bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics/pharmacodynamics (PK/PD) of ivosidenib in patients with mutant IDH1 advanced cholangiocarcinoma from the phase III ClarIDHy study.
Authors: Fan Bin , Abou-Alfa Ghassan K. , Zhu Andrew X. , Pandya Shuchi Sumant , Jia Hongxia , Yin Feng , Jiang Liewen , Gliser Camelia , Yang Hua 
Published: February 2020

539 Background: Mutations in isocitrate dehydrogenase 1 (m IDH1) occur in up to 20% of intrahepatic cholangiocarcinomas (CC), leading to accumulation of 2-hydroxyglutarate (2-HG) and epigenetic dysregulation, promoting oncogenesis. Ivosidenib (IVO; AG-120), a first in-class, oral, targeted inhibitor of the mIDH1 enzyme, showed improved progression-free survival and a positive trend in overall survival versus placebo (PBO) in ClarIDHy, a global, phase 3, multicenter, double-blind study (Abou-Alfa et al. ESMO 2019 LBA10_PR; NCT02989857). Methods: Patients (pts) with unresectable or metastatic m IDH1 CC were randomized 2:1 to IVO (500 mg once daily in continuous 28-day cycles) or matched PBO, stratified by number of prior systemic therapies (1 or 2). Crossover from PBO to IVO was permitted at radiographic progressive disease. Blood samples for PK/PD analyses, a secondary endpoint, were collected predose, 0.5, 2, and 4 h postdose on day (D) 1 of cycles (C) 1–2, predose and 2 h postdose on D15 of C1–2, and predose on D1 from C3 onwards. Plasma IVO and 2-HG were measured using validated or qualified LC-MS/MS methods. Results: As of 31Jan2019, 185 pts were randomized to IVO (n = 124) or PBO (n = 61); 35 pts crossed over to IVO. PK/PD analysis was available from 156 pts receiving IVO. IVO was absorbed rapidly following single and multiple oral doses; exposure, as measured by Cmax and AUC, was higher at C2D1 than after a single dose, with low accumulation. Plasma IVO reached steady state within C1 of daily dosing. In pts receiving IVO, baseline mean plasma 2-HG concentration was reduced from 1108 ng/mL to 97.7 ng/mL at C2D1, close to levels in healthy subjects (72.6±21.8 ng/mL). 2-HG inhibition was robust and persistent up to Cycle 19. An average 2-HG inhibition of 75.0% (up to 97.3%) was observed at steady-state after multiple IVO administrations. No plasma 2-HG decreases were seen with PBO. Analyses of plasma 2-HG levels and association with clinical outcomes will be presented. Conclusions: In pts with advanced m IDH1 CC, oral IVO 500 mg once-daily demonstrated good exposure, and maintained the inhibition of 2-HG to levels observed in healthy subjects, whereas 2-HG remained elevated with PBO. Clinical trial information: NCT02989857.
Ramucirumab for patients with intermediate-stage hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): Pooled results from two phase III studies (REACH and REACH-2).
Authors: Kudo Masatoshi , Finn Richard S. , Morimoto Manabu , Rau Kun-Ming , Ikeda Masafumi , Yen Chia-Jui , Galle Peter R. , Llovet Josep M. , Daniele Bruno , Lim Ho Yeong , Liang Kun , Shinozaki Kenta , Wang Chunxiao , Yoshikawa Reigetsu , Abada Paolo , Widau Ryan C. , Zhu Andrew X. 
Published: February 2020

549 Background: Intermediate-stage HCC, as defined as Barcelona Clinic Liver Cancer (BCLC) Stage B, is a heterogeneous disease in terms of liver function and tumor load. REACH (NCT01140347) and REACH-2 (NCT02435433) investigated ramucirumab (RAM) in patients (pts) with HCC after prior sorafenib (SOR), with REACH-2 enrolling only pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: All pts had HCC (BCLC stage C or B disease refractory/not amenable to locoregional therapy), Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or Placebo (P) Q2W. A pooled meta-analysis of independent pt data (stratified by study) from REACH-2 and REACH (AFP ≥400 mg/mL) was performed. Prognosis of BCLC staging in overall survival (OS) was evaluated by multivariate Cox PH model (adjusted for baseline AFP and treatment (trt) arm); Trt effects in BCLC stage B and C by Cox PH model; median OS/PFS were estimated by Kaplan-Meier method. Objective response rate (ORR) per RECIST v1.1, disease control rate (DCR), and adverse events (AEs) were also reported by BCLC. Liver function was assessed at baseline and prior to each trt with the Albumin-Bilirubin (ALBI) linear predictor. Results: Baseline characteristics were generally balanced between trt arms in each BCLC stage. BCLC staging trended as an independent prognosis factor for OS [B v C; HR = 0.756 (0.546, 1.046)]. A consistent trt benefit for RAM v P was observed across staging (Table). Grade ≥3 AEs were consistent with observations from both individual studies; hypertension was the most frequent grade ≥3 AE. No difference in liver function, as measured by ALBI, was observed between trt arms in either BCLC stage. Conclusions: Acknowledging limitations of sample size, RAM provided a survival benefit irrespective of BCLC stage. RAM was well tolerated and did not alter liver function compared to P. Clinical trial information: NCT01140347, NCT02435433. [Table: see text]
Precision medicine in colorectal cancer: Gaps in patients’ literacy of biomarkers and genetic testing.
Authors: Yarden Ronit , Springer Tamara 
Published: February 2020

55 Background: Colorectal cancer (CRC) is the second leading cause of cancer death in the united states. Despite some advances, mortality is high and the 5-year overall survival from metastatic disease (mCRC) is only 14%. CRC is a heterogeneous disease with multiple subtypes defined by location, microsatellite integrity, specific genetic alterations and potentially age. The identification of specific driving mutation/s led to the development of targeted therapies. Patients are eligible for these treatments based on their personalized tumor biomarker profile. ASCO guidelines recommend that all patients with mCRC are tested for KRAS mutations. This mutation is present in ~40% of CRC patients, and serves as a biomarker for lack of response to EGFR therapy. Similarly, high microsatellite instability (MSI-H) suggests an inferior response to commonly used chemotherapy and favorable response to immunotherapy. Methods: We conducted an online survey to assess patients, survivors and caregivers’ knowledge and understanding of biomarker testing. Results: Among the 210 participants in this cross-sectional study, 81% of participants reported ‘no familiarity’ with the term biomarkers at the time of diagnosis, while 73% reported awareness at the time of the survey. Yet, when presented with specific biomarkers, majority of participants were not familiar with any of those biomarkers. Of the 103 stage IV respondents, only 14% were familiar with the four common CRC biomarkers, and only 1 in 4 reported their tumor was tested prior to treatment initiation. Nearly half of the respondents cited their physician and medical team as the main source of biomarker information (46%) while the other half reported their medical team never informed them of biomarkers. Overall, 50% of participants indicated that advocacy groups, medical websites, and various online resources were their main sources of biomarker information. Disparities of biomarker awareness were noted based on gender, age, and area of residency. Conclusions: Taken together, patients do not fully comprehend the meaning and implications of biomarker testing. Medical teams should make a greater effort to inform their patients early on in their treatment.
The impact of inflammatory biomarkers, BMI, and sarcopenia on survival in advanced hepatocellular carcinoma treated with immunotherapy.
Authors: Akce Mehmet , Liu Yuan , Zakka Katerina Mary , Martini Dylan J. , Draper Amber , Alese Olatunji B. , Shaib Walid Labib , Wu Christina , Wedd Joel , Sellers Marty T. , Bilen Mehmet Asim , El-Rayes Bassel F. 
Published: February 2020

553 Background: Sarcopenia and inflammation are independently associated with worse survival in cancer patients. This study aims to determine the impact of inflammatory biomarkers, BMI and sarcopenia on survival in advanced hepatocellular carcinoma (HCC) patients treated with immunotherapy. Methods: We performed a retrospective review of advanced HCC patients treated with immunotherapy-based therapies at Winship Cancer Institute between 2015 and 2019. Baseline computed tomography and magnetic resonance imaging scans were collected at mid-L3 level, assessed for skeletal muscle density using SliceOmatic (TomoVision, version 5.0) and converted to skeletal muscle index (SMI) by dividing it by height (m)2. Gender-specific sarcopenia was defined by median value of SMI. The optimal cut for continuous inflammation biomarker was determined by bias-adjusted log-rank test. Overall Survival (OS) was set as primary outcome and Cox proportional hazard model was performed. Results: 57 patients were included; 77.2% male, 52.6% Caucasian, 58.5% ECOG PS 0-1, 80.7% Child Pugh A. Treatment was second line and beyond in 71.9%. The median follow-up time was 6 months. Sarcopenia cut-off for males and females was SMI of 43 and 39, respectively. 49.1% of patients had sarcopenia. Median OS was 5 vs. 14.3 months in sarcopenic vs. non-sarcopenic patients (p=0.054). Median OS was 5 and 17.5 months in patients with BMI <25 and BMI ≥25 respectively (p=0.034). Median OS was 3.6 and 14.3 months for patients with neutrophil to lymphocyte ratio (NLR) ≥ 5.15 vs. NLR < 5.15 (p<0.001). In multivariable Cox regression model, higher baseline NLR was associated with worse OS (HR: 4.17, 1.52-11.39, p=0.005). Gender specific sarcopenia showed a trend of worse OS (HR: 1.71, 0.73-4.00, p=0.215) but was not statistically significant. BMI<25 was associated with worse OS (HR: 2.73, 1.15-6.53, p=0.023). In the association with PFS, neither baseline BMI nor gender specific sarcopenia showed statistical significance. Conclusions: Baseline BMI and NLR may predict OS after immunotherapy treatment. After controlling for baseline Child Pugh Score and NLR, gender specific sarcopenia was not associated with OS significantly.
Predictors of immunotherapy (IO) response in hepatocellular carcinoma (HCC).
Authors: Armstrong Samantha Ann , Singh Bhavana Pendurthi , Kulasekaran Monika , Prins Petra , He Aiwu Ruth 
Published: February 2020

555 Background: Despite advances in understanding the molecular pathways of HCC, therapeutic options are limited and patient survival is dismal. IO is a promising HCC treatment. There are currently no indicators to identify which patients (pts) will have a prolonged response. Methods: In this single-institutional retrospective analysis, pts received one of five IO containing regimens with nivolumab, pembrolizumab, atezolizumab plus bevacizumab, durvalumab or cemiplimab until disease progression (PD) or unacceptable toxicity. Relevant factors including: stage, viral etiology, vascular invasion (VI), tumor thrombus (TT), multifocal disease, toxicity grade, steroid use for IO mediated toxicities and derived Neutrophil-to Lymphocyte ratio (dNLR), were correlated to clinical outcome: progression free survival (PFS), overall survival (OS), response rate (RR), using Pearson’s chi-square test or student's t-test . Responses were assessed using RECIST v 1.1 criteria for stable disease (SD), partial response (PR) and PD were correlated with best response and PFS. OS was calculated by the Kaplan-Meier method. Results: Cohort demographics (n = 76) were: 72% male; 38% African American, 30% Caucasian and 16% Asian; 29% of pts had HBV, 41% had HCV, 1% had both HBV/HCV and 13% had no viral etiology (n = 64). The majority of pts were stage III (43%) or IV (38%). At the start of IO, 32% had VI, 32% had TT and 80% had multifocal or metastatic disease. 65% of pts experienced IO toxicity, with 24.3% at grade 3 or higher, and 34% requiring steroids. Best response to IO was SD in 65.7% of pts, PR in 25.7% and PD in 8.6%. Median OS was 13m (95% CI 7.9-18.1) from the start of IO and median PFS (n = 65) was 14m (95% CI 6.8-21.2). Median OS and PFS were significantly improved in pts with PR compared to PD (45 vs 8m, p < 0.0005, PFS 15 vs 3m p = 0.007). Both OS and PFS showed benefits for SD of ≥2 months compared to those with PD (11 vs 8m, p < .0005, PFS 5 vs 3m p = .007). VI, TT, stage, viral etiology, toxicity grade or dNLR did not correlate with OS, PFS and RR, however need of steroid treatment trended toward worse outcome. Conclusions: PR and SD are independent predictors for prolonged PFS and OS in HCC pts receiving IO therapy. Absence of steroid use for toxicity trended toward improved IO response.
Phase II study of copanlisib in combination with gemcitabine and cisplatin in advanced cholangiocarcinoma.
Authors: Tan Elaine , Kim Dae Won , Mehta Rutika , Cao Biwei , Kim Jongphil , Meroni Angel , Centeno Barbara , Kim Richard D. 
Published: February 2020

556 Background: First line therapy for advanced cholangiocarcinoma (CCA) is currently gemcitabine and cisplatin. However, survival rarely exceeds one year with this regimen. PI3K/AKT activation has been shown to increase resistance to chemotherapy in CCA; therefore, inhibiting this pathway may improve chemotherapy’s efficacy. This phase II study evaluated the safety and efficacy of copanlisib, a potent and reversible pan-class I PI3K inhibitor, with gemcitabine and cisplatin in advanced CCA. Methods: Between July 2016 and April 2019, pts with histologically confirmed advanced/unresectable CCA received cisplatin (25 mg/m2), gemcitabine (1000mg/m2), and copanlisib 60mg on day 1 and 8, every 21 days as first line treatment. The primary endpoint was PFS at 6 months. Secondary endpoints were RR, median OS and PFS, and safety profile. A single-arm Simon’s two-stage minimax design with one-sided 10% type I error and 80% power was used. Based on ABC-01 and ABC-02 studies, PFS6 for gemcitabine and cisplatin were 57.1% and 59.3%, respectively. Therefore, PFS6 of 57% was considered not to warrant further study and ≥72% to warrant further investigation. Results: Twenty-four pts received at least one dose of the study drug (62.5% female, median age 64 years), with 70.8% intrahepatic, 16.7% extrahepatic, and 12.5% gallbladder cancer. For all pts, median OS was 13.9 months (95% CI: 6.8-17.9) and median PFS was 6.2 months (95% CI: 1.3-11.1). PFS at 6 and 12 months was 57.0% and 42.2%, and 6 and 12-month OS was 73.9% and 53.2%, respectively. Only 19 pts were considered evaluable for RR. Five pts were either lost to follow up, withdrew consent, or died before a second scan was done. Six pts achieved PR (31.5%) and 11 (57.9%) had SD. Grade 3 or higher adverse events (AE) occurred in 75% of pts. The most common grade 3/4 AEs were decreased neutrophil count (40%) and increased lipase (20%). Treated related AEs led to drug discontinuation for 3 pts (12.5%) and dose modification for 7 pts (29.2%). Conclusions: Gemcitabine, cisplatin, and copanlisib in combination did not meet the primary endpoint of 6-month PFS. However, additional correlative work is ongoing to identify a possible biomarker for copanlisib. Clinical trial information: NCT02631590.
Apurinic/apyrimidinic endonuclease-1 and hepatocellular carcinoma.
Authors: Skill Nicholas James , Maluccio Mary Alice 
Published: February 2020

563 Background: The enzyme apurinic/apyrimidinic endonuclease-1 (APE1) is associated with protection against DNA damage and oxidative damage congruent with cancer. The purpose of this study is to investigate hepatic APE1 levels in association with hepatocellular carcinoma (HCC) in order to better stratify patients with underlying liver disease for the development of HCC and identify novel targets for therapy. Methods: Hepatic APE1 levels were determined by immunohistochemistry staining and ELISA within liver and tumor samples from patients with HepC±HCC. Hepatic APE1 staining was semi-quantitated using a scale of 0-100. Serum APE1 levels were determined by ELISA. In addition, APE1 staining was quantified in hepatic paraffin embedded sections from MDR2−/− mice with HCC and within MDR2−/+ mice controls that do not develop HCC. Results: Hepatocyte APE1 staining was lower in livers from patients with HepC and HCC when compared to patients with HepC without HCC. In a similar manner, hepatic APE1 levels were significantly lower in patients with HepC and HCC patients when compared to HepC controls. In contrast, serum APE1 level was greater in patients with HepC and HCC when compared to patients with HepC and no HCC. Moreover, APE1 levels were greater in HCC tumors when compared to non-malignant liver tissue. Hepatocyte APE1 staining in MDR−/− mice with HCC was lower when compared to MDR2−/+ mice that do not develop HCC. In addition, cytosolic APE1 staining was increased in HCC tumor of MDR2−/− mice when compared to controls. Conclusions: Increased APE1 is a potential biomarker of HCC risk in patients with underlying liver disease and is a novel target for therapy in patients with underlying liver disease whom have a higher risk of developing HCC. Consequently, targeted APE1 inhibition may increase chemotherapy response by reducing tolerance to DNA damage. Additional studies are required to better understand the role of APE1 inhibition in HCC in the face of reduced background hepatic APE1 levels.
Therapeutic targeting of extracellular FGFR2 activating deletions in intrahepatic cholangiocarcinoma.
Authors: Cleary James M. , Raghavan Srivatsan , Li Yvonne Y. , Spurr Liam , Wu Qibiao , Shi Lei , Brais Lauren K. , Odhiambo Zunelly , Goyal Lipika , Patel Anuj K. , Shinagare Atul B. , Clancy Thomas E. , Shapiro Geoffrey , Cerami Ethan , Sellers William R. , Hahn William C. , Cherniack Andrew D. , Bardeesy Nabeel , Meyerson Matthew , Wolpin Brian M. 
Published: February 2020

567 Background: Fibroblast growth factor receptor (FGFR) pathway alterations have been identified in approximately 20% of patients (pts) with intrahepatic cholangiocarcinoma (IHCC), most commonly by FGFR2 fusions. Early phase clinical trials have demonstrated encouraging efficacy of FGFR inhibitors in pts with FGFR2-translocated cholangiocarcinoma, but efficacy in pts with other FGFR2 activating alterations is less clear. Methods: Pts with cholangiocarcinoma underwent CLIA-certified next generation DNA sequencing (NGS) to identify actionable alterations. FGFR2 fusions and other FGFR2 genomic events were assessed, with genomic characterization performed before and after treatment with FGFR inhibitors in appropriate pts. Novel extracellular domain in-frame deletions (INDELs) of FGFR2 and apparent resistance mutations were investigated for oncogenic activity and inhibitor resistance in vitro and in vivo. Results: Cholangiocarcinomas from 284 pts (136 male, 148 female; median age, 64 [20-89], including 139 IHCCs, were sequenced. Among the IHCCs, 16 (11.5%) had FGFR2 fusions, with 9 different gene partners. Surprisingly, 5 (3.6%) IHCCs harbored extracellular domain FGFR2 INDELs. Two of these IHCCs harbored an exon 5 deletion FGFR2 p.H167_N173del. Expression of FGFR2 p.H167_N173del in 3T3 cells resulted in oncogenic transformation. In the clinic, two pts with FGFR2 p.H167_N173del were treated with Debio1347, an oral FGFR-1/2/3 inhibitor. Both patients achieved a durable partial response (PR) of 11 months, with one of the pts still on active treatment with Debio-1347. The patient who developed acquired resistance underwent repeat biopsy, and NGS identified a secondary mutation ( FGFR2 p. L617F) in the kinase domain. In vitro studies demonstrated that this mutation confers resistance to Debio1347. This patient was subsequently treated with another FGFR inhibitor and again experienced a PR lasting 17 months. A third biopsy after disease progression demonstrated a previously undetected L597Q BRAF mutation. Conclusions: Extracellular domain FGFR2 in-frame deletions are a novel genomic alteration in IHCC that are transforming and predict clinical sensitivity to FGFR inhibitors.
Total skeletal, psoas, and rectus abdominis muscle mass as prognostic factors for patients with advanced hepatocellular carcinoma.
Authors: Shao Yu Yun , Wu Chih-Horng , Liang Po-Chin , Hsu Chih-Hung , Shih Tiffany Ting-Fang 
Published: February 2020

568 Background: We investigated whether low skeletal muscle mass (LSMM) defined according to different muscle groups on computed tomography (CT) scans could predict prognosis of advanced hepatocellular carcinoma (HCC). Methods: We analyzed patients who received first-line sorafenib treatment for advanced HCC in a prospective patient cohort between 2007 and 2012. The muscels areas of total skeletal muscle (TSM), paraspinal muscle (PS), psoas muscle (PM), rectus abdominis (RA), and abdominal wall (AW) were evaluated using a single CT slice at the third lumbar vertebra before treatment. LSMM was determined according to the TSM, PS, PM, RA and AW indices, which was calculated as the parameters divided by the square of the body height. Results: We enrolled 137 patients, with a mean age of 57.5 years; 120 were male and 17 were female. Liver disease etiology was hepatitis B virus in 94 (68.6%) patients and hepatitis C virus in 28 (20.4%) patients. All patients had Child–Pugh class A liver reserve. Women had significantly lower TSM index than men did ( p < .001). Among men, the optimal cut points of the TSM, PM and RA indices for LSMM diagnosis were 39.1, 8.3 and 2.9 cm2/m2, respectively. Patients with LSMM exhibited poorer overall survival than patients without LSMM, whether LSMM was defined by TSM index (median 5.1 vs. 8.0 months, p = 0.007), PM index (median 5.8 vs. 11.8 months, p < 0.001), or RA index (median 7.2 vs. 8.1 months, p = 0.003). After adjusting for clinical variables including underweight, age, tumor extent, and performance status, LSMM defined by TSM index (hazard ratio [HR]: 2.123, 95% confidence interval [CI]: 1.124-4.010, p = 0.020), PM index (HR: 1.855, 95% CI: 1.163-2.959, p = 0.009), or RA index (HR: 1.650, 95% CI: 1.004-2.710, p = 0.048) remained independent predictors for poor OS. Conclusions: LSMM defined by TSM, PM and RA indices are independent predictors for poor prognosis of advanced HCC, even after adjusted for body weight.