bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Jiang Di Maria , Sim Hao-Wen , Siu Lillian L. , Shapiro Jeremy David , Liu Geoffrey , Price Timothy Jay , Jonker Derek J. , Karapetis Christos Stelios , Strickland Andrew , Zhang Wenjiang , Jeffery Mark , Tu Dongsheng , Ng Siobhan , Sabesan Sabe S. , Shannon Jenny , Townsend Amanda Rose , Morgen Eric , Xu Wei , O'Callaghan Christopher J. , Chen Eric Xueyu 
Published: September 2018

3600 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for RAS wild-type (WT) mCRC. Limited data suggest a correlation between Cet clearance and progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts with KRAS WT mCRC who participated in the randomized phase III NCIC CO.20 trial. Methods: Standard Cet doses ± brivanib (Briv) were administered. Intermittent blood samples were obtained, and analyzed by ELISA for Cet. Pop-pK analysis was conducted to estimate Cet clearance. Pts were divided into quartiles according to clearance parameters to evaluate exposure-outcome with overall survival (OS), PFS, response rate (RR), and toxicity. Results: Blood samples were available from 703 pts. Cet clearance was best described as a one-compartment model with a saturable elimination (defined by Vmax and Km). Mean values (± standard deviation) were 5.6 ± 1.4 L for V, 10.5 ± 2.8 mg/h for Vmax, and 403.1 ± 2.0 mg/L for Km. Vmax and Km were significantly associated with OS, but not PFS or RR. Median OS for pts in the highest quartile of Vmax was 7.8 versus (vs.) 11.6 ms for pts in the lowest Vmax quartile (HR 1.12, 95% confidence interval (CI) 1.05-1.20, p< 0.001). In the highest Km quartile, median OS was 11.6 vs. 7.6 ms in the lowest Km quartile (HR 0.89, 95% CI 0.83-0.96, p= 0.001). Pts with the lowest clearance parameters (lowest Vmax and highest Km) had significantly longer OS (11.6 ms) compared to pts with the highest clearance (highest Vmax and lowest Km) (7.6 ms) (HR 0.67, 95% CI 0.53-0.83, p< 0.001). Overall incidences of grade 3/4 toxicity were not associated with Cet clearance. However, pts with the lowest clearance parameters had more frequent grade 3 diarrhea (OR 0.23, p= 0.005). Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with lower Cet clearance have significantly improved OS and increased likelihood of grade 3 diarrhea. Further studies are needed to identify individual patient factors associated with Cet clearance, and to optimize Cet dosing based on individual pk assessments.
Differences in systemic and surgical therapy between right (R) and left (L) sided metastatic colorectal cancer (mCRC).
Authors: Kennecke Hagen F. , Yin Yaling , Loree Jonathan M. , Leung Rachel , Gill Sharlene 
Published: September 2018

3602 Background: Patients (pts) with L sided primary tumors and mCRC have a significantly longer overall survival (mOS) than R sided tumors. Reasons for this remain unclear. The objective of this study was to compare systemic and surgical therapy received by tumor side and correlate this with mOS. Methods: Sequential pts with mCRC referred to the British Columbia Cancer Agency in 4 treatment eras were included. Pts with unresected primary tumors were excluded to ensure accurate ascertainment of tumor location. Receipt of systemic therapy includes Òall 3 drugsÓ (irinotecan, oxaliplatin, fluouracil), bevacizumab and epidermal growth factor receptor inhibitors (EGFRi). Cox-regression survival analysis for sidedness was performed controlling for age, sex, tumor grade, lymphovascular/perineural invasion, nodes removed and metastatectomy. Results: Among 3242 pts, a progressive improvement in mOS is documented in both L and R sided tumors since 1995. L and R tumors received Òall 3 drugsÓ, bevacizumab and EGFRi therapy with similar frequency which plateaued after the introduction of EGFRiÕs in 2009. Patients with L sided tumors were significantly more likely to have a hepatic or pulmonary resection. In Cox regression analysis, the mOS difference between L and R sided tumors was more pronounced in more recent eras. Conclusions: Patients with R sided tumors receive similar systemic therapy compared to L sided tumors, but are significantly less likely to undergo resection of distant disease. Resection of distant metastases may be an important consideration to understand the survival differences between R vs L mCRC. [Table: see text]
Genetic correlates of therapeutic toxicities of stage III colon carcinoma patients treated with adjuvant FOLFOX+/-cetuximab (NCCTG N0147, Alliance).
Authors: Newcomb Polly A. , Sun Wei , Hua Xinwei , Banbury Barbara L. , Phipps Amanda I. , Kocarnik Jonathan , Harrison Tabitha A. , Shi Qian , Sinicrope Frank A. , Thibodeau Stephen N. , Chan Emily , Gill Sharlene , Goldberg Richard M. , Kahlenberg Morton S. , Nair Suresh , Shields Anthony Frank , Jahagirdar Balkrishna N. , Peters Ulrike , Alberts Steven R. , Chan Andrew T. 
Published: September 2018

3604 Background: Limited research has investigated the role of variation in the host genome as a determinant of colon carcinoma (CC) outcomes, including toxicity due to therapeutic agents. We examined the relationship between germline genetic factors and treatment-associated serious adverse events (SAEs) in a population of CC patients in which treatment was standardized and follow-up for outcomes was uniformly conducted. Methods: Using existing biospecimens from CC patients with resected stage III disease in a phase III randomized trial of FOLFOX adjuvant chemotherapy with and without cetuximab (NCCTG N0147), genome-wide genotyping arrays were conducted for 2200 patients for a total of ~20 million single nucleotide polymorphisms (SNPs). Using logistic regression models we assessed SNP-specific associations with SAEs, utilizing a discovery-based approach to search the genome in an unbiased manner. Detailed information on SAEs was collected using the Common Toxicity Criteria for Adverse Events (CTCAE, v3.0). Analyses evaluating associations with specific classes of common grade ≥3 SAEs were performed, including gastrointestinal toxicities, neutropenia, and paresthesias. A threshold of P < 5x10-8was used to denote genome-wide significance. Results: Among patients who received FOLFOX, several SNPs on chr 15 near the ANP32A gene and on chr 2 near the CD207 gene were statistically significantly associated with grade ≥3 neuropathy. The strongest SNP-specific associations in these regions were in the range of odds ratio (OR) = 1.3, P = 2.8×10−10 and OR = 1.5, P = 2.7×10−10, respectively. Conclusions: Findings from this genome-wide analysis demonstrate the potential importance of germline genetic variation in influencing CC patients’ experience of specific toxicities to FOLFOX regimens. These results highlight two genomic regions of potential interest for understanding the biological mechanism for such toxicities, although further evaluation and replication is needed. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, CCSRI 021039, R01CA176272, Eli Lilly & Co, Pfizer, Sanofi. Clinical trial information: NCT00079274 .
Second-line tivantinib (ARQ 197) vs placebo in patients (Pts) with MET-high hepatocellular carcinoma (HCC): Results of the METIV-HCC phase III trial.
Authors: Rimassa Lorenza , Assenat Eric , Peck-Radosavljevic Markus , Zagonel Vittorina , Pracht Marc , Rota Caremoli Elena , Mathurin Philippe , Harris William Proctor , Bolondi Luigi , Reig Maria , Damjanov Nevena , Daniele Bruno , Porta Camillo , Mazzaferro Vincenzo , Abbadessa Giovanni , Schwartz Brian E. , Lamar Maria , Goldberg Terri Robin , Santoro Armando , Bruix Jordi 
Published: September 2018

4000 Background: Tivantinib (T), a selective, oral MET inhibitor, improved overall survival (OS) and progression-free survival (PFS) versus placebo (P) in a phase II study in MET-High HCC pts. Methods: This randomized, placebo-controlled phase III trial (NCT01755767) enrolled pts with: advanced HCC; Child Pugh A; ECOG PS ≤1; adequate bone marrow, liver, kidney functions; no liver transplant; radiographic disease progression (PD) after or intolerance to sorafenib; tumor MET-High (MET ≥2+ in ≥50% of tumor cells) by centralized immunohistochemistry. Pts were randomly assigned 2:1 to oral T or P, stratified by vascular invasion (VI), extrahepatic spread (ES), AFP ( < / > 200ng/mL), treated until PD or unacceptable toxicity. Response (RECIST 1.1) was evaluated by CT / MRI every 8 weeks. Primary endpoint of OS and secondary endpoints including PFS and safety were assessed in the intent-to-treat (ITT) population. Results: From Dec 2012 to Dec 2015, 1209 pts were consented in Australia, the Americas, Europe, New Zealand: 589 MET-High, 43 initially randomized at the dose of 240mg BID, then reduced due to high neutropenia rate, 340 randomized at 120mg BID: 226 to T, 114 to P (ITT population). Characteristics of pts were balanced between arms: 306 (90%) male; median age: 67; PS 0: 207 (61%); VI: 117 (34%); ES: 197 (58%); AFP ≤200: 195 (57%); radiographic PD on sorafenib: 275 (81%). Median OS (95% CI) was 8.4 months (m) (6.8-10.0) in T, 9.1 m (7.3-10.4) in P, HR = 0.97 (0.75-1.25), P = 0.81. Median PFS (95% CI) was 2.1 m (1.9-3.0) in T, 2.0 m (1.9-3.6) in P, HR = 0.96 (0.75-1.22), P = 0.72. No OS difference was seen in pts with VI (HR 1.19, 0.79-1.79), ES (HR 1.09, 0.78-1.52), AFP > 200ng/mL (HR 1.00, 0.71-1.41). Grade (G) > 3 AEs were 55.6% in T, 55.3% in P. In T, most common G > 3 AEs were ascites (7.1%), general deterioration (5.8%), anemia (4.9%); most common serious AE was general deterioration (4.9%). Deaths within 30 days of last dose were 22.1% on T vs 15.8% on P (most common causes: general deterioration 3.5%, hepatic failure 2.6%). Conclusion: Tivantinib at the 120mg BID dose did not improve OS or PFS over placebo in patients with advanced MET-High HCC who failed previous treatment with sorafenib. Clinical trial information: NCT01755767.
Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study.
Authors: Primrose John Neil , Fox Richard , Palmer Daniel H. , Prasad Raj , Mirza Darius , Anthoney David Alan , Corrie Philippa , Falk Stephen , Wasan Harpreet Singh , Ross Paul J. , Wall Lucy R. , Wadsley Jonathan , Evans T.R. Jeffry , Stocken Deborah , Praseedom Raaj , Cunningham David , Garden O James , Stubbs Clive , Valle Juan W. , Bridgewater John A. 
Published: September 2018

4006 Background: Despite improvements in multidisciplinary management, BTC has a poor outcome. Approximately 20% of cases are suitable for surgical resection with a 5 year survival of < 10%. BILCAP aimed to determine whether capecitabine (Cape) improves overall survival (OS) compared to observation (Obs) following radical surgery. Methods: Patients with completely-resected cholangiocarcinoma (CCA) or gallbladder cancer (including liver and pancreatic resection, as appropriate), with adequate biliary drainage, no ongoing infection, adequate renal, haematological and liver function, and ECOG PS ≤2, were randomized 1:1 to Cape (1250 mg/m2 D1-14 every 21 days, for 8 cycles) or Obs. Randomization was minimized on tumor site, resection status, ECOG PS and surgical center. The primary outcome was OS in the intention to treat (ITT) population. 410 patients were needed to detect a hazard ratio (HR) of 0.69 (2-sided α = 0.05 and 80% power). HR was estimated by Cox survival model with adjustment for the minimization factors. Primary analysis performed with at least 24 months (m) follow-up. Results: 447 participants were randomized to Cape (n = 223) or Obs (n = 224) from 44 UK sites between 2006-2014. Median age was 63y (IQR 55, 69) and 201 (45%), 232 (52%), and 14 (3%) patients were ECOG PS 0, 1 and 2 respectively. Primary site: 84 (19%) intrahepatic, 128 (28%) hilar, 156 (35%) extrahepatic CCA and 79 (18%) muscle-invasive gallbladder cancers. Resection margins: R0 in 279 (62%) and R1 in 168 (38%); 207 (46%) were node-negative. Follow up was at least 36m in > 80% of surviving patients. By ITT analysis (n = 447), median OS was 51m (95%CI 35, 59) for Cape and 36m (95%CI 30, 45) for Obs, HR 0.80 (95%CI 0.63, 1.04; p = 0.097). Sensitivity analyses with adjustment for nodal status, grade of disease and gender indicated HR 0.71 (95%CI 0.55, 0.92 p < 0.01). In the per-protocol analysis (Cape n = 210, Obs n = 220) median OS was 53m (95%CI 40, NR) for Cape and 36m (95%CI 30, 44) for Obs, HR 0.75 (95%CI 0.58, 0.97; p = 0.028). Median RFS (ITT) was 25m (95%CI 19, 37) for Cape and 18m (95%CI 13, 28) for Obs. Grade 3-4 toxicity was less than anticipated. Conclusions: Cape improves OS in BTC when used as adjuvant and should become standard of care. Clinical trial information: ISRCTN72785446.
ARQ 087, an oral pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced intrahepatic cholangiocarcinoma (iCCA) with FGFR2 genetic aberrations.
Authors: Mazzaferro Vincenzo , El-Rayes Bassel F. , Cotsoglou Christian , Harris William Proctor , Damjanov Nevena , Masi Gianluca , Rimassa Lorenza , Personeni Nicola , Braiteh Fadi S. , Zagonel Vittorina , Papadopoulos Kyriakos P. , Hall Terence , Wang Yunxia , Abbadessa Giovanni , Schwartz Brian E. , Kazakin Julia , Droz Dit Busset Michele , Shaib Walid Labib 
Published: September 2018

4017 Background: FGFR genetic aberrations have been implicated in the development and progression of a number of solid tumor types, including iCCA. Pts with unresectable advanced iCCA who relapse after first-line chemotherapy have limited treatment options with poor prognosis. Recently, FGFR2 fusions, observed in up to 20% of pts, have been recognized as a potential therapeutic target. ARQ 087 is a multi-kinase inhibitor with a potent pan-FGFR activity. Methods: 119 cancer pts were enrolled in the phase 1/2, open-label study of ARQ 087. Study design and results of the phase 1were reported previously. Assessments included response by RECIST v1.1 every 8 wks, safety (physical examination, vital signs, ECOG PS, laboratory tests), plasma concentrations of phosphate and FGF19, 21 and 23 (potential biomarkers). Results: As of 1Feb17, 35 iCCA pts with FGFR2 genetic aberrations were treated with ARQ 087 300 (n = 33) or 400 mg (n = 2) daily. FGFR2 status was identified by FISH or NGS, 29/35 pts were FGFR2 fusion positive (FISH n = 15/18; NGS n = 14/17). Pts were all white, female (60%) with ECOG PS 0 (69%) and median age 58 yrs (31-82). Median number of prior systemic therapies was 1(0-6). Drug-related AEs (all grades) were reported in 89% of pts; the most common (≥10%) included nausea (37%), dry mouth (29%), asthenia (26%), fatigue, vomiting (23%, each), abnormal LFTs, dysgeusia (20%, each), alopecia, diarrhea, vision blurred (14%, each), and conjunctivitis (11%). Grade 3/4 AEs occurring in ≥2 pts were asthenia and abnormal LFTs (6%, each). AEs were mostly (71%) of mild to moderate intensity, manageable and reversible. Median time on treatment was 183 days (95%CI: 166-289). 19 pts were on treatment for > 16 wks, nine are ongoing. 30 pts had at least one post-treatment radiographic assessment: 6 (20%) had PR (32-47% tumor reduction, all FGFR2 fusion positive), 17 SD (7 had tumor reduction between 10 to 25%), and 7 had PD. One pt died prior to scheduled assessment and assessment in 4 pts is pending. Conclusions: ARQ 087 demonstrated encouraging antitumor activity and manageable safety profile. Updated data, including safety, efficacy and biomarkers will be presented. Clinical trial information: NCT01752920.
VIKTORY trial: Report on AZD1775/paclitaxel in TP53 mutation (+) GC, selumetinib/paclitaxel in ras aberrant GC, AZD5363/paclitaxel in PIK3CA mt and biomarker negative, savolitinib/docetaxel in met (+), and vistusertib/paclitaxel in RICTOR(+) GC.
Authors: Lee Jeeyun , Kim Seung Tae , Mortimer Peter G. , Hollingsworth Simon J , Harrington Elizabeth A. , Shepherd Christopher , Kilgour Elaine , Park Se Hoon , Lee Hyuk , Oh Sung Yong , Kang Jung Hun , Park Joon Oh , Park Young Suk , Lim Ho Yeong , Kim Kyoung-Mee , Kang Won Ki 
Published: September 2018

4024 Background: The VIKTORY trial is a biomarker-based umbrella trial in GC. Methods: See table below. Results: From June 2014 to Jan 2017, 432 metastatic gastric cancer patients were enrolled. 124 (28.7%) were treated on one of the associated study protocols. At January 2017, 25 pts were allocated to selumetinib/paclitaxel arm, 25 to AZD1775/paclitaxel arm, 16 to AZD5363/paclitaxel arm, 16 to vistusertib/paclitaxel arm, 4 to savolitinib monotherapy, 19 to savolitinib/docetaxel arm, 19 to phase I AZD6738/paclitaxel arm. Initial efficacy signals have been seen in several arms (selumetinib/paclitaxel, 6 of 21 evaluable patients in PR). Correlative analyses between molecular signatures and treatment response are ongoing and will be presented at the meeting. For vistusertib/paclitaxel in the biomarker negative arm, we found RICTOR amplification as a promising predictive biomarker for response. Two (of three) GC patients with RICTOR amplification achieved PR to vistusertib/paclitaxel. Conclusions: This is one of the first attempts to undertake a biomarker-driven trial in metastatic GC. 28.7% of the patients were guided to one of the parallel arms based on molecular screening outcomes. We were able to identify potential molecular targets in the biomarker-negative arm, for further assessment in new protocols. Clinical trial information: 02299648. [Table: see text]
Clinicopathological features of program death ligand-1 expression with mismatch repair, Epstein-Barr virus status, and cancer genome alterations in metastatic gastric cancer.
Authors: Kawazoe Akihito , Shitara Kohei , Kuboki Yasutoshi , Bando Hideaki , Kojima Takashi , Yoshino Takayuki , Ohtsu Atsushi , Ochiai Atsushi , Togashi Yosuke , Nishikawa Hiroyoshi , Doi Toshihiko , Kuwata Takeshi 
Published: September 2018

4040 Background: Recently, anti-programmed death 1 (PD-1) or its ligand (PD-L1) antibodies have shown promising activities in metastatic gastric cancer (MGC). However, little is known about detailed clinicopathological features of PD-L1 expression in patients (pts) with MGC. Methods: Pts with histologically confirmed MGC were eligible for this prospective observational study. PD-L1 expression on tumor cell (TC) or inflammatory cell (IC) and mismatch repair (MMR) were analyzed by immunohistochemistry (IHC). Epstein–Barr virus (EBV) was detected by in situ hybridization. The expressions of tyrosine kinase receptors (RTKs) such as HER2, EGFR and MET and cancer genome alterations were also evaluated by IHC or next generation sequencing. Results: A total of 237 pts were enrolled from September 2015 to December 2016. Samples of 199 (84.0%) pts were obtained from biopsy. PD-L1 expression on TC and IC was positive in 27 (11.4%) and 167 pts (70.5%), respectively. One hundred and seventy-one pts (72.2%) had positive PD-L1 expression on either TC or IC. MMR deficient (D-MMR) and EBV was detected in 14 (6.9%, n = 203) and 14 pts (5.9%, n = 237), respectively. PD-L1 expression on TC was more frequently observed in pts with D-MMR (P < 0.001) and KRAS mutation (P < 0.001), while that on IC was more frequently observed in pts with EBV+ (P = 0.045), lymph node metastasis (P = 0.001), and lung metastasis (P = 0.045). In contrast, pts with peritoneal metastasis were associated with less frequent PD-L1 expression in IC (P = 0.003). A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. D-MMR was significantly associated with intestinal type (P = 0.026) and absence of liver metastasis (P = 0.022). PD-L1 expression on either TC or IC was not prognostic factor (hazard ratio; 0.92, P = 0.741). Seven pts with D-MMR and seven pts with EBV+ MGC were enrolled in clinical trials of anti-PD-1/PD-L1 antibodies. Conclusions: PD-L1 expression in MGC was associated with some clinicopathological features. Impact of these characteristics on efficacy of anti-PD-1/PD-L1 antibody warrants further evaluation.
Phase II study of afatinib in recurrent and/or metastatic esophageal squamous cell carcinoma (R/M ESCC) (KCSG HN14-18).
Authors: Hong Min Hee , Lee Yun-Gyoo , Kim Hyo Song , Park Keon Uk , Kim Hoon-Gu , Ko Yoon Ho , Chung Ik-Joo , Min Young Joo , Kim Min Kyoung , Kim HyeRyun , Cho Byoung Chul 
Published: September 2018

4051 Background: Afatinib, an irreversible pan-ErbB kinase inhibitor showed anti-tumor activity against esophageal cancer in phase I trial. In this multicenter, open-label, single arm phase II study, we aimed to evaluate the activity and safety of afatinib in R/M ESCC. Methods: Patients (pts) who had ECOG PS 0-2 and had progressed on platinum-based chemotherapy for R/M ESCC were enrolled. Pts were treated with afatinib 40mg/day until disease progression, unacceptable toxicity, or patient’s refusal. Primary endpoint was objective response rate (ORR) per RECIST 1.1. The estimated sample size was 49, using a two-stage minimax design to evaluate incremental response rate from 5 to 15%. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety profile. Additionally, we try to identify biomarker to predict efficacy of afatinib with target capture sequencing and gene expression profile as exploratory endpoints. Results: In a total of 49 enrolled pts (median age 60; range 44 -84), ORR and DCR were 14.3 % and 73.3%, respectively. With a median follow-up of 6.6 months, median PFS and OS was 3.4 months (95% CI 2.2-4.6) and 6.6 months (95% CI 5.2-8.0). Median treatment duration and duration of response were 2.8 months (range, 0.4-15.3) and 7.1 months (range, 2.5-13.9), respectively. Dose reduction and interruption occurred in 19 (38.8%) and 15 (30.6 %) pts. Treatment-related adverse events (TRAE) occurred in 33 pts (67.3%) with most common TRAEs being diarrhea (n=22, 44.9%) and acneiform rash (n=12, 24.5%). G3-4 TRAEs were rare, occurring in 7 pts (14.3 %). Conclusions: Afatinib demonstrated modest efficacy with manageable toxicity in platinum-resistant R/M ESCC patients. Given the modest response rate, identification of predictive biomarkers is essential for further clinical investigation of afatinib in R/M ESCC. Those biomarkers are being analyzed and will be presented in the conference (NCT02353936). Clinical trial information: NCT02353936. [Table: see text]