bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of early recurrence within one year of liver transplant for hepatocellular carcinoma with poor survival.
Authors: Li Bryan Cho Wing , Chiu Joanne Wing Yan , Yau Thomas , Leung Roland Ching-Yu , Tang Vikki , Shing Kit Bong , Kwok Gin Wai , Cheung Tan To , She Wong Hoi , Ma Ka Wing 
Published: January 2021

296 Background: Treatment of hepatocellular carcinoma (HCC) recurrences following liver transplant is challenging. All the clinical trials of systemic therapies for advanced HCC excluded patients with any history of organ transplant. Here we review outcome, and the safety and efficacy of the application of systemic medical therapies in this clinical setting. Methods: This is a retrospective cross-sectional study of consecutive adult patients with recurrence of HCC following liver transplant for the indication of treatment of HCC in Queen Mary Hospital from January 2005 to January 2018. Results: Forty-three consecutive patients with a recurrence of HCC following liver transplant were identified from 2005 to 2018. Median survival from diagnosis of recurrence was 17 months (CI 11.3, 22.7). Early recurrence within 12 months of transplant was associated with a significantly worse median survival of 10 months CI 8.5, 11.4) compared to 26 months (CI 18.8, 33.2) when recurrences occurred after 12 months from transplant (p< 0.001) after adjustment with peritumoural vascular invasion, first line therapy with sorafenib, any second line therapy and use of mTOR inhibitors as immunosuppressants, with a hazard ratio of 0.104 (log-rank test, p<0.001). 41 patients who received medical systemic therapies, 34 (79.1% ) received sorafenib as the first line systemic therapy. 47.1% (N= 16) received subsequent lines of systemic therapies (ranging from 1 to 4 lines). Hand-foot syndrome was most common among the adverse events and it was observed in 34.7% patients treated with sorafenib. It led to dose interruptions in 8.8 % of patients who were given sorafenib. 26.7% had grade 1 diarrhoea. 14.3% had grade 1 transaminase rise. Conclusions: Early recurrence within one year from transplant was the most significant risk factor. Treatment efficacy and adverse events and tolerability of sorafenib were comparable with those in the setting of advanced HCC without transplant.
Advances in the treatment of cholangiocarcinoma: Effect of online education on clinician knowledge and confidence.
Authors: Fisher Geoff Roy , Koekkoek Sanneke , Scot-Smith Camille , Malka David 
Published: January 2021

302 Background: This study determined whether online continuing medical education could improve the knowledge and confidence of clinicianson the latest developments in the treatment of cholangiocarcinoma (CCA). Methods: A 30-minute online video panel discussion was launched for countries outside the USA in March 2020. Data was collected to June 2020. Educational effect assessed with repeated-pairs pre-/post-activity, where individual participants served as their own control. Three multiple-choice, knowledge questions and one self-efficacy, five-point Likert scale confidence question were analyzed. Chi-squared test assessed pre- to post-activity change (5% significance level, P <.05). Magnitude of change in total number of correct responses overall, and for each question, were determined with Cramer’s V (<.06=Modest, 0.06-0.15=Noticeable, .16-.26=Considerable, >.26=Extensive). Results: 85 oncologists (oncs) and 44 gastroenterologists (gastros) completed pre- and post-activity questions. A considerable educational effect was observed for both oncs (V=.174, P<.0001) and gastros (V=.246, p<.0001) with average % of correct responses increasing from 62 to78% and 47 to 71%, respectively. Clinicians with 3/3 answers correct increased post-activity (11 to 48% for oncs, 28 to 51%, for gastros). Improvements in % of correct responses post-activity were seen for questions on the molecular target for pemigatinib, the subtype of CCA where IDH mutations are detectable, and the need for comprehensive molecular testing at diagnosis of metastatic CCA (relative improvements: 31%, 38%, and 11% for oncs; 155%, 50% and 14%, for gastros). 78% of oncologists’ and 72% of gastros’ responses were improved or reinforced post-activity. 21% of all participants stated they would modify treatment plans. Confidence in incorporating routine broad molecular testing in the treatment of CCA improved post-activity with a total average confidence shift of 25% for oncs and 32% for gastros. Conclusions: This on-demand, online video panel discussion resulted in a considerable education effect. Online medical education is valuable in improving knowledge and confidence, as well as identifying areas of continued educational need.
Phase II study of modulation of sorafenib (SOR)-induced autophagy using hydroxychloroquine (HCQ) in advanced hepatocellular cancer (HCC): Planned interim efficacy and safety analysis.
Authors: Arora Sukeshi Patel , Moseley Jennifer L. , Tenner Laura LaNiel , Arellano Luisa , Salazar Mary , Liu Qianqian , Michalek Joel , Mahalingam Devalingam 
Published: January 2021

305 Background: SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report planned interim analysis for our first-line cohort. Methods: Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, response by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Planned interim efficacy and safety analysis approved by DSMB is reported here. Results: For cohort 1, n = 19. Median age 63.5 (51-80). 80% Male; 65% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 32%. Etiology of cirrhosis: HCV 84%, ETOH 26%, NASH 5%. BCLC B 21%, C 70%. AFP > 400: 47%, PVT: 32%, metastases: 64%, post-transplant: 21%. Reason off study: PD (n = 10), toxicity (n = 2), lost to f/u (n = 1), withdrew (n = 1). N = 16 completed C1, n = 2 remain on study. mTTP is 4.2 months (95% CI: 3.7-NA). mOS 13.8 months (95% CI: 13.8-NA). Response Rate (CR+PR): 25%. Best response: CR n = 1 (6%), PR n = 3 (19%), SD n = 7 (44%). 4+ cycles: n = 9 (56%). % alive. Median duration of response 7.6 months (3.67-20). Gr 1/2 AEs as expected from SOR. Gr 3: AST elevated (n = 1), diarrhea (n = 1) due to SOR. Gr 2 rash (n = 1) due to HCQ. No Gr 4/5. Dose reduction: 70% for SOR, 0% for HCQ. PD analysis on the 3 responders show favorable immune profile changes (increase in cytotoxic T cells and decrease T Regs). Conclusions: SOR/HCQ had a better response rate (25%) than historically SOR alone (2%) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may have a role in patients with CP B cirrhosis, transplant or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing. Clinical trial information: NCT03037437.
Penpulimab (Anti-PD-1) combined with anlotinib as first-line therapy for unresectable hepatocellular carcinoma (uHCC): Updated results from a phase Ib/II study.
Authors: Jiao Shun Chang , BAI LI , Dong Jiahong , Bai Chunmei , Hu Chunhong , Shen Liangfang , Qin Qun , Bai Yuxian , Fan Jia , Zang Aimin , Zhu Yanyun , Han Chun , Li Juan , Zhang Pengfei , Ye Sisi , Kang Xindan , Qiao Qian , Wang Zhongmin Maxwell , Li Baiyong , Xia Yu 
Published: January 2021

306 Background: Combined therapy of an immune checkpoint inhibitor with a targeted antiangiogenic agent had been proved to be effective for the treatment of uHCC. Penpulimab was engineered to eliminate FcγR binding and ADCC/ADCP completely, where ADCC/ADCP effects could induce T-cell apoptosis and clearance and then compromise anti-tumor activity. Penpulimab demonstrated a slower PD-1 antigen binding off-rate, which resulted in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1 which could be an advantage to facilitate interaction of PD-1 antibody and might contribute to slower binding off-rate. These structural differentiations offer more robust biological effect and enhance anti-tumor activity of penpulimab. Anlotinib is a multi-targeted tyrosine kinase inhibitor selective for VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit. Methods: In this open-label, multicenter phase Ib/II study, patients (pts) without prior systemic treatment, and classified as BCLC stage B (not amenable for locoregional therapy) or C, Child-Pugh ≤7, and ECOG PS ≤ 1 received Penpulimab (200mg IV Q3W) and Anotinib (8 mg PO 2weeks on/1 week off). Primary endpoint was ORR (RECIST v1.1); secondary endpoints were safety, DCR, DoR, TTP, PFS and OS. Results: 31 pts (median age 56 years [23–74], ECOG 0/1 [64%/36%], BCLC B/C [23%/77%], HBV/HCV [61%/7%]) received combined therapy. As of August 31, 2020, median follow-up time was 11.9 mons (range 3.7-17.7). Median PFS was 7.6 mons with 6-mons PFS rate was 57.6% while median TTP was 8.5 mons with 6-mons TTP rate was 62.7%. Median overall survival had not been met and 6-mons OS rate was 93.2%. The ORR was 31.0% (9/29) and DCR was 82.8% (24/29). At data cutoff, 77.8% of responders remained ongoing and still on treatment. Treatment-related adverse events (TRAEs) occurred in 90.3% of pts (≥G3 in 16.1% [5/31], no G5, treatment discontinuation in 9.7% [3/31]). Most common TRAEs (≥15%) were increased AST (38.7%) and ALT (35.5%), increased blood bilirubin (22.6%),asthenia (22.6%),decreased platelet count (19.4%) and rash (16.1%). Conclusions: Penpulimab plus Anlotinib showed favorable antitumor efficacy and an acceptable safety profile in pts with uHCC. The further randomized, phase 3 study of Penpulimab in combination with Anlotinib at a higher dose (10 mg PO 2 weeks on/1 week off) in this setting is ongoing (NCT04344158).
Phase I study of the novel pro-drug MIV-818 in patients with hepatocellular carcinoma, intra-hepatic cholangiocarcinoma or liver metastases.
Authors: Evans T.R. Jeffry , Van Cutsem Eric , Prenen Hans , Middleton Mark R. , Sarker Debashis , Tunblad Karin , Oberg Fredrik , Morris Tom , Basse Linda , Plummer Elizabeth Ruth 
Published: January 2021

309 Background: MIV-818 is an orally administered troxacitabine (TRX)-based nucleotide prodrug. It is highly metabolized by human hepatocytes, directing high levels of the chain-terminating nucleotide tri-phosphate to the liver, while minimizing exposure to other organs. The tri-phosphate is incorporated into DNA during replication, which leads to DNA double strand breaks, DNA damage responses, and cytotoxicity. Methods: Patients (pts), ≥18 years, ECOG performance status < 1, adequate organ function, with treatment-refractory hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA) or liver metastases (LM) from solid tumors were enrolled. In phase Ia, MIV-818 monotherapy was administered in an intra-patient dose-escalation design with doses of 3-70mg for 3-5 days in cycles of 21 days. Phase Ib is an inter-patient dose escalation in a 3+3 cohort design and is currently ongoing. Treatment is given until disease progression or unacceptable toxicity. The primary objective is to assess safety and tolerability and, for phase Ia, also to establish the starting dose for phase Ib. Key secondary objective was to evaluate the overall response rate based on RECIST v1.1. The pharmacokinetics of MIV-818 and its metabolites were evaluated, and on-treatment liver biopsies were collected to assess the pharmacokinetics and the pharmacodynamic effects of MIV-818. Results: Nine patients (7M; 2F), ECOG performance status 0 (n=3) or 1 (n=6), median age = 57 years (range: 50-84) with HCC (2 pts), iCCA (1) or LM (6) from solid tumors (mainly GI tract), previously treated with median 2 (1-5) lines of therapy, were included in phase Ia. Patients were dosed up to 60 mg 5 days/week. The most common treatment related AEs were those in the hematological system: neutropenia grade (gr) 1-4, neutropenic sepsis gr 4; thrombocytopenia gr 1-2, anemia gr 1-2. Elevated bilirubin gr 1-3 and liver enzymes gr 3 were also reported. Most of the AEs were reversible. Five pts discontinued due to AE and 4 pts discontinued due to progressive disease outside the liver after 2-4 cycles. Starting dose of phase Ib was determined to be 40mg 5 days/week. Tumor biopsies showed evidence of selective DNA damage in tumor tissue, including in hypoxic regions, with minimal or no impact of MIV-818 observed in healthy liver tissue. Conclusions: MIV-818 had an acceptable safety and tolerability profile. Biomarker data of liver biopsies demonstrated a selective effect of MIV-818 on cancer cells. Updated safety and efficacy data from phase Ib will be presented at the meeting. (NCT03781934). Clinical trial information: 2018-000995-14.
A phase I/II study of safety and efficacy of the arginase inhibitor INCB001158 plus chemotherapy in patients (Pts) with advanced biliary tract cancers.
Authors: Javle Milind M. , Bridgewater John A. , Gbolahan Olumide B. , Jungels Christiane , Cho May Thet , Papadopoulos Kyriakos P. , Thistlethwaite Fiona C. , Canon Jean-Luc Re , Cheng Lulu , Ioannidis Sonia , Gogov Sven , Naing Aung 
Published: January 2021

311 Background: Arginase, secreted in the tumor microenvironment by myeloid suppressor cells, is a major regulator of arginine-mediated immune response. Arginase inhibition by INCB001158 increases arginine, which reverses the immunosuppressive effects of neutrophils and myeloid-derived suppressor cells on T cells. The current standard first-line (1L) treatment for advanced biliary tract cancers (BTC) is gemcitabine/cisplatin chemotherapy. The combination of INCB001158 immunotherapy and standard 1L treatment may provide additional clinical benefit in pts with advanced or metastatic BTC. Methods: This open-label phase 1/2 study evaluated the safety, tolerability, and antitumor activity of INCB001158 in pts with advanced or metastatic solid tumors. In phase I, dose escalation of INCB001158 (50, 75, and 100 mg twice daily [BID]) was used to determine the recommended phase II dose (RP2D) of INCB001158 + gemcitabine/cisplatin. Phase II used a Simon 2-stage design and evaluated objective response rate (ORR; RECIST v1.1), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) of INCB001158 RP2D + gemcitabine (1000 mg/m2)/cisplatin (25 mg/m2 Days 1 and 8 of 21-day cycle). Here we report preliminary safety and activity from the cohort of pts with BTC. Results: The phase I dose-escalation group identified a RP2D for INCB001158 of 100 mg BID. At a data cutoff of July 1, 2020, 33 pts with BTC in phase II treated with INCB001158 100 mg BID + gemcitabine/cisplatin were evaluable. Adverse events (AEs) related to INCB001158 and/or chemotherapy occurred in 88% of pts and 73% of pts had AEs related specifically to INCB001158 (Table). Treatment was interrupted due to INCB001158-related TEAEs in 30% of pts (n=10); discontinuation related to INCB001158 occurred in 3% (n=1). Treatment did not result in immune-related or significant additive chemotherapy-associated toxicity. ORR was 24% (8/33; 95% CI, 11.1–42.3) based on confirmed response per investigator’s assessment; stable disease occurred in 42% of pts. Median DOR (95% CI) was 5.8 (4.1–not reached) mo, and the DCR was 67%. Median PFS (95% CI) was 8.5 (5.7–10.1) mo. Conclusions: Preliminary data suggest the combination of INCB001158 100 mg BID + gemcitabine/cisplatin was tolerable and did not result in significant added toxicity. Response rates and PFS suggest that some pts with BTC may benefit from this combination. Clinical trial information: NCT03314935. [Table: see text]
Safety profile of immune checkpoint inhibitors versus sorafenib as first-line treatment in advanced hepatocellular carcinoma: A meta-analysis of randomized controlled trials.
Authors: Rizzo Alessandro , Frega Giorgio , Ricci Angela Dalia , Palloni Andrea , Tavolari Simona , Brandi Giovanni 
Published: January 2021

315 Background: Systemic treatment with tyrosine kinase inhibitors such as sorafenib represents the mainstay of advanced-stage hepatocellular carcinoma (HCC). However, survival outcomes remain disappointing, mostly because of the onset of acquired resistance and a suboptimal safety profile, which frequently requires treatment modifications and early discontinuation of treatment – thus, interfering with compliance and long-term outcomes of patients. With immune checkpoint inhibitors (ICIs) quickly expanding as a novel therapeutic option in advanced HCC, the toxicity profiles of these agents should be kept in mind. We performed a meta-analysis with the aim to compare all-grade (G) adverse drug events (ADEs) of ICIs (alone or in combination with other anticancer agents) versus sorafenib monotherapy across randomized controlled trials (RCTs) of first-line treatment for advanced HCC. Methods: Eligible studies included RCTs comparing ICIs versus sorafenib as first-line treatment in HCC. Safety profile from each selected study was investigated for all-G most common ADEs. Outcomes of interest were as follows: pruritus, diarrhea, hand-foot skin reaction (HFSR), fatigue, aspartate aminotransferase (AST) increase, rash, hypertension and decreased appetite. Results were compared by calculating odds ratios (ORs) with 95% confidence intervals (CIs); ORs were combined with Mantel-Haenszel method. All statistical analyses were performed using R studio software. Results: Two RCTs (CheckMate 459, IMbrave 150) involving 1,228 patients were included in the analysis. Patients treated with ICIs showed higher risk of pruritus (OR 1.99, 95% CI = 1.22-3.24) while sorafenib treatment was associated with higher risk of diarrhea (OR 0.26, 95% CI = 0.18-0.37) and HFSR (OR 0.01, 95% CI = 0-0.04). Conversely, no statistically significant differences were observed in terms of fatigue (OR 0.84, 95% CI = 0.45-1.58), AST increase (OR 1.21, 95% CI = 0.78-1.88), rash (OR 0.71, 95% CI = 0.46-1.11), hypertension (OR 0.28, 95% CI = 0.01-9.76) and decreased appetite (OR 0.41, 95% CI = 0.14-1.21) between the two groups. Conclusions: Although the substantial heterogeneities affecting our analyses, ICIs appear feasible in advanced HCC, being endowed with an acceptable safety profile. Beyond activity and efficacy, careful consideration should be given to toxicity while choosing the appropriate first-line treatment in advanced HCC.
Landmark analysis of overall survival (OS) by objective response (OR) in previously treated patients (pts) with advanced hepatocellular carcinoma (aHCC): Post-hoc analysis of the randomized, phase III KEYNOTE-240 study.
Authors: Edeline Julien , Cattan Stéphane , Merle Philippe , Daniele Bruno , Chan Stephen Lam , Yau Thomas , Bouattour Mohamed , Lim Ho Yeong , Chao Yee , Knox Jennifer J. , Ogasawara Sadahisa , Garrido Marcelo , Cheng Ann-Lii , Zhu Andrew X. , Finn Richard S. , Siegel Abby B. , Rahman Ahmadur , Liu Chih-Chin , Kudo Masatoshi 
Published: January 2021

318 Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE (KN)-224 (NCT02702414) evaluated pembrolizumab (pembro; anti-PD-1) in sorafenib (sora)-treated pts with aHCC and demonstrated an OR rate of 17% that was durable in responders receiving pembro, ultimately leading to its FDA approval. In KN-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KN-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KN-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KN-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to examine the association between survival after the landmark with response achieved prior to the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HRs and 95% CIs for survival after the landmark were calculated from the Cox proportional model with Efron’s method of tie handling with responder status as a single covariate. Analyses were performed in the ITT population. Results: As of Jan 2, 2019, the median time from randomization to data cutoff was 21.2 months (range 13.4-30.4) for pembro. There were 51 pts (18.3%) with a BOR of CR or PR in the pembro arm and 6 pts (4.4%) with a BOR of PR (no CR) in the pbo arm (excluded from landmark analyses). OS after landmark time was longer for responders compared with nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders versus nonresponders were 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis demonstrates that pts with sora-treated aHCC who achieve OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KN-224. Clinical trial information: NCT02702401. [Table: see text]