical benefit of trilaciclib as a myelo-protectant. Ying Liu, Jianqiang Bi, Jianxin Chen, Meifang Chen, Xuesong Chen, Yongxing chen, Yinghua Ji, Yujie Jiang, Lu Li, Qin Liao, Sheng Lin, Jie Liu, Yi Liu, Yu Liu, Zhaoting Meng, Zhuqing Mu, Yunxiang Qi, Yanhong Shang, Ling Xu, Shufeng Xu, Lu Zheng, Jin Zhou, Ying Cheng. Preventive use of trilaciclib in Chinese patient with extensive-stage small cell lung cancer (ES-SCLC) receiving chemotherapy: A multi-center, single-arm, observational real-world study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7218.

LBA8502 Background: Anti-PD-(L) 1 monotherapy has been the standard first-line treatment for PD-L1 positive NSCLC, but its clinical benefit remains unsatisfactory. Benmelstobart (TQB2450) is a humanized monoclonal antibody against PD-L1 and anlotinib is a multikinase inhibitor that has been approved as the standard of care in the third-line treatment of NSCLC in China. This phase 3 study aimed to compare the efficacy of benmelstobart in combination with anlotinib and pembrolizumab as first-line treatment of PD-L1 positive aNSCLC. Methods: This is a randomized, single-blind, multicenter phase Ⅲ study (NCT04964479). Eligible patients (pts) were previous systemic treatment naïve, diagnosed with locally advanced or recurrent/metastatic NSCLC and had PD-L1 positive expression (defined as TPS ≥1%). Pts were randomized in a 2:1 ratio to receive either benmelstobart plus anlotinib (benmel+ anlo) or pembrolizumab plus placebo (pem+placebo). Anlotinib or placebo was administered orally at a dose of 12/0mg QD on days 1-14 of a 21-day cycle, while benmelstobart or pembrolizumab was given intravenously at a dose of 1200mg or 200mg on the first day of each cycle. The primary endpoint was progression-free survival (PFS) assessed by independent review committee (IRC). Results: Between August 2021 and December 2022, 531 pts were randomized (528 treated). At the data cutoff date of 20 May 2023, the median follow-up for PFS was 11.4 months for the benmel+anlo arm and 10.6 months for the pem+placebo arm. The study met its primary endpoint that the median PFS was significantly prolonged to 11.0 months (95% CI 9.2-12.6) in the benmel+anlo arm compared with 7.1 months (95% CI 5.8-9.5) in the pem+placebo arm (P = 0.007). The hazard ratio (HR) was 0.70 (95% CI 0.55-0.91). The HR for pts with squamous cell carcinoma and PD-L1 expression ≥50% was 0.63 (95% CI 0.46-0.86) and 0.60 (95% CI 0.41-0.88). The confirmed objective response rate was also obviously higher with combination therapy (57.3% vs. 39.6%; P < 0.001). The data for overall survival (OS) was immature. In total, 98.3% of pts in the benmel + anlo arm and 88.1% in the pem + placebo arm experienced at least one treatment-related adverse event (TRAE). The incidence of grade ≥3 TRAE was 58.5% and 29.0% in each group, respectively. Only 5.7%/3.7% of pts permanently discontinued benmelstobart/anlotinib since TRAE, while termination of pembrolizumab/placebo due to TRAE occurred in 8.0%/2.3% of pts. Conclusions: To our knowledge, this is the first phase III study to demonstrate the significant PFS benefit of a multikinase inhibitor plus an anti-PD-L1 mAb in the first-line treatment of PD-L1-positive aNSCLC compared to pembrolizumab. Tolerability is favourable with a lower incidence of treatment discontinuation due to TRAE. The data support this combination as a new option for these pts. Clinical trial information: NCT04964479 .

Aumolertinib, a third generation selective EGFR-TKI, is standard of care for the first-line treatment in advanced or metastatic NSCLC with sensitizing EGFR mutations in China. Evidence has shown that combining EGFR-TKIs with chemotherapy can improve outcomes compared to EGFR-TKIs monotherapy. AENEAS2 (NCT04923906) is a randomized, open-label, multicenter, phase 3 study assessing the efficacy and safety of aumolertinib plus chemotherapy versus aumolertinib alone as first-line treatment in locally advanced or metastatic NSCLC with sensitizing EGFR mutations. Patients who were naïve to treatment with locally advanced or metastatic NSCLC harboring EGFR mutations (exon 19 deletion or L858R mutation) were randomly assigned in a 1:1 ratio to receive aumolertinib 110 mg QD in combination with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC5), versus to receive aumolertinib 110 mg QD monotherapy. The primary endpoint is progression free survival (PFS) assessed by IRC (Independent Review Committee) per RECIST v1.1. Data cutoff date: 2024/06/18. A total of 624 patients were randomized to aumolertinib plus chemotherapy (n=310) or aumolertinib monotherapy (n=314) and stratified according to EGFR mutation status (Ex19del verse L858R) and CNS metastases at baseline (yes versus no). Baseline characteristics were balanced between treatment arms (aumolertinib plus chemotherapy versus aumolertinib): median age (range), 58.0 (30-84)/59.0 (31-81) years; 55.5/52.5 % female; 49.0/49.0% Ex19del; 51.0/51.0% L858R; 30.0/30.9% CNS metastases. Median follow-up was 23.4 months. Median PFS assessed by IRC was 28.9 months (95% CI, 26.3 to NA) in combination arm versus 18.9 months (95% CI, 17.8 to 21.1) in monotherapy arm; hazard ratio (HR) 0.471 (95% CI, 0.371 to 0.598; p<0.0001). The PFS benefit was consistent across pre-defined subgroups. The overall survival (OS) was immature with event-patient rate 21.6%; HR 0.442 (95% CI, 0.308 to 0.636; p<0.0001). Median cycles of pemetrexed exposure (range) were 20.0 (1-42) cycles, 88.8% of patients completed 4∼6 cycles of platinum therapy. All causality grade ≥3 AEs (aumolertinib plus chemotherapy versus aumolertinib): 75.7%/23.7%; AEs leading to discontinuation of aumolertinib: 3.0%/1.3%. The safety profile of aumolertinib plus pemetrexed and platinum was consistent with the established profiles of the individual agent. Aumolertinib plus chemotherapy as a first-line treatment in advanced EGFR-mutant NSCLC demonstrated a statistically significant and clinically meaningful PFS improvement over aumoletinib monotherapy, with a manageable safety profile. Shun Lu, Jie Hu, Jianhua Chen, Yan Yu, Xiangjiao Meng, Xiaorong Dong, Yanping Hu, Yinghua Ji, Ying Cheng, Weibo Wang, Fangling Ning, Zhihong Zhang, Zhiye Zhang, Chunling Liu, Qiming Wang, Wei Zheng, Xiujuan Qu, Honghai Wang, Runxiang Yang, Renhua Guo, Jianhua Shi, Feng Wu, Dongqing Lv, Jian Fang, Zhi Xu, Huaqiu Shi, Haichuan Su, Yongxing Chen, Cheng zhi Zhou, Junhong Zhang, Xuewen Liu, Zhaoxia Dai, Wen Li, Zili Meng, Guojun Zhang, Biyong Ren, Lin Wu, Yalun Li, Xinmin Yu, Ziping Wang, Jian Feng, Yueyin Pan, Juan Li, Xiangdong Zhou, Suxian Hu, Tongmei Zhang, Laiyu Liu, Jiming Shen, Shaonan Fan, Zhenming Chen. Aumolertinib with or without chemotherapy as first line treatment in locally advanced or metastatic NSCLC with sensitizing EGFR mutations (AENEAS2) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT053.

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

The fixed-dose combination of beclometasone dipropionate/formoterol fumarate (BDP/FF) delivered via pressurised metered-dose inhaler (pMDI) has demonstrated efficacy in chronic obstructive pulmonary disease (COPD), in studies predominantly conducted in Caucasian adults. The current study evaluated the efficacy and safety of BDP/FF pMDI in Chinese patients with COPD, as part of registration for COPD in China. This double-blind, double-dummy, randomised, parallel-group study was conducted in patients with COPD of Chinese ethnicity aged ≥40 years. After a 4-week open-label budesonide/formoterol fumarate (BUD/FF) run-in period, patients were randomised to BUD/FF or BDP/FF for 24 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF to BUD/FF in terms of change from baseline in pre-dose morning forced expiratory volume in 1 sec (FEV1) at Week 24 (i.e. the lower 95% CI limit of the difference was above the pre-defined non-inferiority margin of -0.07 L). Of 750 patients randomised (377 BDP/FF; 373 BUD/FF), 87.6% completed the study. The primary endpoint was met in both the per-protocol (adjusted mean difference -0.001 L [95% CI: -0.025, 0.022], non-inferiority p < 0.001) and intention-to-treat populations (-0.001 L [-0.024, 0.022]; non-inferiority p < 0.001). There were no statistically significant BDP/FF-BUD/FF differences for the secondary endpoints, and a similar proportion of patients had adverse events (BDP/FF, 51.7%; BUD/FF, 51.2%), with most mild/moderate in severity. In conclusion, BDP/FF pMDI was non-inferior to BUD/FF in terms of pre-dose morning FEV1, supported by a range of secondary endpoints. Both treatments were similarly tolerated. The study supports the use of BDP/FF pMDI in Chinese patients with COPD. STUDY REGISTRATION:China Centre for Drug Evaluation (CTR20180475).

Background:Trilaciclib, an intravenous short acting cyclin-dependent kinase 4/6 inhibitor, has been approved for the prevention of chemotherapy-induced myelosuppression (CIM) in patients with extensive stage small cell lung cancer (ES-SCLC) receiving platinum/etoposide (EP) or topotecan (TPT)-based therapy in United States (US) since February 2021. Trilaciclib use received the priority review and approval in a real-world setting in China. This study thus aimed to collect real-world data and evaluate the protective effect of trilaciclib on CIM in Chinese patients with ES-SCLC. Methods:This single-arm, noninterventional real world study invited all patients with ES-SCLC who received trilaciclib with the platinum and etoposide ± anti-programmed cell death ligand-1 [anti-PD-(L)1] antibodies (EP group) or trilaciclib with TPT (TPT group) in Boao, Hainan China to participate in the study. The primary endpoint was the incidence of the severe (grade four) neutropenia (SN), and the secondary endpoints included other myeloprotection effects, safety and anti-tumor activity. Results:Between August 2021 and December 2022, a total of 30 patients who received trilaciclib with chemotherapy consented to participate in this real-world study. Among the enrolled patients, 26 patients were treated with EP regimen, of these, 18 patients were combined with anti-PD-(L)1 antibodies, and 4 patients were treated with TPT. The incidence of SN was 6.7%, with one patient each in EP group and TPT group. The incidence of grade three hematological toxicities was 30% (9/30), with 19.2% (5/26) in the EP group, and 100% (4/4) in the TPT group. The incidence of grade four hematological toxicities was 5/30 (16.7%), with 3/26 (11.5%) and 2/4 (50%) in EP and TPT group, respectively. Overall, the incidence of those who received intravenous or oral antibiotics was 6/30 (20%), with 4/26 (15.4%) in the EP group, and 2/4 (50%) in the TPT group. No ≥ grade three adverse events, serious adverse events (SAEs), and adverse events of special interest associated with trilaciclib were reported. Conclusions:Trilaciclib decreased the incidence of CIM in Chinese patients when administered prior to an EP-containing regimen [combined with or without PD-(L)1] or TPT for ES-SCLC. The effect of myeloprotection, anti-tumor and safety were all consistent with the studies conducted globally and data from the Chinese Phase three placebo-controlled study (TRACES).

Importance:For patients with non-small cell lung cancer whose disease progressed while receiving EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy, particularly third-generation TKIs, optimal treatment options remain limited. Objective:To compare the efficacy of ivonescimab plus chemotherapy with chemotherapy alone for patients with relapsed advanced or metastatic non-small cell lung cancer with the epidermal growth factor receptor (EGFR) variant. Design, Setting, and Participants:Double-blind, placebo-controlled, randomized, phase 3 trial at 55 sites in China enrolled participants from January 2022 to November 2022; a total of 322 eligible patients were enrolled. Interventions:Participants received ivonescimab (n = 161) or placebo (n = 161) plus pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy of ivonescimab plus pemetrexed or placebo plus pemetrexed. Main Outcomes and Measures:The primary end point was progression-free survival in the intention-to-treat population assessed by an independent radiographic review committee (IRRC) per Response Evaluation Criteria in Solid Tumors version 1.1. The results of the first planned interim analysis are reported. Results:Among 322 enrolled patients in the ivonescimab and placebo groups, the median age was 59.6 vs 59.4 years and 52.2% vs 50.9% of patients were female. As of March 10, 2023, median follow-up time was 7.89 months. Median progression-free survival was 7.1 (95% CI, 5.9-8.7) months in the ivonescimab group vs 4.8 (95% CI, 4.2-5.6) months for placebo (difference, 2.3 months; hazard ratio [HR], 0.46 [95% CI, 0.34-0.62]; P < .001). The prespecified subgroup analysis showed progression-free survival benefit favoring patients receiving ivonescimab over placebo across almost all subgroups, including patients whose disease progressed while receiving third-generation EGFR-TKI therapy (HR, 0.48 [95% CI 0.35-0.66]) and those with brain metastases (HR, 0.40 [95% CI, 0.22-0.73]). The objective response rate was 50.6% (95% CI, 42.6%-58.6%) with ivonescimab and 35.4% (95% CI, 28.0%-43.3%) with placebo (difference, 15.6% [95% CI, 5.3%-26.0%]; P = .006). The median overall survival data were not mature; at data cutoff, 69 patients (21.4%) had died. Grade 3 or higher treatment-emergent adverse events occurred in 99 patients (61.5%) in the ivonescimab group vs 79 patients (49.1%) in the placebo group, the most common of which were chemotherapy-related. Grade 3 or higher immune-related adverse events occurred in 10 patients (6.2%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Grade 3 or higher vascular endothelial growth factor-related adverse events occurred in 5 patients (3.1%) in the ivonescimab group vs 4 (2.5%) in the placebo group. Conclusions:Ivonescimab plus chemotherapy significantly improved progression-free survival with tolerable safety profile in TKI-treated non-small cell lung cancer. Trial Registration:ClinicalTrials.gov Identifier: NCT05184712.

Local recurrence and distant metastasis of non-small cell lung cancer (NSCLC) caused by immune escape is one of the root causes of treatment difficulties. We aim to investigate the mechanism of immune escape in NSCLC. NSCLC tissues were collected. Cell proliferation was detected by CCK-8 assay. Cell migration and invasion ability was measured by Transwell assay. The expressions of E-cadherin, N-cadherin and PD-L1 were detected by Western blot. NSCLC cells were co-cultured with CD8+ T cells to simulate tumor microenvironment in vitro. The proportion of CD8+ T cells and apoptosis were detected by flow cytometry. Dual-luciferase reporter gene assay confirmed the targeting relationship of circDENND2D and STK11. The expressions of circDENND2D and STK1 were down-regulated, while miR-130b-3p expression was up-regulated in NSCLC tissues. Overexpression of circDENND2D or STK11 inhibited NSCLC cells proliferation, migration and invasion, and attenuated the immune escape of NSCLC cells. CircDENND2D targeted miR-130b-3p to competitively promote STK11 expression. STK11 knockdown or miR-130b-3p overexpression attenuated the function of circDENND2D overexpression on NSCLC cells. CircDENND2D inhibited metastasis and immune escape of NSCLC by regulating miR-130b-3p/STK11 axis.

目的 探讨脾多肽注射液联合亚胺培南西司他丁钠治疗老年重症社区获得性肺炎(SCAP)的临床疗效以及对病人炎症反应和免疫功能的影响.方法 选取2018年1月至2020年1月我院收治的92例老年SCAP病人,运用随机数表将其分为观察组与对照组,各46例.对照组予以亚胺培南西司他丁钠治疗,观察组在对照组基础上联合脾多肽注射液治疗,疗程均为14 d.观察2组临床疗效,并比较治疗前后2组炎症反应及免疫功能指标、APACHE Ⅱ评分、住院时间、28 d病死率及不良反应发生情况.结果 观察组总有效率(95.7％,44/46)较对照组(80.4％,37/46)显著提高(P＜0.05).与治疗前相比,2组治疗后血清CRP、IL-6、IL-8水平和APACHE Ⅱ评分均显著降低(P＜0.05),外周血CD3+、CD4+水平及CD4+/CD8+均显著升高(P＜0.05),且观察组改善更显著(P＜0.05).与对照组相比,观察组住院时间显著缩短(P＜0.05).2组不良反应发生率及28 d病死率差异均无统计学意义(P＞0.05).结论 脾多肽注射液联合亚胺培南西司他丁钠治疗老年SCAP的疗效确切,其作用机制可能是通过有效抑制全身炎症反应及增强机体免疫功能来实现的.

The tumor-suppressing role of miR-455-3p has been reported in lung cancer, but the working mechanism remains to be fully elucidated. This study aims to explore the possible mechanism of miR-455-3p in regulating epithelial–mesenchymal transition (EMT) progression and angiogenesis in non-small cell lung cancer (NSCLC) cells. The expressions of miR-455-3p, HSF1, GLS1, and EMT-related proteins (E-cadherin, N-cadherin, vimentin, and Snail-1) in both NSCLC tissues and cell lines were determined by RT-qPCR and western blot. After cell transfection, cell proliferation and angiogenesis ability on NSCLC cells were assessed by MTT and tube formation assay. The binding of miR-455-3p with HSF1 was measured by luciferase reporter gene assay, while the interaction between HSF1 and GLS1 was determined by co-immunoprecipitation assay (Co-IP). HSF1 was highly expressed in NSCLC tissues and cells. Inhibition of HSF1 expression or overexpression of miR-455-3p in NSCLC cells can suppress cell proliferation, angiogenesis ability, and EMT progression. miR-455-3p was found to negatively regulate HSF1 expression. Co-transfection of miR-455-3p overexpression and HSF1 inhibition in NSCLC cells showed that miR-455-3p can partially counteract the effect of HSF1 in NSCLC cells. HSF1 can interact with GLS1 and elevate the expression of GLS1. GLS1 can partially abolish the suppressive effect of miR-455-3p in NSCLC cells. miR-455-3p can bind HSF1 to suppress the GLS1 in NSCLC cells, therefore suppressing EMT progression and angiogenesis of NSCLC cells.

目的 研究小檗碱对实验性肺结核病小鼠炎症因子及其mRNA表达水平的影响.方法 选取实验性肺结核病小鼠48只分为模型组、治疗组(低、中、高剂量组),每组12只,另取8只健康小鼠为对照组.治疗组分别灌胃不同浓度小檗碱溶液,给药1周后,检测各组小鼠体征变化并观察肺病理变化,用免疫组织化学法和实时荧光定量检测肺组织白细胞介素-10(IL-10)、肿瘤坏死因子-α(TNF-α)、干扰素GR1(IFNGR1)、TOLL样受体2(TLR2)因子的mRNA表达水平.结果 模型组与治疗组小鼠体质量低于对照组(P<0.05);治疗组炎症细胞分类计数结果高于对照组(P<0.05);病理切片发现模型组小鼠肺组织明显病变,大量炎性细胞浸润,治疗组症状有不同程度缓解,炎性细胞浸润减少;与对照组相比,模型组、治疗组小鼠肺脏组织的IL-10、TNF-α、IFNGR1、TLR2蛋白表达水平、mRNA相对表达量有统计学差异(P<0.05),模型组表达水平最高,高剂量治疗组最低;随着治疗剂量的增多,水平逐渐接近对照组水平.结论 小檗碱可缓解实验性肺结核病小鼠病理反应,其起效机制可能是小檗碱抑制炎症细胞表达TLR2、TNF-α、IFNGR1,阻断激活炎症信号通路,IL-10释放减少,减轻炎症应激损伤,通过调节免疫发挥抗感染作用.

Nontuberculous mycobacteria (NTM) refer to a large group of mycobacteria other than Mycobacterium tuberculosis complex and Mycobacterium leprae. Mycobacterium szulgai (M. szulgai) is a slow growing species of nontuberculous mycobacteria (NTM), which can cause infection in multiple organs, including the lungs. Using the technique of next-generation sequencing (NGS), we diagnosed disseminated M. szulgai infection in a patient with no obvious immunodeficiency. We report on a 66-year-old female patient who presented with enlarged cervical lymph nodes and an intermittent fever. Imaging showed multiple, enlarged, abnormal lymph nodes, a pulmonary mass and rib lesions that strongly suggested neoplasia. There was no significant improvement in symptoms after intermittent antibiotic treatment. The pathological results of multiple biopsies did not support the diagnosis of tumors. The diagnosis of M. szulgai infection was confirmed by NGS. The patient started standard treatment with clarithromycin, ethambutol, and moxifloxacin in July 2020. Since then and over the 10-month follow-up period, there has been a progressive reduction in the size of the enlarged lymph nodes and lung lesions, and no recurrence of fever or other symptoms. M. szulgai is a potential cause of infection (including of disseminated disease) even in patients with no obvious immunosuppression. The potential usefulness of the NGS of clinical samples should be highlighted.

Permeability coefficients for amino acid classes, including neutral, polar, hydrophobic, and charged species, were measured and compared with values for other ionic solutes such as phosphate. The rates of efflux of glycine, lysine, phenylalanine, serine and tryptophan were determined after they were passively entrapped in large unilamellar vesicles (LUVs) composed of egg phosphatidylcholine (EPC) or dimyristoylphosphatidylcholine (DMPC). The following permeability coefficients were obtained for: glycine, 5.7 x 10(-12) cm s-1 (EPC), 2.0 x 10(-11) cm s-1 (DMPC); serine, 5.5 x 10(-12) cm s-1 (EPC), 1.6 x 10(-11) cm s-1 (DMPC); lysine, 5.1 x 10(-12) cm s-1 (EPC), 1.9 x 10(-11) cm s-1 (DMPC); tryptophan, 4.1 x 10(-10) cm s-1 (EPC); and phenylalanine, 2.5 x 10(-10) cm s-1 (EPC). Decreasing lipid chain length increased permeability slightly, while variations in pH had only minor effects on the permeability coefficients of the amino acids tested. Phosphate permeability was in the range of 10(-12)-10(-13) cm s-1 depending on the pH of the medium. The values for the polar and charged amino acids were surprisingly similar to those previously measured for monovalent cations such as sodium and potassium, which are in the range of 10(-12)-10(-13) cm s-1, depending on conditions and the lipid species used. This observation suggests that the permeation rates for the neutral, polar and charged amino acids are controlled by bilayer fluctuations and transient defects, rather than partition coefficients and Born energy barriers. The results are relevant to the permeation of certain peptides into lipid bilayers during protein translocation and membrane biogenesis.

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible and progressive airflow limitation and encompasses a spectrum of diseases, including chronic obstructive bronchitis and emphysema. Pyroptosis is a unique form of inflammatory cell death mediated by the activation of caspase-1 and inflammasomes. The long non-coding RNA (lncRNA) growth arrest-specific 5 (GAS5) is a well-documented tumor suppressor, which is associated with cell proliferation and death in various diseases. The aim of the present study was to evaluate whether lncRNA GAS5 is associated with the pyroptosis in COPD. To create a COPD cell model, MRC-5 cells were treated with 10 mu g/ml lipopolysaccharide (LPS) for 48 h. Then the level of pro-caspase 1, caspase 1, IL-1 beta, IL-18, NLRP3 and cleaved gasdermin D (GSDMD) was examined by western blotting. GAS5 mRNA level was detected by qualitative PCR following LPS treatment in MRC-5 cells. Subsequently, IL-2, IL-6, IL-10 and TNF-alpha in MRC-5 cells was measured by ELISA. Then the proliferation ability of MRC-5 cells was detected by CCK-8. Cell death was detected by TUNEL assay. LDH release was measured using an LDH Cytotoxicity Assay kit. The Magna RIP kit was used to validate the interaction between GAS5 and miR-223-3p. The present study revealed that increased expression levels of caspase-1, IL-1 beta, IL-18 and cleaved GSDMD were observed in LPS-treated MRC-5 cells, indicating that pyroptosis is involved in COPD progression. Additionally, LPS induced the increase in GAS5 mRNA expression levels and the release of inflammatory factors (IL-2, IL-6, IL-10 and TNF-alpha), suggesting that GAS5 is implicated in pyroptosis in COPD. Furthermore, upregulation of GAS5 promoted cell death and inhibited proliferation in the MRC-5 cell line. Additionally, increased GAS5 expression significantly promoted the production of caspase-1, IL-1 beta, IL-18, cleaved GSDMD and NLR pyrin domain containing protein 3 (NLRP3). A dual-luciferase assay demonstrated that GAS5 could directly bind to microRNA-223-3p (miR-223-3p), and NLRP3 is a direct target of miR-223-3p. Furthermore, GAS5 reduced the expression levels of miR-223-3p, while it increased the expression levels of NLRP3. The present study concluded that lncRNA GAS5 promoted pyroptosis in COPD by targeting the miR-223-3p/NLRP3 axis, implying that GAS5 could be a potential target for COPD.