bluuebunny/crossref_metadata_2025_split huggingface dataset:
Trilaciclib (G1T28): A cyclin dependent kinase 4/6 inhibitor, in combination with etoposide and carboplatin (EP) for extensive stage small cell lung cancer (ES-SCLC)—Phase 1b results.
Authors: Rocha Lima Caio Max S. , Roberts Patrick J. , Priego Victor M. , Divers Stephen G. , Thomas Melanie B. , Boccia Ralph V. , Stabler Katie , Andrews Elizabeth , Malik Rajesh K. , Aljumaily Raid , Hamm John Turner , Chiu Vi Kien , Richards Donald A. , Nikolinakos Petros , Hussein Maen A. , Schuster Steven Robert , Hoyer Robert John , Shapiro Geoffrey , Dragnev Konstantin H. , Owonikoko Taofeek Kunle 
Published: September 2018

8568 Background: Chemotherapy (chemo) has significant clinical utility, however consequent damage to hematopoietic stem and progenitor cells (HSPCs) and the immune system may limit activity. If chemo-mediated anti-tumor activity was maximized, while minimizing myelosuppression and immunosuppression, patient outcomes would be improved. Trilaciclib (T) is an intravenous CDK4/6 inhibitor in development to reduce myelosuppression and preserve immune system function during chemo. HSPCs are dependent on CDK4/6 for proliferation. Preclinical data demonstrated that transient T-induced G1 cell cycle arrest renders HSPCs resistant to chemo cytotoxicity, allowing faster hematopoietic recovery, preservation of long-term function, and enhancement of anti-tumor immunity and activity. Methods: Objectives of this ongoing multicenter Phase 1b/2a study are to assess dose limiting toxicities (DLTs), safety, tolerability, hematological profile, PK, and anti-tumor activity of T administered prior to EP. Phase 1b was open-label, dose-finding, and the ongoing Phase 2a is randomized (1:1), double-blind. Eligible pts had confirmed diagnosis of ES-SCLC, adequate organ function, ECOG PS 0-2, no prior chemo, and no symptomatic brain metastases. Results: 19 pts were enrolled in the Phase 1b: 10 pts received T 200 mg/m2 + EP and 9 pts received T 240 mg/m2 + EP. T + EP was well tolerated. 2 pts at T 200 mg/m2 and 1 pt at T 240 mg/m2 experienced asymptomatic DLTs in cycle 1. 2 pts (1 at each dose) had an ANC < 1500 on cycle 2 day 1, delaying the start of cycle 2, and 1 pt at the T 200 mg/m2dose had grade 4 thrombocytopenia. There were no cases of febrile neutropenia or bleeding. PK analysis showed no drug interactions between T and EP. 17/19 pts were evaluable: 1 pt had CR, 14 had PR (confirmed ORR = 88%); 1 pt had SD (clinical benefit rate = 94%). Conclusions: In the Phase 1b part of the study, T + EP was well tolerated. Early activity results are promising with a confirmed objective response rate of 88%. This novel approach allowing the administration of chemotherapy while preserving HSPC and immune system function could potentially improve treatment outcomes for SCLC pts. Clinical trial information: NCT02499770.
Histology determination of lung cancers: A report on genomic profiling of lung cancer of mixing histology.
Authors: Tang Ming , Kalhor Neda , Ramineni Maheshwari , Fujimoto Junya , Zhang Jianhua , Li Jun , Chow Chi-Wan , Mao Xizeng , Song Xingzhi , Little Latasha , Gumbs Curtis , Behrens Carmen , William William N. , Weissferdt Annikka , Lee J. Jack , Swisher Stephen , Heymach John , Wistuba Ignacio Ivan , Futreal Andrew , Zhang Jianjun 
Published: September 2018

8570 Background: Histopathology, largely determined by morphology, plays a critical role in choosing appropriate treatment for lung cancer. The understanding of molecular determination of lung cancer histology is rudimentary. Our recently published data (Zhang, Science, 2014 and Liu, Nature Communications, 2016) have demonstrated that within the same patients with identical genetic background and identical exposure, tumor regions with different morphologic appearances may have very similar genomic profiles while tumors with the same morphology may have distinct genomic landscape. Methods: We collected 12 lung cancers of mixing histology with 2 to 4 histologic components within each tumor. In total, 26 tumor regions including 9 adenocarcinomas, 6 large-cell neuroendocrine carcinoma, 6 small cell carcinomas and 4 squamous cell carcinomas and one poorly differentiated lung carcinoma were microdissected and subjected to whole exome sequencing. Results: A substantial number of identical mutations were shared between different histologic components within the same tumor in all 12 patients. However, the proportion of shared mutations varies in different patients ranging from as little as 4% to as much as 99%. Mutation spectrum is also similar between different histologic components within the same tumors suggesting similar mutational process in place. Identical canonical cancer gene mutations including TP53, KRAS, PIK3CA, SOS1 and STK11 are generally shared between different histologic components within the same tumors. Canonical mutations in FBXW7 and MTHFR were detected in squamous component, but not small-cell component in one patient. Conclusions: Different histologic components of lung cancers of mixing histology are likely derived from the same progenitor cells, but the molecular timing of branch separation of subclones giving rise to different histologic components varies in different tumors. Although genomic aberrations may play a role in a subset of tumors, histologic features may not be determined at genomic level for most lung cancers. Gene expression and methylation analyses from these tumors are underway.
Efficacy and safety of lorlatinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) with one or more prior ALK tyrosine kinase inhibitor (TKI): A phase I/II study.
Authors: Shaw Alice Tsang , Ou Sai-Hong Ignatius , Felip Enriqueta , Bauer Todd Michael , Besse Benjamin , Gadgeel Shirish M. , Camidge D. Ross , Lin Chia-Chi , Seto Takashi , Soo Ross A. , Chiari Rita , James Leonard P. , Clancy Jill S. , Martini Jean-Francois , Abbattista Antonello , Pithavala Yazdi K. , Solomon Benjamin J. 
Published: September 2018

9006 Background: Lorlatinib is a selective, potent, brain-penetrant, next generation ALK/ROS1 TKI active against most known resistance mutations. In Ph I of this Ph I/II study, lorlatinib showed robust clinical activity in ALK+ or ROS1+ advanced NSCLC pts, most of whom had CNS metastases (mets) and were heavily pre-treated. In Ph II of this study, efficacy was explored based on prior ALK TKI tx as well as safety across all patients treated at the recommended Ph II dose. Methods: In this ongoing Ph II study (NCT01970865), pts with ALK+ or ROS1+ NSCLC, ± asymptomatic untreated or treated CNS mets, were enrolled into 6 expansion cohorts (EXP) based on prior tx (EXP 1-5, ALK+) and rearrangement status (EXP 6, ROS1+). Pts received lorlatinib 100mg QD. Primary objective was ORR and intracranial ORR (IC-ORR) by independent central review (ICR). Results: Efficacy (ALK+ pts with prior tx): At data cut-off (15 Aug 2016), 82 ALK+ pts were enrolled in cohorts EXP 2-5, received C1 no later than 31 Mar 2016 and were evaluated for ORR (ITT population); 52 were evaluated for IC-ORR and 35 were evaluated for IC-ORR response based on target lesions only (≥5mm; no prior radiotherapy or progression post prior radiotherapy). Confirmed response rates by ICR are reported in the table below. Safety (all pts): 116 ALK/ROS1+ pts were evaluated for safety at data cut-off. Most common tx-related AEs (TRAEs) and grade 3/4 TRAEs were hypercholesterolemia (90%, 17%) and hypertriglyceridemia (72%, 17%). Dose interruptions and reductions due to TRAEs were reported in 29% and 20% of pts, respectively. 14% of pts had tx-related SAEs. 5 pts (4%) discontinued tx due to TRAEs and there were no tx-related deaths. 74/116 pts (64%) remain on tx. Conclusions: Lorlatinib showed compelling clinical activity, with substantial IC activity, in ALK+ pts who received ≥1 prior ALK TKI, many of whom were heavily pre-treated. Clinical trial information: NCT01970865. [Table: see text]
KEYNOTE-001: 3-year overall survival for patients with advanced NSCLC treated with pembrolizumab.
Authors: Leighl Natasha B. , Hellmann Matthew David , Hui Rina , Carcereny Costa Enric , Felip Enriqueta , Ahn Myung-Ju , Eder Joseph Paul , Balmanoukian Ani Sarkis , Aggarwal Charu , Horn Leora , Patnaik Amita , Gubens Matthew A. , Ramalingam Suresh S. , Lubiniecki Gregory M. , Zhang Jin , Piperdi Bilal , Garon Edward B. 
Published: September 2018

9011 Background: Pembrolizumab (pembro) is approved as first-line (1L) treatment for advanced NSCLC patients (pts) with PD-L1 tumor proportion score (TPS) ≥50% and as treatment for previously treated advanced NSCLC pts with PD-L1 TPS ≥1%. Here we present 3-y OS results for pts enrolled in KEYNOTE-001 (NCT01295827), the first trial evaluating pembro in advanced NSCLC pts. Methods: 550 pts received pembro 2 or 10 mg/kg Q3W or 10 mg/kg Q2W until intolerable toxicity, progression, or investigator or pt decision to withdraw. PD-L1 expression was assessed by IHC using the 22C3 antibody. Survival was assessed every 2 mo after treatment discontinuation. Results: 550 advanced NSCLC pts enrolled; 101 were first line (1L), and 449 were previously treated. As of the Sept 1, 2016, data cutoff, median follow-up duration was 34.5 mo (range, 25.7-51.5 mo); 8 (7.9%) 1L pts and 28 (6.2%) previously treated pts were still on treatment. 3-y OS was 26.4% (95% CI, 14.3%-40.1%) in 1L pts and 19% (95% CI, 15.0%-23.4%) in previously treated pts. 3-y OS rate and median OS by PD-L1 status are in the Table. Additional description of the pts with long-term survival, including updated safety data as well as 3-y OS by smoking history, histology, EGFRstatus, and prior radiation therapy, will be presented. Conclusions: Pembro provides promising long-term OS benefit for 1L and previously treated advanced NSCLC pts expressing PD-L1. The current data represent the longest efficacy and safety follow-up for pts with advanced NSCLC treated with pembro. Clinical trial information: NCT01295827. [Table: see text]
MET amplification (amp) as a resistance mechanism to osimertinib.
Authors: Piotrowska Zofia , Thress Kenneth Stephen , Mooradian Meghan , Heist Rebecca Suk , Azzoli Christopher G. , Temel Jennifer S. , Rizzo Coleen , Nagy Rebecca J , Lanman Richard B. , Gettinger Scott N. , Evans Tracey L. , Hata Aaron N. , Shaw Alice Tsang , Sequist Lecia V. 
Published: September 2018

9020 Background: Osimertinib (osi) is an EGFR T790M inhibitor. Mechanisms (mech) of acquired resistance (AR) are under study. We report a cohort of osi-AR pts with extensive pre/post-osi tissue and plasma. Methods: We analyzed 23 pts with AR to osi. Tumor biopsies (bx) underwent NGS (SNaPshot, MGH) and FISH for EGFR, MET amp (target:CEP7 > 2.2.) Plasma underwent ctDNA NGS (Guardant360). Results: Of the 23 osi-treated EGFR-mutants (13 with EGFR del19, 10 L858R), 2 had de novo T790M, 21 acquired T790M. 13 had prior 3rd gen EGFR TKIs before osi - rociletinib(11), ASP8273(1), EGF816(1). Median time on osi was 12 mo (range 2-25), med total time on 3rd-gen EGFR TKIs was 18 mo. Bx types were tissue (16), plasma (18), and both (11, med interval 31d). All pts retained their founder EGFR mutation, but 15/23 (65%) “lost” T790M post-osi, suggesting AR arose from a T790wt subclone (Table). Common AR mech were MET amp (7/23; 30%) and EGFR C797S (5/23; 22%). 1 pt each had SCLC transformation, PIK3CA E545K/PIK3CA amp and FGFR1 D60N/FGFR1 amp. 2 pts had 2 distinct post-osi tissue bx showing heterogeneity. Pt 8 had plasma and a lung nodule with C797S/T790M while a mediastinal LN was wt at both loci. Pt 22 had MET-amp in pleural fluid but no MET amp on lung bx. Plasma identified AR mech not seen in tissue in 2/11 pts with both bx types. Among 7 pts with MET amp, 3 received combo EGFR/ MET TKI; all 3 had a RECIST PR. Conclusions: In this osi-resistant cohort, we commonly saw MET amp (30%) and C797S (22%). MET amp seems more common post-osi than after 1st-line TKIs, and 3/3 pts responded to EGFR+MET TKIs. AR heterogeneity was seen in 2 pts with matched tissue/plasma and 2 with >1 tissue bx, underscoring the complementary roles of plasma and tissue. [Table: see text]
NGS to reveal heterogeneity between cerebrospinal fluid and plasma ctDNA among non-small cell lung cancer patients with leptomeningeal carcinomatosis.
Authors: Jiang Ben-Yuan , LI Yangsi , Chuai Shaokun , Zhang Zhou , Yang Jin-Ji , Zhong Wenzhao , Zhou Qing , Wu Yi-Long 
Published: September 2018

9022 Background: In current clinical setting, NSCLC patients harboring specific driver mutation were usually treated guiding by prior profiling of the primary tumor when developed to brain metastasis. Some studies have shown that circulating tumor DNA (ctDNA) derived from cerebrospinal fluid (CSF) can reveal unique genomic alterations present in brain malignancies. We assessed CSF as a liquid biopsy media and compared to matched plasma. Methods: We performed capture-based ultra deep sequencing on ctDNA derived from matched CSF, plasma of 40 non-small cell lung cancer (NSCLC) patients with suspected leptomeningeal carcinomatosis (LC) using a panel consisting of 168 genes. Results: Among the 40 suspected LC cases, 35 were confirmed to have LC, ctDNA in CSF from the 5 non-LC cases are all undetectable. Circulating tumor DNA was detected in 93.8% of CSF and 66.7% of plasma. We compared mutation profiles and identified 86 and 46 SNVs from CSF and plasma, respectively, with 42 SNVs overlapping. Furthermore, ctDNA from CSF revealed many copy number variations (CNVs) that were not detected from plasma (189 CNVs vs. 3 CNVs). The average maximum allelic fraction (AF) of CSF ctDNA is significantly higher than in plasma (56.7% vs. 4.4% p < 10^-6). Twenty-eight patients were pre-treated with EGFR-TKIs and developed subsequent resistance. EGFR T790M and MET amplification were detected in 21% and 39% in CSF, respectively, showing a unique resistance profile among leptomeningeal metastases patients compared to the general population. Interestingly, 60% of CSF samples harbor TP53 loss of heterozygosity, only 11% of which were detected in the matched plasma samples. Such heterogeneity may reflect unique biological themes for brain metastatic tumor sub-clones. Furthermore, 26 patients received molecular targeted therapy based on the results from CSF, and 23 reported alleviation of symptoms at subsequent evaluations. Conclusions: Collectively, our data reveal that ctDNA derived from CSF provides a unique and more comprehensive characterization of genomic alterations of leptomeningeal carcinomatosis than plasma, supporting the importance of CSF as a liquid biopsy media.
Evaluation of stored liquid biopsies for molecular profiling in patients with non-small cell lung cancer (NSCLC).
Authors: Bradbury Penelope Ann , Ding Keyue , Ellis Peter Michael , Seymour Lesley , De Kievit Frank , Jones Greg , Morris Clive D. , Green Emma , Goss Glenwood D. , Tsao Ming Sound , Shepherd Frances A. 
Published: September 2018

9024 Background: Molecular profiling is often limited by access to sufficient tumour tissue for comprehensive analysis and due to tumour heterogeneity, the complete range of tumor DNA abnormalities may not be represented nor accurately reflect the clinical evolution of disease. Circulating tumour DNA (ctDNA) can be used as a liquid biopsy for molecular abnormalities detection, quantification and monitoring for personalised treatment strategies. Methods: Plasma was collected at baseline (BL) and during study therapy from advanced NSCLC patients (pts) enrolled in a placebo controlled phase III trial of a novel irrerversible EGFR inhibitor; all patients had received standard therapy with chemotherapy and gefitinib or erlotinib. Archival tissue was collected when available but biopsy was not required prior to enrolment. BL Plasma ( < 3ml), stored for ~8 years was used to extract DNA and analysed using InVision (enhanced tagged-amplicon sequencing). Results: BL plasma from 387 pts was tested; 289 pts had available tissue results (from archival tissue collected at diagnosis) for EGFR (174WT/115Mut) and 243 for KRAS (205WT/38Mut). Despite age of plasma samples, ctDNA analysis detected cancer mutations in 310 pts (82%): TP53 (45%), KRAS (15%), and EGFR (43%; 56% were EGFR del19 and 29% L858R); T790M was detected in 80 patients. EGFR mutations were identified in 29 patients and KRAS in 10 patients with unknown tissue status. Also of note, STK11 (32 pts, 12 with KRAS), BRAF (5pts, 3 with V600E), MET(7 pts, 4 with METamp), ERBB2 (16pts, 10 with ERBB2amp) were identified in ctDNA analysis. Median time and median number of lines of systemic therapy between tissue biopsy and blood was 714 days and 3 lines respectively. Further analyses of ctDNA analyses in context of patient and trial outcomes are in progress. Conclusions: Liquid biopsies provide opportunity to evaluate molecular mutation profile in NSCLC patients. We demonstrate a highly sensitive method for ctDNA analysis which is complementary to tissue molecular analysis.
The predictive value of uncommon EGFR mutation in patients with non-small-cell lung cancer.
Authors: Tu Haiyan , Ke Ee , Sun Yue-Li , Zheng Ming-Ying , Yang Jin-Ji , Wang Zhen , Wu Si-Pei , Su Jian , Zhang Xuchao , Bai Xiao-Yan , Yang Xue-Ning , Zhong Wenzhao , Yan Hong-Hong , Zhou Qing , Wu Yi-Long 
Published: September 2018

9028 Background: Non-small-cell lung cancers with uncommon epidermal growth factor receptor ( EGFR) mutations are regarded as a heterogeneous group with variable responses to EGFR-targeted drugs. Here we designed this retrospective study to describe the epidemiology and clinical outcomes of uncommon EGFR mutations in a Chinese cohort of lung cancer patients. Methods: Between June 2007 and June 2014, 5363 lung cancer patients whose EGFR genotyping was performed successfully at Guangdong Lung Cancer Institute (GLCI, Guangzhou, China) were screened. 1837 patients were included in the epidemiological analysis. The clinical outcome was analyzed in 97 advanced-stage patients harboring uncommon EGFR mutations with follow-up data. Results: 218 patients harbored uncommon EGFR mutations, making up 11.9% of all cancers with documented EGFR mutations. Compared with common mutants, those with uncommon mutations were more commonly found in smokers and male patients. The most frequently detected uncommon mutations were exon 20 insertions, G719X mutations and L858R complex mutations, occurring in 30.7%, 21.1% and 17.0% of all EGFR-uncommon-mutation cases. G719X and L858R complex mutations were associated with similar benefit from EGFR-TKI; median PFS was 15.2 (95% CI 8.7-21.7) and 11.6 (95% CI 3.6-19.6) months, respectively. T790M or 20INS was associated with a poorer EGFR-TKI response; median PFS was 1.0 (95% CI 0.0-2.2) and 3.0 (95% CI 1.3-4.7) months, respectively. Of note, two patients with 23% and 65% tumor shrinkages had N771_P772insN and H773_V774insQ, with PFS of 5.7 and 6.1 months respectively. Conclusions: Favorable responses were observed in specific subtypes including complex L858R and G719X, and our results suggested first-line EGFR-TKI should be preferable in such patients.
The novel detection of EGFR-T790M mutations in exhaled breath condensate.
Authors: Smyth Robert , Toomey Sinead , Sartori Alexander , Hanrahan Emer O. , Cuffe Sinead , Murray Hazel , McDonnell Deirdre , Breathnach Oscar S. , Finn Stephen P. , Grogan William , Morris Patrick G. , Morgan Ross , Hennessy Bryan 
Published: September 2018

9032 Background: The EGFR-T790M somatic mutation is the most common mechanism of resistance to Tyrosine Kinase Inhibitors (TKI) in NSCLC. However patients with advanced disease are not always amenable to repeat biopsy for further molecular analysis. Developing non-invasive methods to detect T790M in cell-free DNA (cfDNA), in the absence of tissue is being actively investigated. Furthermore these 'liquid biopsies' may also overcome the problem of tumour genomic heterogeneity. Unfortunately the sensitivity of plasma for T790M detection has been disappointing with a significant chance of a false negative result. Exhaled breath condensate (EBC) is an easily collected sample and is known to harbour cfDNA, including lung cancer mutations. We explored the potential of EBC as a novel method of T790M detection. Methods: We recruited 26 patients who were either 1) known T790M positive pre/during Osimertinib therapy or 2) other mEGFR positive patients on 1st/2nd generation TKI. We collected matched plasma and EBC samples in the majority of cases. EBC samples were collected using the RTube device. Plasma was collected using standard EDTA tubes and extracted within 90 minutes. Using UltraSEEK chemistry, a targeted PCR for ultra-sensitive somatic mutation profiling on the MassARRAY system (Agena Bioscience), we compared the performance of EBC to plasma for the detection of T790M. Results: See Table. Conclusions: In this pilot study we describe the first ever report of the successful and consistent detection of T790M in the EBC of patients with EGFR mutated NSCLC, using a commercially available targeted assay. Our results suggest EBC is responsive to recognised dynamic molecular changes that occur on TKI treatment. We believe this makes EBC analysis an attractive avenue for future research, to optimise the detection of T790M mutations in liquid biopsies. [Table: see text]
EGFR analysis of 21,039 patients with NSCLC: Age-related gradual increase of the L858R mutation frequency in adenocarcinomas and high occurrence of ex19del/L858R mutations in squamous cell carcinomas from females and/or nonsmokers.
Authors: Imianitov Evgenii , Demidova Irina , Gordiev Marat , Filipenko Maxim , Kekeeva Tatiana , Moliaka Yuri , Gervas Polina , Kozhemyako Valeriy , Vodolazhsky Dmitriy I. , Aleksakhina Svetlana , Kharitonova Ekaterina , Tsimafeyeu Ilya , Tjulandin Sergei 
Published: September 2018

9040 Background: EGFR testing in Russia is carried out upon the patronage of Russian Society of Clinical Oncology (RUSSCO), and the results are accumulated in a centralized database. Squamous cell carcinomas (SCC) constitute 60-70% of NSCLC incidence in Russia, however physicians are often discouraged to send NSCLC-SCC for EGFR testing due to low frequency of mutations. Methods: We considered all NSCLC patients analyzed by means of PCR for the presence of EGFR mutations (ex19del and L858R) within years 2012-2017. Results: 21,039 NSCLC patients were tested. EGFR analysis was successful in 20,768 patients (98.7%). EGFR mutations were detected in 3566/17717 (20.1%) adenocarcinomas (AdCa) of the lung (ex19del: 2203 (12.4%); L858R: 1363 (7.7%)). There was an evident age-related increase in the frequency of L858R substitution in AdCa patients (p =0.000, Table). This set of patients included 1,139 NSCLC-SCC cases, and the EGFR mutation was observed in 41 (3.6%) subjects. Among 189 females with NSCLC-SCC, ex19del or L858R were detected in 25 (13.2%) cases. Stratification by smoking status revealed EGFR mutation in 19/242 (7.9%) non-smokers. Conclusions: Elderly NSCLC patients have particularly increased probability to be diagnosed with L858R mutation. In the real-world setting, patients with NSCLC-SCC may have high frequency of EGFR mutations, either due to imprecise histological subtyping or due to yet unknown reasons. All female and non-smoking patients with NSCLC have to undergo EGFR testing irrespectively of tumor histology. [Table: see text]