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BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Compuestos de Platino , Humanos , Carbazoles/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirugía , Recurrencia Local de Neoplasia/tratamiento farmacológico , Piperidinas/uso terapéutico , Proteínas Tirosina Quinasas Receptoras , Resultado del Tratamiento , Administración Oral , Administración Intravenosa , Compuestos de Platino/uso terapéutico , Antineoplásicos/uso terapéuticoRESUMEN
BACKGROUND: The cancer genome contains several driver mutations. However, in some cases, no known drivers have been identified; these remaining areas of unmet needs, leading to limited progress in cancer therapy. Whole-genome sequencing (WGS) can identify non-coding alterations associated with the disease. Consequently, exploration of non-coding regions using WGS and other omics data such as ChIP-sequencing (ChIP-seq) to discern novel alterations and mechanisms related to tumorigenesis have been attractive these days. METHODS: Integrated multi-omics analyses, including WGS, ChIP-seq, DNA methylation, and RNA-sequencing (RNA-seq), were conducted on samples from patients with non-clinically actionable genetic alterations (non-CAGAs) in lung adenocarcinoma (LUAD). Second-level cluster analysis was performed to reinforce the correlations associated with patient survival, as identified by RNA-seq. Subsequent differential gene expression analysis was performed to identify potential druggable targets. RESULTS: Differences in H3K27ac marks in non-CAGAs LUAD were found and confirmed by analyzing RNA-seq data, in which mastermind-like transcriptional coactivator 2 (MAML2) was suppressed. The down-regulated genes whose expression was correlated to MAML2 expression were associated with patient prognosis. WGS analysis revealed somatic mutations associated with the H3K27ac marks in the MAML2 region and high levels of DNA methylation in MAML2 were observed in tumor samples. The second-level cluster analysis enabled patient stratification and subsequent analyses identified potential therapeutic target genes and treatment options. CONCLUSIONS: We overcome the persistent challenges of identifying alterations or driver mutations in coding regions related to tumorigenesis through a novel approach combining multi-omics data with clinical information to reveal the molecular mechanisms underlying non-CAGAs LUAD, stratify patients to improve patient prognosis, and identify potential therapeutic targets. This approach may be applicable to studies of other cancers with unmet needs.
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Adenocarcinoma del Pulmón , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/metabolismo , Análisis por Conglomerados , Genómica/métodos , Mutación , Biomarcadores de Tumor/genética , Femenino , Masculino , Secuenciación Completa del Genoma , Pronóstico , Terapia Molecular Dirigida , Perfilación de la Expresión Génica , Anciano , Persona de Mediana Edad , MultiómicaRESUMEN
BACKGROUND: In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. METHODS: We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. RESULTS: We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. CONCLUSIONS: Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.
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Adenocarcinoma del Pulmón , Elementos de Facilitación Genéticos , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , Receptor ErbB-2 , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Mutación , Biomarcadores de Tumor/genética , Femenino , Masculino , Variación Estructural del Genoma , Genómica/métodos , Persona de Mediana Edad , Pronóstico , AncianoRESUMEN
BACKGROUND: The treatment of lung cancer has made dramatic progress in the past decade, but due to the high cost of drugs, the total pharmaceutical cost has been rising explosively. There are currently no data available in Japan on which regimens are used, to what extent they are used, and what their total cost is. METHODS: Sixty Japanese centers belonging to the Lung Cancer Study Group of the Japan Clinical Oncology Group were surveyed for information about the first-line treatment for advanced lung cancer in practice from July 2021 to June 2022. Three types of cancer were included: driver gene mutation-negative NSCLC, EGFR mutation-positive NSCLC, and extensive-stage small cell lung cancer (ES-SCLC). RESULTS: Recent treatment costs for ICIs or ICI plus chemotherapy were about 20-55 times higher than those for conventional chemotherapy. Of the 3738 patients with driver gene aberration-negative NSCLC, 2573 (68.8%) received treatments with monthly cost of 500 000 Japanese yen (JPY) or more; 2555 (68.4%) received ICI therapy. Of the 1486 patients with EGFR mutation-positive NSCLC, 1290 (86.8%) received treatments with a monthly cost of 500 000 JPY or more; 1207 (81.2%) received osimertinib. ICI treatments with a monthly cost of 500 000 JPY or more were administered to 607 (56.3%) of 1079 patients with ES-SCLC. Elderly NSCLC patients received slightly more high-cost treatment than younger patients. CONCLUSION: Recent treatments cost many times more than conventional chemotherapy. This study revealed that high-cost treatments were widely used in advanced lung cancer and some of high-cost treatments were used despite the lack of clear evidence. Physicians should pay attention to the cost of treatments they use.
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OBJECTIVE: As first-line treatment for stage IV or recurrent non-small cell lung cancer, combination immunotherapy with nivolumab and ipilimumab, with or without chemotherapy, had demonstrated survival benefits over chemotherapy; however, data on Japanese patients are limited. METHODS: LIGHT-NING was a multicenter, observational study and retrospectively collected data. In this interim analysis, we analyzed patients who received combination immunotherapy between 27 November 2020 and 31 August 2021 for the treatment status, safety objectives (treatment-related adverse events and immune-related adverse events incidences), and effectiveness objectives (objective response rate and progression-free survival) to determine the characteristics and early safety information. RESULTS: We analyzed 353 patients, with a median follow-up of 7.1 (interquartile range, 5.0-9.7) months. Overall, 60.1 and 39.9% received nivolumab plus ipilimumab with and without chemotherapy, respectively. In these cohorts, the median age was 67 and 72 years; 10.8 and 35.5% were aged ≥75 years; 80.2 and 79.4% were male; 5.2 and 13.5% had a performance score ≥ 2; 32.1 and 27.0% developed grade 3-4 immune-related adverse events; treatment-related deaths were observed in 6 (2.8%) and 5 (3.5%) patients, respectively. Grade 3-4 immune-related adverse event incidence was the highest within the first month of treatment in both cohorts, although the immune-related adverse event risk persisted throughout. No new safety signals were observed at this interim analysis. The median progression-free survival was 6.0 (95% confidence interval, 5.2-7.6) and 5.8 (4.3-7.0) months in nivolumab plus ipilimumab with and without chemotherapy cohorts, respectively. CONCLUSIONS: LIGHT-NING offers valuable insights into combination immunotherapy for untreated patients with stage IV or recurrent non-small cell lung cancer in Japanese real-world settings.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Masculino , Anciano , Femenino , Nivolumab/efectos adversos , Ipilimumab/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Japón/epidemiología , Estudios Retrospectivos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/etiología , Recurrencia Local de Neoplasia/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: MET exon 14 skipping mutations occur in 3-4% and MET high amplifications occur in < 1% of patients with non-small-cell lung cancer (NSCLC). Crizotinib, a selective ATP-competitive small-molecule inhibitor of c-Met, ALK, and ROS1 tyrosine kinases, has shown activity in cancer models with various types of MET activation. METHODS: The Co-MET study is a single-arm phase 2 trial to assess the safety and efficacy of crizotinib in MET inhibitor-naïve patients with advanced NSCLC harboring MET exon 14 skipping mutation (cohort 1) or high MET gene copy number of ≥ 7 (cohort 2). The primary endpoint was the objective response rate (ORR) per RECIST v1.1 by independent radiology review in cohort 1. The key secondary endpoints were the duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 28 patients (23 in cohort 1 and 5 in cohort 2) were enrolled between March 2018 and February 2020. The primary endpoint was met as the ORR (90% confidence interval: CI) in cohort 1 was 38.1% (20.6-58.3). Median DoR, PFS, and OS (95% CI) were 7.6 (1.9-NE), 5.7 (2.1-11.3), 9.1 (4.0-19.9) months, respectively, in cohort 1. ORR in cohort 2 was 40.0% (18.9-92.4). The safety signals were generally consistent with the known safety profile of crizotinib. CONCLUSIONS: Crizotinib showed a clinical activity similar to that of tepotinib and capmatinib in patients with NSCLC harboring MET exon 14 skipping mutations. CLINICAL TRIAL INFORMATION: UMIN000031623.
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Carcinoma de Pulmón de Células no Pequeñas , Crizotinib , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas c-met , Humanos , Crizotinib/uso terapéutico , Proteínas Proto-Oncogénicas c-met/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Femenino , Persona de Mediana Edad , Masculino , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Anciano , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Japón , Supervivencia sin Progresión , Exones , Pueblos del Este de AsiaRESUMEN
The role of previous thoracic radiation therapy as a risk factor of immune-related pneumonitis is unclear. Furthermore, some patients develop radiation recall pneumonitis, which is characterized by a radiation pneumonitis-like imaging pattern with consolidation progressing within a previous radiation field. In this multicenter retrospective study, we analyzed the relationship of previous thoracic radiation therapy with immune-related pneumonitis and the characteristics of radiation recall pneumonitis. The medical records of patients with non-small-cell lung cancer who had received nivolumab between December 2015 and March 2017 at five institutions were retrospectively reviewed. Incidence, imaging patterns, clinical course, and risk factors of immune-related pneumonitis and radiation recall pneumonitis were evaluated. A total of 669 patients were evaluated, and the incidences of all-grade and grade 3 or higher immune-related pneumonitis were 8.8% and 2.6%, respectively. The incidences of immune-related pneumonitis were 13.2% (34/257) and 6.1% (25/412) in patients with and those without previous thoracic radiation therapy, respectively. A history of previous thoracic radiation therapy was associated with immune-related pneumonitis (odds ratio, 2.11; 95% confidence interval, 1.21-3.69 in multivariate analysis). Among the patients with previous thoracic radiation therapy, 6.2% (16/257) showed radiation recall pattern. This study found an increased risk of nivolumab-induced immune-related pneumonitis associated with a history of thoracic radiation therapy. Radiation recall pattern was one of the major patterns of immune-related pneumonitis among the patients with previous thoracic radiation therapy. Incidence, risk factors, and clinical outcome of radiation recall pneumonitis were elucidated.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neumonía , Neumonitis por Radiación , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Nivolumab/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Estudios Retrospectivos , Neumonitis por Radiación/etiología , Neumonitis por Radiación/inducido químicamente , Neumonía/inducido químicamente , Neumonía/epidemiologíaRESUMEN
The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m2 every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m2 (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5-24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5-not reached) versus 11.0 (8.6-19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27-1.15). Median PFS (95% CI) was 8.3 (6.1-13.0) versus 7.2 (3.9-8.8) months (HR 0.65; 95% CI, 0.35-1.23). Grade 3-5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/patología , Pueblos del Este de Asia , Paclitaxel , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Delta-like ligand 3 (DLL3) is a therapeutic target in small-cell lung cancer (SCLC). However, how DLL3 expression status affects the tumor microenvironment (TME) and clinical outcomes in SCLC remains unclear. METHODS: This retrospective study included patients with postoperative limited-stage (LS)-SCLC and extensive-stage (ES)-SCLC treated with platinum and etoposide (PE) plus anti-programmed cell death ligand 1 (PD-L1) antibody. We investigated the relationship of DLL3 expression with TME, mutation status, tumor neoantigens, and immunochemotherapy. RESULTS: In the LS-SCLC cohort (n = 59), whole-exome sequencing revealed that DLL3High cases had significantly more neoantigens (P = 0.004) and a significantly higher rate of the signature SBS4 associated with smoking (P = 0.02) than DLL3Low cases. Transcriptome analysis in the LS-SCLC cohort revealed that DLL3High cases had significantly suppressed immune-related pathways and dendritic cell (DC) function. SCLC with DLL3High had significantly lower proportions of T cells, macrophages, and DCs than those with DLL3Low. In the ES-SCLC cohort (n = 30), the progression-free survival associated with PE plus anti-PD-L1 antibody was significantly worse in DLL3High cases than in DLL3Low cases (4.7 vs. 7.4 months, P = 0.01). CONCLUSIONS: Although SCLC with DLL3High had a higher neoantigen load, these tumors were resistant to immunochemotherapy due to suppressed tumor immunity by inhibiting antigen-presenting functions.
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Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Ligandos , Microambiente Tumoral , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Etopósido/uso terapéutico , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
BACKGROUND: Sequential tyrosine kinase inhibitors (TKIs) following immune checkpoint inhibitors (ICIs) increases the incidence of serious adverse events (SAEs). However, the factors and the types of TKIs that affect the incidence of SAEs remain unknown. METHODS: We retrospectively reviewed advanced non-small cell lung cancer (NSCLC) patients who received sequential TKIs following ICIs between November 2015 and April 2021. All AEs were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) ver 5.0. RESULTS: Among 1,638 NSCLC patients who received ICIs, 63 patients received sequential TKIs following ICIs. The types of TKIs included EGFR-TKIs in 48 patients, ALK-TKIs in 10 patients, and others in 5 patients. The median dosing interval was 57 days (range: 7-698). Eighteen (28.6%) patients developed SAEs (Grade 3/4 or hospitalized). The incidence of SAEs and withdrawal of TKIs due to AEs were significantly higher in patients (n = 40) who initiated TKI treatment within 3 months after ICIs than in patients (n = 23) who initiated TKI treatment 3 months after ICIs (SAEs, 40.0% vs. 4.3%, p < 0.01; withdrawal rate: 57.5% vs. 21.7%, p < 0.01). There was no significant difference in the incidence of SAEs and withdrawal rate due to AEs between EGFR-TKIs and other TKIs (SAE, 22.9% vs. 40.0%, p = 0.20; withdrawal rate: 41.7% vs. 53.3%, p = 0.55). CONCLUSION: The dosing interval from last ICI to the initiation of TKI treatment can affects the incidence of SAEs and the withdrawal rate due to AEs regardless of the types of TKIs.
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Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Incidencia , Estudios Retrospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Receptores ErbB/genéticaRESUMEN
Osimertinib, a third-generation EGFR TKI, is the standard therapy for previously untreated EGFR-mutated non-small cell lung cancer patients following the landmark FLAURA study. However, resistance inevitably hinders patient prognosis, increasing the need for new therapeutic strategies beyond osimertinib. Frontline osimertinib-based combination strategies (platinum-based chemotherapy and angiogenesis inhibitors) are currently being tested primarily to prevent initial resistance. In the later-line setting after osimertinib, many next-line therapeutic candidates have been actively examined in clinical trials. Notably, several drugs with novel mechanisms of action, such as antibody-drug conjugates and EGFR -MET bispecific antibodies, have shown promising efficacy despite the resistance mechanisms and are close to clinical application. In addition, genotype-based target strategies have been investigated for a better understanding of osimertinib resistance mechanisms based on molecular profiling tests at relapse. The C797S mutation and MET gene alterations are commonly identified following osimertinib resistance, for which targeting strategies are actively tested. This review describes current pharmacotherapeutic strategies for EGFR-mutated non-small cell lung cancer based on the results of clinical trials and the latest published data, broadly grouped into two sections: 1) EGFR TKIs-based combination therapy in the front-line setting and 2) novel therapeutic strategies after osimertinib resistance.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptores ErbB/genética , Receptores ErbB/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Mutación , Resistencia a Antineoplásicos/genéticaRESUMEN
INTRODUCTION: There are two treatment strategies for non-small cell lung cancer (NSCLC) exhibiting a high expression level of programmed death-ligand 1 (tumor proportion score ≥ 50%): pembrolizumab plus chemotherapy and monotherapy. We retrospectively compared their efficacy and safety. MATERIALS AND METHODS: We reviewed the efficacy and safety of first-line pembrolizumab-containing regimens administered between 2017 and 2020 to consecutive patients. The patients were divided into a pembrolizumab plus chemotherapy group (Combo group) or monotherapy group (Mono group). To compare the efficacy, we monitored the time to failure of strategy (TFS) defined as the time from the start of treatment to the occurrence of one of the following events: the addition of any drug not included in the primary strategy, progression of cancer after complete therapy, progression and no subsequent therapy, or death, whichever occurred first. We used the propensity score matching (PSM) to reduce the bias. RESULTS: A total of 126 patients were identified (89 in the Mono group and 37 in the Combo group). PSM matched 36 individuals from each of the two groups. The overall response rate and median progression-free survival of the Combo group were better than those of the Mono group. However, the median TFS was almost the same (11.3 months vs. 14.9 months; hazard ratio 1.40 [95% confidence interval 0.62-3.15]). The frequency of all serious adverse effects was higher in the Combo group than in the Mono group. DISCUSSION: Due to similar efficacy in TFS, both pembrolizumab plus chemotherapy and monotherapy are valid options for NSCLC.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/genética , Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Manejo de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Terapia Molecular DirigidaRESUMEN
BACKGROUND: Cancer cachexia is a multifactorial syndrome characterized by weight loss leading to immune dysfunction that is commonly observed in patients with advanced non-small cell lung cancer (NSCLC). We examined the impact of cachexia on the prognosis of patients with advanced NSCLC receiving pembrolizumab and evaluated whether the pathogenesis of cancer cachexia affects the clinical outcome. PATIENTS AND METHODS: Consecutive patients with advanced NSCLC treated with pembrolizumab were retrospectively enrolled in the study. Serum levels of pro-inflammatory cytokines and appetite-related hormones, which are related to the pathogenesis of cancer cachexia, were analyzed. Cancer cachexia was defined as (1) a body weight loss > 5% over the past 6 months, or (2) a body weight loss > 2% in patients with a body mass index < 20 kg/m2. RESULTS: A total of 133 patients were enrolled. Patients with cachexia accounted for 35.3%. No significant difference in the objective response rate was seen between the cachexia and non-cachexia group (29.8% vs. 34.9%, P = 0.550), but the median progression-free survival (PFS) and overall survival (OS) periods were significantly shorter in the cachexia group than in the non-cachexia group (PFS: 4.2 months vs. 7.1 months, P = 0.04, and OS: 10.0 months vs. 26.6 months, P = 0.03). The serum TNF-alpha, IL-1 alpha, IL-8, IL-10, and leptin levels were significantly associated with the presence of cachexia, but not with the PFS or OS. CONCLUSION: The presence of cachexia was significantly associated with poor prognosis in advanced NSCLC patients receiving pembrolizumab, not with the response to pembrolizumab.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Caquexia/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Caquexia/inducido químicamente , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease implicated as an independent risk factor for lung cancer. However, optimal treatment for advanced lung cancer with IPF remains to be established. We performed a randomised phase 3 trial (J-SONIC) to assess the efficacy and safety of nintedanib plus chemotherapy (experimental arm) compared with chemotherapy alone (standard-of-care arm) for advanced nonsmall cell lung cancer (NSCLC) with IPF. METHODS: Chemotherapy-naïve advanced NSCLC patients with IPF were allocated to receive carboplatin (area under the curve of 6 on day 1) plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) (100â mg·m-2 on days 1, 8 and 15) every 3â weeks with or without nintedanib (150â mg twice daily, daily). The primary end-point was exacerbation-free survival (EFS). RESULTS: Between May 2017 and February 2020, 243 patients were enrolled. Median EFS was 14.6â months in the nintedanib plus chemotherapy group and 11.8â months in the chemotherapy group (hazard ratio (HR) 0.89, 90% CI 0.67-1.17; p=0.24), whereas median progression-free survival was 6.2 and 5.5â months, respectively (HR 0.68, 95% CI 0.50-0.92). Overall survival was improved by nintedanib in patients with nonsquamous histology (HR 0.61, 95% CI 0.40-0.93) and in those at GAP (gender-age-physiology) stage I (HR 0.61, 95% CI 0.38-0.98). Seven (2.9%) out of 240 patients experienced acute exacerbation during study treatment. CONCLUSIONS: The primary end-point of the study was not met. However, carboplatin plus nab-paclitaxel was found to be effective and tolerable in advanced NSCLC patients with IPF. Moreover, nintedanib in combination with such chemotherapy improved overall survival in patients with nonsquamous histology.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Fibrosis Pulmonar Idiopática , Neoplasias Pulmonares , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/complicaciones , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel , Masculino , FemeninoRESUMEN
BACKGROUND: Nivolumab monotherapy has demonstrated superior efficacy in advanced unresectable gastric cancer (GC), but its impact on resectable GC remains unknown. This phase I study aimed to evaluate safety, feasibility, and potential biomarkers of neoadjuvant nivolumab monotherapy in resectable GC. METHODS: Untreated, resectable, cT2 or more advanced gastric adenocarcinomas with clinical stage I, II, or III were treated with two doses of nivolumab before gastrectomy. Patients were excluded if their tumors may be applicable to neoadjuvant chemotherapy. The primary endpoint was the incidence of adverse event (AE) categories of special interest. RESULTS: All of the 31 enrolled patients completed 2 doses of nivolumab monotherapy. While 30 (97%) patients underwent surgery with curative intent, 1 patient discontinued before the planned surgical intervention because of a newly emerging liver metastasis. Seven patients (23%) had nivolumab treatment-related AEs, and one patient had a treatment-related AE of grade 3-4. The incidences of treatment-related AE categories of special interest ranged from 0 to 6%. Notable surgical complications included two cases of grade 3 anastomotic leakage and two cases of pancreatic fistula. The major pathologic response (MPR) assessed by the independent pathology review committee was achieved in five (16%) patients, of which one patient had a pathologic complete response. The MPR was mostly observed in patients with positive PD-L1 expression, high microsatellite instability, and/or high tumor mutation burden. CONCLUSIONS: Neoadjuvant nivolumab monotherapy is feasible with an acceptable safety profile and induces a MPR in certain patients with resectable GC. (Registration: clinicaltrials.jp, JapicCTI-183895).
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Adenocarcinoma , Nivolumab , Neoplasias Gástricas , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/cirugía , Humanos , Inestabilidad de Microsatélites , Terapia Neoadyuvante/efectos adversos , Nivolumab/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugíaRESUMEN
PURPOSE: Aprepitant is used with dexamethasone and 5-HT3 receptor antagonists as an antiemetic treatment for chemotherapy, including cisplatin. Aprepitant is a substrate of cytochrome P450 (CYP) 3A4 and is known to cause its inhibition and induction. In addition, dexamethasone is a CYP3A4 substrate that induces CYP3A4 and CYP3A5 expression. In this study, we aimed to quantitatively evaluate the profile of CYP3A activity using its endogenous markers in non-small cell lung cancer patients receiving a standard cisplatin regimen with antiemetics, including aprepitant. METHODS: Urinary 11ß-hydroxytestosterone (11ß-OHT)/testosterone concentration ratio and plasma 4ß-hydroxycholesterol (4ß-OHC) concentrations were measured before and after cisplatin treatment (days 1, 4, and 8). CYP3A5 was genotyped, and plasma aprepitant concentrations were measured on day 4 to examine its influence on CYP3A endogenous markers. RESULTS: The urinary 11ß-OHT/testosterone concentration ratio in the 35 patients included in this study increased by 2.65-fold and 1.21-fold on days 4 and 8 compared with day 1, respectively. Their plasma 4ß-OHC concentration increased by 1.46-fold and 1.66-fold, respectively. The mean plasma aprepitant concentration on day 4 was 1,451 ng/mL, which is far lower than its inhibitory constant. The allele frequencies of CYP3A5*1 and CYP3A5*3 were 0.229 and 0.771, respectively. In patients with the CYP3A5*1 allele, the plasma 4ß-OHC concentration was significantly lower at baseline but more potently increased with chemotherapy. CONCLUSION: CYP3A activity was significantly induced from day 4 to day 8 in patients receiving cisplatin and three antiemetic drugs.
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Antieméticos , Aprepitant , Carcinoma de Pulmón de Células no Pequeñas , Cisplatino , Citocromo P-450 CYP3A , Dexametasona , Neoplasias Pulmonares , Antieméticos/uso terapéutico , Aprepitant/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Dexametasona/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Vómitos/inducido químicamente , Vómitos/prevención & controlRESUMEN
Lung cancer is the most common cause of cancer-related death globally. In addition, its incidence increases with age, with approximately half of all cases diagnosed in patients aged ≥70. Molecular targeted therapies and immunotherapies for advanced non-small-cell lung cancer have markedly improved outcomes over the past two decades. Despite the high incidence of lung cancer in older people, most trials excluded such patients from enrollment. Therefore, the optimal treatment strategies for older patients remain unclear. The present review summarizes the published literature and provides guidance on the treatment of older patients with lung cancer within three broad stages: (i) early-stage lung cancer, (ii) locally advanced lung cancer and (iii) metastatic lung cancer. We also discuss the use of the latest evidence for older patients.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Inmunoterapia , Neoplasias Pulmonares/patología , Terapia Molecular DirigidaRESUMEN
INTRODUCTION: The accelerated development of lung cancer treatments has resulted in a single global study that is sufficient for a new agent and indication to be approved. Not all new treatments predominate globally, and differences in standards of care may influence the efficacy of treatments in the real world. METHODS: The results from Japanese domestic trials and global trials that included a subset population of Japanese patients were evaluated for 18 genomic targeted agents and immune therapies approved after 2000. The results were collected from drug applications that were reviewed for treatment approval in Japan. RESULTS: Japan is one of the first countries to approve and fully reimburse new agents around the world. Alectinib and nivolumab, which were first developed by Japanese pharmaceutical companies, were evaluated in an independent domestic trial, which resulted in their early approval. For most other indications, 1.1-15.8% of the patients who participated in pivotal registration studies were Japanese, and their treatment results were comparable to those of the overall population. Overall survival was less likely to be improved by four agents for which the post-protocol therapy might have been different in Japan than in other countries. CONCLUSIONS: Overall, a positive result in a global trial was emulated in Japanese patients and led to the approval of a new standard treatment in Japan. Early approvals were attained by either participating in the global registrational study or conducting a domestic phase II study. The higher efficacy of new agents may be an issue in the future, as Japanese patients had early access to the new agent and may receive better treatment after the trial.
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Antineoplásicos , Neoplasias Pulmonares , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Japón , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
BACKGROUND: Superior sulcus tumours (SSTs) are relatively uncommon and one of the most intractable lung cancers among non-small cell lung cancer (NSCLC). We planned a multicenter, single-arm confirmatory trial of new multidisciplinary treatment using immune-checkpoint inhibitor. The aim is to evaluate the safety and efficacy of new multidisciplinary treatment with perioperative durvalumab after chemoradiotherapy (CRT). METHODS: The primary endpoint is 3-year overall survival. Patients receive induction CRT with sequential two courses of durvalumab, followed by surgical resection for resectable SST. The regimen for CRT is two courses of cisplatin and S-1, and concurrent radiotherapy (66 Gy/33 Fr). After surgery, 22 courses of post-operative durvalumab therapy are administered. For unresectable SST, an additional 22 courses of durvalumab are administered after induction durvalumab. RESULTS: In two cases as a safety cohort, the safety of intervention treatment up to 30 days after surgery was examined, and there were no special safety signals. Patient enrollment has now resumed in the main cohort. CONCLUSIONS: The results of this study may contribute to the establishment of a new standard of care for SST, which is an intractable NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anticuerpos Monoclonales , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioradioterapia/métodos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Estudios Multicéntricos como Asunto , Estadificación de Neoplasias , Estudios ProspectivosRESUMEN
Pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) with manageable safety compared with placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double-blind, phase 3 KEYNOTE-189 study. We present results of Japanese patients enrolled in the KEYNOTE-189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m2 plus the investigator's choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m2 Q3W (all intravenous). Co-primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7-38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed-platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9-29.0) months in the placebo plus pemetrexed-platinum arm (hazard ratio [HR] .29; 95% CI, .07-1.15). The median (95% CI) PFS was 16.5 (8.8-21.1) compared with 7.1 (4.7-21.4) months (HR, .62; 95% CI, .27-1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first-line therapy with pembrolizumab plus pemetrexed-platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.