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

Importance: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.

ABSTRACT Background Anlotinib has shown remarkable efficacy in later‐line treatment of advanced non‐small cell lung cancer (NSCLC). This prospective real‐world study evaluated its efficacy and safety in routine clinical practice. Methods Patients from 13 centers in China received anlotinib (8–12 mg) once daily on days 1–14 of a 21‐day cycle until disease progression, death, or unacceptable toxicity. Primary endpoint was progression‐free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results From July 2019 to October 2021, 352 of 373 enrolled patients received ≥ 2 cycles of anlotinib. Median follow‐up was 35.5 months. Median PFS and OS were 5.8 months (95% CI, 5.0–6.4) and 11.3 months (95% CI, 9.9–13.1), respectively. ORR and DCR were 19.3% and 84.4%. Multivariable analysis indicated that age ≥ 70 years was independently associated with poorer OS, though a clinically meaningful benefit remained (PFS, 5.9 months; OS, 9.6 months). Efficacy appeared generally similar regardless of baseline brain metastases. Median PFS and OS were 6.3 and 12.7 months in the second‐line setting, and 5.5 and 11.3 months in the≥ third‐line setting. Treatment‐related adverse events occurred in 10.5%, with grade ≥ 3 events in 1.4%; no treatment‐related deaths were observed. Conclusion In this real‐world cohort, anlotinib demonstrated effectiveness and acceptable tolerability in advanced NSCLC. Given the observational design, exploratory analyses—including age, treatment line, and baseline brain metastases—should be interpreted with caution. These findings complement limited existing real‐world data and may inform future clinical research and decision‐making. Trial Registration: ClinicalTrials.gov identifier: NCT04871997

BackgroundThe role of adjuvant Ensartinib in patients with stage I ALK-positive non-small cell lung cancer (NSCLC) who exhibit high-risk pathological features remains unclear. This multicenter retrospective study aimed to evaluate the efficacy and safety of adjuvant Ensartinib in this population.MethodsA total of 393 patients with completely resected stage I ALK-positive NSCLC were enrolled from five centers in China between March 2017 and January 2026. Patients were categorized into the Ensartinib group (n=63) and the observation group (n=330). Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were employed to balance baseline characteristics. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety.ResultsAfter IPTW, baseline characteristics were well balanced between groups. The Ensartinib group exhibited a significantly improved 3-year DFS compared to the observation group (100% vs. 90.2%; P=0.014). This benefit was particularly pronounced in patients with high-risk pathological features (micropapillary or solid subtypes or complex glandular pathological subtypes ≥10%, mucinous adenocarcinoma, or spread through air spaces), where the 3-year DFS was 100% in the Ensartinib group versus 86.5% in the observation group (P=0.016). No significant difference in OS was observed between groups. Adverse events were reported in 87.3% of patients in the Ensartinib group, all of which were grade 1–2, with rash being the most common adverse event (85.7%).ConclusionAdjuvant Ensartinib significantly improves DFS in stage I ALK-positive NSCLC patients exhibiting high-risk pathological features, while demonstrating a favorable safety profile. For patients devoid of high-risk factors, observation remains a reasonable strategy. These findings support individualized adjuvant treatment based on pathological risk stratification.

Cancer remains a leading cause of morbidity and mortality worldwide. While classical psychedelics have been used clinically to treat cancer-associated psychiatric disorders, their impact on tumor progression is unclear. Here, we show that by targeting the serotonin receptor 5-HT2AR, lysergic acid diethylamide (LSD) enhances CD8+ T cell-mediated antitumor immunity and suppresses colorectal cancer (CRC) growth. To harness this activity while avoiding psychedelic effects, we developed IHCH-8110, a non-brain-penetrant 5-HT2AR agonist that selectively targets peripheral 5-HT2AR. We show that IHCH-8110 inhibits CRC progression by activating 5-HT2AR on enteric glial cells, thereby inducing CXCL10 and interleukin (IL)-18 expression to promote CD8+ T cell recruitment and effector polarization within the tumor microenvironment. By converting immune-cold CRC into a more immunologically responsive state, IHCH-8110 enhances the efficacy of PD-1 blockade. Together, our findings identify enteric 5-HT2AR signaling as a regulator of antitumor immunity and support peripheral 5-HT2AR agonists as a therapeutic strategy for CRC immunotherapy.

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.

BACKGROUND:MET amplification is recognised as a de novo driver alteration in non-small-cell lung cancer (NSCLC) but treatment responses with existing MET inhibitors remain largely unsatisfactory. We aimed to investigate the antitumour activity and safety of vebreltinib, a potent and highly selective MET inhibitor, in patients with MET amplification-driven NSCLC. METHODS:KUNPENG was a multicentre, multi-cohort, single-arm, phase 2 trial conducted across 17 hospitals in China, in patients with locally advanced or metastatic NSCLC with MET dysregulation. Patients were eligible if they were MET inhibitor-naive, aged 18 years or older with MET amplification-driven NSCLC (gene copy number of six or higher), and progressed after previous standard chemotherapy or were ineligible for chemotherapy (cohort 2) or refused chemotherapy (cohort 3). Patients received 200 mg vebreltinib orally twice daily until disease progression or intolerable toxicity. The primary endpoint was the objective response rate, assessed by a masked independent review committee in the full analysis set. The study was amended to merge cohorts 2 and 3 due to slow accrual and was closed to enrolment on Nov 14, 2023. This trial is registered with ClinicalTrials.gov (NCT04258033). FINDINGS:Between Jan 17, 2020, and Nov 14, 2023, 145 patients were enrolled; of these, 86 patients (30 chemotherapy-treated and 56 untreated) from cohorts 2 and 3 were included in the current analysis. The median age was 65 years (range 48-82; IQR 59-71), 77 (90%) patients were male, and nine (10%) were female. All patients were Chinese. 42 patients had partial response, resulting in an objective response rate of 48·8% (42 of 86; 95% CI 38·3-59·4) per masked independent review committee. The median follow-up was 18·6 months (IQR 15·7-37·3). The incidence of grade 3 or worse treatment-related adverse events was 31% (27 of 86), predominantly abnormal liver function terms reported by the investigators (eight [9%]). Serious adverse events related to treatment were reported by 16 (19%) patients. 11 treatment-emergent adverse events leading to death occurred, of which one patient died of abnormal liver function, which was possibly related to vebreltinib treatment. INTERPRETATION:Vebreltinib showed antitumour activity in patients with MET amplification-driven advanced NSCLC who had previously received chemotherapy or were chemotherapy-naive. Further research is needed to validate these findings. FUNDING:Beijing Pearl Biotechnology and Avistone Biotechnology.

A subset of patients with small cell lung cancer (SCLC) exhibit intrinsic resistance to chemotherapy. However, biomarkers that effectively predict this group of patients are still lacking. We previously reported that high geranylgeranyl diphosphate synthase 1 (GGPS1) expression is associated with poor overall survival (OS) in SCLC, and statin combination therapy is effective in overcoming chemoresistance, especially in GGPP-high SCLC. However, the expression patterns of GGPS1 in SCLC subtypes and its relationship with clinical chemotherapy response remain unclear, and whether GGPS1 indicates statin treatment sensitivity in chemoresistant SCLC needs further validation. Through integrative analyses of 146 real-world SCLC cases, we found that approximately 25% exhibited high GGPS1 expression. Subgroup analysis revealed that GGPS1 expression was higher in the ASCL1/NEUROD1/POU2F3 triple-negative subgroup. Moreover, high GGPS1 expression was significantly correlated with reduced objective response rate (ORR) and progression-free survival (PFS) as well as OS. In addition, analysis of seven paired biopsy samples demonstrated that GGPS1 was upregulated in chemoresistant SCLC. We further showed that the combination of etoposide and cisplatin (E/P) with statins had improved efficacy in a patient-derived xenograft (PDX) model derived from a relapsed patient with high GGPS1 expression. Our findings suggest that GGPS1 is a promising biomarker for predicting chemoresistance in SCLC and may be a potential indicator of sensitivity to statin combination therapy in chemoresistant SCLC.

BackgroundUbiquitination, a critical post-translational modification, plays a pivotal role in regulating protein stability and activity, influencing various aspects of cancer development, including metabolic reprogramming, immune evasion, and tumor progression. However, the specific role of ubiquitination in hepatocellular carcinoma (HCC), particularly in relation to the tumor microenvironment (TME), remains poorly understood. This study aims to systematically explore the role of ubiquitination in shaping the TME of HCC, with a focus on its impact on cancer progression and immune modulation.MethodsWe performed bioinformatics analysis by integrating multiple publicly available HCC datasets to assess the ubiquitination status across various cell types in the TME, including plasma cells, fibroblasts, endothelial cells, and epithelial-mesenchymal transition (EMT) cells. Ubiquitination scores were calculated to categorize these cell types, and survival data, along with spatial transcriptomics, were employed to evaluate how different levels of ubiquitination influence HCC progression. In vitro experiments, such as transwell, CCK8, and wound healing assays, were used to further investigate the role of the key ubiquitination gene UBE2C in HCC phenotypes.ResultsOur study revealed that ubiquitination-related genes are significantly upregulated in HCC tissues, with high expression levels correlating with poor prognosis in patients. Pathway analysis showed that these genes are enriched in key processes such as cell cycle regulation, DNA repair, metabolic reprogramming, and p53 signaling. These pathways contribute to the TME by promoting tumor cell proliferation, facilitating matrix remodeling, and enhancing angiogenesis. Notably, UBE2C, a critical ubiquitination enzyme, appears to play a key role in immune evasion, potentially by inhibiting anti-tumor immune responses and reducing the immune system’s ability to recognize and eliminate tumor cells. Furthermore, experimental data confirmed that UBE2C overexpression promotes HCC cell proliferation, invasion, and metastasis, further supporting its role in tumor progression and TME remodeling.ConclusionThis study reveals the multifaceted regulatory roles of ubiquitination in HCC. Ubiquitination not only supports proliferation and anti-apoptotic functions within tumor cells but also promotes tumor progression by modulating the activity of immune and stromal cells. Among all ubiquitination-related genes, UBE2C emerges as a potential prognostic biomarker and therapeutic target in HCC, offering new directions for precision treatment of HCC in the future.

Microwave ablation (MWA), an innovative therapy for hepatocellular carcinoma (HCC), faces challenges of limited thermal effects and a tumor immunosuppressive microenvironment. Addressing these, we developed an advanced Au@PMO@DOX-Lac nanocomposite, aimed at enhancing the microwave thermal effect, while simultaneously facilitating targeted chemotherapy and immunomodulation. This nanocomposite, incorporating gold-embedded yolk-shell mesoporous organosilica nanoparticles, amplifies microwave thermal effects from two aspects: molecular hotspots created at the gold-silica interface and the confinement effect within its hollow nanostructure. These enhancements facilitate more effective tumor ablation with reduced microwave power requirements and shorter treatment durations. Additionally, surface modification with lactobionic acid and loading with doxorubicin allow the nanocomposite to perform precise, targeted synergistic chemotherapy. After ablation, the nanocomposite increased cytotoxic T cells and reduced regulatory T cells, while shifting macrophages from the immunosuppressive M2 to the anti-tumor M1 phenotype, significantly enhancing localized and systemic anti-tumor immune responses. Overall, this multifunctional nanocomposite not only overcomes the thermal limitations of MWA but also addresses the tumor's immunosuppressive environment, providing a promising approach for treating HCC and potentially other cancers with similar therapeutic challenges.

BACKGROUND:This prospective, observational study evaluated the real-world safety of osimertinib in a broad Chinese population with non-small cell lung cancer (NSCLC). METHODS:Chinese NSCLC patients who received osimertinib were enrolled and followed up for 12 months. The primary endpoint was the incidence of adverse drug reactions (ADRs). RESULTS:From 20 April 2020 to 1 August 2022, 1,700 patients were enrolled from 30 centers, with 706 (41.5%) patients ≥65 years old. Osimertinib was administered as first-line, second-line, third/later-line and adjuvant therapy in 44.9%, 34.2%, 14.3% and 4.5% of the patients, respectively. ADRs, adverse events (AEs), Grade ≥3 AEs, and serious AEs were reported in 627 (36.9%), 959 (56.4%), 165 (9.7%), and 102 (6.0%) patients, respectively. AEs of special interests occurred in 59 (3.5%) patients, with 41 (2.4%) and 19 (1.1%) reporting QTc prolongation and interstitial lung disease/pneumonitis-like events, respectively. The safety profiles in patients ≥65 years old and those usually not included in randomized clinical trials were similar to that in the total population. CONCLUSION:This largest real-world safety study of osimertinib in China demonstrated that osimertinib was well-tolerated in a broad NSCLC population, including patients usually not included in randomized clinical trials, without new safety signals identified. CLINICAL TRIAL REGISTRATION:NCT03485326 (www.clinicaltrials.gov).

The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.

PURPOSE The KUNPENG study aimed to evaluate the efficacy and safety of vebreltinib (also known as bozitinib, APL-101, PLB-1001, and CBT-101), a potent and highly selective inhibitor of c-mesenchymal-epithelial transition ( MET ), in patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring c-Met alterations. METHODS This multicenter, multicohort, open-label, single-arm, phase II trial enrolled patients with c-Met dysregulated, locally advanced or metastatic NSCLC from January 2020 to August 2022 across 17 centers. Cohort 1 included patients with MET exon 14 skipping ( MET ex14)–mutant NSCLC who had not previously received MET inhibitors. Participants were administered vebreltinib at a dosage of 200 mg twice a day in 28-day cycles. The primary end point was the objective response rate (ORR), and the key secondary end point was the duration of response (DoR), both evaluated by a blinded independent review committee according to the RECIST version 1.1. RESULTS As of August 9, 2022, 52 patients had been enrolled in cohort 1, of whom 35 (67.3%) were treatment-naïve. The ORR reached 75% (95% CI, 61.1 to 86). Among treatment-naïve patients, the ORR was 77.1% (95% CI, 59.9 to 89.6), and in previously treated patients, it was 70.6% (95% CI, 44.0 to 89.7). The disease control rate was 96.2%, with a median DoR of 15.9 months, a median progression-free survival of 14.1 months, and a median overall survival of 20.7 months. The most common treatment-related adverse events were peripheral edema (82.7%), QT prolongation (30.8%), and elevated serum creatinine (28.8%). CONCLUSION Vebreltinib has shown promising efficacy and a favorable safety profile in patients with MET ex14-mutant NSCLC.

Abstract Background The study focuses on PD‐L1 expression as an essential biomarker for gauging the response of EGFR/ALK wild‐type NSCLC patients to FDA‐approved immune checkpoint inhibitors (ICIs). It aims to explore clinical, molecular, and immune microenvironment characteristics associated with PD‐L1 expression in EGFR/ALK wild‐type lung adenocarcinoma patients eligible for ICI therapy. Methods In this retrospective study, tumor samples from 359 Chinese EGFR/ALK wild‐type lung adenocarcinoma patients underwent comprehensive evaluations for PD‐L1 expression and NGS‐targeted sequencing. The investigation encompassed the analysis and comparison of clinical traits, gene mutations, pathways, and immune signatures between two groups categorized by PD‐L1 status: negative (TPS < 1%) and positive (TPS ≥ 1%). Additionally, the study explored the link between genomic changes and outcomes following immunotherapy. Results High tumor mutational burden correlated significantly with PD‐L1 positivity in patients with EGFR/ALK wild‐type lung adenocarcinoma. Gene alterations, including TP53, KRAS, and others, were more pronounced in the PD‐L1 positive group. Pathway analysis highlighted higher frequencies of alterations in pathways like RTK/RAS, p53, and Hippo in PD‐L1‐positive patients. The Hippo pathway's relevance was confirmed in separate immunotherapy cohorts, associated with better outcomes. In terms of immune cell infiltration, Hippo mutants exhibited higher levels of CD68+PD‐L1+ macrophages, CD8+ T cells, and CD8+PD‐1− T cells. Conclusions This study offers insights into genomic features of Chinese EGFR/ALK wild‐type lung adenocarcinoma patients based on PD‐L1 expression. Notably, Hippo pathway alterations were linked to improved immunotherapy outcomes. These findings suggest connections between the Hippo pathway and PD‐L1 expression, warranting further clinical and functional investigations. The research advances our understanding of PD‐L1 expression's genomic context and immunotherapy response in EGFR/ALK wild‐type lung adenocarcinoma.