bluuebunny/crossref_metadata_2025_split huggingface dataset:
EATON: An open-label, multicenter, phase I dose-escalation trial of nazartinib (EGF816) and trametinib in patients with EGFR-mutant non-small cell lung cancer – preliminary data on safety and tolerability.
Authors: Michels Sebastian Yves Friedrich , Nogova Lucia , Deschler-Baier Barbara , Felip Enriqueta , Rodriguez-Abreu Delvys , Rosell Rafael , Sebastian Martin , Schuler Martin H. , Wermke Martin , Fischer Rieke Nila , Koleczko Sophia , Abdulla Diana S.Y. , Riedel Richard , Scheffler Matthias , Fassunke Jana , Hellmich Martin , Merkelbach-Bruse Sabine , Buettner Reinhard , Wolf Juergen 
Published: May 2019

e20577 Background: Multiple mechanisms of resistance to EGFR TKIs therapy in EGFR-mutant non-small cell lung cancer (NSCLC) have been described, most often including the acquisition of the secondary resistance mutations in exon 20 of EGFR. Preclinical models and clinical findings have also shown that co-occurring activation of the RAS/MEK pathway may result in reduced EGFR dependency, which may be overcome by co-inhibition of MEK. We thus hypothesize that the combined inhibition of EGFR and MEK may restore sensitivity to EGFR inhibition in patients with acquired resistance to EGFR inhibition and may as well prolong the acquisition of resistance in treatment-naïve patients. Methods: EATON is an international, multicenter, phase I, dose escalation investigator-initiated trial investigating the recommended phase 2 dose (RP2D), safety and preliminary efficacy of the combination of the third-generation EGFR inhibitor EGF816 with the MEK inhibitor trametinib (NCT03516214). Eligibility criteria: Advanced NSCLC harboring EGFR del19 or p.L858R, first-line or after failure of any EGFR TKI including osimertinib, independently of p.T790M status. Patients with high-level MET amplification are excluded. Dose level escalation will be based on a modified traditional cumulative 3+3 design, i.e. “up and down” (dose level 1: 100 mg nazartinib (EGF816) QD + 1 mg trametinib QD). A total number of 24 patients is planned to be enrolled in 8 trial sites in Germany and Spain. At a first stage, 18 (6´3) patients will be treated and evaluated. Exploratory endpoints aim at the identification of potential mechanisms of resistance to the trial treatment by massively parallel sequencing (MPS), FISH, phospho-protein analyses and whole exome/genome sequencing of baseline and PD biopsy tumour tissue. Additionally blood samples for MPS of cell free DNA will be collected throughout the trial treatment. Results: At the time of data-cut off for this abstract, one patient received treatment at dose-level 1. Treatment was withdrawn due to a serious, bacterial soft tissue infection of the hand outside the DLT period. Conclusions: Data on safety and tolerability of the combination of nazartinib and trametinib is premature. Updated results will be presented at the conference. Clinical trial information: NCT03516214.
Third and successive–lines of chemotherapy in NSCLC patients without therapeutic targets: Experience of the Grupo Gallego de Cáncer de Pulmón.
Authors: Afonso Afonso Francisco Javier , Fernández Núñez Natalia , Vilchez Simo Rocio , Firvida Jose-luis , De Dios Alvarez Noemi , Campos Balea Begoña , Ruiz Bañobre Juan , Areses Manrique Maria Carmen , Agraso Busto Sara , Carmona Campos Marta , De Paz Árias Laura María , Cameselle Garcia Soledad , Pereiro Corbacho Diego , Vázquez Estévez Sergio , García Mata Jesús , Casal Rubio Joaquin , Constenla Manuel 
Published: May 2019

e20579 Background: The current treatment of advanced non-small cell lung cancer (NSCLC) is conditioned by the presence of molecular and immunohistochemical biomarkers. In the absence of these, the therapeutic option is the use of chemotherapy with or without antiangiogenic agents. The efficacy of non-target systemic treatments is not proven, beyond a second-line and the experiences in their use are limited to retrospective analyzes. We present the experience of the Grupo Gallego de Cáncer de Pulmón in patients with advanced NSCLC treated exclusively with three or more lines of chemotherapy. Methods: Retrospective analysis of patients with advanced NSCLC, treated with three or more lines of chemotherapy in standard regimen, with or without antiangiogenic agents, in Galicia´s hospitals, Spain. Results: We included 168 patients (134 male and 34 female) treated with three or more chemotherapy lines, with a median age at the time of receiving the first-line, of 60.84 years (41-83). Of these, 51 (30,35%) received a fourth-line and 18 (10,74%) a fifth-line of treatment. None received antitarget therapy or immunotherapy. The median overall survival (OS) was 18.1 months. The median OS after the third line was 6.1 months, with 73% of patients alive at three months and 44% six months after the start of that therapeutic line. We did not appreciate differences in OS between those who received three lines and those who received the largest number of subsequent treatments. Our multivariate analysis (age, gender, histology, performance status at initiation of each teatment-line, response to previous treatments) identified that the individuals who benefited the most were those under the age of 60 years, PS-ECOG 0-1 at diagnosis and those with a more durable response to the first-line. Conclusions: The third-line of chemotherapy can benefit those patients with advanced NSCLC, under 60 years of age at the time of diagnosis, with good performance status and with long-lasting responses to the first line of treatment. We did not see benefit in adding fourth or fifth-line of chemotherapy. All data will be presented in the 2019 ASCO annual meeting.
The efficacy of ado-trastuzumab emtansine in patients with HER-2-aberrant non-small cell lung cancer.
Authors: Xia Yang , Huang Xiu , Jin Rui , Li Wen , Shen Huahao 
Published: May 2019

e20584 Background: HER-2 aberrations, including gene mutation, gene amplification and protein overexpression, have been considered as oncogenic driver alteration in non-small cell lung cancer. However, the therapeutic effect of Ado-trastuzumab emtansine (T-DM1) is varied in HER-2 altered lung cancer. Thus, we aim to elucidate the efficacy of T-DM1 in treating different subtypes of HER-2 aberrations by integrating and reanalyzing the data from current available literatures. Methods: We sought published articles, case reports and ongoing studies that reported efficacy of T-DM1 in lung cancer with HER-2 aberration. Seven studies met the systematic review criteria. The main outcomes were the overall response rate (ORR). Results: 93 patients with various HER-2 aberrations were identified in 7 studies. HER-2 upregulation was prone to occurred in the patients with smoking history and adenocarcinoma, without gender difference, while HER-2 mutations were more common in female non-smoker with adenocarcinoma. The overall ORR of HER-2 aberration was 19.35%. Subgroup analysis showed the ORR was 35.00% for sole HER-2 mutation, 42.86% for HER-2 gene amplification, 2.78% for HER-2 protein overexpression, respectively. Of note, ORR was only 8.33% for HER-2 upregulation (protein overexpression and/or gene amplification), while ORR was significantly increased to 46.15% upon concomitant HER-2 upregulation and mutation. Furthermore, ORR was 25.00% for overexpression plus mutation, but ORR was up to 80.00% for gene amplification plus overexpression and mutation. Conclusions: T-DM1 is a promising agent targeting to HER-2 mutant or amplified lung cancers and the therapeutic efficiency might be more pronounced upon HER-2 mutation alone with amplification. Additional studies of this agent are warranted.
The molecular and immune characteristics, antitumor activity of crizotinib in non-small cell lung cancer (NSCLC) patients with MET exon 14 skipping alterations.
Authors: Gan Jiadi , Fang Wenfeng , Feng Weineng , Zhang Jiexia , Deng Huojin , Zhang Lei , Li Yadan , Qian Juanjuan , Luo Hongli , Chen Yanhui , Yang Ying , Zhang Henghui , Zhang Li 
Published: May 2019

e20588 Background: MET exon 14 ( METex14) skipping caused by certain mutations in splice sites of METex14 has been regarded as a promising target for non-small cell lung cancer (NSCLC) treatment with crizotinib, and was observed with lower responsiveness to immunotherapy (Joshua K. et al ASCO 2017). The molecular and immune characteristics, antitumor activity of crizotinib for Chinese NSCLC patients harboring METex14 skipping alterations remain to be elucidated. Methods: Tumor genomic profiling was performed by next-generation sequencing (NGS) assay (GeneCast Biotechnology Co., Beijing) on 9722 samples (FFPE and/or peripheral blood derived from 9289 Chinese NSCLC patients). PD-L1 expression was determined by qualitative immunohistochemical assay. Multiplex immunohistochemistry (mIHC) analysis was adopted to evaluate the immune microenvironment of selected samples. Retrospective analysis was performed to explore antitumor activity of crizotinib monotherapy in 10 patients harboring METex14 skipping alterations. Results: A total of 62 (0.67%) patients with somatic mutations occurred in METex14 splice sites (± 3bp) were identified. Median age of these patients is 64.5 years and 39% patients are female. Main histologic types are adenocarcinoma (81%, 50/62) and squamous carcinoma (13%, 8/62). 30 patients harbored high frequency METex14 mutations ranged from 1.34% to 79.49% nearly without co-existed known driver variants. Other 32 patients had low frequency mutations (below 1%) with some crucial oncogenic mutations such as EGFR 19del/L858R. In addition, very few CD8+ T cells were observed in tumor region and significantly less infiltrated than in stroma region ( P< 0.01). The overall response rate of crizotinib monotherapy on the ten patients with METex14 skipping alterations was 70% (7/10 achieved partial response), with progression free survival range from 3 to 20 months. Conclusions: The occurrence rate of METex14 skipping mutations in Chinese NSCLC patients is low. Low frequency ( < 1%) METex14 mutations usually co-exist with other driver mutations while high frequency METex14 mutations do not. That little infiltration of CD8+ T cells in tumor region might be associated with poor responsiveness of NSCLC patients carrying METex14 skipping alterations to immunotherapy. Our clinical cases exhibited promising antitumor activity of crizotinib in Chinese NSCLC patients harboring METex14 skipping alterations.
Effect of concurrent TP53 mutation in EGFR/ALK/ROS1 positive non-small cell lung cancer treated with first-line TKI therapy: A Single Institution Retrospective Study.
Authors: Sharma Sandhya , Miao Emily , Fishbein Joanna Stein , Lee Chung-Shien , Sullivan Kevin M. , Seetharamu Nagashree 
Published: May 2019

e20592 Background: Tyrosine Kinase Inhibitors (TKI) are the mainstay of therapy for patients (pts) with EGFR/ALK/ROS1 positive (pos) non-small cell lung cancer (NSCLC), however resistance to these drugs is inevitable and remains a clinical challenge. The cause for early resistance leading to progression has not been fully understood, but several mechanisms have been reported. We conducted a retrospective study to determine the impact of concurrent TP53 mutation (TP53m) in this population. Methods: NSCLC pts treated with first line TKI from 01/2014 to 06/2017 were studied. Descriptive statistics were computed. Progression was equated with TKI resistance (TKIr). We compared time to TKIr among pts with TP53m to those without. Standard survival analysis methods (i.e., Kaplan-Meier curves and multivariable Cox proportional hazards regression) were used. Results: Forty-two subjects on first line treatment TKI were included. The mean (SD) age was 67.2 (14.7) years. 37 (88%) were EGFR, 4 (10%) were ALK and 1 (2%) were ROS pos. 76% were female, 50% White, 74% non-smokers and 50% had a TP53m. The estimated median time to TKIr was 19.4 months. At 24 months from start of therapy, the predicted probability of not reaching TKIr was 46% (95% CI: 26-64%). The estimated median time to TKIr among those without TP53m is 19.4 months vs 14.4 months in those with TP53m (p = 0.13). The predicted probability of no TKIr at 12 months from start of therapy among those with and without TP53m were 59% and 80%, respectively. In multivariable analysis, TP53 status remained nonsignificant (p = 0.08) after adjusting for line of therapy. Conclusions: TP53m has been associated with worse prognosis in various cancers. The results from the studies looking at association between TP53m and NSCLC with targetable mutation have been mixed, with few studies demonstrating the association of TP53m with poor survival and earlier treatment resistance. In our study, although there was a tendency towards improved survival and delayed TKIr in the cohort without TP53m, it was not statistically significant, which may be due to small sample size. Further studies looking at concurrent TP53m and targetable mutation are required, which may help clinicians deciding how to direct therapy in this population.
The HGF-MET signaling pathway is enriched in LUAC brain metastases.
Authors: Velez Maria A , Yochum Zachary A. , Chandran Uma R. , Chakka Anish , Bhattacharya Saveri , Somasundaram Aswin , LaFramboise William , Wallweber Gerald , Ravanera Roy , Kurland Brenda F , Dacic Sanja , Stabile Laura P. , Burns Timothy F. 
Published: May 2019

e20597 Background: Brain metastases occur in over 40% of non-small cell lung cancer (NSCLC) patients leading to a poor prognosis. c-Met (MET) is a receptor tyrosine kinase that upon binding hepatocyte growth factor (HGF), mediates proliferation, epithelial-mesenchymal transition (EMT), invasion, angiogenesis and metastasis. We have previously shown that the EMT transcription factor, TWIST1 is required for proliferation in MET driven NSCLC. Therefore, the HGF/MET/TWIST1 pathway may be a significant determinant of metastatic potential to the brain. Methods: We evaluated 125 lung adenocarcinoma (LUAC) brain metastases for MET amplification by FISH as well as other molecular alterations using targeted next generation sequencing in a subset of brain metastases (N = 74) and primary LUAC (N = 171) samples including 13 paired primary and brain sets. MET activation was examined in paired tumors using a HGF-MET proximity binding, dual-antibody assay (VeraTag; Monogram Biosciences). TWIST1 and EMT markers in the paired sets were measured by immunohistochemistry. Results: Compared to primary LUAC, we found that 17 pathogenic variants including TP53, SMAD4, RB1, RET, APC, ALK, FGFR3, EGFR, STK11 and MET alterations were significantly more common in LUAC brain metastases (adj. p values ≤ 0.02). Specifically, MET amplification was significantly enriched in LUAC brain metastases (23/125, 19%) compared to 2-4% in non-brain metastatic and primary sites. Among paired samples, 2/13 brain metastases had MET amplification that was not found in the primary tumor. MET mutations were also present in 16/74 brain cases (22%) compared to 9% (16/171) observed in the lung. VHL mutations were associated with MET altered cases compared to non- MET altered cases. MET expression was increased in the majority of brain metastases compared to the paired LUAC and there were 3 cases with brain specific MET activation. We found that TWIST1 was induced by HGF and determined response to MET TKIs in vitro. Among paired samples, TWIST1 was increased in brain metastases compared to primary LUAC in a subset of cases. Further analyses of TWIST1 and EMT markers is ongoing. Conclusions: Over a third of brain metastases have MET alterations compared to primary LUAC and may be responsive to MET inhibitors.
A phase I open prospective cohort trial of curcumin plus tyrosine kinase inhibitors for EGFR-mutant advanced non-small cell lung cancer.
Authors: Esfahani Khashayar , Boodaghians Levon , Kasymjanova Goulnar , Agulnik Jason Scott , Pepe Carmela , Sakr Lama , Small David I. , Jagoe Tomas R. , Cohen Victor 
Published: May 2019

e20611 Background: An increasing number of patients with lung cancer use natural products concurrently with conventional treatments, one of which is curcumin, or diferuloylmethane, the main ingredient in the popular spice known as curry. Curcumin has been shown to have anti-carcinogenic effects on human lung cancer cell lines and in vivo models, as well as the potential to modulate all three known pathways accounting for resistance to EGFR-TKIs. More specifically, curcumin dose-dependently suppresses EGFR expression, reduces transactivation of the MET oncogene, and reduces inflammation in the tumor microenvironment by selectively inhibiting TGF-β, IL-6, C-reactive protein (CRP) as well as TNF-α. Despite these promising findings, no studies have yet assessed the safety of introducing curcumin alongside EGFR-TKIs in a lung cancer population. Methods: We performed a phase 1 open prospective cohort study to assess the safety and feasibility of using an enhanced bioavailable formulation of curcumin (CURCUViva TM at 80 mg/ 1 capsule per day) approved and licensed by Health Canada (NPN 80027414) in conjunction with an EGFR-TKI in patients with advanced NSCLC (ClinicalTrials.gov: NCT02321293). The primary objective was to determine safety and feasibility. Exploratory objectives were monitoring changes in health-related quality of life using the standardized FACT-L questionnaire and evaluating anti-inflammatory properties of curcumin by measuring CRP. Results: 55 patients were approached, of whom 75% were interested in using curcumin. Completion rate (80%) and adherence (82%) levels were very high; most patients perceived the product as easy to take and were willing to take it again if it were available. Nine patients refused to participate solely due to frequent clinic visits. A total of 37 adverse events were reported, all of which were mild (Grade 1 or 2). The vast majority were pre-existing and related to TKI treatment. No biochemical or hematological evidence of toxicity was observed. Overall, there was improvement in quality of life, and improvement in the LCS of the FACT-L (p = 0.06). There was no significant change in CRP levels. Conclusions: This study provides preliminary evidence that short-term use of curcumin in EGFR-positive patients treated with TKIs is feasible and safe. We report high treatment adherence and improved quality of life with curcumin. These findings, as well as efficacy data and the effect of curcumin on other inflammation-associated biomarkers, warrant investigation in a larger phase 2 study. Clinical trial information: NCT02321293.
Clinical, pathological and molecular characterization of long-term survivors with advanced non-small cell lung cancer in a multicenter experience in Madrid: Final results.
Authors: Moreno Juan , Ponce Aix Santiago , Alvarez Alvarez Rosa Maria , Olmedo Garcia Maria Eugenia , Falagan Sandra , Mielgo Xabier , Navarro FÃ¡tima , Cruz Patricia , Cabezon-Gutierrez Luis , Muñoz Fernandez de Legaria Marta , Enguita Ana Belen , Cebollero Maria , Benito Amparo , Alemany Isabel , Castillo Torres Carolina , Ramirez de Molina Ana , Casado Enrique , Ramos Ricardo , Colmenarejo Gonzalo , Sereno Moyano Maria 
Published: May 2019

e20621 Background: Long survivors (LS) in non-small-cell lung cancer (NSCLC), defined as an overall survival (OS) greater than 2 years, are less than 10% in most series. Classical prognosis factors include stage, weight loss and ECOG, but more information is missing in the literature. Recently, EGFR, ALK and ROS 1 population (less than 20%) reach OS longer than 2 years. Immunotherapy has demonstrated very promising results with more LS compared to chemotherapy in first and second line setting. In this study, we focused in the analysis of LS patients with advanced NSCLC EGFR wt (wild type) and ALK nt (non-translocated), defined as those with OS greater than 36 months, in 7 hospitals in Madrid. Methods: In this serie, first of all, we will try to make a clinical, histopathological characterization collecting data from clinical reports according to a previously defined information. In a second step, we will carry out a genetic analysis of these patient samples comparing to an opposite extreme short survivors (SS) samples (OS less than 9 months). Initially, we used a NGS method of RNA-seq technology to identify differentiating profiles of gene expression between the two opposite populations. And finally, we confirmed this preliminary profile by RT-PCR in the rest of samples. Results: Ninety-six patients were initially included. The majority were men, smokers or former with adenocarcinoma and ECOG 0- 1. We have obtained a differential transcriptome expression between samples from 6 LS and 6 SS, resulting 13 over-expressed and 42 down-expressed genes in LS comparing to SS transcriptome expression. Some of the genes involved in this initial profile belong to different cellular pathways: Secretin Receptor, Surfactant Protein, Trefoil Factor 1, Serpin Family, Ca-bindings Protein channel and Toll like Receptor family. Finally, we carried on by RT-PCR in 40 samples of SS and LS survivors and only four genes were significantly down-regulated in SS compared to LS in the multivariate analysis. These 4 genes were related to Surfactant Proteins: SFTPA1 (p = 0.023), SFTPA2 (p = 0.027), SFTPB (p = 0.02) and SFTPC (p = 0.047). Conclusions: We present a sequential genetic analysis of a LS population with NSCLC EGFR wt (wild type) and ALK nt (non-translocated), obtaining a differential RNA seq- and RT-PCR gene profile based on different surfactant proteins expression. A further confirmation in a larger sample is ongoing.
Clinical outcomes of NSCLC patients with acquired RET rearrangement after resistance to osimertinib.
Authors: Lu Chang , Cheng Jia-Tao , Kang Jin , Yao Yi-Hui , Li Xiang-Meng , Zhang Xuchao , Zhou Qing , Tu Hai-Yan , Wu Yi-Long , Yang Jin-Ji 
Published: May 2019

e20626 Background: Resistance mechanisms to osimertinib have raised growing concerns, but those with acquired RET rearrangement is poorly characterized. Methods: We retrospectively identified advanced, EGFR-mutant NSCLC (non-small-cell lung cancer) patients treated with osimertinib between April 9th, 2015 and November 1st, 2018 at our institute. Clinicopathologic features and clinical outcomes were analyzed. Subsequent genetic profiling was performed at the time of progression by next-generation sequencing (NGS). Overall survival (OS) since 1st line treatment was calculated from first-line treatment start to death or last follow up, and OS post-progression was calculated from osimertinib progression. Median follow-up time was 43.4 months. Results: In the 192 patients treated with osimertinib, 57 had follow-up NGS information after progression, and six harboured acquired RET rearrangement (11%, 6/57). For patients with RET rearrangements when progressed on osimertinib, OS since 1st line treatment (22.9m vs 59.5m, P = 0.021) and OS post-progression (2.1m vs 10.0m, P = 0.031) were significantly shorter compared with non- RET-rearranged cases, whereas no significant difference was found in demographics at the initial lung cancer diagnosis or progression-free survival (PFS) of osimertinib (12.1m vs 5.8m, P = 0.34). Among these six patients, one received best supportive care, two continued to use drugs targeting EGFR but deteriorating soon, three patients tried osimertinib combined with cabozantinib with one benefit from this combination approach. Conclusions: RET rearrangements could exist in EGFR-mutant NSCLC with acquired resistance to osimertinib and linked to inferior survival. Study on the molecular evolution and heterogeneity during treatment course are warranted for further therapeutic strategies. [Table: see text]