bluuebunny/crossref_metadata_2025_split huggingface dataset:
The utilization of pre-treatment neutrophil to lymphocyte ratio as a predictive marker for response to nivolumab therapy in non small cell lung cancer.
Authors: Preeshagul Isabel Ruth , Sullivan Kevin M. , Paul Doru , Seetharamu Nagashree 
Published: September 2018

e20634 Background:The tumor immune environment is integral in lung cancer progression. Cancer cells attract neutrophils through chemokine signaling pathyways into the tumor stroma. Neutrophils promote angiogenesis, metastasis and inhibit apoptosis whereas lymphocytes assist with tumor defense. Increased peritumoral neutrophil-to-lymphocyte ratio (NLR) has been shown to mediate T cell anergy and tumor immune evasion. In solid tumor pre-clinical models, elevated blood NLR correlates with increased tumor neutrophil infiltration and decreased CD3(+) T-cell infiltration. Immunotherapy is a promising anticancer strategy in Non-Small Cell Lung Cancer (NSCLC). We hypothesized that peripheral blood NLR could serve as a predictive marker for clinical benefit (CB) from this intervention. Methods:A single institution retrospective analysis of 81 patients with NSCLC treated with Nivolumab from July 2015 to November 2016. Each patient’s NLR was calculated prior to starting Nivolumab. A cut-off of 5 categorized NLR as high or low based on prior studies. The presence or absence of CB (objective response or stable disease per RECIST 1.1) after at least 3 months of therapy was determined. Descriptive statistics were utilized to summarize the data. Fischer exact test was used to compare proportions and student t test to compare means. Results:79 patients were included. 54 (68%) had low NLR and 25 (31.6%) had high NLR. 44 patients (81.48%) in the low NLR group and 7 (28%) in the high NLR group experienced CB (28%) at 3 months. This difference was statistically significant (P = 0.0001). The mean time to progression(TTP) for the low NLR population was 5.53 months, as compared to 2.39 months in the high NLR group( p = 0.0001) (95% confidence interval 1.59 to 4.55).The mean TTP in the CB cohort was 6.42 months in the low NLR group and 4.43 months in the high NLR group (p = 0.0052 ) (95% CI 0.61 to 3.39). Conclusions:The immune response to cancer is lymphocyte dependent. In our study, the majority of patients with low NLR experienced CB from Nivolumab whereas most of the patients with elevated NLR did not. NLR as a predictive biomarker should be further investigated in large prospective studies.
Costs and values of the immune check point inhibitors antibodies in non-small cell lung cancer.
Authors: Guirgis Helmy M. , Langer Corey J. 
Published: September 2018

e20644 Background: Costs (C) and values (V) of the check point inhibitors antibodies have not been compared. Our objectives were to weigh and compare C and V of Nivolumab (Nivo), Atezolizumab (Atezo) and Pembrolizumab (Pembro) vs. Docetaxel (Doc) in 2nd-line non-small-cell lung cancer (NSCLC). Methods: Median overall survival gain over control (OS), hazard ratios (HR), doses and prices posted by parent companies were quoted. Probability of survival (PoS) was calculated as (1.0- HR). Values were computed at 4-week (w) as 4wC/PoS and one-year as C/life-year gain (LYG). Results: Doc OS was 72 days, HR not reported, generic 4wC < $500 and C/LYG 26,896. In comparison, in non-enriched non-squamous (sq-) Nivo C/LYG was 558,313, Atezo 618,244, Pembro 659,059. Nivo OS was 84, HR 0.73, 4wC $10,021 and 4wV 37,115 improving in > 10% PD-L1 positive to OS 264, HR 0.27 and 4wV 13,727. Atezo OS was 87, HR 0.73, 4wC $11,493 and 4wV 42,567 improving in medium- high PD-L1 to 150, 0.46 and 4wV 21,283 respectively. Pembro demonstrated OS 57, HR 0.71, 4wC $8,027 and 4wV 27,679 improving in > 50% PD-L1 to 201, 0.54 and 4wV 17,450. Conclusions: Doc, without accounting for adverse events and quality of life, remains a valuable drug in 2nd-line NSCLC. In PD-L1- enriched non-sq, Nivo, Atezo and Pembro consistently demonstrated marked V improvement to justify their C. The limited available data and the inherent problems of drug comparison preclude favoring one ICPIA over another. References: Doc: Shepherd FA et al. JCO 18:2095, 2000; Nivo: Checkmate 057, Brahmer JN et al. NEJM 373: 123, 2015; Atezo: POPLAR; Pembro: KEYNOTE-010.
MET exon 14 mutations in advanced lung adenocarcinoma: Frequency and coexisting alterations.
Authors: Bruno Rossella , Lupi Cristiana , Landi Lorenza , Alì Greta , Sensi Elisa , Proietti Agnese , Giannini Riccardo , Condello Vincenzo , Denaro Maria , Giordano Mirella , Macerola Elisabetta , Poma Anello Marcello , Nuti Simona , Niccoli Cristina , Pelliccioni Serena , Tiseo Marcello , Cappuzzo Federico , Fontanini Gabriella 
Published: September 2018

e20656 Background: In lung cancer the evaluation of MET, a tyrosine kinase receptor involved in tumor growth and invasiveness, for copy number amplification and point mutations is relevant for prognosis and therapy. In lung adenocarcinoma (ADC) MET amplification is observed in 1-2% and MET mutations in 3-4% of cases. Mutations mainly occur in exon 14 (ex14), which encodes for the juxtamembrane negative regulatory domain, including splice site alterations and missense mutations within the exon.Commonly, MET ex14 alterations, in particular splice site ones, are mutually exclusive with other driver mutations, but co-occurrence with MET and MDM2 amplification and KRAS mutations was described. We evaluated METex14 mutation frequency and coexistence with additional driver alterations in a prospective cohort of Italian ADC patients. Methods: 315 ADC patients were tested (January-December 2016) for MET ex14 alterations by Sanger Sequencing on formalin-fixed paraffin-embedded tissues and cytological smears (tumor cells > 40%). MET positive cases were screened also for other oncogenes, among which KRAS, BRAF and PIK3CA, using a MALDI-TOF platform, and for ROS1 translocations and MET amplification by FISH. Results: 16 patients (5%) were MET positive: 7 splice site mutations (43%) and 9 (57%) other alterations within ex14. Among splice site mutations 1 co-occurred with ROS1 translocation and 1 with MET amplification. Among other mutations we found 5 T1010I missense mutations: 3 co-occurring with G12D/G13C/Q61H KRAS, 1 with G469A BRAF and 1 with a MET intron 13 point mutation; 2 R988C mutations: 1 with G13C KRAS and 1 with G13C KRAS plus ROS1 translocation; 1 P1026S mutation and 1 frameshift deletion (p.A991del;R992fs*999), both with G12C KRAS. Conclusions: Splice site mutations cause MET activation by exon skipping and increase sensitivity to tyrosine-kinase inhibitors, whereas how other ex14 mutations affect MET function is not fully understood. In our cohort we found a high rate of METex14 mutations together with alterations in other oncogenes, mostly KRAS. The interaction of MET with cancer signaling pathways deserve further investigation in order to better define the role of ex14 mutations in the context of target therapy.
Advancing evidence-based decisions in the management of EGFR-mutated metastatic NSCLC.
Authors: Herrmann Tara , Warters Martin , Blevins Douglas , Fidias Panos 
Published: September 2018

e20663 Background: In patients diagnosed with metastatic NSCLC it is now essential to identify targetable mutations and markers of treatment resistance in order to determine the appropriate therapy. A study was conducted to determine if simulation-based educational interventions to address clinical practice gaps could improve decisions of oncologists in the management of EGFR-mutated metastatic NSCLC. Methods: A cohort of US-oncologists who participated in a virtual patient simulation (VPS)-based education was evaluated. The VPS consisted of 2 cases that allowed oncologists to assess the patient and choose from a database of diagnostic possibilities matching the scope and depth of practice. Clinical decisions were analyzed using a decision engine, and instantaneous clinical guidance (CG) employing current evidence-based and expert faculty recommendations was provided after each decision. Oncologists were allowed a second chance at each decision point and decisions before and after CG were compared using a 2-tailed paired T-test to determine differences from pre- to post CG. P values are shown as a measure of significance; with P < .05 statistically significant. Results: 197 oncologists made clinical decisions within the simulation. As a result of CG, significant improvements were observed in: Ordering EGFR mutational testing (16%, P= 0.008) and making an accurate diagnosis (36%) Selecting an EGFR TKI in the first-line setting (24%, P< 0.001) Ordering a PET scan to assess disease progression (10%) and in diagnosing patients with EGFR T790M disease that is resistant (29% , P< 0.001) Evidence-based treatment selection for individuals whose disease progressed on first-line therapy (19%, P= .003) Number of oncologists who ordered adverse event education and counseling (23%, P< .001) Conclusions: This study showed improvements in evidence-based practices of oncologists in the diagnosis and management of EGFR-mutated NSCLC; demonstrating that VPS-based instruction that immerses and engages oncologists for an authentic, practical and16. consequence-free learning experience can result in an increase in appropriate clinical decisions. Therefore, VPS may have a role in improving the quality of patient care.
LungMATCH: Rates of molecular testing in the lung cancer community.
Authors: King Jennifer C. , Ciupek Andrew , Perloff Tara , Blanchard Ashley , Mason Kimberly , Blais Edik , Bender R Joseph , Halverson David , Madhavan Subha , Petricoin Emanuel 
Published: September 2018

e20671 Background: For metastatic non-small cell lung cancer (NSCLC), guidelines include molecular testing for actionable biomarkers and recommend broad profile testing. Yet previous studies indicate that not all patients with NSCLC receive testing, even for actionable mutations in EGFR, ALK, and ROS. We hypothesized low testing rates for patients calling a community HelpLine and that we could increase rates with one-on-one caller education and free precision medicine services. Methods: Caller statistics were collected on the toll-free Lung Cancer Alliance (LCA) HelpLine from Sept 1, 2016 – Jan 31, 2017. Recruitment to the LungMATCH molecular testing program began Nov 10, 2017. Patients are recruited through conversations on the LCA HelpLine, then consented into Perthera Cancer Analysis (PCA) through an IRB-approved registry protocol. PCA includes tissue acquisition, multi-omic molecular profiling, and medical review of testing results and clinical and treatment history. PCA reports are returned to both treating physicians and patients. Data is being collected longitudinally on treatment decisions, patient outcomes including progression-free and overall survival, and patient experience. Results: Data from the LCA Helpline identified a gap in molecular testing. 50% (57/115) of patients asked if they received any kind of molecular testing replied "No". Of 32 patients who were tested and knew the results, patients indicated potentially actionable changes in EGFR(15), ALK(8), PD-L1(3), RET, MET, BRAF, and HER2, along with KRAS (4). Since LungMATCH launch, 23 interested patients were referred for PCA. Six patients consented and are undergoing PCA with seven more in the consent process. Reasons for non-consent include: doctor refusal, initiation of testing at the treating institution, concern about financial implications, and one death. Updated results will be presented. Conclusions: Our data indicate that patients with lung cancer are not receiving molecular testing in accordance to guidelines. To address this, we created a program through nonprofit-corporate partnership that navigates patients and their physicians through comprehensive precision therapy. This type of program is feasible and there is patient interest.
Phase II trial of AZD1775 in combination with carboplatin and paclitaxel in stage IV squamous cell lung cancer (sqNSCLC): Preliminary results.
Authors: Gray Jhanelle Elaine , Tanvetyanon Tawee , Creelan Ben C. , Antonia Scott Joseph , Haura Eric B. , Williams Charles C. , Yaseen Raheel , Schell Michael J. , Godin Robert , Rix Uwe , Monteiro Alvaro 
Published: September 2018

e20672 Background: WEE1, a dual serine/threonine and tyrosine kinase involved in regulation of the G2/M cell cycle checkpoint, is an essential component for proper DNA damage response. In combination with platinum agents, the inhibition of WEE1 is expected to lead to unstable DNA replication structures, inability to repair DNA damage, loss of G2/M arrest and ultimately mitotic catastrophe. In NSCLC cell lines, we previously demonstrated that cisplatin exhibited enhanced effects in combination with AZD1775 (a WEE1 inhibitor). This trial tests AZD1775 combined with a platinum doublet in patients with sqNSCLC. Methods: In this single-arm phase II trial, patients with stage IV sqNSCLC receive intravenous (IV) carboplatin AUC 5, IV paclitaxel 175 mg/m2, and oral AZD1775 225 mg twice/day for 2.5 days every 21 days for 4-6 cycles followed by maintenance AZD1775 at the same doses. Antiemetics prior to each dose of AZD1775 are mandatory. The primary endpoint is response rate per RECIST v1.1, with overall and progression-free survival as secondary endpoints. Archival tissue specimens are collected for correlative analyses of p53, PAXIP1, and WEE1. Results: Interim analysis of the 15 patients [3/15 (20%) female] enrolled through 11/2016 show 14/15 (93%) were ECOG 1, and 1/9/5 (7%/60%/33%) were never/former/current smokers. The most frequent adverse events of any grade were diarrhea (53%), nausea (40%), and vomiting (33%). The 2 most common grade 3-4 adverse events were neutropenia (13%) and fatigue (20%). No patients required treatment discontinuation due to toxicity. Of the 10 patients evaluable for response, 3 (30%) had confirmed partial responses (PR), 1 (10%) had unconfirmed PR, 5 (50%) had stable disease (SD), and 1 (10%) had progressive disease for a disease control rate of 90%. In those with SD, tumors regressed by -15%, -22%, -23%, -26% and -28% at first scan. Conclusions: AZD1775 combined with carboplatin and paclitaxel is tolerable and demonstrates promising activity in advanced sqNSCLC patients. Nausea and vomiting are manageable with antiemetics. The study continues to enroll. Correlative biomarker analyses of the tissue are planned. More mature data will be presented. Clinical trial information: NCT02513563.
Phase II study of amrubicin plus erlotinib in previously treated, advanced non-small cell lung cancer with wild-type EGFR (TORG1320).
Authors: Hosokawa Shinobu , Bessho Akihiro , Otani Sakiko , Sasaki Jiichiro , Igawa Satoshi , Nakahara Yoshiro , Fukamatsu Nobuaki , Kasai Takashi , Sugiyama Tomohide , Seki Nobuhiko , Nakamura Yukiko , Tokito Takaaki , Masuda Noriyuki , Watanabe Koshiro ,   Thoracic Oncology Reserch Group
Published: September 2018

e20677 Background: Amrubicin (AMR) is a totally synthetic 9-aminoanthracycline and clinically active against non-small cell lung cancer (NSCLC). We found that the combination of AMR and erlotinib (ERL) had significant synergistic effect on NSCLC cell line with wild-type EGFR in vitro. We conducted a phase I study of AMR and ERL combination therapy in previously treated patients with advanced NSCLC, and have already reported the safety and the effectiveness. Furthermore we observed a high response rate of 33% in EGFR wild-type NSCLC. Methods: We conducted a multi-center, single-arm phase II trial to evaluate the efficacy of AMR and ERL combination therapy in patients with previously treated, advanced NSCLC, PS 0-1, and aged < 75 years, EGFR wild type. Patients were treated at 3weeks intervals with AMR(35mg/m2, intravenous injection on days 1-3) plus ERL(100mg/day, once daily on days 1-21). The primary endpoint is progression free survival (PFS). Secondary endpoints are response rate (RR), disease control rate (DCR), time to treatment failure (TTF), overall survival (OS), and toxicity. The concentration of trough ERL was measured after first cycle of treatment as additional investigation. Results: From June 2013 to July 2016, 25 patients were enrolled in this trial. The PFS according to the central test was 3.6 months (95%CI 2.1 - 5.1). The RR and the DCR were 24.0% and 64.0%, respectively. We observed grade 3 or 4 hematological toxicities such as leukopenia (68%), neutropenia (72%), anemia (8%) and febrile neutropenia (12%). The grade 3 or 4 non-hematological toxicities were anorexia (12%), oral mucositis (12%) and rash (8%). We had no treatment related death in this study. Conclusions: The PFS of AMR and ERL combination therapy in this study was superior to that of AMR monotherapy in historical setting. This combination therapy might be an option for previously treated NSCLC patients without a driver oncogene mutation. Clinical trial information: UMIN 000010582. Clinical trial information: UMIN 000010582.
The relationship between metastatic sites and progression free survival of nivolumab in non-small cell lung cancer patients.
Authors: Tamiya Motohiro , Tamiya Akihiro , Suzuki Hidekazu , Inoue Takako , Taniguchi Yoshihiko , Nakahama Kenji , Shiroyama Takayuki , Isa Shun-ichi , Nishino Kazumi , Okamoto Norio , Kumagai Toru , Hirashima Tomonori , Atagi Shinji , Imamura Fumio 
Published: September 2018

e20679 Background: Nivolumab (Nivo) is applicable for all metastatic or unresectable non-small cell lung cancer (NSCLC), however only some patients benefit from it. Therefore, identifying biomarkers predicting efficacy is a crucial topic in the “real world’’ setting. We conducted a retrospective study to analyze the impact of metastatic status on the effect of Nivo in NSCLC patients. Methods: This is a retrospective multicenter study conducted by the three medical centers in Japan. All patients treated with Nivo from January 2016 to July 2016 in these centers were retrospectively reviewed. We collected clinical data including age, sex, smoking history, performance status (PS), and metastatic cites (lymph nodes: lym, liver, brain, bone, pleural effusion, and intrapulmonary metastasis: lung) at the time of starting Nivo treatment. We investigated relationship between metastatic sites and progression free survival (PFS) of Nivo. Patients were followed-up until 30th September 2016. Results: Two hundred and one patients treated with Nivo were enrolled. At the time of administration of Nivo, median age was 68 years old, 137 patients were male, 155 patients had history of smoking status, 152 patients were PS 0 or 1, and 46 patients had squamous cell carcinoma (SQ). For all participants, median PFS was 2.5 months. In univariate analysis, female (hazard ratio (HR): 1.43, 95% confidence interval (CI): 1.02-2.00; p = 0.036), never-smoker (HR: 1.51 , 95% CI: 1.05 – 2.17; p = 0. 0262), PS 2 or more (HR: 1.68, 95% CI: 1.17-2.41; p = 0.0045), metastasis to liver (HR: 2.02, 95% CI: 1.30-3.15; p = 0.0015), brain (HR: 1.42, 95% CI: 0.99-2.03; p = 0.0574), bone (HR: 1.42, 95% CI: 1.01-1.98; p = 0.0642), lung (HR: 1.57, 95% CI: 1.13-2.20; p = 0.0076), and malignant pleural effusion (HR: 1.47, 95% CI: 1.06-2.04; p = 0.0195) had significantly correlated with poor PFS. In multivariate analysis, liver metastasis (HR: 1.59, 95% CI: 0.97-2.61; p = 0.0642) and malignant pleural effusion (HR: 1.47, 95%CI: 1.04–2.07; p = 0.0294) had significantly correlated with poor PFS. Conclusions: Liver metastasis and malignant pleural effusion were independent poor prognostic factors of Nivo treatment in NSCLC patients. (UMIN-ID: UMIN000025908)
The role of positron emission tomography fused with computed tomography (PET/CT) versus CT alone in detecting oligoprogressive disease (OPD) in oncogene-addicted non-small cell lung cancer (NSCLC) receiving tyrosine kinase inhibitor (TKI) therapy.
Authors: Ng Terry L. , Morgan Rustain , Patil Tejas , Barón Anna E. , Camidge D. Ross 
Published: September 2018

e20683 Background: OPD represents limited extra-central nervous system (eCNS) progression. In oncogene-addicted NSCLC, OPD can be treated with local ablative therapy to prolong TKI control. The impact of PET/CT vs CT to detect OPD at first eCNS progression has not been assessed previously. Methods: Patients with metastatic EGFR-mutant (EGFR-MT), ALK or ROS-1 rearranged (ALK+, ROS-1+) NSCLC with eCNS progression on a relevant TKI (2010-2016) were identified. Scan methodology at first eCNS progression was noted and progression was categorized as OPD using 2 definitions (≤ 2 or ≤ 4 progressing lesions) or non-OPD. Median time-to-progression (MTTP) was calculated from start of TKI to first eCNS progression. Data was analyzed using Chi squared and log rank tests as appropriate using p < 0.05 as significant. Results: Sixty-seven patients (EGFR-MT = 37, ALK+ = 28, ROS-1 = 2) were analyzable. OPD (≤ 2 lesions) occurred in 62.5% (20/32) noted by PET/CT vs. 54.3 % (19/35) by CT (p = 0.496). OPD (≤ 4 lesions) occurred in 84.4 % (27/32) noted by PET/CT vs. 65.7 % (23/35) by CT (p = 0.080). MTTP in PET/CT-detected OPD (≤ 2) (N = 20) was 332.5 days vs. 143 days in CT-detected OPD (N = 19) (p = 0.0092). MTTP in PET/CT-detected non-OPD ( > 2) (N = 12) was 185 days vs. 109 days in CT-detected non-OPD (N = 17) (p = 0.0503). MTTP in PET/CT-detected OPD (≤ 4) (N = 27) was 298 days vs. 143 days in CT-detected OPD (N = 23) (p = 0.0128). MTTP in PET/CT-detected non-OPD ( > 4) (N = 5) was 167 days vs. 104.5 days in CT-detected non-OPD (N = 12) (p = 0.1090). Conclusions: In this non-randomized retrospective study the proportion of OPD (≤ 2 or ≤ 4 progressing lesions) at first eCNS progression did not differ significantly for PET/CT vs. CT. MTTP was significantly longer for PET/CT vs CT detected OPD, but not for non-OPD progression. Potentially longer MTTP in the PET/CT OPD subgroup may reflect preselecting patients with disease difficult to detect by CT (e.g., bone/lymph node) which is more indolent. A prospective randomized study is required to assess the true impact of PET/CT vs CT on detecting OPD in oncogene-addicted NSCLC on TKI therapy.