bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness analysis of afatinib vs gefitinib in EGFR-mutated population with advanced non-small-cell lung cancer.
Authors: Chouaid Christos , Luciani Laura , Le Lay Katell , De Pouvourville Gerard 
Published: September 2018

e20548 Background: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial (LL7) for first-line treatment of advanced EGFR mutation-positive non-small-cell lung cancer (EGFRm+ NSCLC). We aimed to assess the cost and health outcomes of afatinib and gefitinib in this setting. Methods: A partitioned survival model was designed to assess the cost-effectiveness of afatinib versus geftinib in the French context for EGFRm+ NSCLC.Outcomes and safety are taken primarily from the head-to-head LL7 trial. Only direct medical costs were considered. Resources use and utilities were derived from the trial, expert panel and published literature. Incremental cost-effectiveness ratios (ICER) were calculated in the common EGFR population and also, in the sub-groups with EGFR Exon 19 deletion (del 19) and EGFR Exon 21 L858R (L858R) mutation over a 10 year-time horizon. Deterministic and probabilistic sensitivity analyses were performed. Results: For common EGFR+ NSCLC, the ICER of afatinib versus gefitinib was €45,211 per QALY (with a gain of 0.170 QALYs, and an incremental cost of €7,697). The ICERs for del 19 and L858R populations were €38,970 and €52,518 respectively. Afatinib had a probability of 100% to be cost-effective at a willingness-to-pay threshold of €70,000 for patients with common EGFR mutation, and also in the del 19 and L858R subgroups. Conclusions: Afatinib is a cost-effective treatment compared to geftinib in patients with EGFRm+ NSCLC with an ICER varying between €38,970/QALYs and €52,518/QALYs.
De novo EGFR T790M, KRAS and PIK3CA somatic mutations in cell free DNA in non-small cell lung cancer patients and clinical characteristics.
Authors: Chang Won Jin , Kim Yeul Hong 
Published: September 2018

e20561 Background: Several mechanisms for acquired drug resistance EGFR-TKIs in NSCLC have been suggested. These include EGFR T790M mutation and mutations in KRAS, and PIK3CA. Rarely, a de novoT790M mutation has been reported. However, the clinical significance of these mutations remains controversial. Here, we used highly sensitive methods to detect T790M, KRAS and PIK3CA mutations in cell free DNA (cfDNA) and evaluate the clinical significance of those mutations. Methods: The blood samples were collected from 125 patients with NSCLC. Ion AmpliSeq Cancer Hotspot Panel (ICP) using a targeted ultra-deep sequencing (mean depth 22,868x) was performed in cfDNA, which were validated with droplet digital PCR (ddPCR). Results: ICP detected EGFR T790M mutation in 30 of 125 cfDNA (24%), KRAS mutations in 18 (14.4%) and PIK3CA in 33 (26.4%). ddPCR confirmed concordant T790M results in 22 (73.3%) and KRAS in 13 (72.2%). The 8 of 22 (36.4%) in T790M and 2 of 13 (15.4%) in KRAS had simultaneous activating EGFR mutations in cfDNA or tumor tissue. The most single KRAS mutations appeared in codon 12 (n = 7, 63.6%) (3 in G12C, 2 in G12S, 1 in G12V and 1 in G12D) with three mutations in codon 13 (27.3%) and one mutation in codon 61 (9.1%). About 20% to 50% had bone or brain metastases at diagnosis in patients with these mutations. The 5 (62.5%) (4 PR and 1 SD) of 8 patients in T790M and 8 (61.5%) (All PR) of 13 in PIK3CA showed response or stabilization. The median time to disease progression after EGFR-TKIs treatment was 13.5 months in PIK3CA and not reached in T790M. Conclusions: The de novo T790M, KRAS and PIK3CA mutation was detected in 24%, 14.4% and 26.4% using ICP in cfDNA. In our study, the KRAS and EGFR mutation may not be mutually exclusive and PIK3CA mutations may be a factor associated with metastatic sites rather than predictive factor for EGFR-TKIs. In addition, we suggested that although the clinical presentation is more aggressive in patients with de novo T790M and PIK3CA mutation, the EGFR-TKIs could be used in patients who present with both activating EGFR mutations and those mutations.
A retrospective analysis of apatinib in advanced non-small cell lung cancer patients refractory to chemotherapy.
Authors: Xu Jianping , Liu Xiaoyan , Yang Sheng , Zhang Xiangru , Shi Yuankai 
Published: September 2018

e20562 Background: Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2. A phase II clinical study proved that 750 mg qd apatinib showed clinical benefit in patients with advanced non-squamous NSCLC refractory to two or more lines of chemotherapy (Zhang et al. 2012 ASCO, 7548). In this retrospective study, we assessed the efficacy of apatinib at a more frequently used dose of 500 mg qd in advanced chemo-refractory NSCLC. The preliminary clinical outcome of apatinib in patients with brain metastases was also reported. Methods: Clinical data of 25 advanced NSCLC patients who received oral apatinib 500 mg once daily as second-line and beyond therapy between August 2015 and May 2016 were reviewed. Results: The median progression-free survival (PFS) was 5.17 months (95% CI: 0.76–9.57 months). The response rate (RR) and disease control rate (DCR) were 8.0% and 68.0%, respectively. In the second-line setting (n=13), the mPFS was 7.37 months (95% CI: 0.01–14.72 months), and the RR and DCR were 0.0% and 61.5%, respectively. In the third-line and beyond setting (n=12), the mPFS was 5.17 months (95% CI: 1.78–8.55 months), and the PR and DCR were 16.7% and 75.0%, respectively. The DCR was 57.1% for 7 patients with brain metastases following apatinib administration. All patients were well tolerant to apatinib without any Grade 3 or 4 adverse events. The most common Grade 1 or 2 adverse events included hypertension (72.0%), hand-foot syndrome (24.0%), fatigue (24.0%), abnormal liver function (20.0%), nausea (12.0%) and palpitation (8.0%). Conclusions: Apatinib is effective and well tolerated in patients with advanced NSCLC, even at a dose of 500 mg qd, and might offer a new option for the treatment of such patients with brain metastases.
Liquid biopsy analysis of ALK alterations from advanced NSCLC patients: The value of exosomal RNA cargo (ExoALK).
Authors: Rolfo Christian Diego , Laes Jean-Francois , Reclusa Pablo , Lienard Maxime , Gil-Bazo Ignacio , Malapelle Umberto , Rocco Danilo , Van Meerbeeck Jan , Pauwels Patrick , Peeters Marc , Giallombardo Marco 
Published: September 2018

e20569 Background: About 5% of NSCLCs present alterations in the ALK gene. Among them the most common is EML4-ALK translocation. The gold standard detection method to treat the patient with ALKi is the tissue, thus, it is mandatory to develop new techniques that allow to detect ALK alterations in liquid biopsy. The purpose of this study is, analyze the feasibility to detect ALK alterations in exosomes (Exo-ALK) derived from NSCLC patients. Methods: We recruit 18 NSCLC patients including EML4-ALK and wild-type patients stage- and time-independent. ALK-positive status is identified by IHQ. The isolation of RNA with the exoRNeasy Kit Serum/Plasma (Qiagen) in UZA and the retrotranscription with ProtoScript II First Strand cDNA Synthesis kit. The ALK alteration present in the exosomes is determined by NGS and bio-informatic analysis in OncoDNA. Samples were provided by the Biobank of the University of Navarra, the UZA Biobank and the University of Naples Federico II. Samples and data were processed following the processes approved by the local Ethical and Scientific Committees. Results: Among analyzed patients, 15 patients were EML4-ALK tissue positive, and 3 were EML4-ALK tissue negative. With our analysis, 9 patients were positive, 7 negative and 2 sample were degraded at the time of analysis. Comparing the results, the 9 positive patients in the exosomes were also positive in the tissue. Moreover, the 2 negative patients were also negative for the translocation in the tissue. However, we were unable to detect 4 positive EML4-ALK patients in the exosomes. Nonetheless, these data show a sensitivity of 69% and a specificity of 100%. No correlation was found comparing treatment-naïve and pretreated patients. Conclusions: Exosomes are raising as a very promising tool to determine the tumor profile due to their stability and their cargo. With further study and a larger number of patients, we demonstrate that exosomes isolation and analysis will be feasible tool, and thus we will reduce the tumor biopsy risks and costs in the clinical practice. Our preliminary results show a good specificity for a proof of concept analysis. These results will be cross-validated and amplified with more patients in the following months.
Does blood sugar impact on metastatic non-small cell lung cancer (NSCLC) outcome?
Authors: Gravel Mathieu , Blais Normand , Tehfe Mustapha Ali , Florescu Marie 
Published: September 2018

e20579 Background: Diabetes is a frequent diagnostic (9.3%) in general Western population, and because of its complications, becomes a comorbidity in NSCLC patients that could impact on prognostic. Impact of diabetes on NSCLC prognosis is unknown but the majority of patients fear eating desserts because feeding mostly the NSCLC tumor cells. Methods: Using our SARDO database and hospital files, we retrospectively reviewed 548 patients with metastatic NSCLC diagnosed and treated in our University hospital between 2006 and 2015. Uncontrolled diabetes was established when Hb1Ac > 7% or with more than 2 hospital glycemia over 11 mmol/L. Results: Amongst 418 metastatic NSCLC patients, 294pts (70%) had synchronous metastasis at diagnostic and 117pts (30%) have metachronous metastasis. As expected metachronous metastasis patients had a better survival (mOS 25mo) than synchronous metastasis (mOS 6mo). Then, we divided our patients in 4 subgroups: 1) Patients with diagnosed and uncontrolled diabetes (n = 78); 2) Patients with high glycemia but not previously diabetes diagnostic (n = 19); 3) Patients with controlled diagnosed diabetes (n = 59); 4) Control patients with normal glycemias or HBA1c (n = 262). Some tumor stage and demographic disparities were seen between the 4 groups but we controlled for them. In upfront metastatic NSCLC patients, mOS was 4.0 months for group 1, 4.0 months for group 2, 4.0 months for group 3 and 7.0 months for our control group, not statistically different, which is lower than literature but expected for this unselected population treated before 2015. In metachronous patients, group 1 mOS was 21mo, group 2 was 58mo, group 3 was 30mo and mOS was 23mo for control patients, with no statistically difference between groups. Women had a better mOS 8 mo compared to 4 mo in men (p = 0,003) independently of diabetes or sugar status. Conclusions: This retrospective data is reassuring regarding patients blood glycemia during the metastatic lung cancer treatment. Even in a long term metachronous disease perspective, blood sugar or diabetes diagnostic did not seem to influence the outcome. However, these data should be validated in a prospective study that could acknowledge if blood sugar control could improve lung cancer outcome.
Understanding real-world outcomes in patients with NSCLC who progress on 1st-/2nd-generation EGFR TKIs.
Authors: Fernandes Ancilla , Skinner Karen E , Walker Mark Stephen , Pavilack Melissa , Vanderwalde Ari M. 
Published: September 2018

e20589 Background: Epidermal growth factor receptor (EGFR)tyrosine kinase inhibitors (TKIs) are recommended for patients (pts) with EGFR mutation ( EGFRm) positive non-small cell lung cancer (NSCLC). Limited data are available for real-world outcomes in pts who experience progression on 1st-/2nd-generation EGFR TKIs, which was the focus of this study. Methods: A retrospective chart review of pts with advanced NSCLC (stage IIIb/IV) from 10 US community oncology practices was conducted. Patients were included if they were diagnosed 1/1/2008—1/1/2015, were treated with erlotinib or afatinib (TKIs) either first line (1L) or second line (2L), and had disease progression (per clinician’s assessment) prior to 10/31/2015. Pts were classified into cohorts based on TKI initiation (1L or 2L) and EGFRm status. Progression-free survival (PFS) and overall survival (OS) were evaluated for the TKI treatment period and the post-progression period. Results: The study included 364 pts: 77.7% white, 17.3% African American; mean (SD) age 66.3 (11.3) years. PFS and OS were longer for 1L and EGFRm+ pt cohorts during the TKI treatment period. After progression, 25.3% (80/316) pts continued TKI, while around half received chemotherapy (56.3%; 178/316). The effects of other variables evaluated as predictors of PFS and OS were largely nonsignificant. Conclusions: Outcomes were worse after progression irrespective of EGFRm status and whether TKI was initiated 1L or 2L. This finding highlights the need for therapeutic options that improve outcomes in pts after progression on a 1st-/2nd-generation EGFR TKI. [Table: see text]
Correlation between re-biopsy site and detection of T790M mutation in NSCLC patients treated with EGFR TKI.
Authors: Shigematsu Fumie , Kogure Yoshihito , Saka Hideo , Yamada Arisa , Ishida Akane , Ise Yuko , Hori Kazumi , Oka Saori , Nakahata Masashi , Kitagawa Chiyoe , Oki Masahide 
Published: September 2018

e20620 Background: Re-biopsy is important to decide the treatment after EGFR-tyrosine kinase inhibitor (TKI) failure in non-small cell lung cancer (NSCLC) patients. We hypothesized that the T790M mutation in EGFR might show heterogeneity depending on the re-biopsy site. Methods: NSCLC patients who had received initial EGFR-TKI since January 2009 to December 2016, at any stage and recurrence after surgery and at any line of treatment, were included. Results: In total, 128 patients were included. Median age at EGFR-TKI therapy initiation was 73 (range, 38–97) years; 67% patients were female, all were Asian, 56% had never smoked, and 99% had adenocarcinoma. Of total 128 patients, 109 showed progressive disease. Median progression-free survival (PFS) was 10 (0.56–57) months. Median period since EGFR-TKI failure until the first re-biopsy was 197 (0–1322) days. Re-biopsy was performed 50 times in 42 patients; the number of T790M positive, negative, and pathologically negative patients was 20, 17, and 5, respectively, and the number of re-biopsies in these patients was 20, 22, and 8, respectively. Median PFS was longer in T790M positive patients than in negative patients significantly (17 [11–24] vs. 7.6 [4.3–11] months, P = 0.007). Characteristics such as gender, smoking status, proportion of stage IV, time between EGFR-TKI failure and first re-biopsy, and number of biopsies did not affect the T790M status in the biopsies. T790M positive group had more exon 19 deletions than negative group significantly (75% vs. 23%, P = 0.012). Biopsies at primary lesion, distant, and pleural effusion (PE) were 25% vs. 50%, 60% vs. 36%, and 15% vs. 14%, respectively, in the T790M positive vs. negative groups. Compared with the biopsy-site at diagnosis, the site was same as before in 35% vs. 50% cases (primary lesion [20% vs. 45%], distant [10% vs. 4.5%], and PE [5% vs. 0%]) and was new in 55% vs. 41% cases (distant lesions [45% vs. 27%] and PE [10% vs. 14%]) in the T790M positive vs. negative groups, respectively. Conclusions: In NSCLC patients treated with EGFR-TKI, re-biopsy was performed in distant lesions more frequently in the T790M positive cases than in negative cases. However, the T790M status was not correlated with the re-biopsy site.
Association of early specialist-delivered palliative care with less aggressive chemotherapy in patients with advanced lung cancr.
Authors: Lammers Austin J. , Sullivan Donald Richard 
Published: September 2018

e20621 Background:Advanced stage lung cancer has a poor prognosis with high symptom burden. Early specialist-delivered palliative care (ESDPC) has been shown to improve quality of life (QOL) and may even improve survival, but a minority of patients receive this care. Previous studies have found that > 1 regimen of chemotherapy is associated with reduced QOL near death, but it is unknown how palliative care affects aggressive chemotherapy use. We sought to determine if ESDPC impacted aggressive chemotherapy receipt in patients with advanced lung cancer. Methods: A cohort of Veterans with advanced stage IIIB/IV lung cancer in the national Veterans Health Administration network diagnosed between 2007-2013 were included. Demographic data, cancer characteristics, chemotherapy characteristics and early palliative care consultation (within 90 days of diagnosis) were recorded. Aggressive chemotherapy was defined as receipt of a Bevacizumab/Cetuximab triplet, > / = 2 lines of chemotherapy, and more than 4 cycles of a platinum doublet. Descriptive statistics were used to compare demographic data. Unadjusted p-valves were calculated using two-sample t-test. Results: Among 23,660 patients, mean age 68, 98% male, 71% white, 56% current tobacco users. In total, 45% received chemotherapy and 37% received ESDPC. Mean Charlson comorbidity index (CCI) was 4.5 and functional comorbidity index (FCI) was 3. 89% were stage IV, 82% NSCLC. Patients with ESDPC were notably different in CCI (5.4 vs 4) and stage IV (93 vs 86). Of those receiving ESDPC, patients were less likely to receive triple drug therapy (Bevacizumab or Cetuximab combo), less likely to receive > / = 2 lines of chemotherapy and less likely to receive > / = 4 cycles of platinum doublet (all with p-values < 0.001). Conclusions: Our study found that patients who received ESDPC were less likely to receive aggressive chemotherapy. However, comorbidities, cancer stage, and age may have contributed to this difference. We plan to further analyze this data in an adjusted analysis to determine the association between ESDPC and chemotherapy receipt. Future research should focus on identifying patients that will most benefit from aggressive chemotherapy.
Phase II study of stereotactic radiosurgery or other local ablation followed by erlotinib for patients with EGFR mutation who have previously progressed on an EGFR tyrosine kinase inhibitor (TKI).
Authors: Weiss Jared , Kavanagh Brian D. , Deal Allison Mary , Zagar Timothy , Marks Lawrence Bruce , Stinchcombe Tom , Borghaei Hossein , West Howard Jack , Morris David E. , Villaruz Liza Cosca , Pennell Nathan A. 
Published: September 2018

e20623 Background: For patients with metastatic EGFR mutated NSCLC, 1stline treatment with EGFR TKIs such as erlotinib result in a median PFS of about 10 months. In patients with a limited number of progressing lesions, local ablation therapy (LAT) of progressive lesions followed by re-initiation of TKI has shown promise in retrospective studies but to date this strategy has not been testing in prospective fashion. Methods: As part of an IRB approved open label prospective phase II trial (NCT01573702), patients with EGFR mutated NSCLC and immediate progression on a TKI in < 5 locations were treated with stereotactic radiosurgery (SRS) to progressing lesions followed by re-initiation of erlotinib. Our primary endpoint is PFS, and we hypothesize that it will be at least 3 months. Results: 25/40 planned patients have been enrolled and data is available on 23. By local reporting, 14 had exon 19, 5 had exon 21, 1 had compound exon 18 and exon 20, 1 had compound exon 19 and EML4/ALK and 2 were unknown. 65% were female, all were non-Hispanic white, median age 62.5 (range 43-85), PS0 65.2%/PS1 34.8%, median Charlson Comorbidity Index 6, and 71.4% were never smokers. Median number of lesions treated was 1 (range 1-3). Treated lesions included lung (14), bone (6), liver (3) and brain (2). There were no G3-4 AEs to SRS. Two subjects had grade 3 rash on erlotinib. Median PFS post treatment was 5.8 months (95% CI, 2.5 to 11.3) and median OS was 2.9 years (95% CI 1.1 to 2.9). Conclusions: LAT resulted in a modest extension in the duration of targeted therapy, supporting retrospective data in this population. Accrual to this study has been challenging due to the availability of 3rd generation EGFR TKIs and because LAT is often done outside of a clinical trial. Clinical trial information: NCT01573702.
Co-existance of KRAS and LKB1 mutation as predictor of resistance to Erlotinib: Customized next-generation sequencing (NGS) of TAILOR trial.
Authors: Rulli Eliana , Serafini Mara Serena , Marabese Mirko , Caiola Elisa , Sozzi Gabriella , Moro Massimo , Bria Emilio , Simbolo Michele , Busico Adele , Tamborini Elena , Corrao Giulia , Farina Gabriella , Broggini Massimo , Ganzinelli Monica , Garassino Marina Chiara 
Published: September 2018

e20631 Background: The prognostic and predictive value of KRAS mutation in advanced NSCLC is still debatable. In TAILOR (NCT00637910) trial EGFR wild-type patients were randomized to receive 2nd line erlotinib versus docetaxel, and no interaction was detected according to KRAS mutational status. Recent evidences indicate that the concurrent mutation of KRAS and LKB1 (key factor for cell metabolism) may be associated with worse prognosis. Methods: Availableformalin-fixed embeddedtissue samples with annotated clinical data from TAILOR were gathered. Customized deep sequencing (Ion proton Technology) of 111 genes most frequently associated with cancer, was performed; 5% of frequency was used to identify mutations. Association between genes and clinical features was performed with non-parametric tests; Cox regression analysis was used to assess the prognostic and predictive value of LKB1. Results: 123 out of 222 (55%) randomized patients had available tissue and were successfully sequenced. 42/123 (34%) patients had a KRAS mutation. KRAS and LKB1 mutations were found in 11/42 (26%) KRAS patients, while only 6 patients had a LKB1 mutation without KRAS. The presence of a concurrent KRAS-LKB1 mutation did not adversely influence progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS 1.08, 95% confidence interval (CI) 0.57-2.05, P = 0.81; OS 1.09, 95% CI 0.56-2.14, P = 0.78]. Patients receiving docetaxel experienced longer survival regardless of the KRAS-LKB1 mutational status (mutated KRAS-LKB1 HR 0.42, 95% CI 0.08-2.29; wild-type KRAS-LKB1 HR 1.16, 95% CI 0.72-1.87, P = 0.55; interaction P = 0.10). Conclusions: Although the significant attrition and the limited number, these data generate the hypothesis that the concurrent mutation of KRAS and LKB1 may potentially be associated with resistance to erlotinib. Overall, the coexistence of mutation in KRAS and LKB1 is not associated with worse prognosis in NSCLC. For these patients refractory to EGFR targeting, metabolic strategies represent a future research opportunity.