ABSTRACT
BACKGROUND: Biomarkers for predicting response to the immunotherapy and chemotherapy combination in breast cancer patients are not established. In this study, we report exploratory genomic and transcriptomic analyses of pretreatment tumor tissues from patients enrolled in phase II clinical trial of a combination of eribulin and nivolumab for HER-2-negative metastatic breast cancer (MBC) (KORNELIA trial, NCT04061863). METHODS: We analyzed associations between tumor molecular profiles based on genomic (n = 76) and transcriptomic data (n = 58) and therapeutic efficacy. Patients who achieved progression-free survival (PFS) ≥ 6 months were defined as PFS6-responders and PFS6-nonresponders otherwise. FINDINGS: Analyses on tumor mutation burden (TMB) showed a tendency toward a favorable effect on efficacy, while several analyses related to homologous recombination deficiency (HRD) indicated a potentially negative impact on efficacy. Patients harboring TP53 mutations showed significantly poor PFS6 rate and PFS, which correlated with the enrichment of cell cycle-related signatures in PFS6-nonresponders. High antigen presentation gene set enrichment scores (≥ median) were significantly associated with longer PFS. Naïve B-cell and plasma cell proportions were considerably higher in long responders (≥ 18 months). INTERPRETATION: Genomic features including TMB, HRD, and TP53 mutations and transcriptomic features related to immune cell profiles and cell cycle may distinguish responders. Our findings provide insights for further exploring the combination regimen and its biomarkers in these tumors.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Breast Neoplasms , Furans , Ketones , Nivolumab , Receptor, ErbB-2 , Transcriptome , Humans , Female , Ketones/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Breast Neoplasms/mortality , Furans/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Nivolumab/therapeutic use , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Middle Aged , Genomics/methods , Aged , Biomarkers, Tumor/genetics , Adult , Mutation , Neoplasm Metastasis , Gene Expression Profiling , Polyether PolyketidesABSTRACT
BACKGROUND: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). CONCLUSIONS: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Mutation , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Acrylamides , Adult , Aged , Aged, 80 and over , Aniline Compounds , Antineoplastic Agents/adverse effects , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Disease-Free Survival , Double-Blind Method , Erlotinib Hydrochloride/therapeutic use , Female , Gefitinib , Humans , Kaplan-Meier Estimate , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Male , Middle Aged , Piperazines/adverse effects , Protein Kinase Inhibitors/adverse effects , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinazolines/therapeutic use , Survival RateABSTRACT
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.
Subject(s)
Afatinib/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/therapeutic use , Adult , Afatinib/pharmacology , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , Female , Humans , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Protein Kinase Inhibitors/pharmacologyABSTRACT
BACKGROUND: Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) given EGFR tyrosine kinase inhibitors (TKIs) inevitably become resistant to first-generation or second-generation drugs. We assessed the safety, tolerability, pharmacokinetics, and activity of lazertinib-an irreversible, third-generation, mutant-selective, EGFR TKI-in patients with advanced NSCLC progressing after EGFR TKI therapy. METHODS: This first-in-human, open-label, multicentre, phase 1-2 study had three parts: dose escalation, dose expansion, and dose extension; here, we report results on dose escalation and dose expansion. The study was done in 14 hospitals in Korea. Eligible patients were aged 20 years or older and had advanced NSCLC harbouring an activating EGFR mutation and progressing after first-generation or second-generation EGFR TKI treatment, a defined tumour T790M mutation status, an Eastern Cooperative Oncology Group performance status of 0-1, at least one measurable extracranial lesion, defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and adequate organ function. Patients were enrolled to seven dose-escalation cohorts according to a rolling six design; five cohorts were expanded. Patients were given oral lazertinib 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 240 mg, or 320 mg once daily continuously in 21-day cycles. Primary endpoints were safety and tolerability and secondary endpoints included objective response in evaluable patients. This study is registered with ClinicalTrials.gov, NCT03046992, and the phase 2 extension study is ongoing. FINDINGS: Between Feb 15, 2017, and May 28, 2018, 127 patients were enrolled into the dose escalation group (n=38) and dose expansion group (n=89). No dose-limiting toxicities occurred. There was no dose-dependent increase in adverse events. The most commonly reported adverse events were grade 1-2 rash or acne (in 38 [30%] of 127 patients) and pruritus (in 34 [27%]). Grade 3 or grade 4 adverse events occurred in 20 (16%) patients, with the most common being grade 3 pneumonia (four [3%]). Treatment-related grade 3 or 4 adverse events occurred in four (3%) patients; treatment-related serious adverse events were reported in six patients (5%). There were no adverse events with an outcome of death and no treatment-related deaths. The proportion of patients achieving an objective response by independent central review assessment was 69 (54%; 95% CI 46-63) of 127. INTERPRETATION: Lazertinib had a tolerable safety profile and showed promosing clinical activity in patients with NSCLC progressing on or after EGFR TKI therapy. Our findings provide a rationale for further clinical investigations. FUNDING: Yuhan Corporation.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Brain Neoplasms/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Morpholines/therapeutic use , Mutation , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Aged , Brain Neoplasms/genetics , Brain Neoplasms/secondary , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Dose-Response Relationship, Drug , ErbB Receptors/genetics , Female , Follow-Up Studies , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Prognosis , Response Evaluation Criteria in Solid Tumors , Survival RateABSTRACT
Hepatitis C virus (HCV) alters mitochondrial dynamics associated with persistent viral infection and suppression of innate immunity. Mitochondrial dysfunction is also a pathologic feature of direct-acting antiviral (DAA) treatment. Despite the high efficacy of DAAs, their use in treating patients with chronic hepatitis C in interferon-sparing regimens occasionally produces undesirable side effects such as fatigue, migraine, and other conditions, which may be linked to mitochondrial dysfunction. Here, we show that clinically prescribed DAAs, including sofosbuvir, affect mitochondrial dynamics. To counter these adverse effects, we examined HCV-induced and DAA-induced aberrant mitochondrial dynamics modulated by ginsenoside, which is known to support healthy mitochondrial physiology and the innate immune system. We screened several ginsenoside compounds showing antiviral activity using a robust HCV cell culture system. We investigated the role of ginsenosides in antiviral efficacy, alteration of mitochondrial transmembrane potential, abnormal mitochondrial fission, its upstream signaling, and mitophagic process caused by HCV infection or DAA treatment. Only one of the compounds, ginsenoside Rg3 (G-Rg3), exhibited notable and promising anti-HCV potential. Treatment of HCV-infected cells with G-Rg3 increased HCV core protein-mediated reduction in the expression level of cytosolic p21, required for increasing cyclin-dependent kinase 1 activity, which catalyzes Ser616 phosphorylation of dynamin-related protein 1. The HCV-induced mitophagy, which follows mitochondrial fission, was also rescued by G-Rg3 treatment. CONCLUSION: G-Rg3 inhibits HCV propagation. Its antiviral mechanism involves restoring the HCV-induced dynamin-related protein 1-mediated aberrant mitochondrial fission process, thereby resulting in suppression of persistent HCV infection. (Hepatology 2017;66:758-771).
Subject(s)
Ginsenosides/pharmacology , Hepacivirus/drug effects , Mitochondria, Liver/drug effects , Mitochondrial Dynamics/drug effects , Virus Replication/drug effects , Biopsy, Needle , Blotting, Western , Cell Survival/drug effects , Cells, Cultured , Fluorescent Antibody Technique , Hepacivirus/physiology , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/pathology , Humans , Immunity, Innate/drug effects , Immunohistochemistry , Mitochondrial Dynamics/physiology , Real-Time Polymerase Chain Reaction/methods , Sampling StudiesABSTRACT
OBJECTIVE: The purpose of this study was to investigate the incidence and natural history of incidentally found and untreated pulmonary embolism (PE) at coronary CT angiography after coronary artery bypass grafting. MATERIALS AND METHODS: We retrospectively reviewed the records of 353 patients consecutively registered between January 1, 2010, and November 11, 2015, who underwent coronary artery bypass grafting followed within 2 weeks by coronary CT angiography. All patients received 100 mg of aspirin and 75 mg of clopidogrel after surgery. We collected relevant clinical and CT data, including total follow-up duration after coronary artery bypass grafting, follow-up CT findings, mortality, and incidence of any recurrent PE. RESULTS: PE was diagnosed in 22 of the 353 patients (6.2%) who remained in the study after the exclusion criteria were applied. Most of the PEs occurred at the segmental or subsegmental level. All patients were in hemodynamically stable condition, had no symptoms, and underwent follow-up for a median of 53 months (range 19-74 months). Twenty of the 22 patients did not receive anticoagulation, and all but one of these patients had complete resolution of PE at second follow-up coronary CT angiography (median, 149 days after surgery). There was no associated mortality or recurrent PE. CONCLUSION: Incidental PE after coronary artery bypass grafting is found in approximately 6% of patients undergoing postoperative coronary CT angiography, and most PEs resolve spontaneously without anticoagulation. No patient in this study died or had recurrent PE during a median follow-up period of 53 months.
Subject(s)
Coronary Angiography , Coronary Artery Bypass/adverse effects , Incidental Findings , Postoperative Complications/diagnostic imaging , Pulmonary Embolism/diagnostic imaging , Tomography, X-Ray Computed , Aged , Coronary Artery Disease/complications , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/surgery , Female , Follow-Up Studies , Humans , Incidence , Male , Middle Aged , Postoperative Complications/epidemiology , Pulmonary Embolism/epidemiology , Retrospective StudiesABSTRACT
PURPOSE: The purpose of this study is to evaluate the role of C-reactive protein (CRP) and ferritin blood levels in predicting the incidence of systemic infection among adult patients with acute myeloid leukemia (AML) treated with induction chemotherapy. METHODS: Adult patients with newly diagnosed AML who were initially treated with conventional 3 + 7 induction chemotherapy within 5 days of their diagnosis were included. Patients with previous cytotoxic chemotherapy <3 years, acute promyelocytic leukemia diagnosis, human immunodeficiency virus infection, or significant systemic infection at the time of diagnosis were excluded. Patients were treated with an institutional policy of substantial identity with negligible differences regarding supportive care. RESULTS: Among 110 patients (median age 54.5 years), 39 infectious events in 38 patients were reported, along with 21 episodes of infectious treatment-related mortality (TRM; 19.1%). Elevated pre-treatment CRP (p = 0.032) and ferritin (p = 0.002) were related to the incidence of systemic infection. The degree of increase of blood CRP and ferritin level was correlated with the extent of leukocytosis. However, patients with elevated inflammatory markers above normal range had increased risk of infection irrespective of whether they had leukocytosis or not, suggesting that expansion of leukemic blast is another factor affecting the elevation of the markers independent to infection propensity and therefore the magnitude of the elevation does not quantitatively predict the risk of infection. CONCLUSIONS: Modest elevation of baseline blood inflammatory markers above the normal range could be an indicator for predicting the incidence of systemic infection in patients with AML.
Subject(s)
Biomarkers/blood , C-Reactive Protein/metabolism , Ferritins/metabolism , Induction Chemotherapy/adverse effects , Leukemia, Myeloid, Acute/blood , Sepsis/etiology , Adult , Aged , Aged, 80 and over , Female , Ferritins/blood , Humans , Induction Chemotherapy/methods , Leukemia, Myeloid, Acute/drug therapy , Male , Middle Aged , Remission Induction , Young AdultABSTRACT
BACKGROUND: Single cross-sectional area of muscle at the third lumbar vertebra (L3MA) is gold standard to estimate skeletal muscle mass (SMM), and L3 muscle index (L3MI, L3MA/height(2)) is used to determine sarcopenia. The purposes of this study were to evaluate the relationship between SMM indices determined by routine chest CT and L3MI in patients with small-cell lung cancer (SCLC) and to suggest chest CT-derived diagnostic criteria for sarcopenia. METHODS: Area of pectoralis muscles at the aortic arch (PMA) and at L1 (L1MA) was retrospectively measured on chest CT images of 90 consecutive SCLC patients. Pearson's correlation and multiple linear regression analysis were used to assess relationships between L3MI determined by PET/CT and pectoralis muscle index (PMI) and L1 muscle index (L1MI) determined by chest CT. RESULTS: The correlation between L1MI and L3MI was stronger than that between PMI and L3MI (r = 0.851 vs. r = 0.447, p < 0.001). Multivariable regression analysis showed that L1MI was the only significant predictor of L3MI; L3MI = 0.963 × L1MI + 10.336 (R (2) = 0.689, p < 0.001) for male and L3MI = 0.772 × L1MI + 16.518 (R (2) = 0.777, p < 0.001) for female. Using this relationship, estimated cutoffs of L1MI for sarcopenia were 46 cm(2)/m(2) for male and 29 cm(2)/m(2) for female (L3MI cutoffs for sarcopenia are 55 cm(2)/m(2) for male and 39 cm(2)/m(2) for female). The sensitivity and specificity of L1MI cutoffs to determine sarcopenia were 98.2 and 100 %, respectively. CONCLUSIONS: Chest CT-determined L1MI is highly correlated with L3MI in SCLC patients. L1MI, as determined by chest CT, could be used to determine the presence of sarcopenia with suggested cutoffs of 46 cm(2)/m(2) for men and 29 cm(2)/m(2) for women.
Subject(s)
Lung Neoplasms/complications , Sarcopenia/etiology , Small Cell Lung Carcinoma/complications , Tomography, X-Ray Computed/methods , Aged , Female , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/pathology , Male , Retrospective Studies , Sarcopenia/pathology , Small Cell Lung Carcinoma/diagnostic imaging , Small Cell Lung Carcinoma/pathologyABSTRACT
PURPOSE: Pegylated granulocyte-colony-stimulating factor (G-CSF) is frequently used to prevent febrile neutropenia (FN) in patients undergoing chemotherapy with a high risk of myelosuppression. This phase II/III study was conducted to determine the adequate dose of pegteograstim, a new formulation of pegylated G-CSF, and to evaluate the efficacy and safety of pegteograstim compared to pegfilgrastim. METHODS: In the phase II part, 60 breast cancer patients who were undergoing DA (docetaxel and doxorubicin) or TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy were randomly selected to receive a single subcutaneous injection of 3.6 or 6.0 mg pegteograstim on day 2 of each chemotherapy cycle. The phase III part was seamlessly started to compare the dose of pegteograstim at selected in phase II with 6.0 mg pegfilgrastim in 117 breast cancer patients. The primary endpoint of both the phase II and III parts was the duration of grade 4 neutropenia in the chemotherapy cycle 1. RESULTS: The mean duration of grade 4 neutropenia for the 3.6 mg pegteograstim (n = 33) was similar to that for the 6.0 mg pegteograstim (n = 26) (1.97 ± 1.79 days vs. 1.54 ± 0.95 days, p = 0.33). The 6.0 mg pegteograstim was selected to be compared with the 6.0 mg pegfilgrastim in the phase III part. In the phase III part, the primary analysis revealed that the efficacy of pegteograstim (n = 56) was non-inferior to that of pegfilgrastim (n = 59) [duration of grade 4 neutropenia, 1.64 ± 1.18 days vs. 1.80 ± 1.05 days; difference, -0.15 ± 1.11 (p = 0.36, 97.5 % confidence intervals = 0.57 and 0.26)]. The time to the absolute neutrophil count (ANC) recovery of pegteograstim (≥2000/µL) was significantly shorter than that of pegfilgrastim (8.85 ± 1.45 days vs. 9.83 ± 1.20 days, p < 0.0001). Other secondary endpoints showed no significant difference between the two groups. The safety profiles of the two groups did not differ significantly. CONCLUSIONS: Pegteograstim was shown to be as effective as pegfilgrastim in the reduction of chemotherapy-induced neutropenia in the breast cancer patients who were undergoing chemotherapy with a high risk of myelosuppression.
Subject(s)
Breast Neoplasms/drug therapy , Granulocyte Colony-Stimulating Factor/therapeutic use , Induction Chemotherapy/methods , Neutropenia/chemically induced , Polyethylene Glycols/therapeutic use , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Filgrastim , Granulocyte Colony-Stimulating Factor/administration & dosage , Humans , Maximum Tolerated Dose , Middle Aged , Polyethylene Glycols/administration & dosage , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic useABSTRACT
The aim of the current study is to evaluate the prognostic value of anemia, an easily estimable parameter in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) immunochemotherapy. A total of 157 patients with newly diagnosed diffuse large B-cell lymphoma treated with ≥1 cycle of R-CHOP were included. Hemoglobin level without red cell transfusion within 7 days of initiation of treatment was chosen as a parameter of baseline cancer-induced anemia. To investigate the clinical significance of chemotherapy-induced anemia and its recovery after completion of treatment, 87 patients in complete remission for ≥6 months from the time of the last cycle of R-CHOP were grouped and analyzed separately. Patients with a cancer-induced anemia of hemoglobin <10 g/dL showed inferior event-free and disease-free survival compared to those with hemoglobin ≥10 g/dL. This finding was observed irrespective of the status of pre-treatment bone marrow involvement. In multivariate analysis, hemoglobin <10 g/dL was found to be an international prognostic index-independent prognostic factor. Risk of relapse was significantly higher for patients who were still anemic at 6 months after R-CHOP, compared to those who achieved complete recovery from chemotherapy-induced anemia within 6 months.
Subject(s)
Anemia/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Large B-Cell, Diffuse/drug therapy , Neoplasm Recurrence, Local/diagnosis , Adult , Aged , Aged, 80 and over , Anemia/chemically induced , Anemia/complications , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Biomarkers, Tumor/blood , Cyclophosphamide/therapeutic use , Disease-Free Survival , Doxorubicin/therapeutic use , Female , Humans , Lymphoma, Large B-Cell, Diffuse/blood , Lymphoma, Large B-Cell, Diffuse/pathology , Male , Middle Aged , Multivariate Analysis , Neoplasm Recurrence, Local/blood , Prednisone/therapeutic use , Rituximab , Treatment Outcome , Vincristine/therapeutic use , Young AdultABSTRACT
INTRODUCTION: In patients with non-small cell lung cancer (NSCLC), the predictive value of rare epidermal growth factor receptor (EGFR) exon 20 mutations in determining a patient's response to EGFR tyrosine kinase inhibitor (TKI) treatment is unclear. PATIENTS AND METHODS: We reviewed data for NSCLC patients harboring EGFR exon 20 mutations from two hospitals in Korea. EGFR mutations were analyzed using directional sequencing. RESULTS: We identified eight patients carrying EGFR exon 20 mutations, seven of whom had insertional mutations. Three patients carried previously unreported insertional mutations. Among six patients who were treated with EGFR TKI, one showed stable disease and three showed primary resistance. Response evaluations were not performed for the other two patients because of their clinical deterioration. CONCLUSIONS: EGFR exon 20 insertional mutations, including three that were previously unreported, were associated with the poor response of patients to TKI treatment.
Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Lung Neoplasms/genetics , Protein Kinase Inhibitors/therapeutic use , Adult , Aged , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Erlotinib Hydrochloride , Exons , Female , Gefitinib , Humans , Lung Neoplasms/drug therapy , Male , Middle Aged , Mutation , Quinazolines/therapeutic useABSTRACT
The aim of this study is to explore the association of Ki-67 and p53 expression with prognosis in non-small cell lung cancer (NSCLC) patients who underwent curative resection. We retrospectively identified 116 consecutive patients with stages I-III NSCLC who underwent curative resection at a single center from January 2007 to December 2012. Ki-67 and p53 expression was assessed by immunohistochemistry. Data on clinicopathologic features and survival were collected retrospectively. Ki-67 expression in 109 samples and p53 expression in 115 patients were analyzed. According to the results, 108 patients (99 %) showed at least some expression of Ki-67. The median Ki-67 expression level was 30 %. Positive p53 expression was observed in 91 (79 %) patients. Higher Ki-67 expression (>40 %) was significantly more frequent in male (26 vs. 4 % in female, p=0.002), ever-smoker (31 vs. 10 % in never-smoker, p=0.024), and non-adenocarcinoma (30 vs. 11 % of adenocarcinoma, p=0.012) patients. In univariable analysis, median disease-free survival (DFS) was shorter with higher Ki-67 expression (16.1 vs. 61.9 months in those with lower Ki-67 expression, p=0.005), and p53 expression did not show an association with DFS. Among 42 patients with stage I NSCLC who did not receive adjuvant chemotherapy, DFS was significantly worse in patients with higher Ki-67 expression (2-year DFS rate 57 vs. 88 %, p=0.018). In a Cox regression model, higher Ki-67 expression (>40 %) was a significant independent prognostic factor associated with poorer DFS (HR 2.9, 95 % CI 1.3-6.2) along with TNM stage and age. Higher Ki-67 expression (>40 %) showed an independent association with shorter DFS in NSCLC patients who underwent curative resection.
Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Ki-67 Antigen/analysis , Lung Neoplasms/pathology , Tumor Suppressor Protein p53/analysis , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/chemistry , Carcinoma, Non-Small-Cell Lung/mortality , Disease-Free Survival , Female , Humans , Lung Neoplasms/chemistry , Lung Neoplasms/mortality , Male , Middle Aged , Neoplasm Staging , Proportional Hazards Models , Retrospective StudiesABSTRACT
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.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Morpholines , Pyrazoles , Pyrimidines , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Gefitinib/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Quinazolines , ErbB Receptors/genetics , ErbB Receptors/metabolism , Republic of Korea , Mutation , Protein Kinase Inhibitors/adverse effectsABSTRACT
Although autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are fundamentally different procedures, a tailored approach to bacterial bloodstream infection (BSI) according to the type of HSCT has not yet been suggested. We evaluated the characteristics of BSI after HSCT, with a focus on comparison of BSIs between recipients of autologous HSCT (auto-HSCT) and allogeneic HSCT (allo-HSCT). Among 134 patients (59 received allo-HSCT and 75 received auto-HSCT) who underwent HSCT, BSIs were reported earlier in patients who underwent auto-HSCT, compared with those who underwent allo-HSCT (mean 12.1 ± 3.4 days versus 32.8 ± 27.1 days, P = .006). Among patients receiving allo-HSCT, postneutrophil-engraftment bacterial BSI showed an association with grade ≥ 2 acute graft-versus-host disease (GVHD). In patients who underwent auto-HSCT, results of multivariate analysis showed that not receiving prophylactic antibiotics (P = .004) and having elevated serum C-reactive protein (P = .034) were risk factors of BSI. Elevated CRP (P = .01) and acute GVHD ≥ grade 2 (P = .002) were independent risk factors in patients who underwent allo-HSCT. Those differences originated mainly from the impact of acute GVHD-related postengraftment BSIs of patients who underwent allo-HSCT. To establish the best defense strategy against BSI, the distinctive natures of bacterial BSI after HSCT between auto-HSCT and allo-HSCT should be considered.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Graft vs Host Disease/microbiology , Gram-Negative Bacterial Infections/microbiology , Gram-Positive Bacterial Infections/microbiology , Hematopoietic Stem Cell Transplantation/methods , Neutrophils/immunology , Adolescent , Adult , Aged , Antineoplastic Agents/therapeutic use , Female , Graft Survival , Graft vs Host Disease/complications , Graft vs Host Disease/drug therapy , Graft vs Host Disease/immunology , Gram-Negative Bacterial Infections/complications , Gram-Negative Bacterial Infections/drug therapy , Gram-Negative Bacterial Infections/immunology , Gram-Positive Bacterial Infections/complications , Gram-Positive Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/immunology , Humans , Male , Middle Aged , Retrospective Studies , Survival Analysis , Transplantation, Autologous , Transplantation, HomologousABSTRACT
BACKGROUND/AIMS: Baseline serum lactate dehydrogenase (LDH) level is a well-known prognostic factor in patients with non-Hodgkin's lymphoma; however, its role beyond initial diagnosis has not yet been defined. METHODS: This study was conducted as a retrospective analysis of patients with diffuse large B cell lymphoma (DLBCL) treated with R-CHOP21, who had undergone regular checks for LDH during immunochemotherapy (n = 119) and during the posttreatment follow-up period after complete remission (CR; n = 100). The 119 patients were classified into 4 groups according to their baseline and change in LDH level during treatment, and an analysis of tumor response and survival was performed. The value of LDH as a predictor for relapse was evaluated among the patients with regular follow-up visits after achieving CR. RESULTS: An increased LDH level during immunochemotherapy had no impact on tumor response or survival, and only the LDH status 'before' treatment was a prognostic marker. The sensitivity, specificity, positive predictive value and negative predictive value of serum LDH for detecting relapse after CR were 47.4, 86.5, 9.3 and 98.3%, respectively. CONCLUSION: The measurement of LDH level beyond initial diagnosis has no clear benefit in predicting disease progression or relapse in patients with DLBCL treated with R-CHOP21.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , L-Lactate Dehydrogenase/blood , Lymphoma, Large B-Cell, Diffuse/diagnosis , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Humans , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/mortality , Lymphoma, Non-Hodgkin/diagnosis , Male , Middle Aged , Prednisone/administration & dosage , Prognosis , Retrospective Studies , Rituximab , Treatment Outcome , Vincristine/administration & dosageABSTRACT
PURPOSE: The purpose of this study is to evaluate risk factors for infusion-related reaction (IRR) following rituximab administration in patients with B cell non-Hodgkin lymphoma. METHODS: A retrospective analysis was conducted of patients with newly diagnosed B cell lymphoma who have received rituximab-included immunochemotherapy with appropriate premedication and commonly used schedule of infusion rate. IRRs were graded by review of the patients' electronic medical record according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: One hundred and sixty-nine patients were included in the analysis and most of the patients (150; 88.8 %) had diffuse large B cell lymphoma (DLBCL). Thirty-six patients (21.3 %) had any grade of IRRs: 23 patients were grade (G) 1 (13.6 %), 13 had ≥G2 IRRs (7.7 %), and only 4 had ≥G3 IRRs (2.4 %). All except one patient had IRR during the first cycle and only two had repetitive IRR thereafter. Bone marrow (BM) involvement was the strongest risk factor for IRR in multivariable analysis (odds ratio 4.06, 95 % confidence interval 1.67-9.89; p = 0.002). A subgroup analysis confined to patients with DLBCL showed very similar results when compared with the entire population, and patients with DLBCL who had ≥G2 IRR showed shorter event-free and overall survival when compared to those who did not. CONCLUSIONS: BM involvement is predictive of occurrence of IRR during rituximab administration in patients with B cell lymphoma. More intensive premedication and careful observation for IRR during rituximab administration are required for patients with B cell lymphoma who have BM involvement.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/adverse effects , Antineoplastic Agents/adverse effects , Bone Marrow/drug effects , Immunologic Factors/adverse effects , Lymphoma, B-Cell/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols , Bone Marrow/pathology , Confidence Intervals , Electronic Health Records , Female , Humans , Immunologic Factors/administration & dosage , Lymphoma, B-Cell/pathology , Male , Medical Audit , Middle Aged , Odds Ratio , Republic of Korea , Retrospective Studies , Risk Factors , Rituximab , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: Little information is available on the use of chest computed tomography (CT) to predict breast tumor size in breast cancer, despite the fact that chest CT examinations are being increasingly used. The purpose of this study was to evaluate the value of chest CT for predicting breast tumor size using pathology measurements as reference standards. METHODS: Tumor sizes (defined as greatest diameter) were retrospectively measured on the preoperative chest CT images of 285 patients with surgically proven unifocal, invasive breast carcinoma. Greatest tumor diameters as determined by chest CT and pathologic examinations were compared by linear regression and Spearman's rho correlation analysis. Concordance between CT and pathology results was defined as a diameter difference of <5 mm. Subgroup analyses were also performed with respect to tumor size (<20 mm or ≥20 mm) and histological subtype (invasive ductal carcinoma(IDC) or non-IDC). RESULTS: CT and pathology measured diameters were found to be linearly related (size at pathology = 1.086 × CT determined tumor size - 1.141; Spearman's rho correlation coefficient = 0.84, P<0.001). Most tumors (n = 228, 80.0%) were concordant by chest CT and pathology, but 36 tumors (12.7%) were underestimated by CT (average underestimation, 11 mm; range, 6-36 mm) and 21 tumors (7.4%) were overestimated (average overestimation by CT, 10 mm; range, 6-19 mm). The concordance rate between the two sets of measurements was greater for tumor of <20 mm and for IDC (P<0.001 and P = 0.011, respectively). CONCLUSIONS: Tumor size by chest CT is well correlated with pathology determined tumor size in breast cancer patients, and the diameters of the majority of tumors by chest CT and pathology differed by <5 mm. In addition, the concordance rate was higher for breast tumors of <20 mm and for tumors of the IDC histologic subtype.
Subject(s)
Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/diagnostic imaging , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/diagnostic imaging , Carcinoma, Lobular/pathology , Radiography, Thoracic , Tomography, X-Ray Computed , Adult , Aged , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/surgery , Carcinoma, Lobular/surgery , Female , Follow-Up Studies , Humans , Middle Aged , Neoplasm Grading , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Retrospective Studies , Young AdultABSTRACT
AIM: We evaluated the efficacy and safety of nivolumab and eribulin combination therapy for metastatic breast cancer (BC) in Asian populations. METHODS: In this parallel phase II study, adult patients with histologically confirmed recurrent/metastatic hormone receptor-positive/HER2-negative (HR+HER2-) or triple-negative BC (TNBC) were prospectively enroled from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). They received nivolumab (360 mg) on day 1 plus eribulin (1.4 mg/m2) on days 1 and 8 every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was the investigator-assessed 6-month progression-free survival (PFS) rate in each subtype. Secondary endpoints included investigator-assessed objective response rate (ORR) as per Response Evaluation Criteria in Advanced Solid Tumors version 1.1, disease control rate, overall survival, and treatment toxicity. The association between PD-L1 expression and efficacy was investigated. RESULTS: Forty-five patients with HR+HER2- BC and 45 with TNBC were enroled. Their median age was 51 (range, 31-71) years, and 74 (82.2%) received one or two prior treatments before enrolment. Six-month PFS was 47.2% and 25.1% in the HR+HER2- and TNBC cohorts, respectively. Median PFS was 5.6 (95% confidence interval [CI]: 5.3-7.4) and 3.0 (95% CI: 2.1-5.2) months in the HR+HER2- and TNBC groups, respectively. ORRs were 53.3% (complete response [CR]: 0, partial response [PR]: 24) and 28.9% (CR: 1, PR: 12). Patients with PD-L1+ tumours (PD-L1 expression ≥1%) and PD-L1- tumours (ORR 50% versus 53.8% in HR+HER2-, 30.8% versus 29.0% in TNBC) had similar ORRs. Neutropenia was the most common grade 3/4 adverse event; the most common immune-related adverse events (AEs) were grades 1/2 hypothyroidism and pruritus. Five patients discontinued therapy because of immune-related AEs. CONCLUSION: Nivolumab plus eribulin showed promising efficacy and tolerable safety in previously treated HER2- metastatic BC. TRIAL REGISTRATION: NCT04061863.
Subject(s)
Breast Neoplasms , Triple Negative Breast Neoplasms , Adult , Female , Humans , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , B7-H1 Antigen , Breast Neoplasms/pathology , Nivolumab/therapeutic use , Receptor, ErbB-2/metabolism , Triple Negative Breast Neoplasms/drug therapy , AgedABSTRACT
Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often develop resistance to current standard third-generation EGFR tyrosine kinase inhibitors (TKIs); no targeted treatments are approved in the osimertinib-relapsed setting. In this open-label, dose-escalation and dose-expansion phase 1 trial, the potential for improved anti-tumor activity by combining amivantamab, an EGFR-MET bispecific antibody, with lazertinib, a third-generation EGFR TKI, was evaluated in patients with EGFR-mutant NSCLC whose disease progressed on third-generation TKI monotherapy but were chemotherapy naive (CHRYSALIS cohort E). In the dose-escalation phase, the recommended phase 2 combination dose was established; in the dose-expansion phase, the primary endpoints were safety and overall response rate, and key secondary endpoints included progression-free survival and overall survival. The safety profile of amivantamab and lazertinib was generally consistent with previous experience of each agent alone, with 4% experiencing grade ≥3 events; no new safety signals were identified. In an exploratory cohort of 45 patients who were enrolled without biomarker selection, the primary endpoint of investigator-assessed overall response rate was 36% (95% confidence interval, 22-51). The median duration of response was 9.6 months, and the median progression-free survival was 4.9 months. Next-generation sequencing and immunohistochemistry analyses identified high EGFR and/or MET expression as potential predictive biomarkers of response, which will need to be validated with prospective assessment. ClinicalTrials.gov identifier: NCT02609776 .
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Prospective Studies , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Mutation/genetics , Aniline Compounds/therapeutic use , ErbB Receptors/geneticsABSTRACT
In order to evaluate prognostic value of CD99 expression in patients with diffuse large B-cell lymphoma (DLBCL) who underwent treatment with rituximab-CHOP immunochemotherapy, immunohistochemistry for CD99/CD10/BCL-2/BCL-6/MUM-1 was performed on nodal DLBCL specimens from 70 patients. Patients were classified as either germinal center B-cell (GCB) subtype or non-GCB subtype according to the Muris algorithm. A superior 2-year event-free survival (EFS) was observed in patients with the GCB subgroup, compared to those with the non-GCB subgroup (p = 0.034). The distribution of CD99 expression (29 patients; 41.4 %) did not show deviation according to subtype and was not prognostic for survival in the entire patient population. Among patients with the GCB subgroup, better EFS and overall survival (OS) were observed in CD99+ patients, compared to CD99- patients. Conversely, among patients with the non-GCB subgroup, inferior EFS and OS were reported in CD99+ patients. Superior 2-year EFS (p = 0.004) and 2-year OS (p = 0.003) were observed in patients with GCB/CD99+ and non-GCB/CD99- compared to the others, and the combination classification was found to be an independent prognostic factor.