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BACKGROUND: This study aimed to determine the prognostic value of the sarcopenia on the progression free survival (PFS) and overall survival (OS) of esophageal squamous cell cancer (ESCC) patients who received radiotherapy (RT) or chemoradiotherapy (CRT). METHODS: Data on clinicopathological characteristics and nutritional parameters were analyzed and correlated with PFS and OS, retrospectively. Skeletal muscle, subcutaneous, visceral and total fat tissue cross-sectional areas were evaluated on CT images at the midpoint of the 3rd lumbar vertebrae. A total of 213 patients were enrolled in this study. RESULTS: Sarcopenia was significantly associated with subcutaneous fat content. The univariate analysis demonstrated that OS was superior in patients with non-sarcopenia, non-alcohol, NRI ≥ 100, albumin ≥ 40 g/L, TATI > 83.0, SATI > 27.8, VATI > 49, non-anemia, cervical and upper-thoracic ESCC, T stage 1-2, N stage 0-1 and TNM stage I-II. In the multivariate analysis, sarcopenia, albumin, N stage and TNM stage were identified as independent prognostic factors of survival. This study demonstrated that sarcopenia was related to worse PFS and OS in patients with ESCC who received RT or CRT. CONCLUSIONS: Sarcopenia is considered to be a useful predictor in patients with ESCC who received RT or CRT. This study also provided a conceptual basis for further prospective research on the application of the sarcopenia for patients receiving RT or CRT for intermediate- and advanced-stage ESCC.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Sarcopenia , Albuminas , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/efeitos adversos , Células Epiteliais , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Carcinoma de Células Escamosas do Esôfago/terapia , Humanos , Prognóstico , Estudos Retrospectivos , Sarcopenia/diagnóstico por imagem , Sarcopenia/etiologiaRESUMO
Aim: This study was conducted to evaluate the efficacy of immune checkpoint inhibitors (ICIs) plus anlotinib versus anlotinib alone to provide guidance for clinical treatment of non-small-cell lung cancer. Patients & methods: The records of 139 patients with advanced non-small-cell lung cancer who received at least one dose of ICIs plus anlotinib (IA group) or single-agent anlotinib (AA group) were retrospectively reviewed. The efficacy of the treatments, survival outcomes and adverse events were analyzed. The primary end point was investigator-assessed progression-free survival (PFS). Result: The IA group had a significantly prolonged median PFS (mPFS: 5.8 vs 4.2 months; p = 0.022) compared with the AA group (hazard ratio: 0.68; 95% CI: 0.68-0.97). In patients with brain metastases, the IA group exhibited improved efficacy (mPFS: 6.0 vs 3.8 months; p = 0.034) compared with the AA group (hazard ratio: 0.49; 95% CI: 0.23-1.05). Conclusion: ICIs plus anlotinib significantly improved efficacy compared with anlotinib alone and showed substantial potential for the control of intracranial lesions.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Quinolinas/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Barreira Hematoencefálica , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Indóis/administração & dosagem , Indóis/efeitos adversos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Estudos RetrospectivosRESUMO
MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance of human cancer. Fewer studies were explored the roles of miR-92b on human lung cancer cell growth and resistance to cisplatin (CDDP). In this paper, we utilized real-time PCR to verify miR-92b was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues compared to matched adjacent normal tissues. In vitro assay demonstrated that knock-down of miR-92b inhabits cell growth and sensitized the A549/CDDP cells to CDDP. Furthermore, we found miR-92b could directly target PTEN, a unique tumor suppressor gene, which was downregulated in lung cancer tissues compared to the matched adjacent normal tissues. These data indicate that the miR-92b play an oncogene roles by regulates cell growth, cisplatin chemosensitivity phenotype, and could serve as a novel potential maker for NSCLC therapy.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , MicroRNAs/fisiologia , PTEN Fosfo-Hidrolase/genética , Apoptose , Proliferação de Células , Humanos , MicroRNAs/genética , Regulação para CimaRESUMO
Here, we report the draft genome sequence of Bacillus cereus strain THSB-6-2, which was isolated from cyanobacterial blooms in Lake Taihu, China. The 5,496,658-bp genome assembly of Bacillus cereus consists of 28 contigs, with a GC content of 35% and with 5,587 protein-coding sequences and 58 RNA genes.
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Cyanobacterial harmful algal blooms (CyanoHABs) are longstanding aquatic hazards worldwide, of which the mechanism is not yet fully understood, i.e., the process in which cyanobacteria establish dominance over coexisting algae in the same eutrophic waters. The dominance of CyanoHABs represents a deviation from their low abundance under conventional evolution in the oligotrophic state, which has been the case since the origin of cyanobacteria on early Earth. To piece together a comprehensive mechanism of CyanoHABs, we revisit the origin and adaptive radiation of cyanobacteria in oligotrophic Earth, demonstrating ubiquitous adaptive radiation enabled by corresponding biological functions under various oligotrophic conditions. Next, we summarize the biological functions (ecophysiology) which drive CyanoHABs and ecological evidence to synthesize a working mechanism at the population level (the special mechanism) for CyanoHABs: CyanoHABs are the consequence of the synergistic interaction between superior cyanobacterial ecophysiology and elevated nutrients. Interestingly, these biological functions are not a result of positive selection by water eutrophication, but an adaptation to a longstanding oligotrophic state as all the genes in cyanobacteria are under strong negative selection. Last, to address the relative dominance of cyanobacteria over coexisting algae, we postulate a "general" mechanism of CyanoHABs at the community level from an energy and matter perspective: cyanobacteria are simpler life forms and thus have lower per capita nutrient demand for growth than coexisting eukaryotic algae. We prove this by comparing cyanobacteria and eukaryotic algae in cell size and structure, genome size, size of genome-scale metabolic networks, cell content, and finally the golden standard-field studies with nutrient supplementation in the same waters. To sum up, the comprehensive mechanism of CyanoHABs comprises a necessary condition, which is the general mechanism, and a sufficient condition, which is the special mechanism. One prominent prediction based on this tentative comprehensive mechanism is that eukaryotic algal blooms will coexist with or replace CyanoHABs if eutrophication continues and goes over the threshold nutrient levels for eukaryotic algae. This two-fold comprehensive mechanism awaits further theoretic and experimental testing and provides an important guide to control blooms of all algal species.
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BACKGROUND: Treatment options are limited for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after treatment failure with EGFR tyrosine kinase inhibitors (TKIs). This multicenter open-label, phase II study aims to evaluate the efficacy and safety of tislelizumab plus chemotherapy (cohort 1, TIS+chemo) or tislelizumab plus chemotherapy and bevacizumab (cohort 2, TIS+chemo+ beva) in EGFR-mutated non-squamous NSCLC patients who progressed on EGFR TKI therapies. Here, the primary analysis of the TIS+chemo cohort is reported. METHODS: In the TIS+chemo cohort, patients with EGFR-sensitizing mutations with prior EGFR TKI failure received tislelizumab plus carboplatin and nab-paclitaxel as induction treatment, followed by maintenance with tislelizumab plus pemetrexed. The primary endpoint was 1-year progression-free survival (PFS) rate. The planned sample size was 66 with a historical control of 7%, an expected value of 20%, a one-sided α of 0.05, and a power of 85%. RESULTS: Between July 11, 2020 and December 13, 2021, 69 patients were enrolled. As of June 30, 2022, the median follow-up was 8.2 months. Among the 62 patients in the efficacy analysis set, estimated 1-year PFS rate was 23.8% (90% CI 13.1% to 36.2%), and its lower bound of 90% CI was higher than the historical control of chemotherapy (7%), which met the primary endpoint. The median PFS was 7.6 (95% CI 6.4 to 9.8) months. Median overall survival (OS) was not reached (95% CI 14.0 to not estimable), with a 1-year OS rate of 74.5% (95% CI 56.5% to 86.0%). The objective response rate and disease control rate were 56.5% (95% CI 43.3% to 69.0%) and 87.1% (95% CI 76.1% to 94.3%), respectively. Patients who had progressed on first-generation/second-generation and third-generation EGFR-TKIs at baseline had shorter PFS than those who progressed on first-generation/second-generation EGFR-TKIs (median 7.5 vs 9.8 months, p=0.031). Patients with positive ctDNA had shorter PFS (median 7.4 vs 12.3 months, p=0.031) than those with negative ctDNA. No grade 5 treatment-emergent adverse events (TEAEs) were observed. Grades 3-4 TEAEs occurred in 40.6% (28/69) of patients. Grades 3-4 immune-related AEs occurred in 5 (7.2%) patients. CONCLUSION: The study met the primary endpoint for the TIS+chemo cohort. Tislelizumab plus chemotherapy is effective with an acceptable safety profile for EGFR-mutated non-squamous NSCLC after EGFR TKI failure.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genéticaRESUMO
PURPOSE: The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS: At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION: Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fosfatidilinositol 3-Quinases , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Long-standing cyanobacterial harmful algal blooms (CyanoHABs) are known to result from synergistic interaction between elevated nutrients and superior ecophysiology of cyanobacteria. However, it remains to be determined whether CyanoHABs are a result of positive selection by eutrophic waters. To address this, we conducted molecular evolutionary analyses on the genomes of 9 bloom-forming cyanobacteria, combined with pangenomics and metatranscriptomics. The results showed no positive selection by water eutrophication. Instead, all homologous genes in the species are under strong purifying selection based on the ratio of divergence at nonsynonymous and synonymous sites (dN/dS) and phylogeny. The dN/dS < 0.85 (median = 0.3) for all homologous genes are similar between the genes in the pathways driving CyanoHABs and housekeeping functions. Phylogenetic support for non-positive selection comes from the mixed clustering of strains: strains of the same species from diverse geographic origins form the same clusters, while strains from the same origins form different clusters. Further support lies in the codon adaptation index (CAI) and single nucleotide polymorphism (SNP). The CAI ranged from 0.42 to 0.9 (mean = 0.75), which indicates high-level codon usage bias; the pathways for CyanoHABs and housekeeping functions showed a similar CAI. Interestingly, CAI was negatively correlated with gene expression in 3 metatranscriptomes. The numbers of SNPs were concentrated around 5 to 50. As the SNP number increases, the gene expression level decreases. These negative correlations agree with the population-level dN/dS and phylogeny in supporting purifying selection in bloom-forming cyanobacteria. In summary, superior ecophysiology appears to be acquired prior to water eutrophication. IMPORTANCE CyanoHABs are global environmental hazards, and their mechanisms of action are being intensively investigated. On an ecological scale, CyanoHABs are consequences of synergistic interactions between biological functions and elevated nutrients in eutrophic waters. On an evolutionary scale, one important question is how bloom-forming cyanobacteria acquire these superior biological functions. There are several possibilities, including adaptive evolution and horizontal gene transfer. Here, we explored the possibility of positive selection. We reasoned that there are two possible periods for cyanobacteria to acquire these functions: before the onset of water eutrophication or during water eutrophication. Either way, there should be molecular signatures in protein sequences for positive selection. Interestingly, we found no positive selection by water eutrophication, but strong purifying selection instead on nearly all the genes, suggesting these superior functions aiding CyanoHABs are acquired prior to water eutrophication.
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Cianobactérias , Lagos , Filogenia , Lagos/microbiologia , Cianobactérias/genética , Proliferação Nociva de Algas , ÁguaRESUMO
PURPOSE: The objective of this study was to evaluate the safety and efficacy of immune checkpoint inhibitor (ICI) plus anlotinib as third-line treatment in extensive-stage small cell lung cancer (ES-SCLC). METHODS: A total of 120 patients with ES-SCLC who were admitted to Shandong Cancer Hospital between January 2019 and December 2020 were retrospectively analyzed. They were divided into the observation group (n = 62) and the control group (n = 58) according to their different treatment plans. The observation group was given ICI plus anlotinib, while the control group was given anlotinib alone. The primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were the objective response rate (ORR) and disease control rate (DCR). An efficacy evaluation was carried out every 6 weeks. Univariate and multivariate analyses were performed to identify the prognostic factors. The main treatment-related adverse events were evaluated according to the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: In the observation group and the control group, the DCRs were 87.1% and 72.4% (p = 0.044), and the ORRs were 19.4% and 6.9% (p = 0.045), respectively. The median PFS was longer in the observation group (7.5 months) than in the control group (4.6 months) (p = 0.0033). In Cox regression analysis, the Eastern Cooperative Oncology Group performance status score, brain metastases and metastatic sites were prognostic factors of ICI plus anlotinib. Compared with the control group, grade 1-2 immune-related pneumonia and hypothyroidism of patients in the observation group were significantly increased (p < 0.05), but grade 3-4 treatment-related adverse reactions were not significantly increased (p > 0.05). CONCLUSION: ICI plus anlotinib showed promising efficacy and manageable toxicity in third-line treatment of ES-SCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Indóis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Quinolinas/administração & dosagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , China/epidemiologia , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Indóis/efeitos adversos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Estudos Retrospectivos , Terapia de Salvação , Carcinoma de Pequenas Células do Pulmão/epidemiologia , Carcinoma de Pequenas Células do Pulmão/patologia , Adulto JovemRESUMO
BACKGROUND: Primary lung squamous carcinoma that produces alpha-fetoprotein (AFP) is rare and only four related cases have been reported so far. The specific reasons for elevated serum level of AFP and effective treatment regimens for AFP-producing lung squamous carcinoma are not clear. This paper reports the diagnosis and treatment of AFP-producing lung squamous carcinoma so as to provide some references for similar cases in clinical practice. METHODS: The diagnosis and treatment of an AFP-producing lung squamous carcinoma patient admitted to the Shandong Cancer Hospital on October 23, 2020 was retrospectively analyzed, and literatures were reviewed. RESULTS: A 52-year-old male patient was diagnosed as T4N3M0 stage, IIIc right upper lobe lung squamous cell carcinoma with mediastinal lymph node metastasis and multiple metastases in the lung. The main tumor marker was abnormally increased serum AFP. After the rapid progression of two lines chemotherapy, the patient was given anlotinib combined with carrizumab as third-line treatment. The efficacy evaluation reached to partial response (PR) and stable disease (SD) after 2 and 4 cycles of treatment, respectively. The treatment regimen was replaced with albumin paclitaxel plus carrizumab due to gastrointestinal bleeding after the fifth cycle. The patient's condition was under continuous control. CONCLUSIONS: The AFP-producing lung squamous carcinoma patient had a good response to anlotinib and immunotherapy in the case report, which may provide some guidances for the clinical practice and the research on AFP-producing lung squamous carcinoma.
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Carcinoma de Células Escamosas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas/tratamento farmacológico , Humanos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , alfa-FetoproteínasRESUMO
Anaplastic lymphoma kinase (ALK) fusions have been identified in approximately 5% of non-small cell lung cancer (NSCLC) cases. ALK-tyrosine kinase inhibitors (TKIs) are the standard first-line treatment for patients with ALK-positive (ALK+) advanced NSCLC. Along with widespread use of next-generation sequencing (NGS) for the molecular diagnosis of lung cancer, an increasing number of ALK fusion partners are being reported, with the majority being effective for ALK-TKIs. Here, we present the case of a 42-year-old female with no smoking history who was diagnosed with stage IVB lung adenocarcinoma. Two rare ALK fusions were detected simultaneously by NGS in this patient: latent transforming growth factor beta-binding protein 1 (LTBP1)-ALK and huntingtin-interacting protein 1 (HIP1)-ALK. HIP1-ALK fusion was also detected by further RNA sequencing, but LTBP1-ALK failed to give a positive signal. The patient received alectinib as first-line therapy and consequently achieved a good response. Progression-free survival (PFS) was more than 19 months, and the treatment with alectinib is ongoing currently. During treatment, clinical symptoms disappeared and no significant adverse events occurred. This is the first case report describing a patient with an NSCLC tumor harboring 2 rare ALK fusions who responded to alectinib. Our report enriches the knowledge of ALK fusion sites and provides an effective clinical basis for the screening of sensitive fusions.
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Background: Savolitinib, a selective MET inhibitor, showed efficacy in patients with non-small cell lung cancer (NSCLC), including pulmonary sarcomatoid carcinoma (PSC), harbouring MET exon 14 skipping alteration (METex14). Objective: To analyse post hoc, the association between circulating tumour DNA (ctDNA) biomarkers and clinical outcomes, including resistance, with savolitinib. Design: A multicentre, single-arm, open-label phase 2 study. Methods: All enrolled patients with baseline plasma samples were included. Outcomes were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) by baseline METex14 and post-treatment clearance, coexisting gene alterations at baseline and disease progression. Results: Among 66 patients with baseline ctDNA sequencing, 46 (70%) had detectable METex14. Frequent coexisting baseline gene alterations included TP53 and POT1 mutations. Patients with detectable baseline METex14 exhibited worse PFS [hazard ratio (HR), 1.77; 95% confidence interval (CI), 0.88-3.57; p = 0.108] and OS (HR, 3.26; 95% CI, 1.35-7.89; p = 0.006) than those without, despite showing a numerically higher ORR. Among 24 patients with baseline detectable METex14 and evaluable postbaseline samples, 13 achieved METex14 clearance post-treatment. Median time to first clearance was 1.3 months (range, 0.7-1.5). METex14 post-treatment clearance was associated with better ORR (92.3%; 95% CI, 64.0-99.8 versus 36.4%; 95% CI, 10.9-69.2; p = 0.0078), PFS (HR, 0.44; 95% CI, 0.2-1.3; p = 0.1225) and OS (HR, 0.31; 95% CI, 0.1-1.0; p = 0.0397) versus non-clearance. Among 22 patients with disease progression, 10 acquired pathway alterations (e.g. in RAS/RAF and PI3K/PTEN) alone or with secondary MET mutations (D1228H/N and Y1230C/H/S). Conclusion: ctDNA biomarkers may allow for longitudinal monitoring of clinical outcomes with savolitinib in patients with METex14-positive PSC and other NSCLC subtypes. Specifically, undetectable baseline METex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib. Registration: The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.
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Introduction: Savolitinib has been found to have encouraging antitumor activity and a favorable safety profile in Chinese patients with pulmonary sarcomatoid carcinoma and other NSCLCs with MET exon 14 skipping alterations (MET ex14 positive) at the primary analysis of a phase 2 study. Here, we present the long-term efficacy and safety data of savolitinib, including subgroup analyses. Methods: This multicenter, single-arm, open-label, phase 2 study in the People's Republic of China enrolled MET inhibitor-naive adults with locally advanced or metastatic METex14-positive NSCLC (NCT02897479). Oral savolitinib at a dose of 400 or 600 mg was administered once daily (body weight dependent). The primary objectives of the final analysis were long-term overall survival (OS) and subgroup analyses by previous systemic treatment, NSCLC subtypes, and brain metastases. Results: At the final analysis cutoff date (June 28, 2021), a total of 70 patients were enrolled and receiving savolitinib, and median follow-up was 28.4 (interquartile range: 26.2-36.3) months. The median OS was 12.5 months (95% confidence interval [CI]: 10.5-21.4 [18- and 24-mo OS rates, 42.1% and 31.5%, respectively]). Median OS in pretreated or treatment-naive patients was 19.4 (95% CI: 10.5-31.3) and 10.9 (95% CI: 7.5-14.0) months, respectively; it was 10.6 months (95% CI: 4.6-14.0) in patients with pulmonary sarcomatoid carcinoma, 17.3 months (95% CI: 10.6-23.6) in other NSCLC subtypes, and 17.7 months (95% CI: 10.5-not evaluable) in patients with brain metastases. No new safety signals emerged with prolonged follow-up and exposure. Conclusions: The updated results further confirm the favorable benefit and acceptable safety of savolitinib in Chinese patients with METex14-positive NSCLC.
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BACKGROUND: Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC. METHODS: ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m2 of docetaxel intravenously every 3 weeks, stratified by the Eastern Cooperative Oncology Group performance status. The primary endpoint was overall survival (OS) in the full analysis set (FAS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. RESULTS: Between August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval [CI], 10.28-15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47-9.82) months with docetaxel (hazard ratio [HR]: 0.74; 95% CI, 0.56-0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39-0.68; P < 0.001) and showed higher ORR (25.50% vs. 2.20%, P < 0.001) and DCR (65.50% vs. 37.80%, P < 0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86-25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41-7.23) months in the docetaxel arm (P = 0.045). Treatment-related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P < 0.001) and CTCF (HR: 3.50; P < 0.001)ï¼for sintilimab treatment. CONCLUSIONS: Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Docetaxel/efeitos adversos , Neoplasias Pulmonares/patologia , Taxoides/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Fatores de TranscriçãoRESUMO
BACKGROUND: Lipusu is the first commercialized liposomal formulation of paclitaxel and has demonstrated promising efficacy against locally advanced lung squamous cell carcinoma (LSCC) in a small-scale study. Here, we conducted a multicenter, randomized, phase 3 study to compare the efficacy and safety of cisplatin plus Lipusu (LP) versus cisplatin plus gemcitabine (GP) as first-line treatment in locally advanced or metastatic LSCC. METHODS: Patients enrolled were aged between 18 to 75 years, had locally advanced (clinical stage IIIB, ineligible for concurrent chemoradiation or surgery) or metastatic (Stage IV) LSCC, had no previous systemic chemotherapy and at least one measurable lesion as per the Response Evaluation Criteria in Solid Tumors (version 1.1) before administration of the trial drug. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety profiles. To explore the possible predictive value of plasma cytokines for LP treatment, plasma samples were collected from the LP group at baseline and first efficacy evaluation time and were then subjected to analysis by 45-Plex ProcartaPlex Panel 1 to detect the presence of 45 cytokines using the Luminex xMAP technology. The correlation between treatment outcomes and dynamic changes in the levels of cytokines were evaluated in preliminary analyses. RESULTS: The median duration of follow-up was 15.4 months. 237 patients in the LP group and 253 patients in the GP group were included in the per protocol set (PPS). In the PPS, the median PFS was 5.2 months versus 5.5 months in the LP and GP group (hazard ratio [HR]: 1.03, P = 0.742) respectively. The median OS was 14.6 months versus 12.5 months in the LP and GP group (HR: 0.83, P = 0.215). The ORR (41.8% versus 45.9%, P = 0.412) and DCR (90.3% versus 88.1%, P = 0.443) were also similar between the LP and GP group. A significantly lower proportion of patients in the LP group experienced adverse events (AEs) leading to treatment interruptions (10.9% versus 26.4%, P < 0.001) or treatment termination (14.3% versus 23.1%, P = 0.011). The analysis of cytokine levels in the LP group showed that low baseline levels of 27 cytokines were associated with an increased ORR, and 15 cytokines were associated with improved PFS, with 14 cytokines, including TNF-α, IFN-γ, IL-6, and IL-8, demonstrating an overlapping trend. CONCLUSION: The LP regimen demonstrated similar PFS, OS, ORR and DCR as the GP regimen for patients with locally advanced or metastatic LSCC but had more favorable toxicity profiles. The study also identified a spectrum of different cytokines that could be potentially associated with the clinical benefit in patients who received the LP regimen.
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Carcinoma de Células Escamosas , Neoplasias Pulmonares , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Cisplatino/efeitos adversos , Desoxicitidina/análogos & derivados , Humanos , Lipossomos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Adulto Jovem , GencitabinaRESUMO
BACKGROUND: Programmed cell death 1 or programmed cell death ligand 1 inhibitor (PD-1/PD-L1 inhibitor) and docetaxel, as the standard second-line treatments of advanced non-small cell lung cancer (NSCLC) patients, have limited effects. There are few studies on whether docetaxel combined with PD-1/PD-L1 inhibitor can increase the efficacy and make patients better benefit. The aim of this study is to evaluate the efficacy and safety of docetaxel combined with PD-1/PD-L1 inhibitor for the second-line treatment of stage IV NSCLC patients. METHODS: Stage IV NSCLC patients (n=118) who received treatment at Shandong Cancer Hospital between October 1, 2018, and December 31, 2020, were retrospectively analyzed. They were divided into observation group (n=69) and control group (n=49) according to different treatment plan. Observation group was given docetaxel plus PD-1/PD-L1 inhibitor, while control group was given PD-1/PD-L1 inhibitor. The clinical curative effect and the incidence of adverse reactions of grade 3 and above were compared between the two groups. RESULTS: The disease control rate (DCR) was higher in the observation group (89.9%) than that in the control group (73.5%) (P=0.019), and the objective response rate (ORR) showed no significant difference between observation group (24.6%) and control group (16.3%) (P=0.276). Till June 22, 2021, the 1-year PFS rate showed no difference between observation group (16.5%) and control group (7.7%) (P=0.205). During the treatment period, the adverse reactions of the two groups were mostly grade 1 to 2, and could be tolerated. The incidence of bone marrow suppression in observation group was higher than that in the control group (P<0.05), and the remaining adverse reactions were not statistically different from control group. Cox regression analysis showed that performance status (PS) (P=0.020) and age (P=0.049) were independent prognostic factors for the effect of docetaxel combined with PD-1/PD-L1 inhibitor. CONCLUSIONS: The second-line treatment with docetaxel plus PD-1/PD-L1 inhibitor in patients with stage IV NSCLC can improve the DCR and prolong the PFS, and the adverse reactions are tolerable.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Docetaxel , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Docetaxel/efeitos adversos , Docetaxel/uso terapêutico , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos RetrospectivosRESUMO
BACKGROUND: Recent studies have found that programmed death ligand 1 (PD-L1) might be involved in chemotherapy resistance in non-small cell lung cancer (NSCLC). Arsenic sulfide (As4 S4 ) has been recognized to have antitumor activities and enhance the cytotoxic effect of chemotherapy drugs. In this study, we aimed to verify the relationship between PD-L1 and cisplatin (DDP) resistance and identify whether As4 S4 could reverse DDP resistance through targeting PD-L1 in NSCLC. METHODS: The effect of As4 S4 and DDP on cell proliferation and apoptosis was investigated in NSCLC cell lines. The expression of p53 and PD-L1 proteins was measured by western blotting analysis. The levels of miR-34a-5p, miR-34a-3p and PD-L1 in cells were measured by real-time qPCR analysis. Mouse xenograft models were established by inoculation with A549/DDP (DDP-resistant) cells. RESULTS: Depletion of PD-L1 inhibited DDP resistance in A549/DDP and H1299/DDP cells. As4 S4 was capable of sensitizing A549/DDP cells to DDP by enhancing apoptosis. As4 S4 upregulated p53 expression and downregulated PD-L1 expression in A549/DDP cells. As4 S4 increased miR-34a-5p level in A549/DDP cells. Inhibition of p53 by PFT-α partially restored the levels of PD-L1 and miR-34a-5p. Pretreatment with PFT-α suppressed the apoptosis rate induced by cotreatment of As4 S4 and DDP in A549/DDP cells. Cotreatment of DDP and As4 S4 notably reduced the tumor size when compared with DDP treatment alone in vivo. CONCLUSIONS: Upregulation of PD-L1 was correlated with DDP resistance in NSCLC cells. Mechanistic analyses indicated that As4 S4 might sensitize NSCLC cells to DDP through targeting p53/miR-34a-5p/PD-L1 axis.
Assuntos
Arsenicais/farmacologia , Antígeno B7-H1/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Sulfetos/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo , Humanos , Camundongos , Regulação para CimaRESUMO
BACKGROUND: To study in vitro the effects of anlotinib combined with radiotherapy on the lung cancer H520 cell cycle and apoptosis. METHODS: The log growth period H520 cells were divided into the control group, anlotinib group (A group), radiotherapy group (RT group) and combined group (A + RT group). Cell cycle and apoptosis were detected by flow cytometry and changes in H520 cell cycle and apoptosis were analyzed in each group. RESULTS: Anlotinib was determined to significantly inhibit cell growth in all groups, both alone, or in combination with radiotherapy. After receiving corresponding treatments, the proportions of G2/M-phase cells in the control group, A group, RT group and A + RT group were different, and statistically significant (F = 32.086, P < 0.001). The apoptotic cell statistics of H520 cells in the control group, A group, RT group and A + RT group were significantly different (F = 44.537, P < 0.01). The relative expression of CDK1 in each group of cells was 0.04 ± 0.02, 0.07 ± 0.12, 0.81 ± 0.11, and 0.56 ± 0.16, respectively. There were differences between the groups by analysis of variance which were statistically significant (F = 58.36, P < 0.0001). The relative expression of cycle B in each group of cells was 0.27 ± 0.05, 0.40 ± 0.16, 0.65 ± 0.14, and 0.57 ± 0.13, respectively. There were differences between the groups by analysis of variance which were statistically significant (F = 10.77, P = 0.0002). CONCLUSIONS: Anlotinib had an inhibitory effect on lung cancer H520 cell proliferation. A higher rate of apoptosis and G2/M phase block was observed in the anlotinib-radiotherapy combined group. Anlotinib combined with radiotherapy was able to synergistically inhibit tumor cell growth. KEY POINTS: Anrotinib combined with radiotherapy can synergistically inhibit tumor cell growth.
Assuntos
Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Quinolinas/uso terapêutico , Apoptose , Ciclo Celular , Humanos , Indóis/farmacologia , Neoplasias Pulmonares/patologia , Quinolinas/farmacologiaRESUMO
OBJECTIVE: This phase 3 study aimed to test equivalence in efficacy and safety for QL1101, a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer (NSCLC). METHODS: Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab, 15 mg/kg every 3-week for 6 cycles. This was followed by maintenance treatment with single agent QL1101 every 3-week. The primary end-point was objective response rate (ORR), with secondary end-points being progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs). RESULTS: Of 675 patients, 535 eligible patients were randomized to the QL1101 group (n = 269) and bevacizumab group (n = 266). ORRs were 52.8% and 56.8%, respectively, for the QL1101 and bevacizumab groups, with an ORR hazard ratio 0.93 (95% confidence interval: 0.8-0131.1). The PFS, OS, DCR, and AEs were comparable between the 2 groups, which remained the same after stratification according to epidermal growth factor receptor mutation or smoking history. CONCLUSIONS: QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.
RESUMO
BACKGROUND: Savolitinib is a selective MET tyrosine-kinase inhibitor. We investigated the activity and safety of savolitinib in patients with pulmonary sarcomatoid carcinoma and other non-small-cell lung cancer (NSCLC) subtypes positive for MET exon 14 skipping alterations (METex14-positive). METHODS: We did a multicentre, single-arm, open-label, phase 2 study across 32 hospitals in China. Eligible patients were 18 years or older with locally advanced or metastatic METex14-positive pulmonary sarcomatoid carcinoma or other NSCLC subtypes, had either presented with disease progression or toxicity intolerance towards one or more standard treatments or were deemed clinically unsuitable for standard treatment, were MET inhibitor-naive, and had measurable disease. Patients received either 600 mg (bodyweight ≥50 kg) or 400 mg (bodyweight <50 kg) of oral savolitinib once daily until disease progression, death, intolerable toxicity, initiation of other anti-tumour therapy, non-compliance, patient withdrawal, or patient discontinuation. Radiographic tumour evaluation was done at baseline, every 6 weeks within 1 year of the first dose, and every 12 weeks thereafter. The primary endpoint was objective response rate, defined as the proportion of patients with confirmed complete or partial responses by independent review committee (IRC) assessment. The primary endpoint was assessed in the tumour response evaluable set, which comprised all treated patients with a measurable lesion at baseline and at least one adequate scheduled post-baseline tumour assessment or the presence of radiological disease progression, with a sensitivity analysis done in the full analysis set, which comprised all patients who received at least one dose of savolitinib. Safety was also evaluated in the full analysis set. This study is registered with ClinicalTrials.gov, NCT02897479, and recruitment is complete, with treatment and follow-up ongoing. FINDINGS: From Nov 8, 2016, to Aug 3, 2020, 84 patients with METex14 skipping alterations were screened for eligibility, of whom 70 were enrolled, received savolitinib, and comprised the full analysis set. The IRC-assessed tumour response evaluable set comprised 61 patients. At a median follow-up of 17·6 months (IQR 14·2-24·4), the IRC-assessed objective response rate was 49·2% (36·1-62·3; 30 of 61 patients) in the tumour response evaluable set and 42·9% (95% CI 31·1-55·3; 30 of 70 patients) in the full analysis set. All 70 patients reported at least one treatment-related adverse event. Treatment-related adverse events of grade 3 or more occurred in 32 (46%) patients, the most frequent of which were increased aspartate aminotransferase (n=9), increased alanine aminotransferase (n=7), and peripheral oedema (n=6). Treatment-related serious adverse events occurred in 17 (24%) patients, the most common being abnormal hepatic function (n=3) and hypersensitivity (n=2). One death due to tumour lysis syndrome in a patient with pulmonary sarcomatoid carcinoma was assessed to be probably related to savolitinib by the investigator. INTERPRETATION: Savolitinib yielded promising activity and had an acceptable safety profile in patients with pulmonary sarcomatoid carcinoma and other NSCLC subtypes positive for METex14 skipping alterations. Savolitinib could therefore be a novel treatment option in this population. FUNDING: Hutchison MediPharma and AstraZeneca. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.