bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is there a benefit on survival of tyrosine-kinase inhibitors versus chemotherapy in first line in mutated EGFR patients with advanced non-small cell cancer (NSCLC)? A meta-analysis.
Authors: Des Guetz Gaetan , Uzzan Bernard , Chouahnia Kader , Nicolas Patrick , Morere Jean F. 
Published: March 2020

e18020 Background: Tyrosine-Kinase Inhibitors (TKIs) markedly improve Progression Free Survival (PFS) of advanced NSCLC patients mutated for Epidermal Growth Factor Receptor (EGFR). Results on Overall Survival (OS) are more questionable. Therefore, we performed a publication-based meta-analysis to further assess this issue. Methods: We did a PubMed query using keywords simultaneously (lung neoplasm, TKI, EGFR mutation, survival). We also searched for relevant abstracts in proceedings of ASCO, ESMO, WCLC annual meetings. We cross-checked all references from all articles. Only phase III randomized controlled trials comparing TKI and chemotherapy were included. We used EasyMA software. Results: The 6 eligible studies included 2223 patients (516 males, 1688 females, mostly Asian, median age 60 years, 2155 adenocarcinomas (97 %), 996 mutated tumors, 389 stage IIIB, 1572 Stage IV (71 %), 1989 never smokers (89.5 %). Four studies assessed gefitinib, 2 erlotinib. Chemotherapies were doublets including a platinum salt. Four studies included only mutated patients. Compared to chemotherapy, EGFR TKIs significantly improved PFS (HR=0.39, 95 % CI 0.28-0.53, random effect model). Conversely, OS was similar among patients who first received TKI or chemotherapy (HR=1.00, CI 0.83-1.22, fixed effect model). PFS was significantly worse among non mutated patients in the 2 studies including both mutated and wild-type EGFR patients, whereas OS was unchanged. Concerning side-effects, rash, diarrhoea and interstitial lung disease were significantly more frequent after TKI (RRs 5.00; 2.40 and 6.07). As expected, fatigue (RR 0.41), nausea/vomiting (0.19) and haematological disorders were all significantly more frequent after chemotherapy (RRs for neutropenia, thrombocytopenia and anaemia 0.08; 0.18 and 0.26). Conclusions: The major discrepancy between a markedly improved PFS and a similar OS after TKI compared with chemotherapy could be related to the high level of crossing-over between the 2 groups. We found no detrimental effect on OS of TKIs among wild-type patients.
Comparative effectiveness of regimens of first-line platinum-based chemotherapy for advanced lung squamous cell carcinoma.
Authors: Chen Kuo-Hsing 
Published: March 2020

e18034 Background: Platinum-based cytotoxic chemotherapy remains the standard first-line therapy for patients with lung squamous cell carcinoma. This study aims to compare the effectiveness of first-line platinum-based chemotherapy regimens for advanced lung squamous cell carcinoma in the general population in Taiwan. Methods: We searched the Taiwan Cancer Registry database and the claim database of National Health Insurance, Taiwan for patients with newly diagnosed advanced lung squamous cell carcinoma from 2004 to 2007. Patients who received first-line combination chemotherapy with a platinum compound (cisplatin or carboplatin) plus either gemcitabine (G), docetaxel (D), paclitaxel (T), or vinorelbine (V) were included in the study. Overall survival (OS) was defined as the duration from the start of chemotherapy to death. Kaplan-Meier method was used to estimate the survival, which was univariately compared by the log-rank test. The Cox’s proportional hazard model was used to estimate the adjusted hazard ratios in multivariate analyses. Results: A total of 935 patients with advanced lung squamous cell carcinoma received first-line chemotherapy with a platinum compound (P) plus either G (57.6%), D (14.9%), T (11.3%), or V (16.0%). The proportion of elderly patients (age ≥ 70) who received P+D is lower than that of P+G, P+T, or P+V (35.71% vs 47.68%, 53.77%, 48.00% respectively, p = 0.0264). Patients who received P+G, P+D, P+T, or P+V had similar OS (median, 8.6 vs. 7.9 vs. 8.8 vs. 8.1 months, respectively; p = 0.969). Subgroup analyses based on age (≥ 70 or < 70), gender, stage (IIIB or IV by AJCC 6th edition), and the use of cisplatin revealed no differences in OS, either. In multivariate analyses adjusting for age, gender, and stage, the first-line chemotherapy regimen was still not a predictor of OS. With P+G as the reference group, the adjusted hazard ratios of P+D, P+T, and P+V were 1.02, 0.96, 1.03, respectively (p = 0.945). Conclusions: In patients with advanced lung squamous cell carcinoma, different treatment regimens did not have significant impact on the survival outcomes
EGFR-TKI benefit for NSCLC patients with EML4-ALK rearrangement.
Authors: Wang Zhijie , Wang Jie , Wu Yi Long , Bai Hua , Zhang Xu-Chao , An Tongtong , Zhuo Minglei , Duan Jianchun , Yang Lu , Wu Meina 
Published: March 2020

e18035 Background: EML4-ALK rearrangement defines a new molecular subtype of non-small-cell lung cancer (NSCLC). To identify the biological profiles of these patients, we examined the clinico-pathologic characteristics and treatment outcomes of NSCLC patients based on EML4-ALK and EGFR mutations. Methods: Patients with stage IV NSCLC were screened for EML4-ALK rearrangement and EGFR mutations at Peking University Cancer Hospital. EML4-ALK was identified using fluorescent in situ hybridization (FISH) confirmed by immunohistochemistry (IHC), and EGFR mutations were determined using denaturing high-performance liquid chromatography (DHPLC). Results: Of the 151 patients screened, 113 had complete follow-up data as an analysis set. The incidence of EML4-ALK was 9.7% (11/113) using FISH, in which 10 cases had sufficient specimens for IHC confirmation and all were positive. Overall, EML4-ALK and EGFR mutations were largely mutually exclusive (p = 0.033), although two patients harbored concurrent mutations. EML4-ALK rearrangement was associated with resistance to EGFR-TKIs compared with the EGFR mutant type and WT/Nonrearrangement type (p = 0.001 for objective response rate; p = 0.004 for disease control rate; p = 0.021 for progression-free survival [PFS]). In terms of patients who received platinum-based doublet chemotherapy, no significant differences were observed in PFS between the EML4-ALK type, EGFR mutant type, and WT/Nonrearrangement type. Moreover, two patients with concurrent EML4-ALK and EGFR mutations had superior PFS after EGFR-TKI compared with single EML4-ALK-rearranged patients. Conclusions: This study presents several biological features of EML4-ALK NSCLC. It is largely mutually exclusive to EGFR mutations, resistant to EGFR-TKI. Coexistence of ALK rearrangement and EGFR mutation in patients with advanced NSCLC might represent a separate genotype with unique biological characteristics.
A static diagnostic biopsy in patients with mutated EGFR lung adenocarcinom to guide therapeutic decisions.
Authors: Altavilla Giuseppe , Santarpia Mariacarmela , Arrigo Carmela , Tomasello Chiara , Benecchi Sara , Picone Antonio , Monaco Francesco , Pitini Vincenzo 
Published: March 2020

e18039 Background: Approximately 70% of the pts. whose lung cancers harbor EGFR mutations acquire drug resistence after a response to EGFR tyrosine kinase inhibitors (TKIs) treatment; this acquired resistance is mainly due to a secondary mutation in EGFR (T790 M) in about 50% of patients, amplification of MET in 15%, PIK3CA mutations in 5%, an unknown mechanism in almost 30%, and SCLC transformation in some patients. Furthermore, clinical experience revealed that cancers with acquired resistance can respond again to TKIs, after a drug-free interval. To aid in identification and treatment of these patients we examined a cohort of patients whose cancers were assessed with tumor biopsies at multiple times before and after their treatment with TKIs. Methods: 21 lung adenocarcinomas pts. (10 male, 11 female, median age 53 years) with EGFR mutations at 19 or 21 exons received TKIs, as first line of treatment. All showed a clinical response and all relapsed ( mTTP 10 months). At the time of relapse a new biopsy was performed, histologic samples were reviewed to re-confirm the diagnosis, EGFR and MET amplification were identified by FISH, while EGFR mutations have been tested by DNA sequencing. Results: At the time that drug resistence was acquired all pts. retained their original activating EGFR mutations, 9 pts. developed EGFR T790M resistance mutation with pronunced EGFR amplification in 3, 2 pts. developed MET amplification, 8 biopsies did not reveal any new mutations, two pts. were found to have a diagnosis of small cell lung cancer in their drug resistant tumor biopsies and responded well to conventional chemotherapy regimen.15 of 19 confirmed lung adenocarcinoma patient underwent to a cisplatin - pemetrexed chemotherapy regimen and at the time of progression 10 of them accepted to undergo a new biopsy. Three pts. ( after 4, 5 and 6 months break from treatment with TKIs ) lost T790M mutation and their disease responded to a second-line course of erlotinib. Conclusions: In our cohort of pts. with acquired EGFR resistence some patients lost acquired T790M mutation and become sensitive to EGFR inhibitor, in addition, two pts. underwent the histologic transformation from NSCLC to SCLC at the time of TKI resistence.
Phase Ib study of oral PPARγ agonist efatutazone (CS-7017) in combination with erlotinib in Korean patients with metastatic or unresectable locally advanced non-small cell lung cancer (NSCLC) who progressed after first-line therapy.
Authors: Kim Sang-We , Choi Chang-Min , Lee Dae Ho , Lee Jae Cheol , Suh Cheolwon , Lee Jung Shin 
Published: March 2020

e18052 Background: Efatutazone is a novel, third-generation thiazolidinedione (TZD) showing higher potency over second generation TZDs, such as pioglitazone. In non-Asian patients with advanced solid tumors, the recommended dose is 0.50 mg twice-daily (BID) in accordance with PK, PD and safety analyses in a US phase 1 study. This study assessed the safety, tolerability, PK, antitumor activity, PD, and determined the recommended dose of efatutazone in combination with erlotinib in Korean patients. Methods: This was an open-label, dose-escalation study using a 3+3 design in combination with erlotinib. Each patient participated in only 1 dose group and received oral efatutazone 0.25 or 0.50 mg BID with administration of erlotinib 150 mg QD. After determining the recommended dose of efatutazone, 9 additional patients were enrolled to the recommended dose for further assessment. PK samples were collected at day 1 and 22. PD samples were collected weekly until day 36. All subjects provided written informed consent. Results: A total of 14 patients were enrolled (10 male and 4 female; age range: 39–73 years; 12 Adenocarcinoma and 2 Squamous cell carcinoma; EGFR mutation: 5 positive, 4 negative and 5 not conducted) and received treatment at doses of 0.25 and 0.50 mg BID (n= 3 in 0.25mg, n= 11 in 0.50mg cohort). DLT were not observed, and the MTD was not reached. Efatutazone was well tolerated. The majority of patients experienced edema (78.6%, 11 out of 14 patients) and weight increase (64.3%, 9 out of 14 patients), often requiring diuretics. Five out of 14 patients showed PR (3 confirmed in 0.50mg cohort) and 4 patients showed SD. Efatutazone increased plasma adiponectin levels in a dose-dependent manner. Conclusions: Efatutazone is a novel anticancer therapy and in combination with erlotinib was tolerated and demonstrated early evidence of antitumor activity. Although the MTD for efatutazone was not reached, 0.50 mg BID, corresponding to the global recommended dose, was selected as the recommended dose for Korean patients. Full safety data and clinical activity data will be presented.
Clinicopathologic and molecular factors associated with early progressive disease after front-line platinum-doublet chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC).
Authors: Giroux Leprieur Etienne , Antoine Martine , Vieira Thibault , Duruisseaux Michael , Poulot Virginie , Rabbe Nathalie , Belmont Laure , Gounant Valérie , Lavole Armelle , Milleron Bernard , Lacave Roger , Cadranel Jacques , Wislez Marie 
Published: March 2020

e18075 Background: The majority of cases of NSCLC are diagnosed at an advanced stage and treated with a platinum-doublet CT. However, some patients are resistant to this treatment and develop early progressive disease. We investigated the clinicopathologic and molecular characteristics of such patients. Methods: All consecutive patients with NSCLC IIIB−IV treated with a platinum-doublet CT between 2003 and 2006 were included. Platinum resistance was defined as early progressive disease at the first tumor assessment according to WHO criteria. The clinical, histologic and molecular characteristics (EGFR:exon 19, 20, 21 and KRAS:exon 2 by PCR sequencing; ALK by IHC, confirmed by FISH) and survival of patients with early progression (P) and controlled disease (C) were compared by univariate analysis. Factors differing between the two groups with a p-value <0.25 in univariate analysis were entered into multivariate analysis. Results: 178 patients were included (mean age 59.1 years, 66.3% male, 54.5% smokers). Platinum was associated with gemcitabine (52.2%), paclitaxel (32.6%) or docetaxel (11.8%). The first tumor assessment was carried out after a median of three cycles [range 1−4]. Forty-six (25.8%) patients had early progression. Overall survival of P-group was significantly shorter than that of C-group (median 5 months vs. 15.1 months, respectively; p <0.0001). Clinical presentation was similar in the two groups. The sarcomatoid histologic subtype was more common among P-group than C-group (10.9% vs. 1.5%, respectively; p=0.057). The proportion of EGFR (5.2% vs. 9.6%, respectively; p=0.224) and KRAS mutations (11.1% vs. 5.7%, respectively; p=0.357), and expression of ALK (6.3% vs. 2.5%, respectively; p=0.327) did not differ significantly between the two groups. In multivariate analysis, sarcomatoid histologic subtype was the only factor associated with early progression [OR=7.50, 95%CI: 1.02−55.45; p=0.048]. Conclusions: Patients with early progression had a shorter survival than controlled patients. Sarcomatoid histologic subtype was the only independent factor associated with early progressive disease.
The impact of renal function on therapeutic options for advanced non-small cell lung cancer (NSCLC).
Authors: Kutluk Cenik Bercin , Rasco Drew Warren , Sun Han , Gerber David E. 
Published: March 2020

e18076 Background: Certain commonly used chemotherapeutic agents for advanced NSCLC require minimum threshold renal function for administration. To determine how such requirements affect treatment options, we evaluated renal function patterns in a real-world cohort of patients. Methods: Retrospective analysis of consecutive patients treated for stage IV NSCLC from 2000 to 2007 at the UT Southwestern Medical Center. Clinical data obtained from tumor registries and medical records. Creatinine clearance (CrCl) was determined using the Cockcroft-Gault formula. Mixed model analysis was used to evaluate associations between patient clinical factors and longitudinal renal function. Results: 296 patients (3,930 Cr measurements) were included in the analysis. Mean age was 63 years, 43% were women, and 47% were white. Patients had a median of 5 (IQR 4-18) Cr measurements. The median overall CrCl was 92 (IQR 68-124) mL/min; the median pre-treatment CrCl was 96 (IQR 74-123) mL/min; and the median nadir CrCl was 78 (IQR 56-100) mL/min, occurring a median of 35 (IQR 1-235) d after diagnosis. Renal function was significantly associated with age (P<0.001), race (P=0.009), and gender (P=0.001). 22% of patients had a recorded CrCl < 60 mL/min (a commonly used threshold for cisplatin administration), with median onset of 89 d after diagnosis and median time to recover to ≥ 60 mL of 20 (IQR 3-85) d. The incidence and median duration of CrCl < 60 mL/min varied by age (<65 y: 8%, 17 d; ≥65 y: 30%, 43 d), gender (male: 9%, 15 d; female: 28%, 36 d), and race (white: 30%, 42 d; non-white: 13%, 21 d). 10% of patients had a recorded CrCl < 45 mL/min (threshold for pemetrexed), with median onset 228 d after diagnosis and median time to recover to ≥ 45 mL/min of 33 (IQR 3-73) d. The incidence and median duration of CrCl < 45 mL/min also varied by age (<65 y: 6%, 6 d; ≥65 y: 8%, 72 d), gender (male: 4%, 5 d; females: 9%, 68 d), and race (white: 4%, 68 d; non-white 8%, 8 d). Conclusions: In a real-world cohort of patients treated for stage IV NSCLC, renal function falls below commonly used thresholds for cisplatin and pemetrexed in fewer than a quarter of patients. When such declines in renal function do occur, their duration may preclude administration of these drugs for prolonged periods.
Prognostication in non-small cell lung cancer.
Authors: Gagnon Bruno , Gioulbasanis Ioannis , Cohen Victor , Pepe Carmela , Small David I. , Yang Lin , Perdikouri Eleni Isidora , Kasymjanova Goulnar , Morris David , MacDonald Neil , Agulnik Jason Scott 
Published: March 2020

e18098 Background: For modern evidence-based medicine, a well defined risk scoring system on survival has important clinical implications for identifying patients with a poor prognosis. The objective of this study was to develop a Montreal Prognostic Score (MPS) based on risk scores of the baseline clinical markers. Methods: A training Cohort (TC) and confirmatory cohort (CC) of patients with non small-cell lung cancer were used to develop a Montreal Prognostic Score (MPS) and were assembled of patients from 3 different oncology centres: Jewish General Hospital in Montreal, Quebec, Canada; the University General Hospital of Heraklion Crete, Greece; and at the University General Hospital of Larissa, Greece. Stage, performance status, smoking status, CRP, Albumin, LDH and WBC from TC were entered in a Cox’s model on survival. Independent prognostic factors (p ≤ 0.1) were assigned a relative risk score by dividing their Proportional Hazard by the lowest one rounding to the closest integer. A 3 risk groups’ regression based total score (MPS) was finally developed by regrouping subgroups of patients with similar median survival. The MPS was tested on the CC. C-statistics was used to test the accuracy of the MPS. Results: 638 pts were included in the study: 314 in the TC and 324 in the CC. Majority of patients were stage 4 adenocarcinomas with good performance status treated with platinum-based chemotherapy. Stage, performance status, CRP, Albumin, LDH and WBC retained independent prognostic value and were used to create the MPS. The MPS predicted 3 well defined risk groups of patients with the following median survival and (95% CI) in months: high risk group (87 patients), 5.0 (4.2—7.0); intermediary risk group (98 patients), 9.6 (8.4—11.9); and low risk group (84 patients) 15.2 (12.4—25.1). When the MPS is applied to CC, the results were replicated for each risk group. Overall the TC had a C-stats of 0.673 (95% CI: 0.668, 0.679) while the CC of 0.702 (95% CI: 0.696, 0.708). Conclusions: We have developed a Montreal Prognostic Score based on stage, performance status and the baseline value of CRP, Albumin, LDH, WBC. This MPS has a high capacity of discriminating survival and might have wide implications in clinical practice and research.
A phase I/II trial of erlotinib S-1 therapy in patients with non-small cell lung carcinoma: Thoracic Oncology Reseach Group (TORG) 0808/0913.
Authors: Nogami Naoyuki , Shinkai Tetsu , Kozuki Toshiyuki , Ogino Atsuko , Kato Yuka , Hosomi Yukio , Hida Naoya , Shimokawa Tsuneo , Seki Nobuhiko , Okamoto Hiroaki , Shibuya Masahiko , Watanabe Koshiro ,   Thoracic Oncology Reseach Group (TORG)
Published: March 2020

e18099 Background: Gefitinib has been shown in basic studies to reduce the expression of thymidilate synthase, the target enzyme for the 5-FU-based chemotherapy, at the protein and mRNA levels, and synergistic effects of gefitinib used in combination with S-1 have been reported. Erlotinib also reduced TS expression and activity. The present studies were designed as study aimed at evaluating the efficacy and safety of erlotinib/ S-1 combination therapy as a 2nd/3rd-line therapy for recurrent/advanced NSCLC. Methods: Chemotherapy consisted of two 3-week cycles of erlotinib and S-1 treatment. Erlotinib was orally administered once daily at a dose of 150 mg/body, and patients received an oral dose of S-1 twice daily after meals from days 1 to 14 of each 21-day cycle. In phase I trial(TORG0808), the primary endpoint was to evaluate the DLT and the MTD for the following phase II study, and the secondary endpoint was to evaluate the antitumor activity and safety. Based on the phase I trial, we conducted a phase II trial (TORG0913) of this combination with pretreated EGFR negative NSCLC to determine the ORR. The secondary endpoints were PFS, disease control rate, OS, and safety. Results: 7 patients with good PS (0 or 1) and 10 patients with PS 0-2 participated in phase I and phase II trial. In phase I trial, the recommended doses for the phase II study were determined to be 150mg/body and 80mg/m2. The ORR was 67%, and 3/4 responders are EGFR positive patients. In phase II trial, the ORR was very low (only one patient).Myelosuppression was relatively mild, but Grade 3 or worse non-hematological toxicities including diarrhea, mucositis, and dermatitis were observed in 6 patients, which resulted in two treatment-related deaths. Data and Safety Monitoring Committee recommended the early termination, and the clinical trial was terminated due to adverse events. Conclusions: Phase I study showed the favorable efficacy and moderate safety profiles of this combination especially in EGFR positive patients, but less effective and too toxic in EGFR negative patients in phase II trial.
An analysis of target-specific patient resource utilization in NSCLC clinical trials.
Authors: Somaiah Neeta , Simon George R. 
Published: March 2020

e18112 Background: A plethora of targeted agents are currently being evaluated in patients with NSCLC. The number of targeted agents exceeds the number of targets leading to many targeted agents being evaluated against similar targets. The identification of new targets are likely to increase exponentially in the near future given the numerous currently ongoing molecular profiling efforts. The objective of this analysis is to estimate the target-specific patient resource utilization and its impact on routine clinical care. Methods: A comprehensive search for molecularly targeted agents in clinical testing that have accrued or are accruing NSCLC patients were performed by using publically available search engines and databases. Agents were grouped according to the primary target and the phase of development. We computed the number of patients allocated to completed and ongoing phase III NSCLC trials for advanced NSCLC alone. Results: There are more than 30 categories of molecular targets accruing NSCLC patients in clinical trials. By conservative estimates, approximately 215 agents are currently undergoing clinical testing. The median number of agents per target is 7 (range 2 (HIF-1α and PDGFRα) – 24 (EGFR)). There are 7 EGFR inhibitors and 10 VEGFR inhibitors that were evaluated in phase III trials; with 36,093 and 20,313 stage IV NSCLC patients enrolled or to be enrolled in these trials, respectively. No more than 2 agents per target have been FDA approved for NSCLC to date. Further details of the analyses will be more comprehensively presented at the meeting. Conclusions: Patient resource utilization is unevenly distributed across targets. The optimal number of targeted agents to be evaluated per target remains to be defined. More emphasis on identifying new targets and targeting these with limited number of optimal agents may accelerate the advancement of the field and the impact on patient care.