bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and efficacy of nintedanib (BIBF 1120) plus pemetrexed in Japanese patients with advanced or recurrent non-small cell lung cancer (NSCLC): A phase I study.
Authors: Daga Haruko , Takeda Koji , Okada Hideaki , Miyazaki Masaki , Ueda Shinya , Kaneda Hiroyasu , Okamoto Isamu , Yoh Kiyotaka , Goto Koichi , Konishi Koichi , Sarashina Akiko , Yagi Nobutaka , Mera Kiyomi , Kaiser Rolf , Nakagawa Kazuhiko 
Published: March 2020

8056 Background: Nintedanib (N) is a potent, orally bio-available triple angiokinase inhibitor that targets VEGFRs, PDGFRs and FGFRs, as well as RET and Flt3. The open-label phase I part of this phase I/II study was designed to determine the maximum tolerated dose (MTD) of N when combined with standard-dose pemetrexed (PEM), and to investigate safety and efficacy in Japanese patients (pts) with advanced/recurrent NSCLC. Methods: Eligible pts had histologically/cytologically confirmed stage IIIB/IV or recurrent NSCLC (any histology) after failure of first-line chemotherapy. Pts received PEM 500 mg/m2 iv on day 1 followed by N twice daily (bid) po on days 2–21 every 21 days using a standard 3+3 design. N was started at 100 mg bid and escalated to 200 mg bid in 50 mg bid intervals. Pts received ≥4 cycles of combination therapy with an option of continuing with single-agent N until disease progression or undue adverse events (AEs). Primary endpoints were MTD, defined as the highest dose at which incidence of dose-limiting toxicities (DLTs) was <33.3%, and safety. DLTs were defined as grade 3 non-hematologic or grade 4 hematologic AEs. Secondary endpoints included objective tumor response and pharmacokinetics (PKs). Results: 18 pts (14 male) were treated: 3 at N 100 mg bid, 6 at N 150 mg bid, and 9 at N 200 mg bid. DLTs were observed in 0/3, 1/6, and 2/9 pts in each cohort, respectively; 2 of these pts had liver enzyme elevations. The MTD for N (plus PEM) was 200 mg bid. The most common drug-related AEs were increased GGT, increased AST, decreased appetite, and diarrhea. Grade 3 AEs included neutropenia (22.2%), increased AST, increased ALT, and lymphopenia (each 11.1%); no pts experienced grade 4/5 AEs. Two pts (11.1%) achieved a partial response and 12 (66.7%) had stable disease. At the MTD, N exposure after PEM administration was similar to that seen with N monotherapy in a previous Japanese study. Co-administration of N did not affect the PKs of PEM. Conclusions: The combination of N and standard-dose PEM had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese pts with advanced/recurrent NSCLC. As in Caucasian pts, the MTD of N was 200 mg bid. Clinical trial information: NCT00979576.
Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined non-small cell lung cancer (NSCLC) patients.
Authors: De Greve Jacques , Moran Teresa , Graas Marie-Pascale , Galdermans Daniella , Vuylsteke Peter , Canon Jean-Luc , Chand Vikram K. , Fu Yali , Massey Dan , Vansteenkiste Johan 
Published: March 2020

8063 Background: EGFR mutation+ (M+) NSCLC pts have an improved response to EGFR TKIs vs non-M+ pts. Data on EGFR FISH+ (gene amplified) and HER2 M+ pts are, however, limited. Afatinib is an irreversible ErbB Family Blocker with efficacy in Ph II/III trials in EGFR M+ NSCLC. This exploratory, open-label trial assessed afatinib in 3 genotypically and demographically defined NSCLC groups. Methods: Never/ex-smokers with stage IIIB/IV lung adenocarcinoma with EGFR M+ tumors who had failed prior EGFR TKIs, HER2 M+ tumors independent of prior therapy, or EGFR FISH+ tumors who received ≤3 prior chemotherapies were enrolled. Afatinib 50 mg qd was administered until disease progression or intolerable adverse events. Tumor assessments (RECIST 1.0) were performed every 8 wks. Pts who progressed on afatinib but experienced clinical benefit could continue treatment with afatinib 40 mg qd + paclitaxel 80 mg/m² qw on days 1, 8 and 15 every 28-day cycle. Primary endpoint: Confirmed objective response. Results: 41 pts were treated: 63% female; median age 63 yrs; 68% never smokers; 32% ex-smokers. 33 pts received afatinib monotherapy only; 8 pts received afatinib followed by afatinib/paclitaxel combination therapy. 78% (n=32) of pts were EGFR M+, 5% (n=2) were EGFR FISH+ and 17% (n=7) were HER2 M+. For afatinib monotherapy, 1 confirmed partial response (PR) was observed (EGFR FISH+), stable disease (SD) was seen in 5/7 HER2 M+, 2/2 EGFR FISH+ and 17/32 EGFR M+ pts, and overall disease control (DC) rate was 59% (n=24); mean duration of DC was 26 wks.Median PFS was 16 wks (17 wks in HER2 M+ pts). Of 8 afatinib/paclitaxel-treated pts, 1 had a confirmed PR and 2 had SD; median PFS was 7 wks. Most frequently reported drug-related AEs in afatinib monotherapy pts were diarrhea (n=39; grade ≥3 n=13), rash/acne (n=33; grade ≥3 n=4) and stomatitis (n=19; grade ≥3 n=2). In the combination arm these were diarrhea (n=4; grade ≥3 n=1) and nausea (n=3; grade ≥3 n=0). Conclusions: Efficacy of afatinib in EGFR M+ NSCLC pts has been established in previous trials. Novel activity of afatinib in HER2 M+ and EGFR FISH+ NSCLC pts has been demonstrated here, with a manageable safety profile of afatinib in the overall population. Clinical trial information: NCT00730925.
Whole-exome sequencing in tumor samples from sequenom-wild-type, ALK negative stage IV lung adenocarcinoma (ADC) patients (p).
Authors: Felip Enriqueta , Caratu Ginevra , Silberschmidt Daniel , Martinez Pablo , Martinez Marti Alex , Cedres Susana , Murtra-Garrell Nuria , Navarro-Mendivil Alejandro , Prudkin Ludmila , Jimenez Jose , de la Morena Pilar , Canela Mercedes , Nuciforo Paolo , Palmer Hector G. , Vivancos Ana 
Published: March 2020

8070 Background: The majority of lung ADC tumors are characterized by specific genetic features with KRAS mutations (mut) seen in 20-30%, EGFR mut in 15%, EML4-ALK translocations in 5%, and ERBB2 mut in 2%, among others. Some of these genetic alterations are already being used for selecting targeted therapies. However, identification of additional genomic alterations is required. Methods: In the present ongoing study we perform whole-exome sequencing in paraffin-embedded tumor samples from OncoCarta v1.0 panel wild-type (no mut in hotspots of KRAS, EGFR, ERBB2, AKT1, BRAF, PIK3CA genes) and ALK negative (by FISH) stage IV ADC lung cancer p, and in their matched normal tissue samples. Results: To date, a total of 7 tumors and matched normal tissues have been successfully analyzed. We have detected mut in previously identified ADC genes, such as ERBB2, CTNNB1, TP53, SMAD4 or APC. Interestingly, mut were found in genes belonging to the proposed new cancer hallmark ‘epigenetic and RNA regulation’, such as BRD3, EPC1, PHF1 in almost every p included in our study. Regarding alterations that could be considered relevant for lung tumor pathogenesis/growth or as potential targets for treatment therapies, we were able to identify candidates in 4 of the 7 p. In one p, a case of a transmembrane domain ERBB2mut in exon 20 (p.E770delinsEAYVM) not previously detected by the OncoCarta v1.0 panel (that interrogates L755P, G776S/L/V/C, A775_G776insYVMA, P780_Y781insGSP, S779_P780insVGS mut) was found. In another p, three somatic mut in the BRCA1/2 genes were detected. Additionally, one p had an ALK point mut (p.P336K), for which no functional information is available, together with an APC mutation. In the remaining p, a non-hotspot mutation (although previously detected in a colorectal tumor) was found in CTNNB1. Conclusions: In this limited experience of whole-exome sequencing of a subgroup of stage IV lung ADC p, potentially targetable alterations not formerly detected by other techniques were found. We believe that genomic approaches to detecting alterations may be useful in clinical practice and will hopefully provide assistance in making treatment decisions.
First-line pemetrexed plus cisplatin followed by maintenance pemetrexed versus carboplatin-paclitaxel plus bevacizumab followed by maintenance bevacizumab (ERACLE) in advanced nonsquamous NSCLC: A quality-of-life-oriented, multicenter randomized phase III trial of the GOIM (Gruppo Oncologico Italia Meridionale).
Authors: Galetta Domenico , Pisconti Salvatore , Cinieri Saverio , Gebbia Vittorio , Morabito Alessandro , Borsellino Nicolo , Maiello Evaristo , Febbraro Antonio , Catino Annamaria , Rizzo Pietro , Montrone Michele , Simone Giovanni , Lorusso Vito , Rizzi Daniele , Pappagallo Giovanni L. , Colucci Giuseppe 
Published: March 2020

8071 Background: In absence of oncogenic driver chemotherapy (CT) for advanced non-squamous non-small cell lung cancer (NS-NSCLC) remains palliative with similar efficacy and survival among different regimens. Histotype, maintenance therapy (m) and quality of life (QoL) have been explored to improve patients (pts) outcome. ERACLE trial (NCT01303926), a QoL-oriented phase III trial was designed to compare the QoL for two CT regimens. Methods: Pts with stage IIIB/IV NS-NSCLC (ECOG 0/1) were randomized (1:1) to receive first-line CT. ARM A received 6 cycles of Cisplatin (C) (75 mg/m2) - Pemetrexed (P) (500 mg/m2) q3w, followed by mP (500 mg/m2) while ARM B received Carboplatin (Cb) AUC 6 - Paclitaxel (T) 200 mg/m2plus Bevacizumab (Be) 15 mg/kg q3w for 6 cycles and mBe 15 mg/kg. Both treatments were administered until progression, unacceptable toxicity or death. Stratification was based on Study Centre and disease stage. Co-Primary endpoints were EQ5D Index (EQ5D-I) and EQ5D-VAS (Euro-QoL questionnaire) at 12 weeks during m. Secondary endpoints were QoL over time, activity and safety of CT arms. A sample of 49 pts per arm (not progressed during initial CT and during m therapy for at least 12 weeks) will have 91% chance to have 12-point Minimal Interesting Difference (MID) between arms for EQ5D-VAS, and 87% chance to find 0.137 MID between arms for EQ5D-I. It is assumed that about 20% of pts in both arms experienced a PD before to evaluate primary endpoint. The study sample was then increased to 118. Results: From 1/2011 to 3/2012, 118 pts were randomized to CP (n=60) or CbTBe (n=58). Baseline demographics were well balanced across arms; overall 74% male, 79% PS 0 and 94% stage IV. Treatment differences (mean change from baseline), EQ5D-VAS = 1.82 (95%CI -8.60 to 12.24; P=0.73), EQ5D-I = 0.15 (95%CI 0.01 to 0.29), favoured arm A. Conclusions: CP-mP showed better (over the MID) health profile (EQ5D-I) at 12 weeks as compared to CbBe-mBe. EQ5D-VAS didn’t find any significant difference between treatment arms. Clinical trial information: NCT01303926.
KRAS subset analysis from randomized phase II trials of erlotinib versus erlotinib plus sorafenib or pazopanib in refractory non-small cell lung cancer (NSCLC).
Authors: Waterhouse David Michael , Stults Dawn Michelle , Daniel Davey B. , Griner Paula L. , Greco F Anthony , Burris Howard A. , Hainsworth John D. , Spigel David R. 
Published: March 2020

8091 Background: KRAS mutations are among the most common genetic alterations in NSCLC; however no targeted therapies have been approved to benefit this lung cancer subset. Between 2/2008 and 2/2011 our center conducted two consecutive multicenter randomized phase II trials in patients (pts) with refractory NSCLC comparing erlotinib/placebo versus erlotinib + either sorafenib or pazopanib, both oral multikinase inhibitors (Spigel et al, JCO 2011; Chicago MSTO 2012). Progression-free survival (PFS) was improved with the multikinase regimens in the EGFR wild-type (WT) subsets, but not in the overall populations. An unplanned analysis of the combined KRAS subset data is the subject of this report. Methods: Eligibility criteria for both trials included: stage IIIB/IV NSCLC; 1 to 2 prior regimens; ECOG performance status 0–2; measurable disease. PFS was the primary endpoint of each trial. Treatment groups included: erlotinib/placebo (N=121), erlotinib/sorafenib (N=112), and erlotinib/pazopanib (N=127). 168 pts (47%) in these three groups had sufficient tumor specimens for KRAS analysis. Results: The PFS and OS results based on KRAS results are shown in the Table below. Conclusions: Patients in whom the KRAS mutation status was known achieved a significantly longer PFS with erlotinib and a multikinase inhibitor than with erlotinib alone. Although this unplanned combined analysis has several limitations, the greater PFS and OS benefits in pts with KRAS mutations warrant further study. Clinical trial information: NCT00600015; NCT01027598. [Table: see text]
Detection of ROS1 translocations in triple-negative lung adenocarcinomas.
Authors: McLeer Florin Anne , Mescam-Mancini Lenaig , Moro-Sibilot Denis , Audigier-Valette Clarisse , Decroisette Chantal , Sabourin Jean-Christophe , Souquet Pierre Jean , Lantuejoul Sylvie 
Published: March 2020

8099 Background: After ALK (anaplastic lymphoma kinase) rearrangements, ROS1 (c-ros oncogene 1, located at 6q22) translocations were recently shown to define a new molecular subgroup in non-small cell lung cancers (NSCLC). These translocations, activating a proto-oncogene with a tyrosine kinase domain, are also targeted by the MET and ALK crizotinib. ROS1 rearrangements are found in only 1.2-1.7% NSCLCs, but seemingly only in triple negative (EGFR and KRAS non-mutated and ALK non-rearranged) adenocarcinomas and preferentially in non- or light smokers. Methods: 60 triple negative non- or light-smoking patients with lung adenocarcinoma were screened for ROS1 rearrangements by fluorescent in situ hybridization (FISH). Two commercially available break-apart FISH probe kits containing a mixture of two probes hybridizing on each side of the ROS1 locus, one located in a centromeric (3’) position, and the other one in a telomeric (5’) position relative to the ROS1 gene were used. ROS1 fusions were therefore detected without any preconception on the fusion partner, as multiple fusion partners have been described. At least 100 nuclei were screened, and a tumor was considered positive if it contained more than 15% rearranged nuclei. Results: Forty-nine of the 60 tumors were interpretable. Four (8.2%) of theses 49 tumors were ROS1 rearranged by FISH. Only one of the positive cases showed a “classical” split rearrangement pattern (one fusion, one green and one red signal in more than 15% of nuclei), whereas the three other tumors showed a variant pattern, with a deletion of the telomeric probe, located in a 5’ position relative to the ROS1 gene locus, indicating the presence of a fusion partner upstream of the ROS1 gene. The four positive cases were all at an advanced stage (3 or 4), but did not display any common architectural feature. Conclusions: The prevalence of ROS1 positivity in our selected population was far superior (8.2%) to that of a non-selected NSCLC population, suggesting that this type of screening may be more effective (faster and more cost-worthy) to detect ROS1 positive tumors.
Prognostic value of ECOG performance status in lung cancer assessed by patients and physicians.
Authors: Johansen Jakob , Boisen Mogens Karsboel , Mellemgaard Anders , Holm Bente 
Published: March 2020

8103 Background: Physician-reported Eastern Cooperative Oncology Group (ECOG) performance status (MD-PS) is a reliable prognostic factor of overall survival (OS) and has a major influence on treatment decisions. MD-PS is also used to quantify cancer patients' general well-being and activities of daily life. The extent and prognostic importance of disagreements between MD-PS and cancer patients' self-reported ECOG PS (Pt-PS) have not been adequately evaluated. Methods: Four hundred and sixty consecutive patients with lung cancer (LC) were referred to the Dept. of Oncology at Herlev University Hospital, Denmark, from February 1 2012 to January 31 2013. Three hundred and forty-seven (75%) of these patients were enrolled in a prospective, longitudinal, LC biomarker study, “LUCAS”. Patients assessed their own Pt-PS in a questionnaire at first visit. Treating physicians scored the MD-PS at first visit. Results: Fifty-four (16%) LUCAS patients had missing PS data (39 no Pt-PS; 14 no MD-PS; 1 neither). LUCAS patients were significantly younger than the total LC population (mean age, 68.1 vs. 71.1; t-test: p < 0.01). The MD-PS and Pt-PS were distributed differently in the LUCAS cohort: PS=0 (121 vs. 76), PS=1 (147 vs. 145), PS=2 (39 vs. 54), PS=3 (25 vs. 30), PS=4 (0 vs. 2) (X2 test: p < 0.01). In 170 (58%) cases the physician and patient were in concordance. In 24 (8%) cases the MD-PS scored the patient in poorer PS compared to the Pt-PS. In 99 (34%) cases the MD-PS scored the patient in better PS than the Pt-PS. In 11 (4%) cases the physician scored a PS value more than 1 different from the patient; all were towards a better PS. The median OS in the total cohort (460 patients) was 9.7 months. MD-PS and Pt-PS were both effective in predicting OS. For patients with MD-PS = 0, a poorer Pt-PS did not significantly predict worse outcome. However, for patients with MD-PS = 1, there was a trend (HR 1.98, p = 0.08; log rank test) towards worse outcome if Pt-PS was > 1. Conclusions: Oncologists and patients frequently disagree regarding PS. The physicians tend to note a better PS score than the patients. The differences between MD-PS and Pt-PS could influence the prognostic value. It may be beneficial in clinical practice to involve patients in PS assessments.
A phase I/II trial combining erlotinib with gamma secretase inhibitor RO4929097 in advanced non-small cell lung cancer (NSCLC).
Authors: Gold Kathryn A. , Byers Lauren Averett , Fan You Hong , Fujimoto Junya , Tse Warner H , Lee J. Jack , Gupta Sanjay , Wistuba Ignacio Ivan , Stewart David J. , Gibbons Don Lynn 
Published: March 2020

8104 Background: All NSCLC patients treated with erlotinib (E) eventually develop resistance. Both the epithelial-mesenchymal transition (EMT) and cancer stem cells may contribute to resistance to E. The Notch pathway plays a key role in maintaining stem cell viability and in EMT. Gamma secretase inhibitors such as RO4929097 (R) inhibit Notch activity by preventing cleavage of Notch to its active form. In this CTEP-sponsored study, primary endpoint of phase I was to determine maximum tolerated dose (MTD) of the combination of E and R; primary endpoint of phase II was response rate. Methods: Eligible pts had incurable NSCLC, measurable disease, ECOG PS 0-1, and adequate laboratory parameters. There were no limits on prior therapy. All pts were required to have a tumor biopsy. Patients received E PO daily on a continuous schedule and R PO daily on days 1-3, 8-10, and 14-17 of a 21 day cycle. Dose cohorts (E/R both in mg) were as follows: 100 /20, 150/20, 150/30, 150/45. Imaging was performed every 6 weeks. Patients could remain on therapy until progression. Results: 21 pts were enrolled between 9/2010 and 3/2012. 5 were not eligible and did not receive treatment. For the 16 treated pts: median age was 61 yrs (40-75), 7 (44%) were male, 14 (88%) had adenocarcinoma. All pts had received prior chemotherapy (1-8 regimens); 7 (44%) had prior E. 3 pts had known EGFR mutations; 2 pts had KRAS mutations. Time on therapy ranged from 20 to 248 days. Median PFS was 42 days. Pts with prior progression on E had a median PFS of 64 days. 1 pt (6%) had a partial response, 4 (19%) had stable disease at 6 weeks. Median overall survival is 6.5 months (1.3 to 24.5+ months). Observed dose-limiting toxicity was hypophosphatemia in 1 pt in 150/45 cohort. Other toxicities included rash, neuropathic pain and nausea. MTD was determined to be 150/45. The study was halted early, after completion of the phase I cohort, as production of R was discontinued by the manufacturer. 12 pts (75%) have adequate tumor tissue for analyses. Biomarker studies are pending. Conclusions: Combination of R and E is safe and feasible in pts with NSCLC. Though development of R has been discontinued, other drugs targeting the Notch pathway are in development (NCI R21CA153017). Clinical trial information: NCT01193881.
Exploratory biomarker analyses from ECOG 4508: Three-arm randomized phase II study of carboplatin (C) and paclitaxel (P) in combination with cetuximab (CET), IMC-A12, or both for advanced non-small cell lung cancer (NSCLC) patients (pts).
Authors: Aggarwal Charu , Dahlberg Suzanne Eleanor , Hanna Nasser , Kolesar Jill , Hirsch Fred R. , Ramalingam Suresh S. , Schiller Joan H. 
Published: March 2020

8106 Background: ECOG 4508 was a phase II study that randomized advanced NSCLC pts that were not candidates for bevacizumab to receive: C + P iv on day 1 every 3 wks with either CET iv weekly (arm A, n=39), IMC-A12 iv every 2 wks (arm B, n=42), or both (arm C, n=48). The study was closed prematurely due to safety concerns after 129 eligible pts were treated. The study failed to meet its primary objective (Hanna et al ASCO 2012). Methods: Tumor samples were analyzed by immunohistochemistry (IHC; EGFR, IGF-1R and IGF-2R expression), fluorescent in-situ hybridization (FISH; EGFR gene copy number) and DNA sequencing (EGFR, KRAS gene mutations). Time-to-event distributions were estimated using the Kaplan-Meier method, and differences were tested using the logrank test. Cox proportional hazards models were fitted to estimate hazard ratios. Results: Histology: 38% squamous cell, 39% adenocarcinoma, 2% BAC, 5% NOS and 6% other. OS was similar in EGFR FISH+ (Colorado classification system, n=30/70, 43%) vs EGFR FISH- pts (57%), (9.5 mos vs 8.6 mos, HR=0.62, p=0.08). For EGFR FISH+ pts, there was no difference in outcomes with CET (n=19, OS=9.7 mos, PFS=4.1 mos) vs no CET (n=11, OS=9.5 mos, PFS=5.5 mos). EGFR and KRAS mutations were detected in 6% (5/80) and 22% (6/27) of the pts respectively, but sample sizes were not large enough for robust testing. EGFR and IGFR IHC hybrid (H) scores were assessed on 98/102 available samples (Arm A=29, Arm B=34, Arm C=35). Median H scores (and range): IGF-1R: 190 (30-390), IGF-2R: 145 (20-350), EGFR membrane and cytoplasm: 190 (0-380) and EGFR membrane only: 160 (0-390). With IGF-1R and IGF-2R H score > 200, there was no association with OS (HR 1.3, p=0.26; HR 1.4, p=0.28) or PFS (HR=1.1, p=0.67; HR=1.2, p=0.56), adjusted for whether or not IMCA12 was received. Similarly, no associations with OS or PFS were seen with EGFR membrane H score > 200, adjusted for CET administration (OS HR=0.89, p=0.64; PFS HR 1.1, p=0.62). Conclusions: There was no correlation between EGFR FISH or H score and outcomes with CET. IGF-1R and IGF-2R expression was not predictive of favorable outcome with IMC-A12. Clinical trial information: NCI-2011-01976.