bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regional screening network for characterization of the molecular epidemiology of non-small cell lung cancer (NSCLC) and implementation of personalized treatment.
Authors: Zander Thomas , Heukamp Lukas Carl , Bos Marc Christiaan Allardt , Fassunke Jana , Mattonet Christian , Merkelbach-Bruse Sabine , Ko Yon-Dschun , Schlesinger Andreas , Brockmann Michael , Serke Monika , Gerigk Ulrich , Hekmat Khosro , Engel-Riedel Walburga , Stoelben Erich , Reiser Marcel , Schulz Holger , Schmitz Stephan H. , Frank Konrad , Buettner Reinhard , Wolf Juergen 
Published: February 2017

CRA10529 Background: Personalized treatment of genetically stratified subgroups has the potential to substantially improve outcome in NSCLC. A major challenge now is to implement high-quality molecular diagnostics and personalized treatment strategies in routine clinical practice also outside of highly specialized academic centers. Methods: We have established a molecular screening network in the catchment area of our comprehensive cancer center encompassing about 2.5 million inhabitants in March 2010 after review of the local ethics committee (10-242). Lung adenocarcinoma (AD) was screened centrally for ALK translocations, mutations in KRAS, EGFR, BRAF and PIK3CA and for amplification of ERBB2. Squamous cell carcinoma (SQ) was analyzed for FGFR1 amplifications. Results: 2032 NSCLC samples were acquired of which 1782 in the Cologne-Bonn area indicating a capture rate of 60-70% of all NSCLC samples in the area. Material was suitable for molecular analysis in 77%. Distribution of histological subtypes was as expected (AD 63.4%, SQ 26.7, large cell carcinoma 1.4%, adenosquamous cell carcinoma 1.8%, carcinoid 0.1%, NSCLC NOS 6.7%. In AD the following frequencies of genetic lesions were detected: KRAS (32%), EGFR (13%), ALK (3%), BRAF (2%), PIK3CA (2%), ERBB2 (2%). EGFR mutations were highly enriched in the lepidic and micropapillary subtype of AD (30-32%), whereas the solid subtype only harboured a very small amount of the tested oncogenic lesions. In SQ FGFR1 amplification was detected in 78/500. Overall 40% of all NSCLC samples harboured potentially tractable oncogenic lesions. All patients with ALK translocations received crizotinib when clinically indicated. 75% of the stage IIIB/IV patients with activating EGFR mutations received EGFR-TKI treatment. In addition, clinical trials have been initiated to provide personalized treatment options to all patients with tractable genetic lesions. Conclusions: High-quality molecular diagnostics and identification of patients for personalized treatment approaches is feasible in daily clinical routine for the majority of diagnostic samples also in a non-academic setting.
Anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced solid tumors: Clinical activity, safety, and a potential biomarker for response.
Authors: Topalian Suzanne Louise , Brahmer Julie R. , Hodi F. Stephen , McDermott David F. , Smith David C. , Gettinger Scott N. , Taube Janis M. , Drake Charles G. , Pardoll Drew M. , Antonia Scott , Spigel David R. , Atkins Michael B. , Lawrence Donald P. , McDonald Dan , Jure-Kunkel Maria , Korman Alan , Kollia Georgia , Gupta Ashok Kumar , Wigginton Jon , Sznol Mario 
Published: February 2017

CRA2509 Background: Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression. This study describes the activity and safety of BMS-936558, a fully human mAb blocking PD-1, and highlights the importance of the PD-1/PD-L1 pathway as a target for cancer therapy. Methods: Patients (pts) received BMS-936558 IV Q2WK at doses of 0.1 to 10.0 mg/kg during dose-escalation and/or cohort expansion. Tumors were assessed by RECIST 1.0 after each therapy cycle (4 doses). Pts received up to 12 cycles or until PD or CR. Results: As of July 1, 2011, 240 pts with melanoma (MEL, n=95), renal cell (RCC, n=33), colorectal (CRC, n=19), non-small cell lung cancer (NSCLC, n=75), castrate-resistant prostate cancer (CRPC, n=17), and unknown (n=1) were treated. Median duration of therapy was 15 wk (max 120 wk). MTD was not reached. Grade 3-4 related AEs occurred in 13% of pts. AEs of special interest included pneumonitis, hypophysitis, hepatitis, colitis, and thyroiditis. There were 2 related deaths due to pulmonary toxicity. In evaluable pts receiving ≥2 cycles, OR (objective responses; CR or PR) were observed in MEL, RCC, and NSCLC. Aggregate response rates [(OR +unconfirmed PR)/evaluable pts] were: MEL (0.1-10 mg/kg, 20+4/90; 27%), RCC (1-10 mg/kg, 8+2/32; 31%), and NSCLC (1-10 mg/kg, 10+3/73; 18%). OR were durable: among 38 pts with OR, 28 were enrolled ≥1 yr before data lock, and 18 of these had responses lasting ≥1 yr. Ten pts on study <1 yr had ongoing OR with a duration of 1.8 - 5.6 mo. Several pts had prolonged SD. Some had a persistent reduction in overall tumor burden in the presence of new lesions and were not categorized as responders. To assess PD-1 ligand (PD-L1) as a potential predictive biomarker, IHC was performed on pre-treatment tumor biopsies from 29 pts. Of 16 pts with PD-L1(+) tumors, 50% achieved OR vs. none with PD-L1(-). Conclusions: BMS-936558 produces durable activity in advanced NSCLC, MEL, and RCC. Preliminary data implicate PD-L1 expression on tumor cells as a potential predictive biomarker of response. These findings underscore the importance of the PD-1/PD-L1 pathway and support further clinical development of BMS-936558.
Bevacizumab (Bev) with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients (pts) with metastatic colorectal cancer (mCRC): Efficacy and safety results of the International GERCOR DREAM phase III trial.
Authors: Tournigand Christophe , Samson Benoit , Scheithauer Werner , Lledo Gérard , Viret Frédéric , Andre Thierry , Ramée Jean François , Tubiana-Mathieu Nicole , Dauba Jérôme , Dupuis Olivier , Rinaldi Yves , Mabro May , Aucoin Nathalie , Khalil Ahmed , Latreille Jean , Louvet Christophe , Brusquant David , Bonnetain Franck , Chibaudel Benoist , De Gramont Aimery ,   GERCOR
Published: February 2017

LBA3500^ Background: Therapy targeting VEGF or EGFR demonstrated clinical activity in combination with chemotherapy (CT) in mCRC but monoclonal antibodies cannot be associated. The DREAM trial compares a maintenance therapy (MT) with bev +/- EGFR tyrosine kinase inhibitor erlotinib (E) after a first-line Bev-based induction therapy (IT) in pts with mCRC. Methods: Pts with previously untreated and unresectable mCRC were eligible. After a Bev-based IT with FOLFOX or XELOX or FOLFIRI, pts without disease progression were randomized to MT between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev+E (B 7.5 mg/kg q3w, E 150 mg/day continuously; arm B). Pts were treated until progression or unacceptable toxicity. The primary endpoint was PFS on MT. Results: The study enrolled 700 pts from 01/2007 to 11/2011 in 3 countries (France, Canada, Austria). 446 (63.7%) pts were randomized for MT (arm A, N=224; arm B, N=222). Among the 446 randomized pts, IT regimen was FOLFOX-Bev in 265 pts (59.4%), XELOX-Bev in 135 pts (30.3%), and FOLFIRI-Bev in 46 pts (10.3%). Baseline characteristics of randomized pts were (arm A/B): ECOG PS 0, 60% in both arms; normal LDH level 47%/49%; normal alkaline phosphatase level 48%/50%; synchronous metastasis 83%/82%. The median no of MT cycles was 6 in both arms. With a median follow-up of 31.0 months, 327 PFS events were observed. Median MT-PFS were 4.6 m in arm A vs 5.8 m in arm B (HR 0.73 [95%CI: 0.59-0.91], P=.005). Median PFS from inclusion were 9.2 m vs 10.2 m. During MT, in arm A vs arm B, grade 3-4 diarrhea (<1% vs 9%) and grade 3 skin toxicity (0% vs 19%) were the main differences in toxicity. Severe adverse events from randomization related to B or E were 6 in arm A and 7 in arm B. Overall survival is not mature. Conclusions: The addition of erlotinib to bevacizumab after induction therapy significantly improves the duration of maintenance PFS, following induction with first-line chemotherapy plus bevacizumab, in patients with unresectable metastatic colorectal cancer.
Intergroup Trial of Adjuvant Chemotherapy in Adenocarcinoma of the Stomach (ITACA-S) trial: Comparison of a sequential treatment with irinotecan (CPT-11) plus 5-fluorouracil (5-FU)/folinic acid (LV) followed by docetaxel and cisplatin versus a 5-FU/LV regimen as postoperative treatment for radically resected gastric cancer.
Authors: Bajetta Emilio , Floriani Irene , Di Bartolomeo Maria , Labianca Roberto , Landi Lorenza , Santoro Armando , Casaretti Rossanna , Pasquini Enzo , Di Fabio Francesca , Rondini Ermanno , Pinotti Graziella , Bidoli Paolo , Rosati Gerado , Mambrini Andrea , Ciarlo Andrea , Cordio Stefano Sergio , Ricci Sergio , Frassineti Luca , Di Costanzo Francesco , Bochicchio Anna Maria ,   on behalf of ITACA-S Study Group
Published: February 2017

LBA4001 Background: Following radical resection of gastric or gastroesophageal junction (GEJ) adenocarcinoma, a meta-analysis and randomized studies demonstrated better survival in pts treated with fluoropyrimidine regimens compared to surgery alone. ITACA-S trial is a no-profit, multicenter, randomized, open-label, superiority phase III study aimed at evaluating whether a more intensive postoperative chemotherapy improves efficacy, when replace fluoropyrimidine. Methods: Pts radically resected for gastric or GEJ adenocarcinoma, with ≥D1-lymphadenectomy, node involvement (pN+) or pN0 with pT2b-3-4; within 3-8 weeks after surgery were eligible. Treatment consisted in CPT-11 180 mg/m2 on d1, LV 100 mg/m2 d1-2, 5-FU 400-600 mg/m2 d1-2, q14; for 4 cycles (FOLFIRI regimen) followed by docetaxel 75 mg/m2 d1, cisplatin 75 mg/m2 d1, q 21; for 3 cycles (arm A) vs. LV 100 mg/m2 d1-2, 5-FU 400-600 mg/m2 d1-2, q 14 for 9 cycles (arm B). The primary hypothesis on disease-free survival (DFS) requires 636 events (first recurrence or death) to detect an hazard ratio (HR) of 0.80, with 2-sided 5% significance level for the log-rank test and a power of 80%. Results: From February 2005 to August 2009, 1,106 pts were randomized and 1,100 were analyzed (562 arm A, 538 arm B; 6 major violations) by 123 Italian centers. By March 2012, with a median follow-up of 49 months (quartile range: 36-62) we observed 558 events for DFS (HR 0.98; 95%CI 0.83-1.16;p=0.83) accounting for 88% of the target number and 440 deaths (HR: 1.00; 95%CI 0.83-1.20;p=0.98). Toxicity was consistent with literature. Given the data observed, both under the original hypothesis and the current trend, the probability to reach a statistically significant results at the target events is <0.0001. Conclusions: Adjuvant chemotherapy in gastric cancer with more intensive regimen did not result in a significant prolongation of DFS and OS when compared to bolus/infusion FU/LV regimen.
AURELIA: A randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC).
Authors: Pujade-Lauraine Eric , Hilpert Felix , Weber Béatrice , Reuss Alexander , Poveda Andres , Kristensen Gunnar , Sorio Roberto , Vergote Ignace B. , Witteveen Petronella , Bamias Aristotelis , Pereira Deolinda , Wimberger Pauline , Oaknin Ana , Mirza Mansoor Raza , Follana Philippe , Bollag David T. , Ray-Coquard Isabelle ,   AURELIA Investigators
Published: February 2017

LBA5002^ Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BEV + CT → BEV significantly improved progression-free survival (PFS) vs CT alone. AURELIA is the first randomized trial of BEV in PT-resistant OC. Methods: Eligible patients (pts) had OC (measurable by RECIST 1.0 or assessable) that had progressed ≤6 mo after ≥4 cycles of PT-based therapy. Pts with refractory OC, history of bowel obstruction, or >2 prior anticancer regimens were ineligible. After CT selection by the investigator (pegylated liposomal doxorubicin [PLD], topotecan [TOP], or weekly paclitaxel [PAC]), pts were randomized to CT either alone or with BEV (10 mg/kg q2w or 15 mg/kg q3w depending on CT) until progression (PD), unacceptable toxicity, or withdrawal of consent. Pts in the CT-alone arm could cross over to BEV monotherapy at PD. The primary endpoint was PFS by RECIST. Secondary endpoints included objective response rate (ORR), overall survival, safety, and quality of life. The design provided 80% power to detect a PFS hazard ratio (HR) of 0.7 with 2-sided log-rank test and α=0.05 after 247 events, assuming median PFS of 4.0 mo with CT and 5.7 mo with CT + BEV. Results: Between Oct 2009 and Apr 2011, 361 pts were randomized to receive selected CT (PLD: 126; PAC: 115; TOP: 120) alone or with BEV. Median follow-up after 301 PFS events was 13.5 mo. Conclusions: In PT-resistant OC, BEV + CT provides statistically significant and clinically meaningful improvement in PFS and ORR vs CT alone. Strict inclusion criteria minimized the incidence of BEV AEs. This is the first phase III trial in PT-resistant OC to show benefit with a targeted therapy and improved outcome with a combination vs monotherapy. [Table: see text]
Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.
Authors: Hauschild Axel , Grob Jean Jacques , Demidov Lev V. , Jouary Thomas , Gutzmer Ralf , Millward Michael , Rutkowski Piotr , Blank Christian U. , Mirakhur Beloo , Guckert Mary E. , Swann R. Suzanne , Haney Patricia , Martin Anne-Marie , Ouellet Danielle , Grotzinger Kelly , Goodman Vicki L. , Chapman Paul B. 
Published: February 2017

LBA8500^ Background: Dabrafenib, a selective BRAF inhibitor, has shown activity with a manageable safety profile in phase I/II studies in patients (pts) with BRAFV600E-mutated metastatic melanoma (MM). This phase III trial (NCT01227889) compared progression-free survival (PFS) in pts with advanced MM treated either with dabrafenib or dacarbazine (DTIC). Methods: Pts with previously untreated, unresectable stage III or IV BRAFV600E-mutated melanoma were randomized (3:1) and stratified by stage to dabrafenib (150 mg po bid) or DTIC (1000 mg/m2, IV, q3w). Primary endpoint was investigator-assessed PFS. Primary analysis for PFS was planned after 102 events. Pts on the DTIC arm were allowed to cross over once progression was confirmed by independent review (IR). Secondary endpoints included PFS by IR, overall survival (OS), response rate (RR), duration of response, safety and pharmacokinetics. Results: 250 pts were enrolled at 93 centers globally from February to September 2011. 187 were randomized to dabrafenib and 63 to DTIC. 141pts were on study treatment at the data cut-off at December 19, 2011 (dabrafenib n = 127; DTIC n = 14), including 21/28 DTIC pts crossed over to dabrafenib. Median age was 52 years, 31% of pts were ECOG >1, 66% M1c, 33% LDH > ULN. Demographics were well balanced between the two arms. At the time of the primary analysis, there were 118 events (77 dabrafenib and 41 DTIC). The hazard ratio for PFS was 0.30 (95% CI: 0.18–0.53; p < 0.0001). Median PFS was 5.1 months for dabrafenib and 2.7 for DTIC. OS data were immature, with 30 deaths reported. Confirmed RR was 53% for dabrafenib and 19% for DTIC. Benefits in PFS and RR were observed in all subgroups evaluated. Common adverse events (AEs) on the dabrafenib arm were hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), skin papillomas (24%). Serious AEs (> 1%) on the dabrafenib arm included pyrexia (4%), squamous cell carcinomas (6%), and new primary melanomas (2%). Conclusions: Dabrafenib demonstrated a significant improvement in PFS and ORR over DTIC with an acceptable safety profile.
Early efficacy analysis of the AE37 vaccine in patients with HER2 low-expressing and triple-negative breast cancer.
Authors: Mittendorf Elizabeth Ann , Perez Sonia A. , Hale Diane F. , Vreeland Timothy J. , Sears Alan K. , Clifton Guy T. , Ardavanis Alexandros , Shumway Nathan M. , Murray James L. , Ponniah Sathibalan , Papamichail Michael , Peoples George Earl 
Published: February 2017

109 Background: Peptide vaccines comprised of HLA class II epitopes, which elicit CD4+ T cell responses, play a critical role in potentiating immune responses. We are conducting a randomized phase II trial of AE37, a hybrid peptide created by the addition of the Ii-Key moiety (LRMK) to the HER2 helper epitope, AE36 (HER2 aa776-790). Here, we present efficacy data focusing on outcomes in patients with low HER2 (IHC 1+ or 2+) expression and triple negative breast cancer (TNBC). Methods: The trial is enrolling node positive or high risk node negative breast cancer patients with any degree of HER2 expression (IHC 1+, 2+ or 3+ or FISH > 1.2) rendered disease-free following standard of care therapy. Patients are randomized to receive either AE37+GM-CSF or GM-CSF alone in 6 monthly intradermal inoculations followed by booster inoculations administered every 6 months. Results: The trial has enrolled 254 patients; 105 in the vaccine group (VG) and 149 in the control group (CG). After a median follow-up of 22.3 months, the disease-free survival (DFS) rate in the VG is 90.3% vs 81.1% in the CG (p=.46), a 49% risk reduction. Evaluating patients with low HER2 expression (IHC 1+ or 2+), there are 53 VG patients and 77 CG patients. The groups are well-matched with respect to the percentage of patients with high grade tumors, tumors > 2cm, the rate of node positivity and ER/PR status (all p>.5). The DFS rate in the VG of low HER2 expressers is 89.8% vs 68.2% in the CG (p=.12), a 68% risk reduction. When limiting analyses to patients with TNBC (ER/PR negative, HER2 1+ or 2+), there are 13 VG patients and 23 CG patients. The groups are again well-matched with the exception of control patients having a larger percentage of tumors > 2 cm (70% vs 31%; p=.02). The DFS rate in the VG of TNBC patients is 83.3% vs 47.6% in the CG (p=.23), a 68% risk reduction. Conclusions: Early analyses suggest clinical benefit to vaccination with AE37, particularly in patients with low HER2-expressing tumors. Importantly, the benefit appears to persist in TNBC patients. Patients will continue to be followed per protocol for 5 years; however, these data suggest that a subsequent phase III trial should evaluate the vaccine in patients with low HER2-expressing disease to include TNBC.
Phase II results of tasisulam-sodium in previously treated patients with metastatic breast cancer.
Authors: Schwartzberg Lee Steven , Soliman Hatem Hussein , Conlin Alison Katherine , Ruud Christopher O. , Tezcan Haluk , Bromund Jane , Hogeterp Kevin , Kaiser Christopher , Chen Jian , Chow Kay , Ilaria Robert L. , Miller Kathy 
Published: February 2017

114 Background: Tasisulam, a novel acylsulfonamide antineoplastic agent, promotes apoptosis, exhibits antiangiogenic activities, and demontrates antiproliferative activity against human breast cancer cell lines. In humans, tasisulam is highly albumin bound, with a median half-life of approximately 11 days. Previous phase II studies of tasisulam indicated that an albumin-corrected exposure (AUCalb) range of 1200 to 6400 h*mcg/mL provided the optimal balance of efficacy and safety. This study investigates the drug’s activity in previously treated patients (pts) with metastatic breast cancer (mBC). Methods: Pts with at least 2 prior therapies for mBC andserum albumin level ≥3.0 g/dL received tasisulam by 2-hour infusion every 28 days, dosed by a lean body weight-based dosing algorithm targeting an AUCalb range of 1200 to 6400 h*mcg/mL. Primary objective was to show at least a 10% response rate (RR) using RECIST 1.0. Secondary objectives included progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety. Results: Thirty-three pts received at least 1 dose of tasisulam. All were women, with a mean age of 55.4 (±9.7) years. Pts received a median of 2 cycles (ranges 1-8). The majority of pts achieved the target AUCalb range of 1200 to 6400 h*mcg/mL or higher in cycles 1 and 2 (63% and 69%, respectively). The most common tasisulam-related hematologic toxicities were grade 3 anemia (3.0%) and grade 4 neutropenia (6.1%). Common nonhematological adverse events possibly related to tasisulam were fatigue (39.4%), diarrhea (24.2%), and nausea (18.2%). No deaths were considered related to the study drug. The RR (1 CR, 1 PR) was 6.1% (90% CI: 1.1, 17.9), stable disease rate was 24% (n=8; 90% CI: 12.7, 39.5), with a median PFS of 1.81 months (90% CI: 1.64, 2.17) and a median OS of 6.77 months (90% CI: 4.37, 11.63). Conclusions: Tasisulam was reasonably well tolerated, but did not meet its primary objective of overall RR of 10% in this heavily pretreated mBC patient population. PK analysis of the albumin-tailored dosing regimen indicated that the majority of the patients achieved the target AUCalb or higher, suggesting that the modest activity observed was not due to suboptimal dosing.
Adjuvant chemotherapy for early-stage breast cancer: Choice of regimen and associated hematologic toxicities in a metropolitan Australian hospital.
Authors: Lovat Katherine Mary , Christie Hayden , Che Ricky , Hill Andrew , Sanmugarajah Jasotha 
Published: February 2017

123 Background: The commonly used adjuvant chemotherapy regimens for early breast cancer include 5-fluorouracil, epirubicin, cyclophosphamide and docetaxel (FEC-D), docetaxel and cyclophosphamide (TC), doxorubicin and cyclophosphamide with or without paclitaxel and/or herceptin (AC combination) and docetaxel, carboplatin and trastuzumab (TCH). Hematologic toxicity from these regimens can be life threatening as well as cause significant morbidity for the patient and major costs to the health system. Granulocyte colony stimulating factor (GCSF) is frequently used to try and reduce these complications. In Australia, GCSF is funded for use as primary prophylaxis with docetaxel in combination with an anthracycline and cyclophosphamide. Secondary prophylaxis is available only after demonstration of prolonged severe neutropenia or an episode of febrile neutropenia (FN). Methods: Patients treated with adjuvant chemotherapy for early breast cancer at Gold Coast Hospital, Qld, Australia from February 2010 to February 2012 were identified. Patient charts were reviewed for incidence of neutropenia (neutrophil count <1.0 x 109/L), FN (temp ≥38°C), dose reductions or delays and use of GCSF. Results: 102 patients were treated over this time. Incidence of neutropenia, FN and use of GCSF are summarised below. 30 patients receiving FEC-D had a dose delay or reduction with the majority due to non-haematologic toxicities. 96% patients completed 6 cycles of treatment. Of the patients with FN in the TC group, half had received primary GCSF. No patients who were given primary GCSF experienced a dose delay. Similar trends were observed in the other treatment groups. Conclusions: Our results show that patients receiving FEC-D along with GCSF had lower rates of neutropenia and hospitalisations. Rates of neutropenia and dose delay are higher in the other groups. FEC-D is the most commonly used regimen in our institution likely due to the availability of GCSF. [Table: see text]