RESUMO
Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman's ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.
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BACKGROUND: Zoledronic acid (ZA) reduces the incidence of skeletal-related events (SREs) in patients with bone metastases from solid tumors. However, the optimal dosing interval of ZA for patients with lung cancer is uncertain. METHODS: We conducted a randomized, open-label, feasibility phase 2 trial at eight Japanese hospitals. Patients with bone metastases from lung cancer were randomly assigned to receive either 4 mg of ZA every four weeks (4wk-ZA) or every eight weeks (8wk-ZA). The primary endpoint was the time to the first SRE and the rate and types of SREs after one year. SREs were defined as pathologic bone fracture, bone radiation therapy or surgery, and spinal cord compression. Secondary endpoints were the SRE incidence at six months, pain assessment, changes in analgesic consumption, serum N-telopeptide, toxicity, and overall survival. RESULTS: Between November 2012 and October 2018, 109 patients were randomly assigned to the 4wk-ZA group (54 patients) and the 8wk-ZA group (55 patients). The number of patients who received chemotherapy or molecular-targeted agents was 30 and 23 and 18 and 16 in the 4wk-ZA and 8wk-ZA groups, respectively. The median time to the first SRE could not be calculated because of a low SRE. The time to the first SRE of all patients did not differ between the groups (P = 0.715, HR = 1.18, 95% CI = 0.48, 2.9). The SRE rate of all patients after 12 months was 17.6% (95% CI = 8.4, 30.9%) in the 4wk-ZA and 23.3% (95% CI = 11.8, 38.6%) in the 8wk-ZA group, without significant differences between the groups. There was no difference in any secondary endpoint between groups, and these endpoints did not differ among treatment modalities. CONCLUSIONS: An eight-week ZA interval does not increase the SRE risk for patients with bone metastasis from lung cancer and could be considered clinically.
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Neoplasias Ósseas , Neoplasias Pulmonares , Humanos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Ácido Zoledrônico/uso terapêuticoRESUMO
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 Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , População do Leste Asiático , Paclitaxel , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Since the overall survival (OS) of patients enrolled in the first clinical phase III trial (WJOG5108L) was not recorded owing to time constraints, the present study (WJOG5108LFS) with a longer follow-up (66.6 months) aimed to compare OS of those treated with erlotinib (ER) and gefitinib (GE) for lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation. METHODS: Among 536 enrolled patients, 362 (67.5%) were EGFR mutation-positive, including 182 in the ER arm and 180 in the GE arm. Median survival time (MST) and progression-free survival (PFS) were calculated using Kaplan-Meier survival curves. OS and PFS were determined for patients with EGFR mutation. RESULTS: MSTs of ER (n = 182) and GE arms (n = 180) were 31.97 and 27.98 months, respectively (P = 0.3573, hazard ratio = 1.116). MSTs of exon 19 mutation patients in ER (n = 99) and GE arms (n = 89) were 37.49 and 28.91 months, respectively (P = 0.3791). MSTs of L858 mutation patients in ER (n = 82) and GE arms (n = 89) were 22.98 and 27.79 months, respectively (P = 0.7836). In patients with brain metastasis harboring mutation, response rates were 32.8% and 22.2% (P = 0.160), MSTs were 23.46 and 23.89 months (P = 0.7410), and PFS were 9.49 and 6.98 months (P = 0.1481) in the ER (n = 67) and GE arms (n = 72), respectively. CONCLUSIONS: No significant differences in OS were observed between the ER and GE arms in all patients with EGFR mutation and those with brain metastasis harboring EGFR mutation.
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Adenocarcinoma de Pulmão , Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Gefitinibe/uso terapêutico , Cloridrato de Erlotinib/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Quinazolinas/efeitos adversos , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Receptores ErbB/genética , Estimativa de Kaplan-Meier , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Mutação , Intervalo Livre de DoençaRESUMO
This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or greater evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). The hazard ratio (HR) for progression-free survival by independent central review (data cut-off date, 10 July 2017) was 0.25 (95% confidence interval [CI], 0.10-0.64; one-sided, nominal P = .001). The HR for overall survival (data cut-off date, 15 February 2019) was 0.39 (95% CI, 0.17-0.91; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 patients (52%) and four patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or greater. The trial is registered with ClinicalTrials.gov: NCT02142738.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Tratamento Farmacológico , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Pemetrexede/administração & dosagem , Pemetrexede/uso terapêutico , Análise de Sobrevida , Resultado do TratamentoRESUMO
BACKGROUND: Adjuvant oral uracil-tegafur (UFT) has led to significantly longer postoperative survival among patients with non-small-cell lung cancer (NSCLC). Gemcitabine (GEM) monotherapy is also reportedly effective for NSCLC and has minor adverse events (AEs). This study compared the efficacy of GEM- versus UFT-based adjuvant regimens in patients with completely resected pathological stage (p-stage) IB-IIIA NSCLC. PATIENTS AND METHODS: Patients with completely resected p-stage IB-IIIA NSCLC were randomly assigned to GEM or UFT. The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and AEs. RESULTS: We assigned 305 patients to the GEM group and 303 to the UFT group. Baseline factors were balanced between the arms. Of the 608 patients, 293 (48.1%) had p-stage IB disease, 195 (32.0%) had p-stage II disease and 121 (19.9%) had p-stage IIIA disease. AEs were generally mild in both groups, and only one death occurred, in the GEM group. After a median follow-up of 6.8 years, the two groups did not significantly differ in survival: 5 year OS rates were GEM: 70.0%, UFT: 68.8% (hazard ratio 0.948; 95% confidence interval 0.73-1.23; P = 0.69). CONCLUSION: Although GEM-based adjuvant therapy for patients with completely resected stage IB-IIIA NSCLC was associated with acceptable toxicity, it did not provide longer OS than did UFT.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Quimioterapia Adjuvante , Desoxicitidina/análogos & derivados , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Tegafur , Uracila/uso terapêutico , GencitabinaRESUMO
This pilot study evaluated the pharmacokinetics and clinical outcome of nivolumab, administered every 4 weeks to patients with advanced non-small-cell lung cancer. The interval of nivolumab administration was changed from 2 to 4 weeks in four patients in whom tumor growth had been controlled for more than 6 months. Pharmacokinetics and clinical outcomes of nivolumab were prospectively investigated. The estimated steady-state nivolumab mean plasma concentration (±standard deviation) of each interval in the four patients was 53.1 (±15.0) at 4 weeks and 105.2 (±29.5) µg/mL at 2 weeks. No disease progression was observed in three patients for at least 1 year after the interval change; however, one patient developed interstitial lung disease within 5.6 months after the change. In conclusion, the pharmacological effects of nivolumab continued with doses administered less frequently than the standard schedule. Nevertheless, further research on nivolumab administration intervals is necessary.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Projetos PilotoRESUMO
IMPORTANCE: Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. OBJECTIVE: To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation. DESIGN, SETTING, AND PARTICIPANTS: Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. INTERVENTIONS: The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. RESULTS: From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation. TRIAL REGISTRATION: UMIN Clinical Trials Registry Identifier: UMIN000023761.
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Inibidores da Angiogênese/uso terapêutico , Bevacizumab/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Feminino , Humanos , Japão , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND/AIM: To explore the safety of osimertinib plus ramucirumab in patients with EGFR-mutated lung adenocarcinoma. PATIENTS AND METHODS: Six advanced lung adenocarcinoma patients with EGFR mutation were treated with osimertinib 80 mg/day plus ramucirumab 10 mg/kg, every two weeks. Defined dose-limiting toxicity (DLT) was assessed within the first two treatment cycles. RESULTS: Of those enrolled, five patients had both EGFR exon 20 T790M mutation and sensitizing mutation. DLT was observed in one patient (grade 3 appetite loss). During the entire period, no other severe adverse event was observed. Five patients showed partial response and one disease progression. Median progression-free survival for patients with EGFR T790M was 9.2 months. In an exploratory analysis, changes of cell-free DNA at 2 weeks predicted radiological tumor responses. CONCLUSION: The safety results of osimertinib plus ramucirumab in Japanese lung adenocarcinoma patients with EGFR mutation will lead to further efficacy investigation.
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Acrilamidas/administração & dosagem , Compostos de Anilina/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Acrilamidas/efeitos adversos , Idoso , Compostos de Anilina/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , DNA Tumoral Circulante/genética , Intervalo Livre de Doença , Esquema de Medicação , Receptores ErbB/genética , Feminino , Humanos , Japão , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Resultado do Tratamento , RamucirumabRESUMO
BACKGROUND: Two phase II studies in Japan examined the efficacy and safety of nivolumab, a programmed cell death 1 receptor inhibitor, in patients with advanced squamous and non-squamous non-small cell lung cancer (ONO-4538-05 and ONO-4538-06). We examined the long-term efficacy and safety of nivolumab in these patients treated for up to 5 years. METHODS: Patients with squamous (N = 35) or non-squamous (N = 76) non-small cell lung cancer received nivolumab (3 mg/kg every 2 weeks) until disease progression/death. Overall survival and progression-free survival were assessed at 5 years after starting treatment in separate and pooled analyses. Safety was evaluated in terms of treatment-related adverse events. RESULTS: A total of 17 patients were alive at the database lock (26 July 2019). The median overall survival (95% confidence interval) and 5-year survival rate were 16.3 (12.4-25.2) months and 14.3% in squamous patients, 17.1 (13.3-23.0) months and 19.4% in non-squamous patients and 17.1 (14.2-20.6) months and 17.8% in the pooled analysis, respectively. Programmed death ligand-1 expression tended to be greater among 5-year survivors than in non-survivors (P = 0.0703). Overall survival prolonged with increasing programmed death ligand-1 expression, with 5-year survival rates of 11.8, 21.8 and 41.7% in patients with programmed death ligand-1 expression of <1, ≥1-<50 and ≥50%, respectively. Treatment-related adverse events in ≥10% of patients (pooled analysis) included rash (15.3%), malaise (14.4%), decreased appetite (14.4%), pyrexia (14.4%) and nausea (10.8%). CONCLUSIONS: Long-term survival with nivolumab was observed in patients with squamous or non-squamous non-small cell lung cancer. No new safety signals were reported after ≥5 years of follow-up.
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Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase II como Assunto , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversosRESUMO
This prespecified subanalysis of the global, randomized controlled phase III KEYNOTE-024 study of pembrolizumab vs chemotherapy in previously untreated metastatic non-small-cell lung cancer without EGFR/ALK alterations and a programmed death ligand 1 (PD-L1) tumor proportion score of 50% or higher evaluated clinical outcomes among patients enrolled in Japan. Treatment consisted of pembrolizumab 200 mg every 3 weeks (35 cycles) or platinum-based chemotherapy (four to six cycles). The primary end-point was progression-free survival; secondary end-points included overall survival and safety. Of 305 patients randomized in KEYNOTE-024 overall, 40 patients were enrolled in Japan (all received treatment: pembrolizumab, n = 21; chemotherapy, n = 19). Median progression-free survival was 41.4 (95% confidence interval [CI], 4.2-42.5) months with pembrolizumab and 4.1 (95% CI, 2.8-8.3) months with chemotherapy (hazard ratio [HR], 0.27 [95% CI, 0.11-0.65]; one-sided, nominal P = .001). Median overall survival was not reached (NR) (95% CI, 22.9-NR) and 21.5 (95% CI, 5.2-35.0) months, respectively (HR, 0.39 [95% CI, 0.17-0.91]; one-sided, nominal P = .012). Treatment-related adverse events occurred in 21/21 (100%) pembrolizumab-treated and 18/19 (95%) chemotherapy-treated patients; eight patients (38%) and nine patients (47%), respectively, had grade 3-5 events. Immune-mediated adverse events and infusion reactions occurred in 11 pembrolizumab-treated patients (52%) and four chemotherapy-treated patients (21%), respectively; four patients (19%) and one patient (5%), respectively, had grade 3-5 events. Consistent with results from KEYNOTE-024 overall, first-line pembrolizumab improved progression-free survival and overall survival vs chemotherapy with manageable safety among Japanese patients with metastatic non-small-cell lung cancer without EGFR/ALK alterations and a PD-L1 tumor proportion score of 50% or higher. The trial is registered with Clinicaltrials.gov: NCT02142738.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cisplatino/administração & dosagem , Intervalos de Confiança , Estudos Cross-Over , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Esquema de Medicação , Feminino , Genes erbB-1 , Humanos , Japão , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Pemetrexede/administração & dosagem , Receptor de Morte Celular Programada 1 , Intervalo Livre de Progressão , Resultado do Tratamento , GencitabinaRESUMO
An oesophageal fully covered self-expanding metallic stent (SEMS) was placed in a 54-year-old Japanese man to relieve dysphagia owing to a stage cT1bN3M1c lung adenocarcinoma. High expression of programmed cell death-ligand 1 was microscopically confirmed, and pembrolizumab was subsequently administered. Several days later, the patient was hospitalized with septic shock, and severe mediastinitis and pneumonia caused by oesophageal SEMS-induced oesophageal and bronchial perforations were observed. Thoracoscopic surgery was performed to drain the mediastinal abscess, and an additional oesophageal SEMS was placed to close the oesophageal perforation. The patient gradually recovered from the potentially fatal infection, and the SEMS was retrieved after confirming perforation closure. We re-initiated pembrolizumab administration, and the patient responded well. The present report reveals the potential risk and effectiveness of SEMS, especially when administered with immune checkpoint inhibitors.
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Patients with mixed neuroendocrine-nonneuroendocrine neoplasms (MiNENs) of the colon have poor prognosis. Herein, we report a patient with MiNEN of the colon with metastases to the liver and the thyroid gland, with long-term survival. A 45-year-old man presented with anterior neck swelling. Histopathological examination of the thyroid tumor revealed neuroendocrine carcinoma (NEC), suggesting that a primary NEC in another organ had metastasized to the thyroid gland. Computed tomography to identify a primary NEC revealed two tumors: one in the liver and one in the transverse colon. A biopsy revealed that the histopathology of the liver and colon tumors was NEC and adenocarcinoma, respectively. Thereafter, the patient underwent surgical resection of the colon tumor and was finally diagnosed as colon MiNEN with metastases to the thyroid and liver. The surgical resection of the metastatic liver tumor was performed after several courses of systemic chemotherapy, and the patient survives presently without any recurrence for approximately seven years after the diagnosis. Surgical resection of each metastatic lesion combined with systematic chemotherapy apparently improved the prognosis of MiNEN of the colon with distant metastases.
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Aims: To construct a predictive model for overall survival (OS) in unresectable pancreatic cancer (PaC) undergoing systemic chemotherapy and to confirm its accuracy in an independent cohort. Patients and methods: The training set (Ts) and the validation set (Vs) included 93 patients (median age=71 years) and 75 patients (median age=76 years). In the Ts, we examined variables linked to OS by uni- and multivariate analyses and constructed a predictive model for OS. Next, we evaluated the reproducibility of the proposed model in the Vs. Results: In the multivariate analysis for the Ts, PaC stage IV (P=0.0020) and carbohydrate antigen (CA) 19-9 ≥437.5 IU/l (P=0.0237) were identified to be significant factors associated with OS. Patients with PaC stage IV or not were given a score of 1 or 0, whereas patients with CA19-9 ≥437.5 IU/l or <437.5 IU/l were given a score of 1 or 0. Sum of the point of PaC stage (0 or 1) and CA19-9 (0 or 1) was defined as "PaC-CA score". In the Ts, there were 16 patients with score 0, 40 with score 1 and 37 with score 2, while in the Vs, there were 9 patients with score 0, 32 with score 1 and 34 with score 2. Overall P values reached significance in the Ts (P=0.0002), the Vs (P=0.0029) and the combined Ts and Vs (P<0.0001) among patients with PaC score 0, 1 and 2. Conclusion: PaC-CA score can be helpful for risk stratification in PaC patients undergoing systemic chemotherapy.
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Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) harboring BIM deletion polymorphism (BIM deletion) have poor responses to EGFR TKI. Mechanistically, the BIM deletion induces preferential splicing of the non-functional exon 3-containing isoform over the functional exon 4-containing isoform, impairing TKI-induced, BIM-dependent apoptosis. Histone deacetylase inhibitor, vorinostat, resensitizes BIM deletion-containing NSCLC cells to EGFR-TKI. In the present study, we determined the safety of vorinostat-gefitinib combination and evaluated pharmacodynamic biomarkers of vorinostat activity. Patients with EGFR-mutated NSCLC with the BIM deletion, pretreated with EGFR-TKI and chemotherapy, were recruited. Vorinostat (200, 300, 400 mg) was given daily on days 1-7, and gefitinib 250 mg was given daily on days 1-14. Vorinostat doses were escalated based on a conventional 3 + 3 design. Pharmacodynamic markers were measured using PBMC collected at baseline and 4 hours after vorinostat dose on day 2 in cycle 1. No dose-limiting toxicities (DLT) were observed in 12 patients. We determined 400 mg vorinostat as the recommended phase II dose (RP2D). Median progression-free survival was 5.2 months (95% CI: 1.4-15.7). Disease control rate at 6 weeks was 83.3% (10/12). Vorinostat preferentially induced BIM mRNA-containing exon 4 over mRNA-containing exon 3, acetylated histone H3 protein, and proapoptotic BIMEL protein in 11/11, 10/11, and 5/11 patients, respectively. These data indicate that RP2D was 400 mg vorinostat combined with gefitinib in BIM deletion/EGFR mutation double-positive NSCLC. BIM mRNA exon 3/exon 4 ratio in PBMC may be a useful pharmacodynamic marker for treatment.
Assuntos
Proteína 11 Semelhante a Bcl-2/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Gefitinibe/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Vorinostat/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/genética , Esquema de Medicação , Receptores ErbB/genética , Feminino , Gefitinibe/farmacocinética , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Deleção de Sequência , Análise de Sobrevida , Resultado do Tratamento , Vorinostat/farmacocinéticaRESUMO
BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-PTX) plus gemcitabine (GEM) significantly improved overall survival in patients with metastatic pancreatic adenocarcinoma. Anti-tumor synergy between GEM and nab-PTX was recently demonstrated in a mouse model. We planned to assess the efficacy and safety of the combination of nab-PTX + GEM in patients with non-small-cell lung cancer (NSCLC) previously treated with platinum-based chemotherapy. METHODS: Patients with advanced NSCLC with progressive disease after platinum-based chemotherapy, an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and adequate kidney, liver and bone marrow function were eligible. Treatment consisted of nab-PTX (100 mg/m2) + GEM (1000 mg/m2) on days 1 and 8 of each 3-week cycle until progression disease or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS). RESULTS: Of the 28 patients enrolled, all were evaluable for response and toxicity. The median age was 68 years (range 47-79), and 23 were male and 5 female. The histologic subtypes were: adenocarcinoma in 19 patients, and squamous cell carcinoma in 9 patients. Seventeen patients had ECOG PS 1 and 11 patients had PS 0. Twenty-four patients were second line and 4 patients were third line. The median number of cycles administered was 4 (range 1-10). The overall response rate was 17.9%. The disease control rate was 67.9%. The median progression-free survival was 3.1 months (95% confidence interval [CI] =1.6-4.1). Adverse events were generally tolerable except grade 3 interstitial pneumonia with in 4 patients (14.3%). CONCLUSION: The efficacy of nab-PTX in combination with GEM in advanced second or third-line NSCLC patients was limited and the frequent occurrence of interstitial pneumonia was unacceptable.
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BACKGROUND: Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials. METHODS: SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed. RESULTS: In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found. CONCLUSION: Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC. TRIAL REGISTRATION: JapicCTI-132072; JapicCTI-132073.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Japão , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Resultado do TratamentoRESUMO
Aim: The transitivity of osimertinib to cerebrospinal fluid (CSF) is of clinical concern. A quantitative LC-MS/MS method for the determination of osimertinib in human plasma and CSF was developed to evaluate its transitivity. Results: The calibration range was 40-1000 nM in plasma and 0.8-100 nM in CSF. Accuracy and precision were within 15%. Osimertinib in the CSF but not in plasma strongly adsorbed onto the storage container. The mean adsorbed loss of osimertinib was 45.5% in CSF. Nonspecific binding in CSF was decreased by protein addition (mean loss = 5.8%). Conclusion: A robust validated method was developed for the quantification of osimertinib in human plasma and CSF.
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Acrilamidas/sangue , Acrilamidas/líquido cefalorraquidiano , Compostos de Anilina/sangue , Compostos de Anilina/líquido cefalorraquidiano , Análise Química do Sangue/métodos , Acrilamidas/química , Adsorção , Compostos de Anilina/química , Calibragem , Cromatografia Líquida , Humanos , Limite de Detecção , Espectrometria de Massas em TandemRESUMO
Osimertinib is a standard treatment for epidermal growth factor receptor (EGFR)-mutated, T790M-positive patients with progression during EGFR-tyrosine kinase inhibitor (TKI) therapy. Osimertinib, a third-generation EGFR-TKI, allows progression-free survival of around 10 months, but its toxicity is well-tolerated compared with other EGFR-TKIs. Preclinical and clinical evidence suggests that EGFR-TKI may work synergistically with vascular endothelial growth factor inhibitors. We therefore plan a phase I/II study to investigate this possibility. In phase I, the primary endpoint is assessment of the tolerability of osimertinib and bevacizumab in 6 patients. Phase II then explores the efficacy of combined treatment compared with osimertinib monotherapy with progression-free survival as the primary endpoint. Secondary endpoints are overall response rate, time to treatment failure, overall survival, and safety. Eighty patients will be enrolled in phase II.
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Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Compostos de Anilina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Humanos , Japão , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação/genética , Estudos Prospectivos , Análise de Sobrevida , Adulto JovemRESUMO
A prospective study has previously reported on the incidence of bone metastasis (BM) and skeletal-related events (SREs) in patients with advanced lung cancer. The aim of the present study was to prospectively investigate how the quality of life (QOL) of patients with advanced lung cancer was affected by SREs. Patients with stage IIIB or IV non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) at any stage were followed up every four weeks to determine if they had developed SREs. QOL questionnaires were conducted at enrollment, at 3- and 12-months later and at 1 month after the onset of SREs, using QOL scores including the EuroQOL-5 Dimension (EQ-5D), Functional Assessment of Cancer Therapy-General (FACT-G) and activities of daily living (ADL) scores obtained by the Barthel Index. A total of 274 patients were enrolled in the study. At enrollment the EQ-5D and Barthel Index scores were lower in patients with SREs compared with patients without SREs. A chronological analysis revealed no statistically significant changes in either QOL or ADL in any of the patients. For 14 patients in whom QOL data was collected following the onset of SREs, the evaluation undertaken on the four subscales of the FACT-G revealed a significant decline in emotional functioning following the onset of SREs.