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OBJECTIVE: KINDLE-Korea is part of a real-world KINDLE study that aimed to characterize the treatment patterns and clinical outcomes of patients with stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The KINDLE was an international real-world study that explores patient and disease characteristics, treatment patterns, and survival outcomes. The KINDLE-Korea included stage III NSCLC patients diagnosed between January 2013 and December 2017. RESULTS: A total of 461 patients were enrolled. The median age was 66 years (range: 24-87). Most patients were men (75.7%) with a history of smoking (74.0%), stage IIIA NSCLC (69.2%), and unresectable disease (52.9%). A total of 24.3% had activating EGFR mutation and 62.2% were positive for PDL1 expression. Broadly categorized, 44.6% of the patients received chemoradiation (CRT)-based therapy, 35.1% underwent surgery, and 20.3% received palliative therapies as initial treatment. The most commonly adopted approaches for patients with stage IIIA and IIIB disease were surgery and CRT, respectively. The median PFS was 15.2 months and OS was 66.7 months. Age >65 years, adenocarcinoma histology, and surgery as the initial treatment were significantly associated with longer OS. CONCLUSION: This study revealed the heterogeneity of treatment patterns and survival outcomes in patients with stage III NSCLC before durvalumab consolidation came into clinical practice. There is an unmet need for patients who are not eligible for surgery as an initial therapy. Novel therapeutic approaches are highly warranted to improve clinical outcomes.
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Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Masculino , Humanos , Idoso , Feminino , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Quimiorradioterapia , República da Coreia/epidemiologia , Estudos RetrospectivosRESUMO
OBJECTIVE: This analysis of the first-line cohort of LASER201 study evaluated the efficacy and safety of lazertinib 240 mg as a frontline therapy for epidermal growth factor receptor (EGFR)-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). METHODS: A total of 43 patients, with EGFR mutation-positive (Exon19Del, n = 24; L858R, n = 18; G719X, n = 1) locally advanced or metastatic NSCLC who had not previously received EGFR tyrosine kinase inhibitor (EGFR TKI) therapy, received once-daily lazertinib 240 mg. EGFR mutation status was confirmed by local or central testing. The primary endpoint was objective response rate (ORR) assessed by blinded independent central review. Secondary efficacy endpoints included duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), tumor shrinkage, and overall survival (OS). RESULTS: At the primary data cut-off (DCO; January 8, 2021), the ORR was 70 % (95 % confidence interval [CI]: 56.0-83.5), DCR was 86 % (95 % CI: 75.7-96.4) and the median DoR was 23.5 (95 % CI: 12.5-not reached) months. The median PFS was 24.6 (95 % CI: 12.2-30.2) months. At the final DCO (March 30, 2023), the median OS was not estimable and the median follow-up duration for OS was 55.2 [95 % CI: 22.8-55.7] months. OS rates at 36 months and 54 months were 66 % (95 % CI: 47.5-79.3 %) and 55 % (95 % CI: 36.6-70.7 %), respectively. The most commonly reported TEAEs were rash (54 %), diarrhea (47 %), pruritus (35 %), and paresthesia (35 %). No drug-related rash or pruritus TEAEs of grade 3 or higher were reported. Diarrhea and paresthesia of grade 3 or higher were reported in 3 (7 %) and 1 (2 %) patients, respectively. CONCLUSION: This analysis demonstrated long-term clinical benefit with lazertinib 240 mg in patients with EGFR-mutated NSCLC who had not previously received EGFR TKIs. The safety profile for lazertinib was tolerable and consistent with that previously reported.
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Carcinoma Pulmonar de Células não Pequenas , Exantema , Neoplasias Pulmonares , Morfolinas , Pirazóis , Pirimidinas , 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 , Seguimentos , Parestesia/induzido quimicamente , Parestesia/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptores ErbB/genética , Diarreia/induzido quimicamente , Exantema/induzido quimicamente , Prurido/tratamento farmacológico , MutaçãoRESUMO
PURPOSE: This subgroup analysis of the Korean subset of patients in the phase 3 LASER301 trial evaluated the efficacy and safety of lazertinib versus gefitinib as first-line therapy for epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with locally advanced or metastatic EGFRm NSCLC were randomized 1:1 to lazertinib (240 mg/day) or gefitinib (250 mg/day). The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: In total, 172 Korean patients were enrolled (lazertinib, n=87; gefitinib, n=85). Baseline characteristics were balanced between the treatment groups. One-third of patients had brain metastases (BM) at baseline. Median PFS was 20.8 months (95% confidence interval [CI], 16.7 to 26.1) for lazertinib and 9.6 months (95% CI, 8.2 to 12.3) for gefitinib (hazard ratio [HR], 0.41; 95% CI, 0.28 to 0.60). This was supported by PFS analysis based on blinded independent central review. Significant PFS benefit with lazertinib was consistently observed across predefined subgroups, including patients with BM (HR, 0.28; 95% CI, 0.15 to 0.53) and those with L858R mutations (HR, 0.36; 95% CI, 0.20 to 0.63). Lazertinib safety data were consistent with its previously reported safety profile. Common adverse events (AEs) in both groups included rash, pruritus, and diarrhoea. Numerically fewer severe AEs and severe treatment-related AEs occurred with lazertinib than gefitinib. CONCLUSION: Consistent with results for the overall LASER301 population, this analysis showed significant PFS benefit with lazertinib versus gefitinib with comparable safety in Korean patients with untreated EGFRm NSCLC, supporting lazertinib as a new potential treatment option for this patient population.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Morfolinas , Pirazóis , Pirimidinas , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Quinazolinas , Receptores ErbB/genética , Receptores ErbB/metabolismo , República da Coreia , Mutação , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
INTRODUCTION: Lazertinib, a third-generation mutant-selective EGFR tyrosine kinase inhibitor, improved progression-free survival compared with gefitinib in the phase 3 LASER301 study (ClinicalTrials.gov Identifier: NCT04248829). Here, we report the efficacy of lazertinib and gefitinib in patients with baseline central nervous system (CNS) metastases. METHODS: Treatment-naive patients with EGFR-mutated advanced NSCLC were randomized one-to-one to lazertinib (240 mg/d) or gefitinib (250 mg/d). Patients with asymptomatic or stable CNS metastases were included if any planned radiation, surgery, or steroids were completed more than 2 weeks before randomization. For patients with CNS metastases confirmed at screening or subsequently suspected, CNS imaging was performed every 6 weeks for 18 months, then every 12 weeks. End points assessed by blinded independent central review and Response Evaluation Criteria in Solid Tumors version 1.1 included intracranial progression-free survival, intracranial objective response rate, and intracranial duration of response. RESULTS: Of the 393 patients enrolled in LASER301, 86 (lazertinib, n = 45; gefitinib, n = 41) had measurable and or non-measurable baseline CNS metastases. The median intracranial progression-free survival in the lazertinib group was 28.2 months (95% confidence interval [CI]: 14.8-28.2) versus 8.4 months (95% CI: 6.7-not reached [NR]) in the gefitinib group (hazard ratio = 0.42, 95% CI: 0.20-0.89, p = 0.02). Among patients with measurable CNS lesions, the intracranial objective response rate was numerically higher with lazertinib (94%; n = 17) versus gefitinib (73%; n = 11, p = 0.124). The median intracranial duration of response with lazertinib was NR (8.3-NR) versus 6.3 months (2.8-NR) with gefitinib. Tolerability was similar to the overall LASER301 population. CONCLUSIONS: In patients with CNS metastases, lazertinib significantly improved intracranial progression-free survival compared with gefitinib, with more durable responses.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Gefitinibe/farmacologia , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Quinazolinas/farmacologia , Receptores ErbB/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Sistema Nervoso Central , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , MutaçãoRESUMO
INTRODUCTION: Lazertinib is a third-generation central nervous system-penetrant tyrosine kinase inhibitor targeting mutant EGFR in NSCLC. Lazertinib exhibited improved efficacy versus gefitinib in the LASER301 study; this subset analysis compared lazertinib with gefitinib among Asian patients. METHODS: The phase 3 LASER301 study evaluated lazertinib efficacy and safety in treatment-naive patients with EGFR-mutated (exon 19 deletion or L858R) locally advanced or metastatic NSCLC. Patients were randomized one-to-one and received either lazertinib or gefitinib. The primary end point was investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included overall survival, objective response rate, duration of response, and safety. RESULTS: Between February 13, 2020, and July 29, 2022, among 258 patients of Asian descent, the median progression-free survival was significantly longer with lazertinib than gefitinib (20.6 versus 9.7 mo; hazard ratio: 0.46; 95% confidence interval [CI]: 0.34-0.63, p < 0.001), and the benefit was consistent across predefined subgroups (exon 19 deletion, L858R, baseline central nervous system metastases). Objective response rate and disease control rates were similar between treatment groups. The median duration of response was 19.4 months (95% CI: 16.6-24.9) versus 9.6 months (95% CI: 6.9-12.4) in the lazertinib versus gefitinib group. Adverse event rates in Asian patients were comparable with the overall LASER301 population. Adverse events leading to discontinuation in the lazertinib and gefitinib groups were 13% and 12%, respectively. CONCLUSIONS: In LASER301, efficacy and safety results in Asian patients were consistent with the overall population. Lazertinib exhibited better efficacy than gefitinib in Asian patients with a tolerable safety profile.
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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/induzido quimicamente , Receptores ErbB/genética , Gefitinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/induzido quimicamente , Mutação , Povo AsiáticoRESUMO
INTRODUCTION/OBJECTIVES: This study aimed to identify differentially expressed genes (DEGs) of systemic lupus erythematosus (SLE) using gene expression-based computational methodologies to analyze disease-immune interactions, which affect the development and progression of SLE. METHOD: Twenty-six patients with SLE and 46 healthy controls were selected from the Gene Expression Omnibus (GEO) database. The significantly enriched immune and virus-related gene lists were computed and visualized by using the DEGs from the gene set enrichment analysis (GSEA). Quantification of 38 immune cells was performed in determining the impact of immune cells on the virus mediated immunity in SLE by using ImmQuant algorithm. RESULTS: Thirty-nine upregulated and 57 downregulated were identified in SLE patient compared to the healthy controls. Upregulated genes were significantly implicated in Gene Ontology gene sets as cytokine mediated signaling, secretion, and exocytosis in immune response pathways in 26 female SLE patients. In addition, these genes were enriched in hepatitis C, influenza A, measles, Epstein-Barr virus, and herpes simplex virus 1 infection in Kyoto Encyclopedia of Genes and Genomes pathways. Especially, FCGR1A, IRF7, OAS2, CAMP, MX1, OAS3, OAS1, DEFA3, ISG15, and RSAD2 were involved in virus mediated SLE mechanism, and the expression for OAS1, OAS2, and IRF7 was closely associated with the quantities of colony forming unit-monocyte and colony forming unit-granulocyte. CONCLUSIONS: Identifying virus-mediated SLE genes and quantifies of immune cells were used to understand the pathological process and perform early diagnosis of female SLE, and will lead to clinical tools for treating SLE in patients. Key Points ⢠Using gene expression-based computational methodologies, the 57 immune and viral genes were significantly upregulated in 26 SLE patients. ⢠The identified three key viral genes such as OAS1, OAS2, and IF7 were closely associated with colony-forming unit-monocytes and colony-forming unit-granulocytes, which affect the virus mediated immunity in SLE. ⢠The viral genes and quantifies of immune cells are useful in understanding pathogenesis of SLE, and this will provide clinical strategies of potential treatment choices in SLE patients.
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Infecções por Vírus Epstein-Barr , Lúpus Eritematoso Sistêmico , Humanos , Feminino , Autoimunidade , Herpesvirus Humano 4 , CitocinasRESUMO
INTRODUCTION: Thymic epithelial tumors (TETs) are rare but are the most common tumors of the anterior mediastinum. Platinum-based combination chemotherapy is the standard of care for such tumors and is associated with a 50% to 90% objective response rate (ORR) in metastatic disease. Nevertheless, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with the cell cycle, including pRB, p16INK4A, and cyclin D1, are most often observed in TETs. On the basis of these results, we conducted a phase 2 trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs. METHODS: This is a phase 2, multicenter, open-label, single-arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapies. The patients received 125 mg of oral palbociclib daily for 21 days, followed by a 7-day break. The primary end point was progression-free survival (PFS). The secondary end points were ORR, duration of response, overall survival, and safety. RESULTS: Between August 2017 and October 2019, a total of 48 patients were enrolled. The median number of previous chemotherapies was one (range: one to four), and 21 (43.7%) of 48 patients received thymectomy. By the WHO classification, the patients were type A (n = 1), type B1 (n = 2), type B2 (n = 8), type B3 (n = 13), thymic carcinoma (n = 23), and unknown (n = 1). With a median follow-up of 14.5 months (range: 0.8-38.2), the median number of cycles of palbociclib monotherapy was 10 (range: 1-40). The ORR was 12.5% (four partial responses in thymoma and two partial responses in thymic carcinoma). The PFS at 6 months was 60.2%, and the median PFS was 11.0 months (95% confidence interval: 4.6-17.4). The median overall survival was 26.4 months (95% confidence interval: 17.4-35.4). The most common treatment-related adverse events of any grade were neutropenia (62.5%), anemia (37.5%), and thrombocytopenia (29.1%), and the most common grade 3/4 treatment-related hematologic adverse event was neutropenia (41.7%). Neutropenia above grade 3 was reversible, and there were no cases with neutropenic fever. CONCLUSIONS: Palbociclib monotherapy was well tolerated and had encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy.
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Neoplasias Pulmonares , Neoplasias Epiteliais e Glandulares , Neutropenia , Timoma , Neoplasias do Timo , Humanos , Timoma/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias do Timo/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
AXL, along with MER and TYRO3, is a receptor tyrosine kinase from the TAM family. Although AXL itself is not thought to be a potent oncogenic driver, overexpression of AXL is known to trigger tumor cell growth, survival, invasion, metastasis, angiogenesis, epithelial to mesenchymal transition, and immune suppression. Overexpression of AXL is associated with therapy resistance and poor prognosis. Therefore, it is being studied as a marker of prognosis in cancer treatment or as a target in various cancer types. Recently, many preclinical and clinical studies on agents with various mechanisms targeting AXL have been actively conducted. They include small molecule inhibitors, monoclonal antibodies, and antibody-drug conjugates. This article reviewed the fundamental role of AXL in solid tumors, and the development in research of AXL inhibitors in recent years. Emphasis was placed on the function of AXL in acquired therapy resistance in patients with non-small cell lung cancer (NSCLC). Since clinical needs increase in NSCLC patients with acquired resistance after initial therapy, recent research efforts have focused on a combination treatment with AXL inhibitors and tyrosine kinase inhibitors or immunotherapy to overcome resistance. Lastly, we deal with challenges and limitations encountered in the development of AXL inhibitors.
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INTRODUCTION: This integrated analysis of a phase 1/2 study (NCT03046992) evaluated the efficacy and safety of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), in patients with advanced EGFR T790M-positive NSCLC after previous EGFR TKI therapy. METHODS: Adults with EGFR mutation-positive NSCLC that progressed after prior EGFR-directed TKIs received once daily oral lazertinib 240 mg continuously until disease progression. Prior TKIs to treat T790M-positive NSCLC were prohibited. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included progression-free survival, overall survival, and intracranial ORR. RESULTS: A total of 78 patients received lazertinib 240 mg at 17 centers in South Korea. Among patients with T790M-positive tumors at baseline (N = 76), one (1.3%) had a complete response and 41 (53.9%) had partial responses, giving an ORR of 55.3% (95% confidence interval [CI]: 44.1-66.4). Median progression-free survival was 11.1 months (95% CI: 5.5-16.4). Median overall survival was not reached (median follow-up = 22.0 mo). In patients with measurable intracranial lesions (n = 7), one (14.3%) had a complete intracranial response and five (71.4%) had partial responses, giving an intracranial ORR of 85.7% (95% CI: 59.8%-100.0%). The most common treatment-emergent adverse events were rash (37.2%), pruritus (34.6%), and paresthesia (33.3%); most were mild to moderate in severity. Serious drug-related adverse events occurred in three patients (gastritis, pneumonia, pneumonitis). The major mechanism of resistance was EGFR T790M loss. CONCLUSIONS: Lazertinib 240 mg/d has a manageable safety profile with durable antitumor efficacy, including brain metastases, in patients with advanced T790M-positive NSCLC after previous EGFR TKI therapy.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adulto , Carcinoma Pulmonar de Células não Pequenas/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Morfolinas , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis , PirimidinasRESUMO
BACKGROUND: Afatinib is approved globally for EGFR-TKI treatment-naïve patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this Korean expanded access program, we evaluated its 'real-world' safety and efficacy. METHODS: EGFR-TKI treatment-naïve patients with EGFR mutation-positive NSCLC received afatinib 40 mg/day until disease progression or other withdrawal criteria. Dose reductions were permitted for adverse events (AEs). The primary endpoint was the number of patients with AEs (CTCAE version 3.0). Other endpoints included progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and changes in investigator-assessed cancer-related symptoms. RESULTS: Eighty-eight patients received afatinib, including 27 (31%) with brain metastases and 16 (18%) with uncommon EGFR mutations. Median PFS was 17.0 months (95% confidence interval [CI] 12.9-23.3 months). Grade 3 treatment-related AEs (TRAEs) were reported in 51 (58%) patients; the most common were diarrhea (22%) and rash/acne (20%). No grade > 3 TRAEs were reported. AEs leading to dose reduction occurred in 49 (56%) patients. Treatment discontinuation due to TRAEs occurred in 4 (5%) patients. ORR was 81% overall, 89% in patients with brain metastases, and 55% in patients with uncommon mutations (excluding T790M/exon 20 insertions). Median DOR was 15.1 months (95% CI 12.4-21.4 months). Cancer-related symptoms were improved/unchanged/worsened in 34-66%/36-66%/0-3% of patients over the first year. CONCLUSIONS: No unexpected safety signals for afatinib were observed. AEs were manageable; the treatment discontinuation rate was low. Afatinib showed encouraging efficacy in a broad patient population including those with brain metastases or tumors harboring uncommon EGFR mutations. TRIALS REGISTRATION: ClinicalTrials.gov NCT01931306 ; 29/08/2013.
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Afatinib/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Afatinib/farmacologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologiaRESUMO
With the advent of checkpoint inhibitors, it has opened up opportunities for numerous cancer patients. However, as is the case with every treatment, complications need to be weighed. Gastrointestinal adverse effects, such as diarrhea and colitis are well-known complications for checkpoint inhibitors. In severe cases, colitis-induced colonic perforation may occur with an estimation of 1.0% to 1.5% in anti-CTLA-4 antibodies. However, only a handful of cases of such devastating complications have been reported in anti-PD-1 antibodies such as pembrolizumab and nivolumab. We here report a case of intestinal perforation in a patient treated with nivolumab.
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Non-small-cell lung cancers (NSCLCs) are largely classified into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), which have different therapeutic options according to its molecular profiles and immune checkpoint expression, especially PD-L1, which is a suppressive factor in the tumor microenvironment. The tumor microenvironment can be altered by the genomic mutations on specific innate immune genes as well as tumor suppressor genes, so it is essential to comprehend the association between tumor microenvironment and tumor suppressor genes to discover the promising immunotherapeutic strategy to overcome the resistance of immune check point blockade. In this study, we aimed to analyze how the somatic mutations in tumor suppressor genes affect the tumor immune microenvironment through a comprehensive analysis of mutational profiling on the representative tumor suppressor genes (TP53, CDKN2A, PTEN, RB1, BRCA1, BRCA2) and immune gene expression in The Cancer Genome Atlas (TCGA) 155 lung squamous cell carcinoma (LUSC) and 196 lung adenocarcinoma (LUAD) samples. Several microenvironmental factors, such as the infiltrating immune and stromal cells, were suppressed by the mutated tumor suppressor genes in LUSC, unlike in the LUAD samples. In particular, infiltrating immune cells such as macrophage, neutrophil, and dendritic cells were significantly reduced in tumors with mutated tumor suppressor genes' group. In addition, the gene expressions for interleukin production and lymphocyte differentiation and PGC, C7, HGF, PLA2G2A, IL1RL1, CCR2, ALOX15B, CXCL11, FCN3 were significantly down-regulated, which were key immune genes for the cross-talk between LUSC microenvironment and tumor suppressors. Therefore, we generated evidence that TSG mutations in LUSC have an impact on tumor immune microenvironment, which suggests that TSG non-mutated patients will have the more inflamed tumors and are more likely to respond to immune checkpoint blockade therapy.
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Carcinoma de Células Escamosas/etiologia , Perfilação da Expressão Gênica , Genes Supressores de Tumor , Genômica , Neoplasias Pulmonares/etiologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Biomarcadores Tumorais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Mutação , Modelos de Riscos Proporcionais , TranscriptomaRESUMO
PURPOSE: We report the final analysis of JVDL (NCT02789345), which examined the combination of the EGFR tyrosine kinase inhibitor (TKI) osimertinib plus the VEGFR2-directed antibody ramucirumab in patients with T790M-positive EGFR-mutant non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: This open-label, single-arm phase I study enrolled patients with EGFR T790M-positive NSCLC, who had progressed following EGFR TKI but were third-generation EGFR TKI-naïve. A dose-limiting toxicity (DLT) period with as-needed dose deescalation was followed by an expansion cohort. Patients received daily oral osimertinib and intravenous ramucirumab every 2 weeks until progression or discontinuation. RESULTS: Twenty-five patients were enrolled. No DLTs were observed. Median follow-up time was 25.0 months. Common grade 3 or higher treatment-related adverse events (TRAE) were hypertension (8%) and platelet count decreased (16%); grade 5 TRAE (subdural hemorrhage) occurred in 1 patient. Patients with (N = 10) and without central nervous system (CNS) metastasis (N = 15) had similar safety outcomes. Five patients remain on treatment. Objective response rate (ORR) was 76%. Median duration of response was 13.4 months [90% confidence interval (CI): 9.6-21.2]. Median progression-free survival (PFS) was 11.0 months (90% CI: 5.5-19.3). Efficacy was observed in patients with and without CNS metastasis (ORR 60% and 87%; median PFS 10.9 and 14.7 months, respectively). Exploratory biomarker analyses in circulating tumor DNA suggested that on-treatment loss of EGFR Exon 19 deletion or L858R mutations, detectable at baseline, correlated with longer PFS, but on-treatment loss of T790M did not. Emergent genetic alterations postprogression included C797S, MET amplification, and EGFR amplification. CONCLUSIONS: Ramucirumab plus osimertinib demonstrated encouraging safety and antitumor activity in T790M-positive EGFR-mutant NSCLC.See related commentary by Garon, p. 905.
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Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Acrilamidas/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , RamucirumabRESUMO
Oncolytic viruses selectively replicate and destroy cancer cells while sparing normal cells, prompting their recognition as promising antitumor agents. Herpes simplex virus (HSV) is suitable as an anticancer agent, given its considerable therapeutic gene capacity and excellent safety profile in clinical trials. Interleukin (IL)-12 induces a Th1-type immune response that mediates interferon (IFN)-γ release from natural killer (NK), CD4+ and CD8+ T cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the generation of antigen-presenting cells and promotes dendritic cell differentiation. We established a novel oncolytic HSV-1 (∆6/GM/IL12) co-expressing IL-12 and GM-CSF and tested its effects against a B16-F10 murine melanoma model. ∆6/GM/IL12 administration diminished tumor growth and prolonged survival compared to treatment with ∆6/GM or ∆6/IL12 expressing each individual cytokine. Flow cytometry and histological analysis showed increased activation of CD4+ and CD8+ T cells in ∆6/GM/IL12-treated mice. Enzyme-linked immunosorbent spot assay showed an increase in the phenotypically characterized IFN-γ-producing cell population in ∆6/GM/IL12-treated mice. Moreover, ∆6/GM/IL12 induced a B16-F10-specific cytotoxic immune response that enhanced IFN-γ production by CD3+CD8+ T cells. Therefore, IL-12 and GM-CSF from an engineered oncolytic HSV have a synergistic effect, boosting the immune response to increase their antitumor effects.
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Herpesvirus Humano 1 , Vírus Oncolíticos , Animais , Linfócitos T CD8-Positivos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Herpesvirus Humano 1/genética , Interleucina-12/genética , Camundongos , Vírus Oncolíticos/genéticaRESUMO
BACKGROUND: This study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC). METHODS: One-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m2) or belotecan (0.5 mg/m2), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tolerability and toxicity. The study statistical plan was non-inferiority design with ORR as the endpoint. RESULTS: In the belotecan vs. topotecan groups, ORR (primary endpoint) was 33% vs. 21% (p = 0.09) and DCR was 85% vs. 70% (p = 0.030). PFS was not different between groups. Median OS was significantly longer with belotecan than with topotecan (13.2 vs. 8.2 months, HR = 0.69, 95% CI: 0.48-0.99), particularly in patients aged <65 years, with more advanced disease (i.e., extensive-stage disease, time to relapse: 3-6 months), or Eastern Cooperative Oncology Group performance status 1 or 2. More belotecan recipients completed all treatment cycles (53% vs. 35%; p = 0.022). CONCLUSIONS: The efficacy/safety of belotecan warrants further evaluation in Phase 3 trials. Belotecan potentially offers an alternative to topotecan for sensitive-relapsed SCLC, particularly in patients aged <65 years, with more advanced disease, or poor performance.
Assuntos
Camptotecina/análogos & derivados , Neoplasias Pulmonares/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Topotecan/uso terapêutico , Idoso , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores da Topoisomerase I/efeitos adversos , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/efeitos adversosRESUMO
BACKGROUND: Pulmonary sarcomatoid carcinoma (PSC) is rare with a poor outcome and is resistant to conventional cytotoxic chemotherapy. The efficacy and safety of durvalumab and tremelimumab for treating recurrent or metastatic PSCs were assessed by a nonrandomized, open-label, phase II study. METHODS: A total of 18 patients with recurrent or metastatic PSC received 1500 mg of durvalumab and 75 mg of tremelimumab every four weeks, followed by 750 mg of durvalumab every two weeks until the disease progressed, or an unacceptable toxicity level was reached. The primary endpoint was the objective response rate (ORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Genomic profiling of PSC by next-generation sequencing (NGS) and determination of peripheral blood lymphocyte subsets using flow cytometry were performed for exploratory analysis. RESULTS: A total of 15 out of 18 patients were evaluated for the analysis of the primary endpoint. At the data cutoff point, the ORR of 26.7% (95% confidence interval [CI]: 7.8-55.1) was achieved with the median follow-up duration of 12.0 months (range, 8.4-16.1). Median PFS and OS were 5.9 months (95% CI: 1.1-11.9) and 15.4 months (95% CI: 11.1-not reached), respectively. Treatment-related adverse events (AEs) of any grade were reported in 16 patients; the most common AEs were pruritus (n = 5), pneumonitis (n = 4), and rash (n = 4). Treatment was discontinued in two patients due to AEs of grade ≥ 3. CONCLUSIONS: Durvalumab and tremelimumab demonstrated clinical benefit with a prolonged survival and manageable toxicity profile in patients with recurrent or metastatic PSC.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoterapia/métodos , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: The introduction of immune checkpoint inhibitors represents a major advance in the treatment of lung cancer, allowing sustained recovery in a significant proportion of patients. Nivolumab is a monoclonal anti-programmed death cell protein 1 antibody licensed for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy. In this study, we describe the demographic and clinical outcomes of patients with advanced NSCLC treated with nivolumab in the Korean expanded access program. MATERIALS AND METHODS: Previously treated patients with advanced nonsquamous and squamous NSCLC patients received nivolumab at 3 mg/kg every 2 weeks up to 36 months. Efficacy data including investigator-assessed tumor response, progression data, survival, and safety data were collected. RESULTS: Two hundred ninety-nine patients were treated across 36 Korean centers. The objective response rate and disease control rate were 18% and 49%, respectively; the median progression-free survival was 2.1 months (95% confidence interval [CI], 1.87 to 3.45), and the overall survival (OS) was 13.2 months (95% CI, 10.6 to 18.9). Patients with smoking history and patients who experienced immune-related adverse events showed a prolonged OS. Cox regression analysis identified smoking history, presence of immune-related adverse events as positive factors associated with OS, while liver metastasis was a negative factor associated with OS. The safety profile was generally comparable to previously reported data. CONCLUSION: This real-world analysis supports the use of nivolumab for pretreated NSCLC patients, including those with an older age.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/secundário , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Fatores de Proteção , República da Coreia/epidemiologia , Fatores de Risco , Fumar/epidemiologiaRESUMO
INTRODUCTION: In the phase II ATLANTIC study, durvalumab provided durable responses with acceptable tolerability in heavily pretreated patients with advanced NSCLC, across three independent patient cohorts defined by EGFR/ALK status and tumour PD-L1 expression. Preliminary overall survival (OS) data were encouraging. We now report final OS and updated safety data. METHODS: Patients with advanced NSCLC with disease progression following ≥2 previous systemic regimens received durvalumab 10 mg/kg every 2 weeks. The primary endpoint was objective response rate among patients with increased PD-L1 expression (defined as ≥25 % or ≥90 % of tumour cells [TCs], cohort-dependent). Secondary endpoints included OS and safety. RESULTS: 444 patients received durvalumab: 111 in Cohort 1 (EGFR+/ALK+), 265 in Cohort 2 (EGFR-/ALK-), and 68 in Cohort 3 (EGFR-/ALK-; TC ≥ 90 %). Median (95 % CI) OS was 13.3 months (6.3-24.5) in patients with EGFR+/ALK+ NSCLC with TC ≥ 25 %, 10.9 months (8.6-13.6) in patients with EGFR-/ALK- NSCLC with TC ≥ 25 %, and 13.2 months (5.9-not reached) in patients with EGFR-/ALK- NSCLC with TC ≥ 90 %. Median (95 % CI) OS was slightly shorter in patients with TC < 25 % (9.9 months [4.2-13.3] in patients with EGFR+/ALK+ NSCLC and 9.3 months [5.9-10.8] in those with EGFR-/ALK- NSCLC). Treatment-related adverse events of special interest occurred with similar incidences as reported previously. CONCLUSIONS: After additional follow-up, final OS data remain encouraging across all cohorts, further supporting the clinical activity of durvalumab in patients with heavily pretreated advanced NSCLC, including those with EGFR+/ALK+ tumours. There were no new safety signals.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Anticorpos Monoclonais/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos de Coortes , Humanos , Neoplasias Pulmonares/tratamento farmacológicoRESUMO
Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were characterized. Nine (43%) showed a durable clinical benefit (DCB), while the remaining 12 (57%) patients showed non-durable benefit (NDB). The M1 and peripheral T cell signatures showed the best performance for discriminating DCB from NDB (sensitivity, specificity, accuracy = 0.89, 1.0, 0.95, respectively). Progression-free survival (PFS) was significantly longer in patients with high M1 signature or high peripheral T cell signature scores. CD137 and PSMB9 mRNA expression was higher in the DCB group than in the NDB group. Patients with high PSMB9 expression showed longer PFS. M1 signature, peripheral T cell signature and high mRNA expression level of CD137 and PSMB9 showed better predictive performance than known biomarkers, such as PD-L1 immunohistochemistry, tumor mutation burden, or tumor-infiltrating lymphocytes.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/terapia , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/imunologia , Idoso , Carcinoma Pulmonar de Células não Pequenas/imunologia , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Feminino , Previsões , Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Resultado do Tratamento , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
INTRODUCTION: Non-small-cell lung cancer (NSCLC) is a heterogeneous disease. Front-line therapy may affect responses to subsequent treatment regimens, thus influencing second-line therapy decision making. In the randomised phase 3 REVEL study, second-line ramucirumab plus docetaxel (ram+doc) versus docetaxel (doc) improved survival of patients with metastatic NSCLC. We explore efficacy, safety and quality-of-life (QoL) in REVEL based on front-line therapy. METHODS: Patients were grouped by specific front-line therapy received. Overall survival (OS), progression-free survival (PFS), objective response rate, safety and QoL were assessed descriptively. Kaplan-Meier estimation and Cox proportional hazards modelling were used; frequencies reported in percentages. RESULTS: Baseline characteristics of 1253 patients were generally well balanced between treatment arms within each front-line therapy subgroup. For patients with non-squamous disease (n=912), induction therapies included platinum-based chemotherapy plus a taxane (n=227; 25%) or pemetrexed (n=449; 49%), with (n=172; 19%) or without bevacizumab. For patients with squamous disease (n=328), induction therapies included platinum-based chemotherapy plus gemcitabine (n=176; 54%) or a taxane (n=69; 21%). A highly selected subgroup (n=127; 14%) received pemetrexed continuation maintenance therapy. Ram+doc improved median OS and PFS versus doc across front-line therapy subgroups, as reflected by HRs ranging from 0.78 to 0.91 and 0.66 to 0.92, respectively, similar to results in the overall intention-to-treat cohort (HRs: 0.86 and 0.76, respectively). High-grade treatment-emergent adverse events of special interest (including neutropenia, febrile neutropenia, leucopenia and hypertension) were generally higher in ram+doc-treated patients relative to doc-treated patients regardless of front-line therapy. No clear differences in safety or QoL were seen across front-line therapy subgroups; outcomes were consistent with those reported in the overall intention-to-treat cohort. CONCLUSIONS: Results of this exploratory analysis suggest that second-line ram+doc may be effective regardless of prior treatment with platinum-based chemotherapy plus a taxane, pemetrexed, gemcitabine or bevacizumab. Overall, ram+doc is clinically beneficial across a wide range of patients with metastatic NSCLC who have progressed after various front-line therapies. TRIAL REGISTRATION NUMBER: NCT01168973.