bluuebunny/crossref_metadata_2025_split huggingface dataset:
Post hoc analysis in patients (pts) with unresectable hepatocellular carcinoma (uHCC) who progressed to Child-Pugh B (CPB) liver function in the phase III REFLECT study of lenvatinib (LEN).
Authors: Huynh Jasmine , Cho May Thet , Kim Edward Jae-Hoon , Ren Min , Robbins Carol , Amaya-Chanaga Carlos , Vogel Arndt 
Published: January 2021

298 Background: The treatment landscape for pts with uHCC has recently expanded. However, there is an unmet need for effective treatment options in CPB pts. LEN is approved first-line in uHCC based on the REFLECT study (Child-Pugh A [CPA] pts were allowed, per inclusion criteria). In a prior analysis of REFLECT, pts treated with LEN benefited irrespective of baseline liver function (ALBI grade 1 or 2; Child-Pugh score 5 or 6). To determine outcomes in pts with reduced liver function, we report a post hoc analysis of key efficacy and safety results in LEN-treated pts from REFLECT who progressed to CPB and those who did not within the first 8 weeks of treatment. Methods: In REFLECT, pts with uHCC were randomized 1:1 to LEN (per bodyweight: 12 mg/day for ≥60 kg; 8 mg/day for < 60 kg) or sorafenib (400 mg twice daily) in 28-day cycles. This analysis assessed ORR. Landmark analyses (starting at week 8) of PFS, time-to-progression (TTP), and OS in CPB pts and in pts who remained CPA at 8 weeks post-randomization were also conducted. Tumors were assessed by mRECIST by independent imaging review. Safety was also assessed from baseline. Results: This subgroup analysis included LEN-treated pts (n = 60) who progressed to CPB within the first 8 weeks of treatment (CPB pts) and 413 pts who did not (CPA pts). At baseline, 26.7% and 73.1% of pts had an ALBI grade of 1 and 73.3% and 26.9% of pts had an ALBI grade of 2 in CPB and CPA pts, respectively. ORR was 28.3% (95% CI 16.9–39.7) for CPB pts and 42.9% (95% CI 38.1–47.6) for CPA pts. A landmark analysis showed a median PFS of 3.7 mos (95% CI 1.8–7.4) for CPB pts and 6.5 mos (95% CI 5.6–7.4) for CPA pts from the week 8 timepoint. Landmark analyses at week 8 also showed that the median TTP was 5.6 mos (95% CI 3.5–9.3) for CPB pts and 7.3 mos (95% CI 5.6–7.4) for CPA pts; the median OS was 6.8 mos (95% CI 2.6–10.3) for CPB pts and 13.3 mos (95% CI 11.6–16.1) for CPA pts per week 8 landmark analyses. As expected, efficacy appeared to be greater in CPA pts versus CPB pts; however, OS of 6.8 months in CPB pts after the week 8 landmark is notable. Moreover, median duration of treatment was 3.2 mos for CPB pts and 6.9 mos for CPA pts, thereby suggesting CPB pts can remain on LEN. The incidence of grade ≥3 treatment-related AEs (TRAEs) was 71.7% in CPB pts and 54.7% in CPA pts. TRAEs leading to discontinuation occurred in 18.3% of CPB pts and 7.5% of CPA pts. Conclusions: In this post hoc analysis of pts in REFLECT, we examine the key efficacy and safety results for LEN-treated pts who progressed to CPB by week 8. This post hoc analysis is limited by its descriptive nature; however, the results indicate that further study of LEN in CPB pts with uHCC is warranted. Clinical trial information: NCT01761266.
Real-world outcomes of patients with intrahepatic cholangiocarcinoma treated with trans-arterial radioembolization: Results from the CIRSE Registry for SIR-Spheres Therapy (CIRT), a large European prospective multi-center observational study.
Authors: Helmberger Thomas , Arnold Dirk , Balli Tugsan , Golfieri Rita , Pech Maciej , Ronot Maxime , de Jong Niels , Sangro Bruno 
Published: January 2021

308 Background: Trans-arterial radioembolization (TARE) is a treatment option for patients with intrahepatic cholangiocarcinoma (ICC). The CIRSE Registry for SIR-Spheres Therapy (CIRT) is the first European prospective multi-centre observational study designed to evaluate the clinical outcomes of patients treated with TARE with SIR-Spheres Y90 resin microspheres for ICC in the multi-institutional real-life clinical setting. The study was conducted by the Cardiovascular and Interventional Radiological Society of Europe (CIRSE). Methods: Patients were enrolled prospectively between Jan 2015 and 31 Dec 2017. Eligible patients were adults treated with TARE with Y90 resin microspheres for ICC. Data on baseline characteristics and treatment intention/clinical context and dosimetry were collected, as well as follow-up data (every 3 months; for 24 months after treatment), including overall survival (OS), (hepatic) progression-free survival [(h)PFS], safety and Global Health Status (GHS, using the European Organisation for the Research and Treatment of Cancer QLQ-C30). Results: 120 patients were included from 18 sites in 8 European countries. Median age was 63 years (range: 29-86) and 54.2% were male. Median tumour to liver percentage was 12.8%. Median prescribed activity was 1.32 GBq for whole liver treatments (n = 49), 1.20 GBq for right lobe treatments (n = 56) and 0.82 GBq for left lobe treatments (n = 51). 97.5% of the delivered activity was within 90% of the prescribed activity. TARE treatment as a first line (L1) global strategy was applied in 39.1%, 27.4% as second line (after systemic therapy). Treatment intention was predominantly palliative (69.2%) or tumour shrinkage (20.8%). Median OS was 14.7 months (95% confidence interval (CI) 10.9 – 17.9). Median PFS was 5.7 months (95% CI 3.9 – 7.5), whereas hPFS was 6.2 months (95% CI 4.1 – 8.5). Mean GHS was 59.3 at baseline, 61.0 after 3 months, 56.0 at 6 months, 54.4 at 9 months and 63.0 after 1 year. Severe adverse events (grade 3 and 4) were found in 13 (10.8%) patients: (abdominal pain 3.3%, fatigue 1.7%, gastrointestinal ulceration 0.8%, gastritis 0.8%, radiation cholecystitis 0.8%, radiation-induced liver disease 1.7%, other 5.8%). Detailed subgroup analyses are currently being performed. Updated data describing OS, PFS and hPFS for L1 TARE vs TARE after systemic chemotherapy, as well as prognostic factors for OS, PFS and hPFS will be shown. Conclusions: The results from this large prospective multi-centre observational study shows that in the real-world context, TARE is applied early and successfully in the treatment pathway. TARE is shown to be an effective and safe treatment with no meaningful deterioration of quality of life. Clinical trial information: NCT02305459.
Alliance/CALGB 80802: Impact of hepatitis C (HCV) on doxorubicin (DO) + sorafenib (S) versus S in patients (pts) with advanced hepatocellular carcinoma (aHCC).
Authors: El Dika Imane H. , Geyer Susan Michelle , Nixon Andrew B. , Innocenti Federico , Shi Qian , Jacobson Sawyer B. , Yaqubie Amin , Lopez Juan C. , Huang Binhui , Tang Yi-Wei , Wen Yujia , Schwartz Lawrence Howard , Bertagnolli Monica M. , Meyerhardt Jeffrey A. , O'Reilly Eileen Mary , Venook Alan P. , Abou-Alfa Ghassan K. 
Published: January 2021

325 Background: Alliance/CALGB 80802 randomized phase III trial evaluated DO+S vs. S in pts with aHCC, and showed no improvement in median OS. Multi-drug resistant pathway mitigation by the Ras/Raf/MEK/ERK pathway and bFGF-mediated activation of Raf-1 promotes the formation of antiapoptotic Raf-1 and ASK1 complex, induced by anthracyclines. S efficiently blocks NS5A-recruited c-Raf mediated HCV replication and viral gene expression. Once inhibited by S, VEGF expression of HepG2 may limit HCV cellular entry. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via S putatively differ in the presence or absence of DO. We hypothesize treatment with S reduces HCV titer levels (TL) and influence pts’ outcome. Methods: In 80802 HCV pts, TL were evaluated in both arms at baseline and post-baseline at Day 1 of Cycles 2, 3, and every 2 cycles and at progression or discontinuation of therapy. HCV undetectable (HCV-UN) levels were defined as < 50 copies/mL. TL were evaluated in relation to OS and PFS. HCV RNA levels were measured by TaqMan PCR and by genotype. Results: Of 356 pts, 83 were HCV+ with more Black/African American (25/50 = 50%) vs. White (54/239 = 23%) or other race groups (4/67 = 6%) (p < 0.0001). HCV titer data were available on 54 pts (S: 28, DO+S: 26). At baseline, 12 pts (S: 7, DO+S: 5) were HCV-UN, and post-baseline HCV TL did not significantly differ between treatment arms; one patient in each arm went from detectable (HCV-D) to HCV-UN. Post-baseline, 40 pts were HCV-D vs. 14 who were HCV-UN (S+DO: 8, S: 6 pts). Except for the two pts who became HCV-UN, baseline HCV-D vs. HCV-UN titers was similar to that status post-baseline. PFS and OS between HCV-D and HCV-UN both at baseline and post-baseline are delineated in the table. Conclusions: We observed that S did not influence HCV TL. Pts treated with DO+S vs. S had worse PFS if they had HCV-UN, and further that higher levels of HCV titers at baseline were associated with significantly improved PFS. Given the small sample size, these findings warrant further prospective evaluation. Support: U10CA180821, U10CA180882, U24CA196171; Bayer, Bristol-Myers-Squibb, and Sanofi. https://acknowledgments.alliancefound.org . Clinical trial information: NCT01015833. [Table: see text]
Safety and efficacy of combination of GT90001, an anti-activin receptor-like kinase-1 (ALK-1) antibody, and nivolumab in patients with metastatic hepatocellular carcinoma (HCC).
Authors: Hsu Chiun , Chang Yi-Fang , Yen Chia-Jui , Lu Li-Chun , Zhu Xiaoyan , Xu Yuwei , Zhou Qiaoxia , Dong Xunwei , Tong Youzhi 
Published: January 2021

326 Background: GT90001, a fully human anti-ALK-1 mAb (IgG2) that may inhibit ALK-1/ TGF-β signaling and tumor angiogenesis, has shown good single-agent safety profile in humans. This study aimed to assess the safety and efficacy of GT90001 in combination with nivolumab in patients with advanced HCC who had progressive disease after or were intolerant to first-line sorafenib or lenvatinib therapy (NCT03893695). Methods: We did a phase I/II, open-label, single arm, dose de-escalation and expansion trial of GT90001 in combination with nivolumab in patients with histologically or cytologically confirmed HCC with Child-Pugh class A, ECOG performance status of 0 or 1 at three sites in Taiwan. Patients previously treated with immune checkpoint inhibitors were excluded. Stage 1 (dose de-escalation cohort) tested 3 doses of GT90001 (7 (starting dose), 4.5, and 3 mg/kg every 2 weeks) plus nivolumab 3 mg/kg every 2 weeks in 6 subjects at each dose level. Dose-limiting toxicity (DLT) was defined as any treatment-emergent grade 3-4 adverse events (AEs) (CTCAE V5.0) in the first 28 days of treatment. Stage 2 (expansion cohort) tested the combination regimen in 14 patients until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was investigator-assessed objective response as per RECIST v1.1. Results: Between July 9th, 2019 and June 26th, 2020, twenty eligible patients were treated. No DLT was observed in stage 1, and GT90001 7.0 mg/kg + nivolumab 3.0 mg/kg every 2 weeks were given in stage 2. The pharmacokinetics of GT90001 and nivolumab were similar to those observed in monotherapy. As of June 26, 2020, 20 patients were evaluable for safety. The common AEs (occurring to more than 20%) included platelet count decreased, rash, fatigue, dizziness, peripheral edema, and constipation. Three patients had treatment-related serious AEs (renal dysfunction, autoimmune hepatitis, hyperamylasemia). Nine patients had GT90001 dose interruption due to AEs and the most common reasons were platelet count decrease (3 patients). No patient discontinued the treatment due to AEs. The median duration of follow-up was 3.7 months (range 0.6-11.1). An objective response assessed was observed in 7 patients (43.75%) out of 16 evaluable patients, all were partial response and 4 of them had confirmed responses. The disease control rate (complete response + partial response + stable disease) was 56.2%. Updated efficacy data will be presented at the congress. Conclusions: The combination of GT90001 with nivolumab showed a manageable safety profile, and no new safety signals were identified. The promising preliminary antitumor activities show the potential of GT90001 combined with nivolumab as second-line treatment for advanced HCC. Clinical trial information: NCT03893695.
Role of ctDNA to predict risk of recurrence following potentially curative resection of biliary tract and pancreatic malignancies.
Authors: Lamarca Angela , McNamara Mairead Geraldine , Hubner Richard , Valle Juan W. 
Published: January 2021

336 Background: The potential role of ctDNA to identify residual disease after potentially curative resection has been suggested in some malignancies; its role in resected pancreatico(P)-biliary(B) malignancies is unknown. Methods: Patients diagnosed with PB malignancies underwent molecular profiling (ctDNA) using FoundationMedicine Liquid (72 cancer-related genes) following potentially curative resection. Baseline patient characteristics and molecular profiling outcomes, including mutant allele frequency (MAF) for pathological alterations were extracted. Primary objective: prevalence of ctDNA identification and its correlation with recurrence (relapse-free survival (RFS) and relapse rate). Results: Total of 11 individuals had ctDNA analysed following potentially curative resection for PB malignancies: 8 B (4 extra-hepatic cholangiocarcinoma (eCCA), 2 ampulla, 1 intrahepatic cholangiocarcinoma (iCCA), 1 gallbladder cancer (GBC)) and 3 P. Baseline characteristics: 6 female (54.55%), median age 71.59 years (range 39.98-81.19). Most were pT2 (45.45%), pN0 (54.55%) and R0 (63.64%). Following surgery, 6 patients were started on adjuvant chemotherapy; at the end of follow-up (data cut-off 25/6/2020; median follow-up 11.15 months (range 5.45-13.52); 5 relapsed (45.45%) and 2 died (18.18%). Estimated median RFS was 11.43 months (95% CI 2.28-not reached); median overall survival was not reached. No sample failed ctDNA analysis; presence of ctDNA was identified in 3/11 (27.27%) of the samples; 2 and 1 samples had 2 and 1 pathological alterations identified, respectively: ALK fusion (1 sample; GBC), TP53 mutation (2 samples; eCCA and GBC), CHEK2 mutation (1 sample; pancreas), IDH2 mutation (1 sample; eCCA). Mean maximum MAF was 1.47 (2 in biliary; 0.43 in pancreas). Variants of unknown significance were identified in 72.73% of the samples (87.5% in B; 33.33% in P; p-value 0.152). None of the baseline characteristics explored correlated with presence of ctDNA. There was a trend towards increased relapse risk in the patients with ctDNA present following potentially curative surgery; Cox regression for RFS [HR 2.64 (95% CI 0.36-19.31); median RFS 11.44 months (95% CI 2.28-not reached) vs 10.87 (95% CI 2.21-not reached)]; relapse rate 37.5% (ctDNA absent) vs 66.67% (ctDNA present); statistical significance was not reached (p-value 0.340 and p-value 0.545, respectively). Conclusions: This pilot study demonstrates the feasibility of testing for ctDNA following potentially curative resection in PB malignancies. Presence of ctDNA may be associated with increased relapse risk; further studies are required to increase sample size and assess clinical implications.
Phase Ib/II study of pembrolizumab with lanreotide depot for advanced, progressive gastroenteropancreatic neuroendocrine tumors (PLANET).
Authors: Morse Michael , Halperin Daniel M. , Uronis Hope Elizabeth , Hsu David S. , Hurwitz Herbert , Bolch Emily , Warren Dana , Haley Sherri , John Lisa , Moyer Ashley , Rushing Christel N. , Niedzwiecki Donna 
Published: January 2021

369 Background: Pembrolizumab has antitumor activity in a subset of GEP-NETs patients. We hypothesized that the lanreotide, by its antitumor effects and reduction of serotonin, a modulator of immunity, would synergize with pembrolizumab in low/intermediate grade GEPNETs. Methods: GEP-NETs patients who had progressed on a prior somatostatin analogue received lanreotide 90mg sq and pembrolizumab 200mg IV every 3 weeks until progressive disease or intolerable toxicity. The primary endpoint was ORR at any time on study and secondary endpoints were PFS and OS. Results: 22 patients were treated (F/M 10/12; Caucasian/AA/other 10/7/5; GI/pancreatic 14/8; median Ki67 5%, median time since diagnosis 5.3 yrs (IQR 2.3-7.9 yrs)). Prior octreotide LAR/lanreotide/both was administered to 20/1/1. Patients had a median of 2 prior systemic therapies (range 1-9) and six had prior locoregional therapy and 3 external beam radiotherapy. Of the 12 tumors analyzed thus far, 4 had detectable PD-L1 expression and 11 had detectable TILs. A median of 6 pembrolizumab doses (range 2-15) and 7 lanreotide doses (range 2-15) were administered. Six patients experienced treatment related SAEs (abdominal pain, pneumonitis, colitis, and hyperglycemia, all related to the pembrolizumab). Selected treatment related adverse events included: Hypothyroidism 23%, colitis 9%, hyperglycemia 14%, and pneumonitis 5%. Best response by RECIST 1.1 was SD/PD/Not available:39/52/9% and by irRECIST was 43/48/9%. Median PFS was 5.4 months (95% CI 1.7-8.3 mo). The median overall survival at a median follow-up of 15 months was not reached. Peripheral blood immunologic correlates will be reported subsequently. Conclusions: In a population of GEP-NET patients, progressing on a median of 2 prior therapies, including prior somatostatin analogue therapy, a minority of whom had PD-L1 expressing tumors, the combination of lanreotide and pembrolizumab produced stable disease in approximately 40% of patients. No new safety signals were identified. Clinical trial information: NCT03043664.
Preliminary safety analysis of phase II open-label NIVACOR trial (GOIRC-03-2018) in patients with advanced colorectal cancer RAS or BRAF mutated.
Authors: Damato Angela , Berselli Annalisa , Iachetta Francesco , Romagnani Alessandra , Larocca Mario , Garcia Arias Alicia , Antonuzzo Lorenzo , Nasti Guglielmo , Bergamo Francesca , Pinto Carmine 
Published: January 2021

37 Background: NIVACOR trial is an open-label, multicentric Italian phase II trial of FOLFOXIRI/bevacizumab in association with an anti-PD1 antibody, nivolumab, in patients (pts) with metastatic colorectal cancer (mCRC). We report preliminary safety analysis by an Independent Monitoring Committee. Methods: Pts with mCRC RAS or BRAF mutated, regardless microsatellite status and eligible to receive a first line treatment will be enrolled. FOLFOXIRI/bevacizumab (BEV) in association with nivolumab (NIV) was administered every 2 weeks for 8 cycles (induction) followed by BEV plus NIV every 2 weeks (maintenance) until PD or unacceptable toxicities. BEV was administered intravenously at dose of 5 mg/kg and NIV intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint was the ORR. The safety is assessed after the inclusion of the 10th patient, receiving ≥1 dose. Results: As of September 20, 2020, 25/70 pts are enrolled. The first 10 pts were evaluated for preliminary safety analysis. Median age was 58 years (32-66), 60% of pts were male, median cycles of treatment was 5.5 (1-9). 100% were KRAS G12D mut and BRAF wild type, respectively, and 2% MSI-H/dMMR. 7/10 pts experienced at least one AE related to FOLFOXIRI/BEV and 2/10 related to NIV. The most frequent grade 1-2 AEs related to FOLFOXIRI/BEV were nausea and vomiting 4(57%), fatigue 5(71%), and diarrhea 5(71%); 3(43%) pts had grade 3-4 neutropenia, and 1(14%) febrile neutropenia. Only 2 pts developed grade 1-2 AEs related to NIV represented by rash (50%) and salivary gland infection (50%); no grade 3-4 was reported. One of pts with dose delay because of serious AES (proteinuria) BEV related, and one patient discontinued due to serious AEs (ileo-urethral fistula) not related to NIV. Conclusions: Combination of FOLFOXIRI/BEV and NIV was generally well tolerated and showed an acceptable toxicity profile. The final analysis will be scheduled at the end of enrollment. Clinical trial information: NCT04072198.
Ampullary neuroendocrine tumors: A window into a rare tumor using a national database.
Authors: Ruff Samantha M , Deutsch Gary B , Weiss Matthew John , Deperalta Danielle 
Published: January 2021

373 Background: Ampullary neuroendocrine tumors (NET) make up < 1% of all gastrointestinal NETs. Information about their behavior and prognosis is reliant on small case series. This study set out to describe the population of patients who are diagnosed with ampullary NETs and compare them to patients with duodenal and pancreatic head NETs. Methods: The National Cancer Database (2004 – 2016) was queried for patients with ampullary, duodenal, and pancreatic head NETs. Clinicopathologic and treatment characteristics were compared. Subset analysis was performed on patients who underwent surgery. Kaplan Meier (KM) analysis and Cox regression were used to analyze the survival of patients with ampullary NETs. Results: Overall, 872 patients were identified with ampullary NET, 9692 with duodenal NET, and 6562 with pancreatic head NET. Patients with ampullary NET had an average age of 60.9 +/- 14.5 years, were evenly split among men and women (N = 437, 50.1% vs N = 435, 49.9%, respectively), and primarily Caucasian (N = 663, 76.0%). 72.1% underwent local tumor destruction or surgery (N = 629). Most did not receive radiation (N = 832, 95.4%), chemotherapy (N = 627, 71.9%), or hormone therapy (N = 788, 90.4%). Patients with ampullary NETs had more poorly differentiated tumors (N = 119, 13.6%) than patients with duodenal (N = 159, 1.6%) or pancreatic head (N = 602, 9.2%) NETs. Patients with ampullary NETs had more positive lymph nodes (N = 288, 33%) than patients with duodenal (N = 915, 9.4%) or pancreatic head (N = 1381, 21%) NETs. At five years, the overall survival for patients with ampullary, duodenal, and pancreatic head NETs was 57%, 68%, and 46%, respectively. Within the surgical population, five-year survival for patients with ampullary (N = 367), duodenal (N = 991), and pancreatic head (N = 1961) NETs was 60%, 74%, and 72%, respectively. When compared, there was a statistically significant difference between the mean overall survival of patients with ampullary (98 +/- 4.7 months), duodenal (112 +/- 2.5 months), and pancreatic head (108 +/- 1.7 months) NETs (p < 0.001). In the cox regression analysis, sex, Charlson-Deyo score, lymph node positivity, lymph-vascular invasion, mitotic rate, chromogranin A level, 5-HIAA level, and tumor size did not correlate with survival. Increasing age (HR 1.04, CI 1.01 – 1.07, p = 0.008) and worse tumor differentiation (poorly differentiated HR 3.33, CI 1.38 – 8.04, p = 0.008 and undifferentiated HR 8.31, CI 2.77 – 24.92, p < 0.001 compared to well differentiated) were associated with increased mortality. Conclusions: This study sheds light on a rare tumor histology. When compared to patients who underwent surgical resection for duodenal or pancreatic head NETs, patients with ampullary NETs had a significantly worse prognosis. Identifying prognostic factors allows us to create more concrete treatment recommendations and provide patients with improved prognostic information.