143 research outputs found
Pharmacokinetics of Weekly Paclitaxel and Feasibility of Dexamethasone Taper in Japanese Patients with Advanced Non–small Cell Lung Cancer
AbstractPurposeWeekly paclitaxel combined with a platinum-based agent has been advocated as an alternative regimen for patients with advanced non–small cell lung cancer (NSCLC). Limited studies exist on the tolerability of weekly paclitaxel in Japanese patients with advanced NSCLC. Furthermore, the feasibility of dexamethasone taper in the premedication regimen for weekly paclitaxel has not been examined in these patients. To address this issue, we assessed the maximum tolerated dose, dose-limiting toxicity, and pharmacokinetics of weekly paclitaxel in Japanese patients with advanced NSCLC in a dose-escalation Phase I trial and examined the feasibility of dexamethasone taper in these patients.MethodsWeekly 1-hour infusions of paclitaxel were administered at doses of 80 to 120 mg/m2 (dose escalation of 20 mg/m2). The 7-week treatment cycle consisted of 6 infusions followed by a 2-week treatment interval. Pharmacokinetics were assessed during the first cycle. Dexamethasone was commenced at 16 mg and doses were successively halved if hypersensitivity reactions were absent.FindingsA total of 15 patients with either Stage IIIB or IV NSCLC were enrolled. Although no dose-limiting toxicity was observed at 120 mg/m2, 4 of 6 patients with peripheral neuropathy required discontinuation of treatment. The maximum accepted dose and the recommended dose were 120 and 100 mg/m2, respectively. No grade ≥3 adverse events were observed at 100 mg/m2. The maximum drug concentration and AUC correlated with dose escalation. The pharmacokinetic parameters after the first and sixth infusions were similar, indicating that repeated administration of paclitaxel did not result in drug accumulation or affect its pharmacokinetic profile. Partial response was observed in 3 of 15 patients. Plasma adrenocorticotropic hormone and cortisol levels decreased during treatment but approached baseline levels after a dexamethasone-free interval.ImplicationsWeekly paclitaxel at 100 mg/m2 given as a 1-hour infusion for 6 weeks followed by a 2-week treatment interval was well tolerated by Japanese patients with advanced NSCLC. Dexamethasone taper was feasible in these patients, and no clear trend in plasma adrenocorticotropic hormone or cortisol levels was observed
Comparative Chemotherapeutic Efficacy in Non-small Cell Lung Cancer Patients with Postoperative Recurrence and Stage IV Disease
BackgroundWhether chemotherapy would be equally effective in non-small cell lung cancer patients with stage IV disease (group A) and postoperative recurrence (group B) remains unclear.Patients and MethodsIn a total of 642 non-small cell lung cancer patients with distant metastases treated by chemotherapy, the baseline patient characteristics, responses to chemotherapy and survival were compared between group A (n = 480) and group B (n = 162).ResultsAdenocarcinoma was the predominant histologic type, accounting for 78% of the patients in group A and 90% of the patients in group B (p < 0.001). Bone and brain metastases were more common in group A (p = 0.034 and p = 0.014, respectively), although pulmonary metastases were more common in group B (p < 0.001). The chemotherapy regimens used for the treatment did not differ between groups A and B. The response rates in group A and group B were 32 and 33%, respectively (p = 0.65). In contrast, the median progression-free survival (5.5 versus 4.2 months, p = 0.0065) and overall survival (21.3 versus 13.3 months, p < 0.001) were better in group B than in group A.ConclusionSurvival was superior in patients with postoperative recurrence than in those with stage IV disease, although the two groups showed comparable responses to chemotherapy
TRUST-II: a global phase II study of taletrectinib in ROS1-positive non-small-cell lung cancer and other solid tumors
Brain metastasis; Non-small-cell lung cancer; TaletrectinibMetástasis cerebral; Cáncer de pulmón de células no pequeñas; TalerectinibMetà stasi cerebral; Cà ncer de pulmó de cèl·lules no petites; TaletrectinibCrizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1+) non-small-cell lung cancer. However, unmet needs remain, including treatment of patients with resistance mutations, efficacy in brain metastasis and avoidance of neurological side effects. Taletrectinib was designed to: improve efficacy; overcome resistance to first-generation ROS1 inhibitors; and address brain metastasis while conferring fewer neurological adverse events. All of these features are demonstrated and supported by the interim data from the regional phase II TRUST-I clinical study. Here we describe the rationale and design of TRUST-II, a global phase II study of taletrectinib in patients with locally advanced/metastatic ROS1+ non-small-cell lung cancer and other ROS1+ solid tumors. The primary end point is confirmed objective response rate. Secondary end points include duration of response, progression-free survival, overall survival and safety. This trial is enrolling patients in North America, Europe and Asia
Candidates for Intensive Local Treatment in cIIIA-N2 Non-Small Cell Lung Cancer: Deciphering the Heterogeneity
PurposeThe purpose of this study was to refine the heterogeneous clinical stage IIIA non-small cell lung cancer (NSCLC) with N2 nodes status (cIIIA-N2) by clinicopathological characteristics before treatment.Methods and MaterialsWe analyzed data of consecutive patients with cIIIA-N2 NSCLC diagnosed between 1997 and 2010 and treated by chemoradiation therapy (CRT). The appearance of the mediastinal lymph nodes (MLNs) was classified into discrete or infiltrative according to the criteria proposed by the American College of Chest Physicians. In addition, the extent of MLN involvement (MLNI) was classified as limited (close to the primary tumor) or extensive (including upper MLNI in the case of tumors in the lower lobes and vice versa).ResultsA total of 148 patients with cIIIA-N2 NSCLC was treated by CRT. The patient characteristics were as follows: males: 118; females: 30; median age: 62Â years; appearance of the involved MLNs: 85 discrete, 63 infiltrative; extent of MLNI: 82 limited, 66 extensive; histology: 36 squamous, 112 nonsquamous. The median progression-free survival (PFS) and median overall survival (OS) in the entire subject population were 9.9 and 34.7Â months, respectively. A discrete appearance of the involved MLNs and a limited extent of MLNI contributed significantly to a better PFS and OS. The percentages of cases with relapses within the irradiated field classified according to the characteristics of the MLNs were as follows; appearance of the MLNs (24.6% discrete, 18.9% infiltrative); extent of MLNI (25.9 limited, 17.9% extensive).ConclusionsThose with a discrete appearance of the involved MLNs and a limited extent of MLNI at diagnosis could show relatively more favorable outcomes and could be candidates for multimodality therapy
Immunologic Significance of CD80/CD86 or Major Histocompatibility Complex-II Expression in Thymic Epithelial Tumors
Introduction: Unresectable or recurrent thymic epithelial tumors (TETs) have a poor prognosis, and treatment options are limited. This study aimed to investigate the immunologic significance of CD80/CD86 or major histocompatibility complex class II (MHC-II) expression in TETs, as potential predictive biomarkers for immune checkpoint inhibitors (ICIs).
Methods: We analyzed CD80, CD86, MHC class I (MHC-I), and MHC-II expression in TETs using immunohistochemistry and investigated their association with T-cell infiltration or ICI efficacy. In addition, we generated CD80- or MHC-II–expressing mouse tumors, evaluated the effects of ICIs, and analyzed tumor-infiltrating lymphocytes. We also performed tumor-rechallenge experiments in vivo.
Results: We found that approximately 50% and 30% of TETs had high expression of CD80/CD86 and MHC-II in tumor cells, respectively, and that this expression was related to T-cell infiltration in clinical samples. In mouse models, both CD80 and MHC-II increase the effects of ICIs. In addition, senescent T cells and long-lived memory precursor effector T cells were significantly decreased and increased, respectively, in tumor-infiltrating lymphocytes from CD80-expressing tumors, and rechallenged tumors were completely rejected after the initial eradication of CD80-expressing tumors by programmed cell death protein 1 blockade. Indeed, patients with CD80-high thymic carcinoma had longer progression-free survival with anti–programmed cell death protein 1 monoclonal antibody.
Conclusions: Half of the TETs had high expression of CD80/CD86 or MHC-II with high T-cell infiltration. These molecules could potentially increase the effects of ICIs, particularly inducing a durable response. CD80/CD86 and MHC-II can be predictive biomarkers of ICIs in TETs, promoting the development of drugs for such TETs
Postprogression Outcomes for Osimertinib versus Standard-of-Care EGFR-TKI in Patients with Previously Untreated EGFR-mutated Advanced Non–Small Cell Lung Cancer
Abstract
Purpose:
In the phase III FLAURA study, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib significantly improved progression-free survival (PFS) versus standard-of-care (SoC) EGFR-TKI (gefitinib or erlotinib) in patients with previously untreated EGFR (exon 19 deletion or L858R) mutation-positive advanced non–small cell lung cancer (NSCLC). Interim overall survival (OS) data were encouraging, but not formally statistically significant at current maturity (25%). Here we report exploratory postprogression outcomes.
Patients and Methods:
Patients were randomized 1:1 to receive osimertinib (80 mg orally, once daily) or SoC EGFR-TKI (gefitinib 250 mg or erlotinib 150 mg, orally, once daily). Treatment beyond disease progression was allowed if the investigator judged ongoing clinical benefit. Patients receiving SoC EGFR-TKI could cross over to receive osimertinib after independently confirmed objective disease progression with documented postprogression T790M-positive mutation status.
Results:
At data cutoff (June 12, 2017), 138 of 279 (49%) and 213 of 277 (77%) patients discontinued osimertinib and SoC EGFR-TKI, respectively, of whom 82 (59%) and 129 (61%), respectively, started a subsequent treatment. Median time to discontinuation of any EGFR-TKI or death was 23.0 months [95% confidence interval (CI), 19.5–not calculable (NC)] in the osimertinib arm and 16.0 months (95% CI, 14.8–18.6) in the SoC EGFR-TKI arm. Median second PFS was not reached (95% CI, 23.7–NC) in the osimertinib arm and 20.0 months (95% CI, 18.2–NC) in the SoC EGFR-TKI arm [hazard ratio (HR), 0.58; 95% CI, 0.44–0.78; P = 0.0004].
Conclusions:
All postprogression endpoints showed consistent improvement with osimertinib versus SoC EGFR-TKI, providing further confidence in the interim OS data
Risk factors associated with fatal pulmonary hemorrhage in locally advanced non-small cell lung cancer treated with chemoradiotherapy
<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to identify the risk factors associated with fatal pulmonary hemorrhage (PH) in patients with locally advanced non-small cell lung cancer (NSCLC), treated with chemoradiotherapy.</p> <p>Methods</p> <p>The medical records of 583 patients with locally advanced NSCLC, who were treated with chemoradiotherapy between July 1992 and December 2009 were reviewed. Fatal PH was defined as PH leading to death within 24 h of its onset. Tumor cavitation size was defined by the cavitation diameter/tumor diameter ratio and was classified as minimum (< 0.25), minor (≥ 0.25, but < 0.5), and major (≥ 0.5).</p> <p>Results</p> <p>Of the 583 patients, 2.1% suffered a fatal PH. The numbers of patients with minimum, minor, and major cavitations were 13, 11, and 14, respectively. Among the 38 patients with tumor cavitation, all 3 patients who developed fatal PH had major cavitations. On multivariate analysis, the presence of baseline major cavitation (odds ratio, 17.878), and a squamous cell histology (odds ratio, 5.491) proved to be independent significant risk factors for fatal PH. Interestingly, all patients with fatal PH and baseline major cavitation were found to have tumors with squamous cell histology, and the occurrence of fatal PH in patients having both risk factors was 33.3%.</p> <p>Conclusions</p> <p>Patients at high risk of fatal PH could be identified using a combination of independent risk factors.</p
Pemetrexed for advanced non-small cell lung cancer patients with interstitial lung disease
Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients
Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control
Figitumumab combined with carboplatin and paclitaxel in treatment-naïve Japanese patients with advanced non-small cell lung cancer
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