bluuebunny/crossref_metadata_2025 huggingface dataset:
Insurance status and cholangiocarcinoma: A NCDB analysis.
Authors: Ahmed Hibah , Law Nathan , Wolfe Katrina , Silberstein Peter T.
Published: February 2020

500

Background: There is an increasing rise of cholangiocarcinoma though the cause is unclear. Cholangiocarcinoma is more often than not incurable at diagnosis and associated with a high mortality rate. Our goal was to compare survival of patients with differing insurance types diagnosed with cholangiocarcinoma identified in the National Cancer Database (NCDB). Methods: We identified 5,638 patients with cholangiocarcinoma in the NCDB diagnosed between 2004-2014. Patients included were categorized as having no insurance, private insurance, Medicaid, or Medicare were included. Between-insurance survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < .05 indicated statistical significance. Results: Statistically significant survival differences were indicated between all insurance groups (all adjusted p < 0.05), such that privately insured patients had the highest median survival. The discrepancy in survival between uninsured and privately insured patients was the largest (6.5 months vs 13.1 months, respectively). Medicaid patients on average had a survival of 7.5 months, while Medicare patients had a median survival of 7.8 months. 2.8% of uninsured patients presented with stage I cholangiocarcinoma, whereas 34% of privately insured patients presented with stage I cholangiocarcinoma. More Medicare patients were treated at community cancer programs compared to privately insured patients (56.7% vs 30.7%, respectively). Likewise, more Medicare patients were treated at academic/research programs compared to those with private insurance, Medicaid, or those who were uninsured (44.7% vs 38.7% vs 7.2% vs 3.7%, respectively). Conclusions: Our study shows the discrepancies in survival between patients with differing insurance statuses. Of all insurances, those privately insured had the largest median survival.

[Table: see text]
Sociodemographic characteristics as predictors of outcomes in hepatocellular carcinoma: A retrospective cohort study.
Authors: Beutler Bryce David , Ulanja Mark Bilinyi , Aluru Vijay , Gullapalli Nageshwara
Published: February 2020

503

Background: It has been established that race, insurance status, and socioeconomic class play an important role in predicting health care outcomes. However, the impact of these factors has yet to be investigated in the setting of hepatocellular carcinoma (HCC). Methods: We designed a retrospective cohort study utilizing data from the SEER program (2007-2015) to identify patients with resectable HCC (N = 28518). Exposures of interest were race (Asian [AS], Black [BL], Native American/Alaska Native [NA/AN], or White [WH]), insurance status (Medicare/Private Insurance [ME/PI], Medicaid [MAID], or No Insurance [NI]), and median household income. Endpoints included: (1) likelihood of surgical recommendation and (2) overall survival. Multinomial logistic regression for relative risk ratio (RRR) and Cox models were used to identify pertinent associations. Results: Race, insurance status, and socioeconomic class had statistically significant effects on the likelihood of surgical recommendation and overall survival. AS were more likely to receive a recommendation for hepatic resection (RRR = 1.60; 95% CI: 1.42 – 1.80; Reference Race: BL) and exhibited prolonged overall survival (HR = 0.77; 95% CI: 0.73 – 0.82) as compared to members of other ethnic groups; there was no difference in these endpoints between BL, NA/AN, or WH individuals. Patients who had ME/PI were more likely than those with MAID or NI to receive a surgical recommendation. ME/PI was also associated with superior overall survival. Individuals with a household income in the highest quintile were less likely to receive a surgical recommendation than those in the lower quintiles, but nevertheless demonstrated prolonged survival. Conclusions: Race, insurance status, and socioeconomic class have measurable effects on HCC management and outcomes. The underlying causes of these disparities warrant further investigation.

[Table: see text]
Impact of facility type, insurance status, and income on use of single agent chemotherapy (SACT) for advanced hepatocellular carcinoma (AHCC): Analysis of National Cancer Database (NCDB).
Authors: Lee Richard T. , Cioffi Gino , Opneja Aman , Alahmadi Asrar , Patil Nirav , Jones Nelroy , Bajor David Lawrence , Saltzman Joel N. , Mohamed Amr , Mangla Ankit , Barnholtz-Sloan Jill
Published: February 2020

504

Background: This study analyzes the pattern of use of SACT in the treatment and survival of AHCC before and after sorafenib was FDA approved in late 2007. Methods: Adult patients diagnosed with HCC and treated with only chemotherapy (CT) from 2004 – 2014 were identified in NCDB database. Patients were analyzed during 3 time frames: 2004–2006 (pre-sorafenib (PS), 2007–2011 (early sorafenib (ES) and 2012–2014 (late sorafenib (LS)). Cox proportional hazards models and Kaplan-Meier method were used for analyses. Results: The NCDB contained 31,107 patients with HCC diagnosed from 2004–2014 and treated with CT alone. Patients were generally men (77.3%), >50 years of age (92.5%), and with a variety of T-stages - T1 (31.0%), T2 (23.9%), T3 (28.3%), and T4 (16.9%). The use of SACT was only 6.2% in the PS period, increased to 15.5% in the ES period, and to 22.3% in the LS period (p<0.0001). During this later period, the highest proportion of SACT is among academic and integrated network facilities (23.4%) as compared to community facilities (16.4%, p<0.0001). The MS of patients with AHCC treated only with CT has improved significantly over the study periods from 10 months (m) (95% CI: 9.5-10.6) to 12.5m (12.0-12.9) to 16m (15.6-16.4, p< 0.001). Significant differences in MS were found between facility types in all time frames (Table). Multivariate analysis indicates worse outcomes for patients treated at community cancer programs (HR 1.66, 1.53-1.79) as compared to academic programs as well as for no insurance (HR 1.13, 1.05-1.22) and estimated household income of <$63,000 (HR 1.09, 1.05-1.13). Conclusions: Despite an overall improvement in survival for AHCC patients treated with only CT, significant differences in the utilization of SACT and survival exist by facility type, insurance status, and income.

[Table: see text]
Celecoxib versus parecoxib versus oxycodone in pain control for transcatheter chemoembolization in patients with hepatocellular carcinoma.
Authors: Zhao Ming , Lyu Ning , Kong Yanan , Li Xiaoxian
Published: February 2020

509

Background: Abdominal pain is one of the most common side effects of transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma. Previous studies reported that perioperative controlled-release oxycodone (CRO) intake or administration of parecoxib resulted in adequate pain control after TACE. However, there are currently no studies comparing opioids with nonsteroidal anti-inflammatory drugs (NSAIDs) in controlling postoperative pain. Therefore, we conducted a clinical trial to compare the analgesic effect and safety among celecoxib (oral COX-2 inhibitor), parecoxib (injectable COX-2 inhibitor), and CRO (oral opioids) in patients undergoing TACE. Methods: The study was a prospective, randomized, paralleled trial in which 213 patients were enrolled between September 2016 and March 2019. Patients were randomly assigned at the ratio of 1:1:1 to receive celecoxib, parecoxib or CRO 1 h before TACE (T0) and once every 12 h for 2 days after TACE. Pain level, morphine consumption and adverse events were evaluated and compared among the three regimens. Results: Highest incidence of pain occurred within the first 12 hours (T12) after TACE. Analysis of pain control showed no significant difference among the mean highest pain scores, percentage distribution of pain categories and mean morphine consumption in the three groups at T0, T12, T24, T36, and T48. At T24, 11 patients (15.7%) in oxycodone group had fever, which was higher than parecoxib regimen (1 patient [1.5%], P = 0.003). At T36, 13 patients (18.6%) in oxycodone regimen had fever, which was higher than celecoxib regimen (2 patients [2.9%], P = 0.003) and parecoxib regimen (1 patient [1.5%], P < 0.001). At T48, 11 patients (15.7%) in oxycodone regimen had fever, which was higher than celecoxib regimen (2 patients [2.9%], P = 0.010) and parecoxib regimen (0 patients, P = 0.001). Conclusions: The results suggested that patients obtained celecoxib, parecoxib or CRO once every 12 hours can have the same level of analgesic effect during each time period of TACE. However, body temperature balance in oxycodone regimen was significantly worse than celecoxib regimen and parecoxib regimen. Clinical trial information: NCT03059238.
The comparison of mFOLFOXIRI with CAOX/SOX as neoadjuvant chemotherapy for locally advanced rectal cancer.
Authors: Terazawa Tetsuji , Kodama Hiroyuki , Yukami Hiroki , Aoki Masahiko , Miyamoto Takahiro , Asaishi Ken , Yamaguchi Toshifumi , Kii Takayuki , Goto Masahiro , Tanaka Keitaro , Okuda Junji , Higuchi Kazuhide
Published: February 2020

51

Background: The standard therapy for the locally advanced rectal cancer (LARC) (Ra or Rb, T2Npsitive, T3/4Nany) is chemoradiotherapy (CRT) followed by surgery. The CRT prevents local recurrence, although problems such as complications or the improvement of distant recurrence still remain. Several studies about the neoadjuvant chemotherapy (NAC) without radiation showed favorable R0 resection rate and outcome, however the best regimen of NAC is unclear. The aim of this study is to investigate the efficacy and safety of mFOLFOXIRI and CAPOX/SOX as NAC. Methods: We examined the patients (pts) with LARC who were planned to receive mFOLFOXIRI (5FU 2400mg/m2/day1-2, leucovorin 200mg/m2, oxaliplatin 85mg/m2, irinotecan 150mg/m2, every 2 weeks) or CAPOX/SOX(capecitabine 2000mg/m2 or S-1 mg/m2 80day1-14, oxaliplatin 130mg/m2, day1, every 3weeks) for 8-12 weeks as NAC, retrospectively. Results: Forty-nine pts received mFOLFOXIRI and thirty-two pts received XELOX/SOX between Jan 2015 and Mar 2019. The characteristics of mFOLFOXIRI and XELOX/SOX were as follows; median age, 64 (37-80) and 65 (33-68); PS 0/1, 46(94%)/3(6%) and 14(44%)/18(56%); Ra/Rb-P, 4(8%)/45(92%) and 0/32; clinical T2/3/4, 4(7%)/27(55%)/19(39%) and 1(3%)/18(56%)/13(41%); clinical N0/1/2, 13(27%)/26(53%)/10(20%) and 7(22%)/17(53%)/8(25%). The pathological response rate which was defined as tumor affected area over one-third were 61.2% in mFOLFOXIRI and 65.6% in CAPOX/SOX including complete remission of 4.1% and 12.5%, respectively. Six of 49 pts withdrew from mFOLFOXIRI due to toxicities, whereas one of 32 pts from CAPOX/SOX. One pt received CRT after SOX because of lack of efficacy. The major grade 3/4 toxicities of mFOLFOXIRI were neutropenia (n = 22, 45%), thrombocytopenia and febrile neutropenia (n = 4, 8%) and anorexia (n = 3, 6%), whereas CAPOX/SOX neutropenia (n = 3. 9%), thrombocytopenia (n = 1, 3%) and hand-foot syndrome (n = 1, 3%). The one year of relapse free survival rate were 85.4% and 83.6%. Conclusions: Although the pathological response of mFOLFOXIRI was comparable with CAPOX/SOX, CAPOX/SOX was less toxic.The further investigation including 5 year overall survival rate rate was needed.
Effect of neoadjuvant immunotherapy and targeted therapies on surgical resection in patients with solid tumors: A systematic review and meta-analysis.
Authors: Serrano Aybar Pablo Emilio , Parpia Sameer , Ruo Leyo , Tywonek Kasia , Lee Sandra , O'Neill Connor , Faisal Noor , Alfayyadh Ali , Gundayao Marylrose , Meyers Brandon M.
Published: February 2020

511

Background: Neoadjuvant immunotherapy with anti-programmed cell death protein-1 (PD-1) or anti-programmed cell death ligand-1 (PD-L1) and tyrosine kinase inhibitor (TKI) therapy is currently being used to treat certain solid tumours prior to surgery. Neoadjuvant therapy may cause delays to resection potentially losing a window of opportunity. We explored the pooled proportion of patients with solid tumours receiving neoadjuvant therapy who completed planned surgical resection. Methods: Medline, CENTRAL and Embase databases were searched for single arm or randomized controlled trials studying neoadjuvant PD-1/PD-L1 immunotherapy or TKI therapy. Random-effects model was used to estimate the pooled proportion of patients undergoing planned resection, and weights were estimated using inverse variance method. Statistical heterogeneity was calculated using the I2 and chi-squared test. Results: From 368 relevant articles, eleven studies with a total of 382 patients receiving neoadjuvant PD-1 immunotherapy (n = 234) or neoadjuvant TKI therapy (n = 148) were analyzed. The types of tumours included hepatocellular carcinoma (1 study), renal cell carcinoma (8 studies), bladder carcinoma (1 study) or non-small cell lung cancer (1 study). The pooled proportion of patients who completed planned surgery after neoadjuvant therapy was 95% (95% CI 0.92 to 0.99). The overall partial response rate prior to surgery was 12% (95% CI 0.07 to 0.16) in the PD-1 therapy group and 46% (95% CI -0.12 to 1.03) in the TKI group. The pooled serious adverse events rate was 17% (95% CI 0.02 to 0.32) in the PD-1 therapy group and 29% (95% CI -0.10 to 0.68) in the TKI group. For all patients receiving neoadjuvant therapy, the pooled median overall survival was 23.41 months (95% CI 16.21 to 30.62) and median progression free survival was 7.46 months (95% CI 4.41 to 10.51). Conclusions: Neoadjuvant PD-1 or TKI therapy prior to surgery for solid tumours is safe, does not delay surgical resection and can result in a partial radiological response prior to surgery.
Major impact of personalized dosimetry using 90Y loaded glass microspheres SIRT in HCC: Final overall survival analysis of a multicenter randomized phase II study (DOSISPHERE-01).
Authors: Garin Etienne , Tzelikas Lambros , Guiu Boris , Chalaye Julia , Edeline Julien , De Baere Thierry , Tacher Vania , Robert Corentin , Assenat Eric , Terroir-Cassou-Mounat Marie , Regnault Hélène , Palard Xavier , Laffont Sophie , Campillo-Gimenez Boris , Rolland Yann
Published: February 2020

516

Background: 90Y loaded microsphere SIRT (radioembolization) is a treatment option in advanced HCC. However, no personalized dosimetric endpoints are currently used. The goal of this study was to compare the efficacy of 90Y loaded glass microsphere SIRT in HCC using a standard versus a personalized dosimetric approach. Methods: DOSISPHERE-01 was a multicenter, randomized phase 2 trial in unresectable HCC patients with at least one tumor ≥7cm. Treatment arm was randomly assigned (1:1) to standard dosimetry arm (SDA), with a goal to deliver 120±20Gy to the treated volume or to personalized dosimetry arm (PDA) with a goal to deliver at least 205Gy to the index lesion. The primary endpoint was the response rate (RR) of the index lesion according to EASL criteria. Secondary endpoints included dose response evaluation, safety and overall survival (OS). Results: Sixty HCC patients were randomized (PDA 31, SDA 29, intent to treat population-ITTP-), and 56 treated (28 in each arm). RR was significantly increased in the PDA versus the SDA, in the ITTP, respectively 64.5% versus 31% (p=0.0095) as in the safety population -SP- (treatment effectively received, personalized 35, standard 21), respectively 74.3% versus 14.3% (p<0.0001). Median OS was significantly increased in the PDA versus the SDA, in the ITTP, respectively 26.7m (CI 95%:11.7-NR) versus 10.6m (CI 95%:6-16.8), p=0.0096, HR=0.421 (95%CI:0.215-0.826), p=0.0119, as in the SP, respectively 26.7m (CI 95%:11.7- NR) versus 9.5m (CI 95%:4.8-14.9), p=0.0015, HR=0.342 (95%CI:0.171-0.683), p=0.0023. Median OS was 26.7m (CI 95%:13.5-NR) versus 6.0m (CI 95%:3.8-14.9) for the patients who received a tumor dose ≥205 Gy or <205 Gy respectively, p=0.0106, HR=0.336 (95%CI:0.154-0.735), p=0.0063. Treatment-related clinically relevant hepatic ≥grade 3 AEs were observed in 5.7% and 14.2% of the patients of the PDA and SDA arms, respectively, (p=ns). Conclusions: MAA SPECT/CT based personalized dosimetry is safe and dramatically increased RR and OS of HCC patients. These results question the interpretation of all phase 3 trials of SIRT designed without personalized dosimetry in HCC. Clinical trial information: 2015-A00894-45.
Analysis of OX40 agonist antibody (PF-04518600) in patients with hepatocellular carcinoma.
Authors: El-Khoueiry Anthony B. , Spano Jean-Philippe , ANGEVIN ERIC , Doi Toshihiko , Bullock Andrea J. , Harris William Proctor , Hamid Omid , Gougis Paul , Forgie Alison , Yang Wenjing , Liao Ken , Li Ruifeng , Taylor Carrie T. , Chou Jeffrey , Eskens Ferry
Published: February 2020

523

Background: PF-04518600 (PF-8600) is a humanized agonist IgG2 monoclonal antibody to the tumor necrosis factor superfamily receptor OX40. PF-8600 was given to patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC) in dose expansion of a phase 1 study (NCT02315066). Safety and tolerability were primary endpoints and exploratory endpoints included biomarker analyses. Methods: Pts received either 30 mg (Arm 1) or 250 mg (Arm 2) of PF-8600 intravenously Q2W. Pts had pathologic diagnosis of advanced HCC, a Child-Pugh score of A or B7, and had ≤2 prior lines of therapy, or if treatment naïve, had declined standard of care. Radiological tumor assessments were conducted Q8W. Biopsy samples collected at baseline and wk 6 were analyzed by immunohistochemistry and RNA sequencing for pharmacodynamic (PD) analyses. Whole blood samples were collected longitudinally for DNA extraction for high-throughput sequencing of the T cell receptor β-chain. Results: Arm 1 enrolled 16 pts (mean age 65.6 yrs; range 54-81 yrs; prior PD-1/PD-L1: 5 pts) and Arm 2 enrolled 19 pts (mean age 61.7 yrs; range 26-79 yrs; prior PD-1/PD-L1: 3 pts). All grade treatment related adverse events (TRAEs) occurred in 69% of pts in Arm 1 and 58% of pts in Arm 2. The rate of ≥Grade 3 TRAEs was 31% and 16% in Arms 1 and 2, respectively. For both arms combined, the most common (≥10%) TRAEs were rashes and pruritus. In Arm 1, 8 pts (50%) and in Arm 2, 10 pts (53%) achieved stable disease (SD), with a mean duration of 18.4 (range: 14.0-30.3 wks) and 17.4 wks (range: 8.0-31.9 wks), respectively. PD effects were more evident in Arm 1 than Arm 2, including increased OX40 tumor expression and positive changes in gene signatures, reflecting an active anti-tumor immune response. Conclusions: PF-8600 was generally well tolerated and provided meaningful disease control. While safety and efficacy were not significantly different between the 2 doses, there were potential differences in the PD data. The safety and relative durability of SD in HCC pts may provide a rationale for exploration of combination therapy in this pt population. Clinical trial information: NCT02315066.
Nivolumab (NIVO) and drug eluting bead transarterial chemoembolization (deb-TACE): Preliminary results from a phase I study of patients (pts) with liver limited hepatocellular carcinoma (HCC).
Authors: Harding James J. , Yarmohammadi Hooman , Reiss Kim Anna , Chou Joanne F. , Capanu Marinela , Do Richard K. G. , Khalil Danny , El Dika Imane H. , Giardina Joseph Daniel , Merghoub Taha , Jarnagin William R. , Nadolski Gregory , Erinjeri Joseph Patrick , Soulen Michael C. , Tan Benjamin R. , Abou-Alfa Ghassan K.
Published: February 2020

525

Background: Regional therapies in HCC impact the immune microenvironment and may augment the effects of immune checkpoint inhibitors. Methods: This is a multicenter phase 1 study of NIVO and deb-TACE in unresectable HCC pts (BCLC Stage B) and Child Pugh A cirrhosis (NCT03143270). The primary objective is to assess safety. Secondary objectives include response rate by RECIST v1.1, progression-free and overall survival by Kaplan-Meier methodology, and blood/tumor immune correlates. A 3 + 3 design sequentially evaluates 3 cohorts of differing schedules of NIVO relative to deb-TACE. Deb-TACE (75mg of doxorubicin) is administered on Day 0. NIVO is dosed at 240mg IV every 14 days for 1 year (Cohort 1: NIVO begins day +14 after deb-TACE; Cohort 2, interrupted NIVO dosing begins at Day -28 but is held on the Day 0 then restarted on Day +14; Cohort 3, continuous NIVO dosing begins on Day -28 without interruption). Results: As of July 2019, 9 pts have been treated [median 65 years (range: 54-76), male (89%), viral (44%;1 HBV, 3 HCV), non-viral (56%;2 EtOH, 1 NASH, 2 unknown), prior resection (44%), prior regional therapy (44%), 3 pts in each cohort]. No cases of treatment related liver failure, dose-limiting toxicity, or Grade 5 adverse events (AEs) were observed. Grade ≥3 AEs possibly related to nivolumab, deb-TACE, or both included: transaminase elevation (1 pt: day 1 post TACE resolved in 7 days without treatment; 2 pts: ≥30 days post TACE resolved with steroids between 20-41 days), post-embolization syndrome (1 pt: resolved in 5 days), asymptomatic lipase increase (1 pt: resolved in 14 days), post-procedural groin hematoma (1 pt: resolved in 2 days). All 9 pts were evaluable for efficacy: 2 (22%) confirmed PR and 7 (78%) SD. 4/9 pts remain on study with SD or better—2 pts continue > 18 months post embolization with durable PRs. 12 months OS rate was 71%. Ongoing correlates will be presented at a separate meeting. Conclusions: Nivolumab given at various times relative to deb-TACE appears safe and tolerable. Cohort 3 continues to accrue to provide a better estimate of safety and antitumor activity of the combination. Clinical trial information: NCT03143270.
Impact of baseline and concomitant corticosteroid therapy on the outcomes of hepatocellular carcinoma treated with immune checkpoint inhibitor therapy.
Authors: Pinato David James , Kaseb Ahmed Omar , Wang Yinghong , Saeed Anwaar , Szafron David , Jun Tomi , Naqash Abdul Rafeh , Lee ChiehJu , Khan Uqba , Nimkar Neil Satish , Paul Sonal , Bettinger Dominik , Hildebrand Hannah , Pressiani Tiziana , Abugabal Yehia I. , Personeni Nicola , Huang Yi-Hsiang , Rimassa Lorenza , Ang Celina , Marron Thomas Urban
Published: February 2020

531

Background: The impact of corticosteroid treatment (CT) on the efficacy of immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) is undefined. We evaluated whether CT administered at baseline (bCT) or concurrently to ICI (cCT) influences clinical outcomes of HCC patients treated with ICI. Methods: This retrospective, multi-center observational study was conducted across 9 tertiary academic referral centers collected 341 HCC patients who received ICI across 3 continents between January 1, 2016 and April 1, 2019. Outcome measures included overall (OS) and progression-free survival (PFS) calculated from time of ICI commencement and overall response rates (ORR) defined by Response Evaluation Criteria in Solid Tumors (v1.1) on 6-8 weekly periodic restaging. Results: Of 331 eligible patients, 254 (76%) had BCLC-C stage HCC and received mostly PD(L)-1 ICI monotherapy (n=250, 85%). Median OS was 12.1 months (95%CI 9.2-15.0 months) and median PFS was 8.1 months (95%CI 6.3-10 months). In total 81 patients (24%) received >10 mg prednisone equivalent daily either as bCT (n=15, 4%) or cCT (n=66, 20%). Indications for CT included procedure/prophylaxis (n=37, 45%), management of irAE (n=31, 37%), cancer-related symptoms (n=5, 2%) or comorbidities (n=8, 3%). Neither overall CT, bCT nor cCT predicted for worse OS, PFS nor ORR in uni- and multi-variable analyses (p>0.05). CT for cancer-related indications predicted for shorter PFS (2.4 vs. 11.3 months, p=0.01), OS (4.5 vs. 12.8 months, p=0.05) and reduced ORR (p=0.03) compared to cancer-unrelated indications. Conclusions: This is the first study to demonstrate that neither bCT nor cCT appear to influence response and OS following ICI in HCC. Worse survival and ORR in CT recipients for cancer-related indications appears driven by the poor prognosis associated with symptomatic HCC.
Immunotherapy versus biologics as second-line therapy in advanced hepatocellular carcinoma (HCC).
Authors: Al-Jumayli Mohammed , Hildebrand Hannah , Abbasi Saqib , Kasi Anup , Saeed Anwaar
Published: February 2020

533

Background: Sorafenib or lenvatinib are the current frontline options for advanced HCC. Multiple biologic agents including multi-Tyrosine Kinase Inhibitors (TKI) cabozantinib & regorafenib have been recently approved for the previously treated population. Immunotherapy (IO) agent Nivolumab have also been approved in the same setting. Due to lack of prospective head to head comparison, there is no standardized way for alternating those agents beyond frontline. Methods: We performed a retrospective review of KU cancer registry. Patients with advanced HCC were divided into 2 groups based on the 2nd line systemic regimen (IO vs non-IO). Kaplan–Meier and Cox proportional hazards models were utilized to evaluate progression free survival (PFS) and overall survival (OS). Results: Between 2016-2019, 98 patients were identified, 41 received IO, while 57 received biologics. All patients had sorafinib as 1st line therapy. Most patients have ECOG 0-1 and Child-Pugh class A or B. 55% had hepatitis C, 6% hepatitis B and 27 % have history of alcohol misuse. Almost 50% of patients have received prior liver directed therapy. Comparing IO vs non-IO groups, median PFS was 3.9 months vs 3 months and median OS was 10 months vs 10 months. There was no statistically significant difference in PFS & OS but there was a delay separation in the survival curve favoring IO. Similar outcome was seen in a sub-group analysis of the hepatitis C patients. Conclusions: This retrospective comparative review of current 2nd line regimens is one of the first & largest studies reported. In this study population, IO was not superior to multi-TKI as a 2nd line regimen. The late survival curve separation favoring IO might suggest a delay IO effect in a subgroup of patients. Future studies should define specific biomarkers that could predict response and allow treatment to be optimized depending on patient and tumor characteristics. Furthermore, combining IO plus multi-TKI might be a promising next step in development. A number of ongoing trials are testing this strategy including our CAMILLA trial of Cabozantinib plus Durvalumab, currently enrolling patients at the University of Kansas Cancer Center NCT03539822 .
Biomarker exploration for SHR-1210 plus GEMOX as first-line treatment in advanced biliary tract cancer.
Authors: Chen Xiaofeng , Wu Hao , Wu Xiaofeng , Shao Qianwen , Zhu Feipeng , Qian Xiaofeng , Zhao Fengjiao , Mao Weidong , Sun Jing , Wang Jian , Han Gaohua , Li Huajun , Zhu Dongqin , Zhu Liuqing , Li Changxian , Seesaha Poshita kumari , Shao Yang , Gu Yanhong , Li Xiangcheng , Shu Yongqian
Published: February 2020

536

Background: We conducted a trial to evaluate the efficacy and safety of SHR-1210 (a humanized anti-programmed cell death receptor 1 antibody) plus gemcitabine and oxaliplatin (GEMOX) as in untreated patients (pts) with biliary tract cancer (BTC) (NCT03486678). This study is to explore the predictive biomarkers for efficacy. Methods: Baseline lymphocyte count and lactate dehydrogenase (LDH) level were obtained from routine tests. Gene mutation and tumor mutation burden (TMB) from baseline tissue and blood samples were tested by the next generation sequencing (NGS) with a 425-gene panel. The expressions of PD-L1 and markers for lymphocyte, natural killer cells, and macrophages in baseline tumor tissue samples were analyzed by immunohistochemistry (IHC). Results: The median progression free survival (PFS) and overall survival (OS) in this trial was 6.2m and 12.1m, respectively. Firstly, pts with normal LDH level (≤271 U/L) had a tendency for longer PFS (6.2m vs 5.0m, p = 0.053) and significantly longer OS (p = 12.6m vs 6.8m, p < 0.001) than those with elevated LDH ( > 271 U/L). Low baseline lymphocyte count (≤ 1.1×109/L) was related to worse OS (12.6m vs 6.9m, p < 0.001) and PFS (6.2m vs 3.9m, p = 0.021). Secondly, baseline tissue and ctDNA gene mutations were detected in 33 and 30 pts, respectively. Tissue analysis showed that pts with STK11 (p = 0.0254), CTNNB1 (p < 0.001) and SMARCA4 (p = 0.0181) wild type showed significantly longer PFS than those with mutations. Pts with ARID1A gene wild type showed a tendency for longer PFS (p = 0.0634) and significantly longer OS (p = 0.0149). Gene mutations from baseline ctDNA revealed that pts with wild type SMARCA4, CTNNB1, STK11, and NF1 had longer PFS than those with mutations. Lastly, IHC meant that PD-L1 positivity may be related to longer PFS (TPS > 1%, p = 0.08; IPS > 1%, p = 0.05). Besides, pts with CD68+ HLA-DR+ macrophages > 0.01%, CD68+ HLA-DR- macrophages>2.5%, and CD56bright>1.7% and CD56dim > 0.05 also got PFS benefits (all p < 0.05). TMB (cutoff = 7 muts/mbp) was not associated with PFS. Conclusions: Despite limited sample size, biomarkers from routine blood test, gene mutation and immune microenvironment can be helpful to stratify pts who are sensitive to immunotherapy in advanced BTC. Clinical trial information: NCT03486678.
Treatment of hepatocellular carcinoma and liver metastases with hafnium oxide nanoparticles activated by SBRT: A phase I/II trial.
Authors: Jaksic Nicolas , Pracht Marc , Rolland Yann , De Baere Thierry , Durand-Labrunie Jerome , Nguyen France , Bronowicki Jean-Pierre , Vendrely Veronique , Sa Cunha Antonio , Croisé-Laurent Valérie , Rio Emmanuel , Le Sourd Samuel , Said Patricia , Freund Sebastian , Baskin-Bey Edwina , Gustin Pierre , Perret Christophe , Peiffert Didier , Deutsch Eric , Chajon Enrique
Published: February 2020

537

Background: Treatment of unresectable liver cancer or liver metastases (mets) by stereotactic body radiotherapy is well tolerated but limited by the need to preserve liver function. Increasing energy deposition in the tumor while at the same time maintaining the dose in healthy tissue remains a major challenge in radiation oncology that could be achieved by NBTXR3 (hafnium oxide nanoparticles) when activated by radiotherapy (RT). NBTXR3 augments energy dose deposit within tumor cells, increasing tumor cell death compared to RT alone, while sparing healthy tissues. Patients (pts) with hepatocellular carcinoma (HCC) or liver metastasis (mets) may benefit from the mode of action of NBTXR3. A phase I/II clinical trial has been conducted to evaluate NBTXR3 activated by SBRT in these pts [NCT02721056]. Methods: The Phase I used a 3+3 dose escalation scheme with 5 NBTXR3 dose levels: 10, 15, 22, 33, and 42% of baseline tumor volume. NBTXR3 was administered by intratumoral injection (ITI) followed by SBRT (45 Gy / 3 fractions / 5 to 7 days or 50 Gy / 5 fractions / 15 days). Primary endpoints were identification of the recommended Phase II Dose and early DLTs. Secondary endpoints included safety profile, liver function evaluated by Child-Pugh score (CPS), AST to Platelet Ratio Index (APRI), and early efficacy by response rate (mRECIST/RECIST 1.1). Results: The dose escalation levels of 10, 15, 22 and 33% are completed (n = 17): 6 pts at 10% (2 SBRT doses tested due to organ constraints), 4 pts each at 15% and 22% (due to fiducial displacement and ITI shift) and 3 pts at 33%. No early DLT was observed and only one SAE (bile duct stenosis) related to NBTXR3 and RT occurred. CPS and APRI did not show clinically meaningful changes post-treatment and CT-scan showed no leakage of NBTXR3 into surrounding tissues. Best response for HCC (n = 8) were 5CR, 3PR and for mets (n = 6) the results were: 3 PR, 3SD. Conclusions: ITI of NBTXR3 is feasible, demonstrated a very good safety and tolerability profile up to the 33% dose level. Recruitment needs to be finalized at the 42% dose level. Based on early efficacy results NBTXR3 has the potential to address an unmet medical need in pts with unresectable primary or metastatic liver cancer. Clinical trial information: NCT02721056.
Expansion part of phase I study of E7090 in patients with cholangiocarcinoma harboring FGFR2 gene fusion and with gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression.
Authors: Morizane Chigusa , Ueno Makoto , Ioka Tatsuya , Tajika Masahiro , Ikeda Masafumi , Yamaguchi Kensei , Hara Hiroki , Yabusaki Hiroshi , Miyamoto Atsushi , Iwasa Satoru , Muto Manabu , Takashima Tsutomu , Minashi Keiko , Komatsu Yoshito , Nishina Tomohiro , Nakajima Takako Eguchi , Sahara Takatoshi , Funasaka Setsuo , Yashiro Masakazu , Furuse Junji
Published: February 2020

538

Background: E7090 is a selective tyrosine kinase inhibitor against FGFR1-3. This first-in-human phase I study has been conducted in Japan and consists of 2 parts. Based on the toxic, pharmacokinetic, and pharmacodynamic profiles in Part 1, dose escalation study, the recommended dose was determined to be 140 mg QD for Part 2, an expansion study part restricted to patients with tumors harboring FGFR gene alterations. Here we provide the interim analysis results of Part 2. Methods: In Part 2, patients with cholangiocarcinoma harboring FGFR2 gene fusion (CCA cohort) and gastric cancer harboring FGFR2 gene amplification or FGFR2 protein high expression (GC cohort) were enrolled. Patients received oral dosing of E7090 until disease progression or unacceptable toxicity. Safety was assessed using CTCAE version 4.03. Tumor response was evaluated by site investigators using RECIST 1.1. Results: As of 31 March 2019, 16 patients including 6 patients in CCA cohort and 10 patients in GC cohort received E7090 in Part2. Median age was 63 years, 25% were female, ECOG PS of 0 and 1 were 50% respectively. 5 patients (83%) in CCA cohort and 1 patient (10%) in GC cohort achieved partial response as the best overall response. The disease control rates were 100% in CCA cohort and 30% in GC cohort, respectively. Median progression-free survivals were 8.3 months in CCA cohort and 2.8 months in GC cohort at the cut-off date. 2 patients with CCA remain on treatment. The most common treatment-related TEAEs occurring in 30% or more of patients in Part 2 were hyperphosphatemia (100%), palmar–plantar erythrodysesthesia syndrome (56%), paronychia (50%), dysgeusia (38%), stomatitis (31%), diarrhea (31%), increased AST (31%) and blood creatinine increased (31%). Grade≥3 treatment-related TEAEs were reported in 2 out of 16 patients (13%); they were increased AST, lipase increased and retinopathy. Conclusions: This study indicated that E7090 has a manageable safety profile in Part 2 and the promising clinical activity in CCA patients with FGFR2 gene fusion.
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

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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

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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.