Publications by authors named "Chun-Ming Tsai"

110 Publications

Comparative Study of Li-CO and Na-CO Batteries with Ru@CNT as a Cathode Catalyst.

ACS Appl Mater Interfaces 2021 Jan 29;13(1):480-490. Epub 2020 Dec 29.

Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.

Alkali metal-carbon dioxide (Li/Na-CO) batteries have generated widespread interest in the past few years owing to the attractive strategy of utilizing CO while still delivering high specific energy densities. Among these systems, Na-CO batteries are more cost effective than Li-CO batteries because the former uses cheaper and abundant Na. Herein, a Ru/carbon nanotube (CNT) as a cathode material was used to compare the mechanisms, stabilities, overpotentials, and energy densities of Li-CO and Na-CO batteries. The potential of Na-CO batteries as a viable energy storage technology was demonstrated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.0c17373DOI Listing
January 2021

Final Overall Survival and Other Efficacy and Safety Results From ASCEND-3: Phase II Study of Ceritinib in ALKi-Naive Patients With ALK-Rearranged NSCLC.

J Thorac Oncol 2020 04 25;15(4):609-617. Epub 2019 Nov 25.

Department of Medicine and Pathology, Massachusetts General Hospital, Boston, Massachusetts.

Introduction: The phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)-naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results.

Methods: Eligible patients (including those with asymptomatic or neurologically stable brain metastases) received oral ceritinib (750 mg/day, fasted). The primary end point was investigator-assessed overall response rate (ORR). Secondary end points were Blinded Independent Review Committee-assessed ORR; investigator- and Blinded Independent Review Committee-assessed overall intracranial response rate, duration of response, time to response, disease control rate, and progression-free survival (PFS); overall survival (OS); and safety. Exploratory end points included patient-reported outcomes.

Results: Of the 124 patients enrolled, 122 (98.4%) had received previous antineoplastic medications (31 patients [25.0%] received at least three regimens), and 49 (39.5%) had baseline brain metastases. The median follow-up time (data cutoff: January 22, 2018) was 52.1 (range, 48.4-60.1) months. The investigator-assessed ORR was 67.7% (95% confidence interval [CI]: 58.8-75.9), and the median PFS was 16.6 months (95% CI: 11.0-23.2). The median OS was 51.3 months (95% CI: 42.7-55.3). Most common adverse events (all grades, ≥60% of patients, all-causality) were diarrhea (85.5%), nausea (78.2%), and vomiting (71.8%). Overall, 18 patients (14.5%) had an adverse event leading to treatment discontinuation. Health-related quality of life was maintained during ceritinib treatment.

Conclusions: Ceritinib exhibited prolonged and clinically meaningful OS, PFS, and duration of response in chemotherapy-pretreated (at least three lines), ALKi-naive patients with ALK+ NSCLC. The safety profile was consistent with that reported in previous studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.11.006DOI Listing
April 2020

Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: Osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer.

Cancer 2020 01 26;126(2):373-380. Epub 2019 Nov 26.

State Key Laboratory of South China, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China.

Background: This study assesses different technologies for detecting epidermal growth factor receptor (EGFR) mutations from circulating tumor DNA in patients with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and platinum-pemetrexed according to the plasma T790M status.

Methods: Tumor tissue biopsy samples were tested for T790M during screening with the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at screening and at the baseline and were retrospectively analyzed for EGFR mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS; Guardant360, Guardant Health).

Results: With cobas tissue test results as a reference, the plasma T790M positive percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of 189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for T790M-negative; P < .0001) and the presence of extrathoracic disease (58% for M1b-positive vs 39% for M0-1a-positive; P = .002). Progression-free survival (PFS) was prolonged in randomized patients (tissue T790M-positive) with a T790M-negative cobas plasma result in comparison with those with a T790M-positive plasma result in both osimertinib (median, 12.5 vs 8.3 months) and platinum-pemetrexed groups (median, 5.6 vs 4.2 months).

Conclusions: PPA was similar between ddPCR and NGS assays; both were more sensitive than cobas plasma. All 3 test platforms are suitable for routine clinical practice. In patients with tissue T790M-positive NSCLC, an absence of detectable plasma T790M at the baseline is associated with longer PFS, which may be attributed to a lower disease burden.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32503DOI Listing
January 2020

A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation-Positive NSCLC Patients.

J Thorac Oncol 2020 01 14;15(1):80-90. Epub 2019 Oct 14.

Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Republic of School of Medicine, National Yang-Ming University, Taipei, Republic of China.

Introduction: The hepatocyte growth factor receptor mesenchymal-epithelial transition (MET) is reported to be a negative prognostic marker in EGFR-mutant NSCLC and involved in resistance to EGFR inhibitors. Emibetuzumab, a humanized immunoglobulin G4 monoclonal bivalent MET antibody, blocks ligand-dependent and ligand-independent hepatocyte growth factor/MET signaling. This phase 2 study compared erlotinib with and without emibetuzumab in first-line treatment of EGFR-mutant metastatic NSCLC.

Methods: Patients with stage IV EGFR-mutant NSCLC and disease control after an 8-week lead-in with erlotinib (150 mg daily) were randomized to continue taking erlotinib with or without emibetuzumab (750 mg every 2 weeks). The primary end point was progression-free survival (PFS). Additional end points included overall survival, overall response rate, safety, pharmacokinetics, and exploratory analysis of MET expression.

Results: No significant difference in median PFS was observed in the intent-to-treat population (9.3 months with emibetuzumab + erlotinib versus 9.5 months with erlotinib monotherapy [hazard ratio (HR) = 0.89, 90% confidence interval (CI): 0.64-1.23]). The median overall survival was 34.3 months with emibetuzumab plus erlotinib versus 25.4 months with erlotinib (HR = 0.74, 90% CI: 0.49-1.11). Emibetuzumab plus erlotinib was well tolerated, with peripheral edema and mucositis as the only adverse events occurring 10% or more frequently relative to erlotinib. Exploratory post hoc analysis showed an improvement of 15.3 months in median PFS for the 24 patients with the highest MET expression (MET expression level of 3+ in ≥90% of tumor cells) (20.7 with emibetuzumab + erlotinib versus 5.4 months with erlotinib [HR = 0.39, 90% CI: 0.17-0.91]).

Conclusions: No statistically significant difference in PFS was noted in the intent-to-treat population. Exploratory analysis confirmed that high MET expression is a negative prognostic marker for patients treated with erlotinib, indicating that emibetuzumab plus erlotinib may provide clinically meaningful benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2019.10.003DOI Listing
January 2020

Osimertinib in patients with T790M mutation-positive, advanced non-small cell lung cancer: Long-term follow-up from a pooled analysis of 2 phase 2 studies.

Cancer 2019 03 4;125(6):892-901. Epub 2018 Dec 4.

Division of Medical Oncology, The Ottawa Hospital Cancer Center, University of Ottawa, Ottawa, Ontario, Canada.

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that is selective for both EGFR-TKI-sensitizing and T790M (threonine-to-methionine substitution at codon 790)-resistance mutations. The authors present long-term follow-up data from a preplanned, pooled analysis of phase 2 studies, the AZD9291 First Time in Patients Ascending Dose Study (AURA) extension trial (clincialtrials.gov identifier NCT01802632) and the AURA2 trial (NCT02094261).

Methods: Patients with centrally confirmed, T790M mutation-positive, advanced non-small cell lung cancer received osimertinib 80 mg once daily until disease progression or study discontinuation. Response was assessed by a blinded, independent, central review using Response Evaluation Criteria in Solid Tumors, version 1.1. The primary endpoint was the objective response rate.

Results: In total, 411 patients received osimertinib (second line, 129 patients; third line or later, 282 patients). At the data cutoff date of November 1, 2016, the median treatment exposure was 16.4 months (range, 0-29.7 months), the objective response rate was 66% (95% confidence interval [CI], 61%-70%), the median response duration was 12.3 months (95% CI, 11.1-13.8 months), and the median progression-free survival was 9.9 months (95% CI, 9.5-12.3 months). At the data cutoff date of May 1, 2018, 271 patients (66%) had died, and 140 patients (34%) had discontinued before death. The median overall survival was 26.8 months (95% CI, 24.0-29.1 months); and the 12-month, 24-month, and 36-month survival rates were 80%, 55%, and 37%, respectively. Grade ≥3 possibly causally related (investigator assessed) adverse events were reported in 65 patients (16%), and the most common were rash (grouped terms; 42%; grade ≥3, 1%) and diarrhea (39%; <1%).

Conclusions: This pooled analysis represents the most mature clinical trial data for osimertinib in patients with pretreated, T790M-positive, advanced non-small cell lung cancer, further establishing osimertinib as a standard of care for this patient population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.31891DOI Listing
March 2019

Clinical activity of ASP8273 in Asian patients with non-small-cell lung cancer with EGFR activating and T790M mutations.

Cancer Sci 2018 Sep 9;109(9):2852-2862. Epub 2018 Aug 9.

Kindai University Hospital, Osaka, Japan.

Epidermal growth factor receptor (EGFR)-activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small-cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose-escalation/dose-expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ≥20 years) with NSCLC previously treated with ≥1 EGFR TKI received escalating ASP8273 doses (25-600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M-positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two-stage design (threshold response = 30%, expected response = 50%, α = 0.05, β = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received ≥1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9-54.0). Median duration of progression-free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment-related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR-activating and T790M mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.13724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125469PMC
September 2018

Results of PROFILE 1029, a Phase III Comparison of First-Line Crizotinib versus Chemotherapy in East Asian Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer.

J Thorac Oncol 2018 10 14;13(10):1539-1548. Epub 2018 Aug 14.

Department of Clinical Oncology, State Laboratory of South China, The Chinese University of Hong Kong, Hong Kong, People's Republic of China.

Introduction: The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first-line chemotherapy in prolonging progression-free survival (PFS) in previously untreated patients with ALK receptor tyrosine kinase gene (ALK)-positive advanced nonsquamous NSCLC. This result was consistent with that in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population.

Methods: In this open-label phase III study (PROFILE 1029), patients were randomized 1:1 to receive orally administered crizotinib 250 mg twice daily continuously (3-week cycles) or intravenously administered chemotherapy (pemetrexed 500 mg/m, plus cisplatin 75 mg/m, or carboplatin [at a dose to produce area under the concentration-time curve of 5-6 mg·min/mL]) every 3 weeks for a maximum of six cycles. PFS confirmed by independent radiology review was the primary end point.

Results: Crizotinib significantly prolonged PFS (hazard ratio, 0.402; 95% confidence interval [CI]: 0.286-0.565; p < 0.001). The median PFS was 11.1 months with crizotinib and 6.8 months with chemotherapy. The objective response rate was 87.5% (95% CI: 79.6-93.2%) with crizotinib versus 45.6% (95% CI: 35.8-55.7%) with chemotherapy (p < 0.001). The most common adverse events were increased transaminase levels, diarrhea, and vision disorders with crizotinib and leukopenia, neutropenia, and anemia with chemotherapy. Significantly greater improvements from baseline in patient-reported outcomes were seen in crizotinib-treated versus chemotherapy-treated patients.

Conclusions: First-line crizotinib significantly improved PFS, objective response rate, and patient-reported outcomes compared with standard platinum-based chemotherapy in East Asian patients with ALK-positive advanced NSCLC, which is similar to the results from PROFILE 1014. The safety profiles of crizotinib and chemotherapy were consistent with those previously published.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2018.06.012DOI Listing
October 2018

Afatinib as First-line Treatment of Older Patients With EGFR Mutation-Positive Non-Small-Cell Lung Cancer: Subgroup Analyses of the LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7 Trials.

Clin Lung Cancer 2018 07 17;19(4):e465-e479. Epub 2018 Mar 17.

Division of Hematology/Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background: Afatinib is approved in the US, Europe, and several other regions for first-line treatment for epidermal growth factor receptor mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC).

Patients And Methods: Treatment-naive patients with advanced EGFRm NSCLC were randomized to afatinib (40 mg/d) versus cisplatin/pemetrexed (LUX-Lung 3 [LL3]) or cisplatin/gemcitabine (LUX-Lung 6 [LL6]), or versus gefitinib (250 mg/d; LUX-Lung 7 [LL7]). We report subgroup analyses according to age, including 65 years or older versus younger than 65 years (preplanned; LL3/LL6) and additional cutoffs up to 75 years and older (exploratory; LL7). Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated.

Results: Among the 134 of 345 (39%) and 86 of 364 (24%) patients aged 65 years and older in LL3 and LL6, median PFS was improved with afatinib versus chemotherapy (LL3: hazard ratio [HR], 0.64 [95% confidence interval (CI), 0.39-1.03]; LL6: HR, 0.16 [95% CI, 0.07-0.39]). Afatinib significantly improved OS versus chemotherapy in elderly patients with Del19 NSCLC in LL3 (HR, 0.39 [95% CI, 0.19-0.80]). Among the 40 of 319 patients (13%) aged 75 years or older in LL7, median PFS (HR, 0.69 [95% CI, 0.33-1.44]) favored afatinib, consistent with the overall population. Afatinib-associated AEs in older patients were consistent with the overall populations.

Conclusions: Subgroup analyses of the LL3, LL6, and LL7 trials show that afatinib is an effective and tolerable treatment for patients with EGFRm NSCLC, independent of age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2018.03.009DOI Listing
July 2018

Effect of postoperative systemic therapy on pulmonary adenocarcinoma with unexpected pleural spread detected during thoracotomy or thoracoscopy.

Oncotarget 2018 Jan 26;9(4):5435-5444. Epub 2017 Dec 26.

Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Background: Occasionally, malignant pleural disease is only detected unexpectedly during surgery in patients with pulmonary adenocarcinoma. Previous studies mostly focused on the role of main tumor resection on patient's outcome, barely addressing the position of postoperative systemic therapy.

Methods: The medical records of 5321 non-small cell lung cancer patients who underwent thoracic surgery between January 1990 and December 2012 were reviewed. Pulmonary adenocarcinoma patients with unexpected pleural spread noted during surgery were included. The clinical and postoperative treatment variables were assessed for correlation with overall survival.

Results: In 134 patients identified, main tumor resection was performed in 87 (64.9%) patients, while 89 (66.4%) and 57 (42.5%) patients received postoperative chemotherapy and epidermal growth factor receptor- tyrosine kinase inhibitor (EGFR -TKI) therapy, respectively. Overall, the 5-year survival rate was 30.2% and median survival time was 29.3 months. Multivariate analysis showed main tumor resection and EGFR-TKI therapy were associated with better survival. Mutational status of EGFR was available in 57 patients and 43 (75.4%) had activating mutations. Resection of the main tumor conferred a better outcome in patients without EGFR mutation or with unknown EGFR mutation status and had not been treated with EGFR-TKI therapy ( = 0.003), but not in those with activating EGFR mutation and had been treated with EGFR-TKI ( = 0.857).

Conclusions: In pulmonary adenocarcinoma patients with unexpected pleural spread detected during surgery, main tumor resection and EGFR-TKI therapy correlated with better survival. Identifying EGFR mutation status before surgery can provide useful information for clinical decision during surgery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.23686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797062PMC
January 2018

Global named patient use program of afatinib in advanced non-small-cell lung carcinoma patients who progressed following prior therapies.

Future Oncol 2018 Jun 29;14(15):1477-1486. Epub 2018 Jan 29.

Taipei Veterans General Hospital & National Yang-Ming University, No. 201, Sec. 2, Shih-Pai Rd, Taipei, Taiwan.

Aim: A global afatinib named patient use program in non-small-cell lung carcinoma (NSCLC) commenced in 2010.

Materials & Methods: Eligible NSCLC patients had progressed after clinical benefit on prior erlotinib/gefitinib and/or had activating EGFR/HER2 mutations, exhausted all other treatments, and were ineligible for afatinib trials.

Results: Data, as of January 2016, were reported on 3966 heavily pretreated NSCLC patients (41 countries; six continents). Among 2595/3966 (65.4%) patients with tumor EGFR status, 2407 (92.8%) were EGFR mutation positive. Median time to treatment failure (2862/3966 [72.2%] patients with available data) was 4.4 months. Among 1141/2862 (39.9%) patients with response reported, objective response rate was 23.4% (267/1141). Safety findings were as expected.

Conclusion: Time to treatment failure durations and objective response rates were encouraging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fon-2017-0666DOI Listing
June 2018

EGFR mutation, smoking, and gender in advanced lung adenocarcinoma.

Oncotarget 2017 Nov 12;8(58):98384-98393. Epub 2017 Oct 12.

Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.

Purpose: In the current targeted therapy era, information on the effect of smoking in epidermal growth factor receptor ()-mutant lung cancer patients is scarce.

Results: In total, 11,678 adenocarcinoma patients were enrolled. Of these, 33.3% and 91.8% of male and female patients were non-smokers, respectively. An increased amount of smoking ( < 0.001 for trend), fewer smoke-free years ( < 0.001 for trend), and younger age of smoking initiation ( = 0.034 for trend) were all associated with significantly lower mutation rates. Smokers had a shorter median overall survival (OS) among both -mutant and -wild type patients (17.8 vs. 21.1 months, and 7.9 vs. 11.4 months respectively; both < 0.001). Among patients with -mutant adenocarcinoma, younger smokers were associated with shorter OS ( = 0.047). In multivariate analysis, female gender was an independent prognostic factor for OS (hazard ratio: 0.86 [95% confidence interval {CI}: 0.80-0.93]; < 0.001 in the -mutant group and 0.88 [95% CI: 0.81-0.96]; = 0.004 in the -wild type group).

Materials And Methods: We reviewed the National Lung Cancer database (Taiwan) to assess the impact of smoking on the mutation rate and survival in advanced lung adenocarcinoma patients during 2011 and 2014 retrospectively.

Conclusions: Smoking was associated with lower incidence of mutation rate and reduced OS of advanced lung adenocarcinoma patients in a dose-dependent manner. In addition to mutation and smoking, gender also plays an important role in survival among these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.21842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716737PMC
November 2017

First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.

Lancet 2017 03 24;389(10072):917-929. Epub 2017 Jan 24.

Instituto do Câncer do Estado de São Paulo, São Paulo, Brazil.

Background: The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients.

Methods: This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m or carboplatin AUC 5-6 plus pemetrexed 500 mg/m] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1-2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099.

Findings: Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6-27·2) in the ceritinib group and 8·1 months (5·8-11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42-0·73]; p<0·00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group.

Interpretation: First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC.

Funding: Novartis Pharmaceuticals Corporation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(17)30123-XDOI Listing
March 2017

Effect of walking on circadian rhythms and sleep quality of patients with lung cancer: a randomised controlled trial.

Br J Cancer 2016 Nov 3;115(11):1304-1312. Epub 2016 Nov 3.

School of Nursing, College of Nursing, Taipei Medical University, Taipei, Taiwan.

Background: Sleep disturbances and poor rest-activity rhythms, which can reduce the quality of life, are highly prevalent among patients with lung cancer.

Methods: This trial investigated the effects of a 12-week exercise intervention including home-based walking exercise training and weekly exercise counseling on 111 lung cancer patients. Participants were randomly allocated to receive the intervention or usual-care. Outcomes included objective sleep (total sleep time, TST; sleep efficiency, SE; sleep onset latency, SOL; and wake after sleep onset, WASO), subjective sleep (Pittsburgh Sleep Quality Index, PSQI), and rest-activity rhythms (r24 and I
Results: The PSQI (Wald χ=15.16, P=0.001) and TST (Wald χ=7.59, P=0.023) of the patients in the exercise group significantly improved 3 and 6 months after intervention. The moderating effect of I
Conclusions: The walking program is an effective intervention for improving the subjective and objective sleep quality of lung cancer patients and can be considered an optional component of lung cancer rehabilitation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/bjc.2016.356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5129819PMC
November 2016

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study.

Lancet Oncol 2016 Dec 14;17(12):1643-1652. Epub 2016 Oct 14.

Kindai University Faculty of Medicine, Osaka-Sayama, Japan.

Background: Osimertinib (AZD9291) is an oral, potent, irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations, and the EGFR Thr790Met resistance mutation. We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor.

Methods: In this phase 2, open-label, single-arm study (AURA2), patients aged at least 18 years with centrally confirmed EGFR Thr790Met-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit. Patients with asymptomatic, stable CNS metastases not requiring steroids were allowed to enrol. The primary endpoint was the proportion of patients achieving an objective response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the evaluable for response analysis set (ie, all patients who received at least one dose of osimertinib and had measurable disease at baseline according to blinded independent central review). Other endpoints and safety were assessed in all patients receiving at least one osimertinib dose (full analysis set). The study is ongoing and patients are still receiving treatment. This study is registered with ClinicalTrials.gov, number NCT02094261.

Findings: Between May 20, 2014, and Sept 12, 2014, 472 patients were screened, of whom 210 started osimertinib treatment between June 13, 2014, and Oct 27, 2014; 11 patients were excluded from the evaluable for response analysis set (n=199) due to absence of measurable disease at baseline by blinded independent central review. At data cutoff (Nov 1, 2015), 122 (58%) patients remained on treatment. The median duration of follow-up was 13·0 months (IQR 7·6-14·2). 140 (70%; 95% CI 64-77) of 199 patients achieved an objective response by blinded independent central review: confirmed complete responses were achieved in six (3%) patients and partial responses were achieved in 134 (67%) patients. The most common all-causality grade 3 and 4 adverse events were pulmonary embolism (seven [3%]), prolonged electrocardiogram QT (five [2%]), decreased neutrophil count (four [2%]), anaemia, dyspnoea, hyponatraemia, increased alanine aminotransferase, and thrombocytopenia (three [1%] each). Serious adverse events were reported in 52 (25%) patients, of which 11 (5%) were investigator assessed as possibly treatment-related to osimertinib. Seven deaths were due to adverse events; these were pneumonia (n=2), pneumonia aspiration (n=1), rectal haemorrhage (n=1), dyspnoea (n=1), failure to thrive (n=1), and interstitial lung disease (n=1). The only fatal event assessed as possibly treatment-related by the investigator was due to interstitial lung disease.

Interpretation: Osimertinib showed clinical activity with manageable side-effects in patients with EGFR Thr790Met-positive NSCLC. Therefore, osimertinib could be a suitable treatment for patients with EGFR Thr790Met-positive disease who have progressed on an EGFR tyrosine-kinase inhibitor.

Funding: AstraZeneca.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(16)30508-3DOI Listing
December 2016

Characteristics of young lung cancer: Analysis of Taiwan's nationwide lung cancer registry focusing on epidermal growth factor receptor mutation and smoking status.

Oncotarget 2016 Jul;7(29):46628-46635

Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.

Lung cancer is relatively rare in young patients as the median age at diagnosis is 65-70 years. The main objective of this nationwide study was to investigate the characteristics of young lung cancer in Taiwan, especially the relationships among smoking behavior, epidermal growth factor receptor (EGFR) mutation, and age. The National Taiwan Lung Cancer Registry, a database contain detailed cancer statistics, was analyzed in this study for the period 2011-2012. Young lung cancer was defined as age ≦ 45 years. There were 21,536 lung cancer patients (13,187 men and 8349 women). Among these patients, 1074 (5.0%) were in the younger group, and 20,462 patients (95.0%) were in the older group. Female gender (48.8% versus 38.2%, P < 0.001), never-smokers (47.3% versus 43.8%, P = 0.015), and adenocarcinoma (70.4% versus 58.1%, P < 0.001) were more frequent in the younger group. While the EGFR mutation rate was lower in the younger group (52.5% versus 60.6%, P = 0.001), the primary site of lung cancer and stage distribution were not significantly different. If only adenocarcinoma patients were included in the analysis, female gender, older age, and never-smokers were more likely to have EGFR mutation. In conclusion, lung cancer in young patients (≦ 45 year-old) was associated with unique characteristics, with greater percentages of female patients, adenocarcinoma, and never-smokers and a lower EGFR mutation rate compared with older patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.9338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216823PMC
July 2016

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial.

Lancet Oncol 2016 05 12;17(5):577-89. Epub 2016 Apr 12.

Hospital Universitario Doce de Octubre and CNIO, Madrid Spain.

Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting.

Methods: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660.

Findings: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure.

Interpretation: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.

Funding: Boehringer Ingelheim.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(16)30033-XDOI Listing
May 2016

Radiation recall pneumonitis induced by epidermal growth factor receptor-tyrosine kinase inhibitor in patients with advanced nonsmall-cell lung cancer.

J Chin Med Assoc 2016 May 29;79(5):248-55. Epub 2016 Mar 29.

Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. Electronic address:

Background: Radiation recall pneumonitis (RRP) is a special form of radiation pneumonitis precipitated by certain pharmacological agents. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is an effective treatment for advanced nonsmall-cell lung cancer (NSCLC) and has been reported as a potent radiation sensitizer. The incidence and general characteristics of EGFR-TKI-related RRP in patients with NSCLC remain unclear.

Methods: Clinical records and serial chest images of consecutive patients with advanced NSCLC who had received thoracic radiotherapy (TRT) and EGFR-TKI treatment were retrospectively reviewed. EGFR-TKI-related RRP was diagnosed according to history, clinical manifestations, and radiographic characteristics. Potential risk factors were analyzed.

Results: In total, 160 patients with NSCLC who received EGFR-TKI after TRT were identified. Of these patients, seven (4.4%) developed EGFR-TKI-related RRP. The median time interval between the end of radiotherapy and RRP was 124 days (range, 80-635 days) and that between the initiation of EGFR-TKI and RRP was 43 days (range, 18-65 days). No risk factor for the development of RRP was identified except that patients in whom EGFR-TKI was initiated within 90 days after the completion of radiotherapy had significantly higher rates of RRP than those of patients who began receiving EGFR-TKI treatment after 90 days (21% vs. 2.1%, p = 0.005).

Conclusion: In patients with NSCLC who have a history of TRT, treatment with EGFR-TKI may induce not only interstitial lung disease but also RRP. Physicians should be aware of both unexpected adverse events when using EGFR-TKI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcma.2016.01.008DOI Listing
May 2016

Identifying cancer origin using circulating tumor cells.

Cancer Biol Ther 2016 04;17(4):430-8

a Graduate Institute of Life Sciences, National Defense Medical Center , Taiwan.

Circulating tumor cells (CTCs) have become an established clinical evaluation biomarker. CTC count provides a good correlation with the prognosis of cancer patients, but has only been used with known cancer patients, and has been unable to predict the origin of the CTCs. This study demonstrates the analysis of CTCs for the identification of their primary cancer source. Twelve mL blood samples were equally dispensed on 6 CMx chips, microfluidic chips coated with an anti-EpCAM-conjugated supported lipid bilayer, for CTC capture and isolation. Captured CTCs were eluted to an immunofluorescence (IF) staining panel consisting of 6 groups of antibodies: anti-panCK, anti-CK18, anti-CK7, anti-TTF-1, anti-CK20/anti-CDX2, and anti-PSA/anti-PSMA. Cancer cell lines of lung (H1975), colorectal (DLD-1, HCT-116), and prostate (PC3, DU145, LNCaP) were selected to establish the sensitivity and specificity for distinguishing CTCs from lung, colorectal, and prostate cancer. Spiking experiments performed in 2mL of culture medium or whole blood proved the CMx platform can enumerate cancer cells of lung, colorectal, and prostate. The IF panel was tested on blood samples from lung cancer patients (n = 3), colorectal cancer patients (n = 5), prostate cancer patients (n = 5), and healthy individuals (n = 12). Peripheral blood samples found panCK(+) and CK18(+) CTCs in lung, colorectal, and prostate cancers. CTCs expressing CK7(+) or TTF-1(+), (CK20/ CDX2)(+), or (PSA/ PSMA)(+) corresponded to lung, colorectal, or prostate cancer, respectively. In conclusion, we have designed an immunofluorescence staining panel to identify CTCs in peripheral blood to correctly identify cancer cell origin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15384047.2016.1141839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910938PMC
April 2016

First-Line Pemetrexed Plus Cisplatin Followed by Gefitinib Maintenance Therapy Versus Gefitinib Monotherapy in East Asian Never-Smoker Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-cell Lung Cancer: Quality of Life Results From a Randomized Phase III Trial.

Clin Lung Cancer 2016 Mar 17;17(2):150-60. Epub 2015 Dec 17.

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Background: The efficacy results from an open-label, randomized, multicenter study found no significant difference in progression-free survival between pemetrexed plus cisplatin followed by maintenance gefitinib (PC/G) and gefitinib monotherapy (G) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC) and unknown epidermal growth factor receptor (EGFR) mutation status (hazard ratio favored PC/G). The present report describes the quality of life (QoL) results from that trial.

Patients And Methods: Chemotherapy-naive, East Asian, light ex-smokers or never-smokers with advanced nonsquamous NSCLC and unknown EGFR mutation status (n = 236) were randomly assigned (1:1) to PC/G or G. EGFR mutation status was subsequently determined for 74 patients. The symptoms and QoL were assessed using the Lung Cancer Symptom Scale (LCSS). The time to worsening of symptoms (TWS) was analyzed using the Kaplan-Meier method.

Results: In the overall population, the TWS was generally longer in the G group (n = 109) than in the PC/G group (n = 109) for the LCSS symptoms classified as treatment-related (loss of appetite, fatigue) and tumor-related (cough, dyspnea, hemoptysis, pain). In the subgroup of patients with wild-type EGFR, the TWS was generally longer in the PC/G group (n = 13) than in the G group (n = 8) for the tumor-related LCSS symptoms.

Conclusion: In this study population clinically selected to respond to gefitinib, the LCSS scores were more favorable in the G group than in the PC/G group. Patients with wild-type EGFR tended to show greater improvement in tumor-related LCSS symptoms with chemotherapy than with gefitinib alone. These LCSS outcomes provide further evidence that patients with wild-type EGFR might not benefit from first-line treatment of advanced NSCLC with gefitinib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cllc.2015.12.004DOI Listing
March 2016

First-Line Pemetrexed plus Cisplatin followed by Gefitinib Maintenance Therapy versus Gefitinib Monotherapy in East Asian Never-Smoker Patients with Locally Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer: Final Overall Survival Results from a Randomized Phase 3 Study.

J Thorac Oncol 2016 Mar 25;11(3):370-9. Epub 2015 Dec 25.

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Introduction: The primary analysis of this open-label, randomized, multicenter phase 3 study revealed no significant difference in progression-free survival between pemetrexed plus cisplatin followed by maintenance gefitinib (PC/G) and gefitinib monotherapy (G) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) and unknown epidermal growth factor receptor gene (EGFR) mutation status; however, the hazard ratio favored PC/G. This report describes the final overall survival (OS) results.

Methods: Chemonaive, East Asian light ex-smokers/never-smokers with advanced nonsquamous NSCLC and unknown EGFR mutation status were randomized (1:1) to PC/G (n = 118) or G (n = 118). EGFR mutation status was retrospectively determined for 76 patients, 52 (68.4%) of whom had EGFR-mutated tumors (exon 19 deletions in 26 and L858R point mutation in 24). OS was analyzed by the Kaplan-Meier method. The study was registered at ClinicalTrials.gov (NCT01017874).

Results: Median OS was similar in the PC/G (26.9 months) and G (27.9 months) groups (hazard ratio = 0.94, 95% confidence interval: 0.68-1.31, p = 0.717). Median OS was longer with PC/G than with G in patients with EGFR wild-type tumors (28.4 versus 8.9 months) and longer with G than with PC/G in patients with EGFR-mutated tumors (45.7 versus 32.4 months), especially those with exon 19 deletions. Second-line postdiscontinuation therapy was common and included chemotherapy (PC/G, 41 of 118 [34.7%]; G, 73 of 118 [61.9%]) and rechallenge with an EGFR tyrosine kinase inhibitor (PC/G, 27 of 118 [22.9%]; G, 9 of 118 [7.6%]).

Conclusions: The progression-free survival and OS results from this study further demonstrate the importance of determining EGFR mutation status to select the most appropriate first-line treatment for patients with advanced NSCLC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2015.11.008DOI Listing
March 2016

First-Line Erlotinib Therapy Until and Beyond Response Evaluation Criteria in Solid Tumors Progression in Asian Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer: The ASPIRATION Study.

JAMA Oncol 2016 Mar;2(3):305-12

State Key Laboratory of South China, Hong Kong Cancer Institute, Chinese University of Hong Kong, Sha Tin, Hong Kong.

Importance: Continuing molecularly targeted treatment beyond disease progression in non-small-cell lung cancer (NSCLC) has appeared promising in retrospective analyses, highlighting the challenge to identify whether progression is the optimal time to switch treatment.

Objective: To study the efficacy of first-line erlotinib therapy in patients with NSCLC with activating EGFR mutations and postprogression erlotinib therapy.

Design, Setting, And Participants: ASPIRATION (Asian Pacific trial of Tarceva as first-line in EGFR mutation) was a phase 2, open-label, single-arm study conducted from 2011 to 2012 in 23 centers in Hong Kong, Korea, Taiwan, and Thailand of adults with stage IV, EGFR mutation-positive NSCLC, with ECOG performance status 0 to 2.

Interventions: Patients received erlotinib 150 mg/d orally until disease progression, after which erlotinib therapy could be continued at patient and/or investigator discretion.

Main Outcomes And Measures: The primary end point was progression-free survival (PFS1; time to Response Evaluation Criteria in Solid Tumours 1.1 progression or death). Secondary end points included PFS2 (time to off-erlotinib progression if erlotinib therapy was extended beyond progression at patient and/or investigator discretion), objective response rate, disease control rate, overall survival, and safety. The use of plasma-based assessment of EGFR mutations was also investigated.

Results: Of 359 patients screened, 208 were enrolled. Median follow-up was 11.3 (95% CI, 10.9-13.0) months. Of the 207 intent-to-treat patients (62.3% female; median age, 60.8 [range, 28-89] y), 176 had a PFS1 event (171 progression and 5 deaths); of these, 78 discontinued and 93 continued erlotinib therapy following progression. Median PFS1 was 10.8 (95% CI, 9.2-11.1) months. Median PFS1 and PFS2 in the 93 continuing patients was 11.0 (95% CI, 9.2-11.1) and 14.1 (95% CI, 12.2-15.9) months, respectively. Median PFS1 and PFS2 was 11.0 (95% CI, 9.3-12.0) and 14.9 (95% CI, 12.2-17.2) months in patients with exon 19 deletions or L585R mutations. Overall response rate was 66.2%; disease control rate was 82.6%. Median overall survival was 31.0 months (95% CI, 27.3 months to not reached). In the safety population (n = 207) serious adverse events were reported in 27.1%, with events of at least grade 3 experienced by 50.2%. Sensitivity and specificity of plasma-based EGFR mutation analysis was 77% and 92%, respectively.

Conclusions And Relevance: ASPIRATION supports the efficacy of first-line erlotinib therapy in patients with EGFR mutation-positive NSCLC and that treatment beyond progression is feasible and may delay salvage therapy in selected patients.

Trial Registration: clinicaltrials.gov Identifier: NCT01310036.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2015.4921DOI Listing
March 2016

Adjuvant Erlotinib Versus Placebo in Patients With Stage IB-IIIA Non-Small-Cell Lung Cancer (RADIANT): A Randomized, Double-Blind, Phase III Trial.

J Clin Oncol 2015 Dec 31;33(34):4007-14. Epub 2015 Aug 31.

Karen Kelly, University of California, Davis, Comprehensive Cancer Center, Sacramento, CA; Nasser K. Altorki, New York Presbyterian Hospital-Weill Cornell Medical Center, New York, NY; Wilfried E.E. Eberhardt, University Hospital Essen, Essen, Germany; Mary E.R. O'Brien, Royal Marsden Hospital, London, United Kingdom; David R. Spigel, Sarah Cannon Research Institute, Nashville, TN; Lucio Crinò, Ospedale S. Maria della Misericordia, Perugia, Italy; Chun-Ming Tsai, Taipei General Hospital and National Yang-Ming University, Taipei, Taiwan; Joo-Hang Kim, Yonsei University Health System, Seoul; Eun Kyung Cho, Gachon University, Incheon, Korea; Philip C. Hoffman, The University of Chicago Medical Center, Chicago; Jiuzhou Wang and Margaret A. Foley, Astellas Pharma, Northbrook, IL; Sergey V. Orlov, I.P. Pavlov Medical University, St Petersburg, Russia; Piotr Serwatowski, Specjalistyczny Szpital, Sokolowskiego, Szczecin, Poland; Julie D. Horan, Novella Clinical, Boulder, CO; and Frances A. Shepherd, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.

Purpose: Epidermal growth factor receptor (EGFR) -tyrosine kinase inhibitors have proven efficacy in advanced non-small-cell lung cancer (NSCLC). We hypothesized that erlotinib would be efficacious in the adjuvant setting.

Patients And Methods: An international randomized, double-blind, placebo-controlled study was conducted in patients with completely resected IB to IIIA NSCLC whose tumors expressed EGFR protein by immunohistochemistry or EGFR amplification by fluorescence in situ hybridization. Patients were assigned 2:1 to erlotinib 150 mg once per day or placebo for 2 years. Stratification factors were stage, histology, previous adjuvant chemotherapy, smoking status, EGFR amplification status, and country. The primary end point was disease-free survival (DFS); key secondary end points were overall survival (OS) and DFS and OS in patients whose tumors had EGFR-activating mutations (EGFRm-positive).

Results: A total of 973 patients were randomly assigned (November 26, 2007, to July 7, 2010). There was no statistically significant difference in DFS (median, 50.5 months for erlotinib and 48.2 months for placebo; hazard ratio, 0.90; 95% CI, 0.74 to 1.10; P = .324). Among the 161 patients (16.5%) in the EGFRm-positive subgroup, DFS favored erlotinib (median, 46.4 v 28.5 months; hazard ratio, 0.61; 95% CI, 0.38 to 0.98; P = .039), but this was not statistically significant because of the hierarchical testing procedure. OS data are immature. Rash and diarrhea were common adverse events occurring in 528 (86.4%) and 319 (52.2%) patients treated with erlotinib, respectively, versus 110 (32.1%) and 54 (15.7%) patients receiving placebo. The most common grade 3 adverse events in patients treated with erlotinib were rash (22.3%) and diarrhea (6.2%).

Conclusion: Adjuvant erlotinib did not prolong DFS in patients with EGFR-expressing NSCLC or in the EGFRm-positive subgroup. Further evaluation of erlotinib is warranted in the EGFRm-positive subgroup.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2015.61.8918DOI Listing
December 2015

Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.

Lancet Oncol 2015 Jul 4;16(7):830-8. Epub 2015 Jun 4.

Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, China. Electronic address:

Background: Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations.

Methods: In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb-IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18-21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393.

Findings: Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71·1%, 95% CI 54·1-84·6) patients in group 1 had objective responses, as did two (14·3%, 1·8-42·8) in group 2 and two (8·7%, 1·1-28·0) in group 3. Median progression-free survival was 10·7 months (95% CI 5·6-14·7) in group 1, 2·9 months (1·2-8·3) in group 2; and 2·7 months (1·8-4·2) in group 3. Median overall survival was 19·4 months (95% CI 16·4-26·9) in group 1, 14·9 months (8·1-24·9) in group 2, and 9·2 months (4·1-14·2) in group 3. For the most frequent uncommon mutations, 14 (77·8%, 95% CI 52·4-93·6) patients with Gly719Xaa had an objective response, as did nine (56·3%, 29·9-80·2) with Leu861Gln, and eight (100·0%, 63·1-100·0) with Ser768Ile.

Interpretation: Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations.

Funding: Boehringer Ingelheim.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(15)00026-1DOI Listing
July 2015

MLH1 V384D polymorphism associates with poor response to EGFR tyrosine kinase inhibitors in patients with EGFR L858R-positive lung adenocarcinoma.

Oncotarget 2015 Apr;6(10):8407-17

Department of Medicine, National Yang-Ming University, Taipei, Taiwan.

A significant fraction of patients with lung adenocarcinomas harboring activating epidermal growth factor receptor (EGFR) mutations do not experience clinical benefits from EGFR tyrosine kinase inhibitor (TKI) therapy. Using next-generation sequencing, we screened 739 mutation hotspots in 46 cancer-related genes in EGFR L858R-mutant lung adenocarcinomas from 29 patients who received EGFR-TKI therapy; 13 had short (< 3 months) and 16 had long (> 1 year) progression-free survival (PFS). We discovered MLH1 V384D as a genetic variant enriched in the group of patients with short PFS. Next, we investigated this genetic variation in 158 lung adenocarcinomas with the EGFR L858R mutation and found 14 (8.9%) patients had MLH1 V384D; available blood or non-tumor tissues from patients were also tested positive for MLH1 V384D. Patients with MLH1 V384D had a significantly shorter median PFS than those without (5.1 vs. 10.6 months; P= 0.001). Multivariate analysis showed that MLH1 V384D polymorphism was an independent predictor for a reduced PFS time (hazard ratio, 3.5; 95% confidence interval, 1.7 to 7.2; P= 0.001). In conclusion, MLH1 V384D polymorphism is associated with primary resistance to EGFR-TKIs in patients with EGFR L858R-positive lung adenocarcinoma and may potentially be a novel biomarker to guide treatment decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480762PMC
http://dx.doi.org/10.18632/oncotarget.3511DOI Listing
April 2015

Enhancement of tumor initiation and expression of KCNMA1, MORF4L2 and ASPM genes in the adenocarcinoma of lung xenograft after vorinostat treatment.

Oncotarget 2015 Apr;6(11):8663-75

Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan.

Cancer stem cells (CSCs) are usually tolerant to chemotherapy and radiotherapy and associated with tumor relapse. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), is currently being used in clinical trials of lung cancer. However, SAHA facilitates the formation of induced pluripotent stem cells from somatic cells. We hypothesized that SAHA would mediate the CSCs properties and subsequently confer a more malignant phenotype in lung cancer. Transfected H1299 lung cancer cells, which stably expresses a triple fused reporter gene (DsRedm-Fluc-tTKsr39) under the control of CMV promoter was used to establish a xenograft mouse model. After the treatment of SAHA, H1299 cell line and tumor xenografts were sorted by fluorescence-activated cell sorting (FACS) based on aldehyde dehydrogenase (ALDH) activity. We found that SAHA could suppress the growth of xenografted H1299 tumors with decreased proportion of ALDHbr lung cancer cells indicating that SAHA may target CSCs. However, SAHA significantly enhanced the tumor initiating capacity and the expression of malignant genes such as KCNMA1, MORF4L2 and ASPM in the remaining living ALDHbr cells. These findings suggested that SAHA treatment created a more drug-resistant state in residual ALDHbr cells. The in vivo imaging technique may facilitate searching and characterization of CSCs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496174PMC
http://dx.doi.org/10.18632/oncotarget.3536DOI Listing
April 2015

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Lung Adenocarcinomas with G719X/L861Q/S768I Mutations.

J Thorac Oncol 2015 05;10(5):793-799

Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan.

Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. Preclinical studies have suggested that uncommon G719X, L861Q, and S768I mutations are also sensitive to EGFR-TKIs. However, the efficacy of EGFR-TKIs in patients with these uncommon mutations remains unclear.

Methods: A nationwide survey was performed to collect data from gefitinib and erlotinib treatment outcomes of patients with stage IIIB/IV lung adenocarcinoma bearing EGFR G719X/L861Q/S768I mutations. The results were compared with those regarding patients with exon 19 deletions or L858R mutations.

Results: One hundred and sixty-one patients with uncommon EGFR mutations were enrolled from 18 institutes throughout Taiwan. Mutations of G719X, L861Q, S768I, G719X + L861Q, and G719X + S768I were observed in 78, 57, 7, 9, and 10 patients, respectively. After receiving EGFR-TKI treatment, patients with uncommon mutations exhibited a significantly inferior tumor response rate (41.6% vs. 66.5%; p < 0.001) and progression-free survival (median, 7.7 vs. 11.4 months; p < 0.001) than patients with common mutations. Among the patients who used EGFR-TKIs as first-line treatment, there was a significant difference in overall survival between these two groups of patients (median, 24.0 vs. 29.7 months; p = 0.005).

Conclusion: Gefitinib and erlotinib are active in patients with G719X/L861Q/S768I mutations; however, less effective than in those with common mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JTO.0000000000000504DOI Listing
May 2015

Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.

Lancet Oncol 2015 Feb 12;16(2):141-51. Epub 2015 Jan 12.

Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background: We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials.

Methods: Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393.

Findings: Median follow-up in LUX-Lung 3 was 41 months (IQR 35-44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31-37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28.2 months (95% CI 24.6-33.6) in the afatinib group and 28.2 months (20.7-33.2) in the pemetrexed-cisplatin group (HR 0.88, 95% CI 0.66-1.17, p=0.39). In LUX-Lung 6, median overall survival was 23.1 months (95% CI 20.4-27.3) in the afatinib group and 23.5 months (18.0-25.6) in the gemcitabine-cisplatin group (HR 0.93, 95% CI 0.72-1.22, p=0.61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33.3 months (95% CI 26.8-41.5) in the afatinib group versus 21.1 months (16.3-30.7) in the chemotherapy group (HR 0.54, 95% CI 0.36-0.79, p=0.0015); in LUX-Lung 6, it was 31.4 months (95% CI 24.2-35.3) versus 18.4 months (14.6-25.6), respectively (HR 0.64, 95% CI 0.44-0.94, p=0.023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27.6 months (19.8-41.7) in the afatinib group versus 40.3 months (24.3-not estimable) in the chemotherapy group (HR 1.30, 95% CI 0.80-2.11, p=0.29); in LUX-Lung 6, it was 19.6 months (95% CI 17.0-22.1) versus 24.3 months (19.0-27.0), respectively (HR 1.22, 95% CI 0.81-1.83, p=0.34). In both trials, the most common afatinib-related grade 3-4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3-4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3-4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]).

Interpretation: Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.

Funding: Boehringer Ingelheim.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(14)71173-8DOI Listing
February 2015

EGFR mutation testing practices within the Asia Pacific region: results of a multicenter diagnostic survey.

J Thorac Oncol 2015 Mar;10(3):438-45

*Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan; †Department of Pathology, Aberdeen University Medical School, Aberdeen, United Kingdom; ‡KalGen Laboratory, Stem-cell and Cancer Institute (SCI), Jakarta, Indonesia; §School of Medicine, Monash University Malaysia & Sime Darby Medical Center, Kuala Lumpur, Malaysia; ‖Center for Gene and Protein Research, Hanoi Medical University, Hanoi, Vietnam; ¶Department of Pathology, Fudan University Shanghai Cancer Center; Institute of Pathology, Fudan University, Shanghai, China; #Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; **Research and Biotechnology Division, St. Luke's Medical Center, Quezon City & COS-CENSER, De La Salle University, Manila, Philippines; ††Department of Pathology, National Cancer Center, Goyang-si, Gyeonggi-do, Korea; ‡‡Department of Pathology, Singapore General Hospital, Singapore, Singapore; §§Chulalongkorn GenePRO Center, Chulalongkorn Hospital, Bangkok, Thailand; ‖‖Seoul National University Bundang Hospital, Seoul, Korea; ¶¶Department of Respiratory Medicine, Saitama Medical University, Saitama, Japan; ##Peking Union Medical College Hospital, Beijing, China; ***Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS, Naples, Italy; †††Division of Hematology/Oncology, Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; ‡‡‡Clinical Genomic Medicine/Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; §§§Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; ‖‖‖University of Melbourne, Melbourne, VIC, Australia; ¶¶¶Sun Yat-Sen University Cancer Center, Guangzhou, China; ###Personalised Healthcare, AstraZeneca, Macclesfield, United Kingdom; ****Clinical Science Division, Astr

Introduction: The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in EGFR mutation-positive non-small-cell lung cancer (NSCLC) patients necessitates accurate, timely testing. Although EGFR mutation testing has been adopted by many laboratories in Asia, data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods.

Methods: A retrospective survey of records from NSCLC patients tested for EGFR mutations during 2011 was conducted in 11 Asian Pacific countries at 40 sites that routinely performed EGFR mutation testing during that period. Patient records were used to complete an online questionnaire at each site.

Results: Of the 22,193 NSCLC patient records surveyed, 31.8% (95% confidence interval: 31.2%-32.5%) were tested for EGFR mutations. The rate of EGFR mutation positivity was 39.6% among the 10,687 cases tested. The majority of samples were biopsy and/or cytology samples (71.4%). DNA sequencing was the most commonly used testing method accounting for 40% and 32.5% of tissue and cytology samples, respectively. A pathology report was available only to 60.0% of the sites, and 47.5% were not members of a Quality Assurance Scheme.

Conclusions: In 2011, EGFR mutation testing practices varied widely across Asia. These data provide a reference platform from which to improve the molecular diagnosis of NSCLC, and EGFR mutation testing in particular, in Asia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JTO.0000000000000422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342317PMC
March 2015

Should EGFR mutations be tested in advanced lung squamous cell carcinomas to guide frontline treatment?

Cancer Chemother Pharmacol 2014 Oct 23;74(4):661-5. Epub 2014 Jul 23.

Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

There is no argument over using epidermal growth factor receptor (EGFR) mutation status to guide the frontline treatment for advanced lung adenocarcinoma (LADC); however, the role of the testing in lung squamous cell carcinoma (LSQC) remains controversial. Currently, the guidelines/consensus statements regarding EGFR mutation testing in LSQC are not consistent among different oncology societies. American Society of Clinical Oncology recommends performing EGFR mutation testing in all patients; European Society for Medical Oncology, College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology, and National Comprehensive Cancer Network suggest for some selected group. EGFR mutation is rarely found in LSQC; however, more importantly, it is not a valid predictive biomarker for EGFR tyrosine kinase inhibitors (EGFR-TKI) in LSQC as it has been shown in LADC. Available data showed that the response rate and progression-free survival in EGFR mutant LSQC patients treated with EGFR-TKI are not better than that observed in patients treated with platinum-doublet chemotherapy in the first-line setting. Therefore, in contrast to advanced LADC, EGFR mutation testing may not be necessarily performed upfront in advanced LSQC because not only the mutation rate is low, but also the predictive value is insufficient. For LSQC patients with known sensitizing-EGFR mutations, both conventional chemotherapy and EGFR-TKI are acceptable frontline treatment options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00280-014-2536-3DOI Listing
October 2014

Physician-patient end-of-life care discussions: correlates and associations with end-of-life care preferences of cancer patients-a cross-sectional survey study.

Palliat Med 2014 Dec 25;28(10):1222-30. Epub 2014 Jun 25.

Chest Department, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: Honoring patients' treatment preferences is a key component of high-quality end-of-life care. Connecting clinical practices to patients' preferences requires effective communication. However, few cancer patients reported discussing end-of-life-care preferences with their physicians.

Aim: To identify correlates of physician-patient end-of-life-care discussions and to investigate associations of physician-patient end-of-life-care discussions with patient end-of-life-care preferences.

Design: A cross-sectional survey from April 2011 through November 2012.

Setting/participants: A convenience sample of 2467 cancer patients (89.3% participation rate) whose disease was diagnosed as terminal and unresponsive to current curative cancer treatment was recruited from 23 teaching hospitals throughout Taiwan.

Results: Only 7.8% of respondents reported discussing end-of-life-care preferences with their physicians. Physicians were more likely to discuss end-of-life-care preferences with cancer patients who accurately understood their prognosis but less likely to do so if patients were married or received care in a hospital with an inpatient hospice unit. Furthermore, physician-patient end-of-life-care discussions were significantly, positively associated with the likelihood of preferring comfort-oriented care and hospice care, but negatively associated with preferences for receiving cardiopulmonary resuscitation when life is in danger and aggressive life-sustaining treatments at end of life, including intensive care unit admission, cardiac massage, intubation, and mechanical ventilation support.

Conclusion: Physician-patient end-of-life-care discussions are correlated with accurate prognostic awareness, marital status, and institutional characteristics and negatively associated with terminally ill cancer patients' preferences for aggressive end-of-life care. Interventions should be developed to facilitate timely end-of-life-care discussions between at-risk patients and their physicians, thus honoring patients' end-of-life-care preferences and possibly avoiding futile life-sustaining treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0269216314540974DOI Listing
December 2014