bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).
Authors: Finn Richard S. , Qin Shukui , Ikeda Masafumi , Galle Peter R. , Ducreux Michel , Kim Tae-You , Lim Ho Yeong , Kudo Masatoshi , Breder Valeriy Vladimirovich , Merle Philippe , Kaseb Ahmed Omar , Li Daneng , Verret Wendy , Shao Hui , Liu Juan , Li Lindong , Zhu Andrew X. , Cheng Ann-Lii 
Published: January 2021

267 Background: Atezo + bev has been approved globally for pts with unresectable HCC who have not received prior systemic therapy, based on results from IMbrave150 (NCT03434379). At a median of 8.6 mo follow-up, both coprimary endpoints were met, with statistically significant and clinically meaningful improvements observed with atezo + bev vs sor for OS (HR, 0.58 [95% CI, 0.42, 0.79]; P<0.001) and independently-assessed progression-free survival (PFS; per RECIST 1.1; HR, 0.59 [95% CI, 0.47, 0.76]; P<0.001) (Finn, et al. N Engl J Med 2020). Here, we report an updated OS analysis for IMbrave150. Methods: The global, multicenter, randomized, open-label, Phase III study IMbrave150 enrolled 501 systemic treatment–naive pts with unresectable HCC, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Pts were randomized 2:1 to receive either atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. This post hoc, descriptive OS analysis was conducted with 12 mo of additional follow up from the primary analysis. Results: 501 pts were enrolled, including 336 to atezo + bev and 165 to sor. At the clinical cut-off date of Aug 31, 2020, median follow-up was 15.6 mo and 280 OS events were observed. Median OS was 19.2 mo with atezo + bev vs 13.4 mo with sor (HR, 0.66 [95% CI, 0.52, 0.85]; P=0.0009). Survival at 18 mo was 52% with atezo + bev and 40% with sor. Survival benefit with atezo + bev over sor was generally consistent across subgroups and with the primary analysis. The updated objective response rate (ORR; 29.8% per RECIST 1.1) with atezo + bev was in line with the primary analysis, with more pts achieving complete response (CR; 7.7%) than previously reported. Additional response data are in Table. Safety was aligned with the primary analysis, with no new signals identified. Conclusions: IMbrave150 showed consistent clinically meaningful treatment benefit and safety with 12 mo of additional follow-up. The combination provides the longest survival seen in a front-line Phase III study in advanced HCC, confirming atezo + bev as a standard of care for previously untreated, unresectable HCC. Clinical trial information: NCT03434379. [Table: see text]
When will it be better? Lenvatinib combined with TACE for unresectable hepatocellular carcinoma: A retrospective analysis of real-world evidence in China.
Authors: Zhang Lan , Wang Yanhong , Ge Ningling , Gan Yu-Hong , Ren ZhengGang , Chen Yi 
Published: January 2021

281 Background: TACE and lenvatinib has each shown to prolong overall survival in patients with unresectable HCC, combination of which may also improve clinical outcomes and have been widely used in the real world accordingly. However, the optimal timing of adding on lenvatinb to TACE remains unclear. We are aiming to evaluate the efficacy and safety between two combination strategies. Methods: From Nov 2018 to Jun 2020, 79 consecutive patients had received a combination treatment of lenvatinib and TACE. Patients followed up for more than 2 months were included in this analysis. They were classified as early-combination group(add on lenvatinib before or after the first TACE ) and late-combination group(add on lenvatinib after at least two procedures of TACE ). Tumor response and progression-free survival (PFS,time from the first day of prescribing lenvatinib to progression or death) were assessed according to RECIST1.1 criteria. Liver function were also evaluated at baseline and every 2 months later. AEs were recorded during the combination treatment period according to CTCAE 5.0. Results: A total of 48 u-HCC patients was finally enrolled. Median follow-up in all patients was 9.3(5.3-14.3)months. Patients’ baseline characteristics were similar in two groups. For early-combination group(n=22)and late-combination group(n=26), the mean age was 65±9.7 and 61±11.6years(p=0.2);BCLC stage C HCC was 59% and 54%(p=0.89);and Child-Pugh A proportion was 81.8% and 77%(p=0.73) respectively. The objective response rate(ORR) was 22.9% in total 48 cases. There was no significant difference in response rate (18.2% vs 26.9%, P=0.51) or disease control rate (90.9% vs 92.3%, P=1.00). Median PFS was significantly longer in the early-combination group than that in late-combination group (14.5 vs 8.9 months; p=0.048). The safety profile was similar between two groups. Grade 3/4 adverse events were 3 (13.6%) and 2 cases(7.7%) respectively (P=0.65). Conclusions: This is to date the first real-world data of the combination timing of lenvatinib with TACE in u-HCC patients. Early-combination strategy may be a better option for the u-HCC patients with a longer mPFS.
Treatment patterns and outcomes of hepatocellular carcinoma (HCC) patients (pts) in the CancerLinQ Research Database (CLQ).
Authors: Kabadi Shaum , Luo Linlin , Moren Andrew (Scott) , Baria Katherine 
Published: January 2021

283 Background: Treatment and management of pts with HCC is complicated by the presence of underlying chronic liver disease. Clinical trials with unresectable HCC pts are generally limited to Child-Pugh A or pts with good performance status. Therefore there is limited data for less fit HCC pts, particularly those treated in the community practice setting. Methods: The study design was a retrospective cohort study using the US-based CancerLinQ Discovery Database (CLQ). CLQ was launched by the American Society of Clinical Oncology in 2016 and consists of longitudinal, demographically, and geographically diverse data aggregated from oncology practice Electronic Health Record databases. Eligible pts were ≥18 years at time of HCC diagnosis, had a diagnosis of stage IV HCC within the record, and had ≥2 clinical encounters on separate dates during follow-up after the date of diagnosis. The study period and patient identification period was Jan 1997–Aug 2019; follow up continued through May 2020. Patient demographics, clinical characteristics, and general treatment characteristics were summarized using descriptive statistics. Results: 460 pts were eligible for analysis. Of these, 141 pts (31%) had a Child-Pugh score as reported in medical charts or imputed based on structured and curated data. 76 (54%) pts were Child-Pugh class A, 59 (42%) Child-Pugh class B, and 6 (4%) Child-Pugh class C. The proportion of pts with chronic hepatitis C infection and liver cirrhosis was higher in pts with Child-Pugh classes B and C compared to A. Time from diagnosis to first systemic therapy decreased from a median of 126 days for pts with Child-Pugh class A, to 47 and 16 days for class B and C, respectively. Sorafenib was the most common regimen regardless of line of therapy, followed by PD-1 pathway inhibitors and chemotherapy. Median duration of sorafenib therapy decreased from Child-Pugh class A to C (table). There was a similar decrease in duration of therapy for pts receiving PD-1 pathway inhibitors and chemotherapy when moving from class A to class C. Conclusions: This is the first published retrospective study in HCC using the CLQ. Pts with Child-Pugh class B or C, who are typically excluded from clinical trials, represented 48% of the pts with a Child-Pugh score included in this analysis. Duration of therapy was numerically lower for pts with Child-Pugh class B or C compared to Child-Pugh class A. Further research is needed to describe real-world evidence outside the context of a clinical trial for HCC pts. Funding: AstraZeneca. [Table: see text] Avg, average; obs, observed; TKI, tyrosine kinase inhibitor
DEDUCTIVE: A study of tivozanib in combination with durvalumab in subjects with untreated advanced hepatocellular carcinoma—Phase Ib results.
Authors: Iyer Renuka V. , Li Daneng , Dayyani Farshid , Phan Alexandria T. , Needle Michael N. , Abrams Thomas Adam 
Published: January 2021

294 Background: A recent ph3 study combining bevacizumab (VEGF-A Mab) with atezolizumab (PD-L1 inhibitor) has shown significant improvements in OS and PFS demonstrating that a combination of VEGF and PDL1 inhibition can improve patient outcomes over sorafenib. Tivozanib (T, a potent and selective VEGFR 1, 2 & 3 TKI) and durvalumab (D, a PD-L1 antibody) have both demonstrated single agent activity in HCC and have been combined safely with other therapies. T blocks all three VEGF receptors, and when combined with a PD-L1 inhibitor may improve patient outcomes. The ph1 portion of this study combines T with D to establish the recommended phase II dose (RP2D) and provide preliminary safety and efficacy data. Methods: Major eligibility criteria are adults with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, creatinine clearance > 40 ml/min. Major exclusion criteria are co-infection with HBV and HCV and significant organ dysfunction. The starting dose is the combination of T 1 mg orally for 21 days followed by 7 days off treatment and D 1500 mg intravenously every 28 days. A DLT is generally defined as the occurrence of any Grade ≥3 immune or non-immune adverse event (AE) in Cycle 1 that is at least possibly related to the investigational regimen other than any grade of vitiligo or alopecia or Grade 3 controllable hypertension in cycle 1. The primary objective is to establish the RP2D and the safety and tolerability for this combination in patients with advanced HCC. Patients will be treated until progression of disease, unacceptable side effects, or death. Outcome measures will be AEs per CTCAE v.5 and cross-sectional imaging performed every 8 weeks. Results: Seven patients were enrolled in phase I. Six were male; the median age was 75 (range 40 to 82). One patient had mild elevation of LFTs and did not complete the 21-day course of T and was replaced. No patient experienced a >=grade 3 AE in cycle 1. The most common AEs, each seen in two of seven patients, were anorexia, cough, diarrhea, dysphonia, fatigue, hypertension, and palmar-plantar erythrodysesthesia. Two of seven have achieved a partial response. Conclusions: The combination of T with D in patients with untreated advanced HCC is well tolerated. The RP2D for the combination is T 1 mg orally for 21 days on treatment followed by 7 days off treatment and D 1500 mg intravenously every 28 days. In the phase II portion of the study an additional 30 patients will be treated at the RP2D. Secondary objectives are to assess the objective response rate, progression free survival, and overall survival in this population. Clinical trial information: NCT03970616.
Preliminary results of the phase II ALTER-H003 trial: Anlotinib plus toripalimab as a first-line treatment for patients with unresectable hepatocellular carcinoma.
Authors: Lin Haifeng , Ma Jie , Zhuo Manyun , Zhang Chengsheng , Luo Jingru , Zhuang Xiaohong , Zeng Zhiming , Yang Lihua 
Published: January 2021

314 Background: Hepatocellular carcinoma (HCC) is particularly prevalent in China because of the high prevalence of chronic hepatitis B infection. In the last decade, sorafenib was the first molecular target drug approved for the treatment of advanced liver cancer. Until recently, the combination of angiogenic inhibitor with anti-PD-1 /L1 monoclonal antibody has represented significant efficacy over sorafenib monotherapy in the first-line regimen of unresectable HCC. Nevertheless, there are still unmet needs in clinical practice due to limited choice of drugs. Anlotinib is a novel oral multi-targeted tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit, and has been approved for standard treatment of non-small cell lung cancer, small cell lung cancer and soft tissue sarcoma in China. Toripalimab, a humanized IgG4 mAb against PD-1, is the first Chinese-produced PD-1 inhibitor marketed, which has been approved as a second-line treatment for metastasis melanoma. This study aims to evaluate the efficacy and safety of anlotinib plus toripalimab as the first-line treatment for unresectable HCC. Methods: This was a single-arm, multicenter, phase II trial. 30 patients with unresectable HCC, Child-Pugh ≤7 and ECOG PS <2 will be enrolled if they had not been treated with prior treatment. Pts received anlotinib (12 mg, p.o., qd, d1-14, q3w) and toripalimab (240 mg, iv, d1, q3w) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigator according to mRECIST and irRECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DoR) and safety. Results: By the cutoff date of September 21, 2020, 11 pts were enrolled and of those 8 pts were evaluable. 9 pts (81.8%) experienced treatment related adverse events (TRAEs) and grade 3 TRAEs occurred in 5 pts (45.5%). No grade 4 or above TRAEs occurred. The most common TRAEs were decreased appetite (n =6, 54.5%) and fatigue (n =5, 45.5%).Among 8 evaluable pts, unconfirmed ORR was 25% (95% CI 0.032-0.651) with 1 unconfirmed CR and 1 unconfirmed PR, and DCR was 87.5% (95% CI 0.473-0.997) according to mRECIST. Conclusions: Anlotinib in combination with toripalimab showed tolerant toxicity and preliminary anti-tumor efficacy in first-line regimen for uHCC patients. Furthermore, it is needed to be proved in update results and large scale studies. Clinical trial information: ChiCTR1900028295.
Real-world data on overall survival associated with biweekly versus weekly cetuximab among metastatic colorectal cancer (mCRC) patients in the United States.
Authors: Agg Himani , Han Yimei , Cui Zhanglin Lin 
Published: January 2021

33 Background: Cetuximab 250mg/m2 weekly (Q1W) after an initial dose of 400mg/m2 is approved for treatment of K-Ras wild-type mCRC. In real world 29% of patients received cetuximab 500mg/m2 biweekly (Q2W). In this study overall survival (OS) associated with Q2W vs Q1W dosing of cetuximab for mCRC in real world was compared. Methods: This study utilized Flatiron Health electronic health record-derived database to identify adult patients with stage IV or recurrent K-Ras wild-type mCRC who received cetuximab+FOLFIRI/FOLFOX/irinotecan, or cetuximab monotherapy in first, second or third-line therapy from 01/01/2013 to 12/31/2019. Patients were assigned to Q1W or Q2W cohort if they had 70% or more cetuximab infusions with a gap of 4-10 days or 11-18 days from previous infusion. Patients who did not fall into either cohort were excluded from analysis. Propensity score (PS) matching was used to balance cohorts on their baseline demographic, clinical and treatment characteristics. Kaplan-Meier methods and Cox proportional hazards regressions were used to compare OS. Results: Baseline characteristics for Q2W (N = 422) vs Q1W (N = 653) cohorts before PS matching- median age 62 vs 65 years, male 58.5% vs 59.3%, white 68.3% vs 66.5%, stage IV 56.6% vs 58.5%, ECOG PS 0/1 61.6% vs 52.1%, ECOG PS 2+ 9.2% vs 9.5%. After PS matching, baseline characteristics were balanced. Hazard ratios (HRs) comparing OS in PS-matched Q2W vs Q1W cohorts were not significant for overall or line of therapy populations (Table). Conclusions: Weekly and biweekly cetuximab had comparable effectiveness in this real-world study. [Table: see text]
Dissecting novel mechanisms of hepatitis B virus-related hepatocellular carcinoma using meta-analysis of public data.
Authors: Aljabban Jihad , Rohr Michael , Syed Saad A , Cohen Eli , Hashi Naima , Syed Sharjeel , Khorfan Kamal , Boateng Emmanuel , Nemer Mary , Panahiazar Maryam , Hadley Dexter , Jalil Sajid , Mumtaz Khalid , Aljabban Hisham 
Published: January 2021

333 Background: Hepatitis B is a cause of hepatocellular carcinoma (HCC) globally, irrespective of viral loads. Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation, and has implications in early diagnosis and treatment. Methods: We employed our Search, Tag, Analyze, Resource (STARGEO) platform to conduct a meta-analysis of public data from NCBI's Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples. We present the results from the meta-analysis in Ingenuity Pathway Analysis. Results:Our analysis revealed LXR/RXR activation, LPS-IL-1 mediation inhibition of RXR, and FXR/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene RABL6. The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. Additionally, HOXA10 was a top upstream regulator and was strongly upregulated in our analysis. While described in other cancer, HOXA10 has not been well documented in HBV-related HCC and our causal analysis suggests it mediates pathogenesis through downregulation of tumor suppressors and its protective effect from oxidative stress. Conclusions: This meta-analysis describes possible role of viral regulatory proteins such as RABL6 and HOXA10 in the pathogenesis of HBV -related HCC. Further prospective studies are needed to confirm our findings.
Characterization of hyperprogressive disease in patients with advanced biliary tract cancer treated with anti-PD-1 inhibitor: A multicenter retrospective study.
Authors: Lee Choong-kun , Cheon Jaekyung , Kim Eo Jin , Kim Chang Gon , Kim Sunkyu , Kim Chan , Kang Beodeul , Choi Hye Jin , Yoo Changhoon , Chon Hong Jae 
Published: January 2021

339 Background: Immunotherapy, including anti-PD-1 inhibitor, represents a promising breakthrough treatment in poor prognostic cancers such as biliary tract cancer (BTC). However, subset of pts suffer from unexpected acceleration of tumor growth following the initiation of immunotherapy, termed hyperprogressive disease (HPD). We assessed HPD in BTC pts treated with anti-PD-1 inhibitor in association with clinicopathologic features. Methods: This retrospective study included pts with BTC who were treated with pembrolizumab 200mg IV as palliative second or third line treatment in 4 tertiary hospitals in South Korea. Previous proposed tumor dynamic parameters including time to treatment failure (TTF), tumor growth kinetics (TGK) and tumor growth rate (TGR) were calculated per RECIST v1.1. Neural network modeling technique was adopted to find clinicopathologic features that can predict HPD. Results: Total of 223 pts with BTC were treated with palliative second or third line pembrolizumab between December 2015 to August 2020. ORR was 11.2% (n=1 for CR, n=24 for PR, n=70 for SD, n=118 for PD, and 10 pts not evaluable). Among patients with best response as PD (n=118), 41 patients (18.4% from total pts) met the criteria for HPD definition (>2-fold increase in both TGK and TGR in the experimental period compared to the reference period). HPD pts had worse prognosis compared to non-HPD pts in terms of TTF (median 1.4 vs 2.7 months, P =<0.0001) and OS (median 3.57 vs 5.27 months, P =0.03). Clinicopathologic features including age, ECOG performance status, primary tumor site, pathology, metastatic organ, previous treatment history (surgery or radiotherapy), pretreatment PD-L1 score, tumor markers, and baseline laboratory results (LDH, albumin, or neutrophil-to-lymphocyte ratio) did not predict HPD (compared to non-HPD pts or PD without HPD pts). By neural network modeling and plotting with hidden vectors, we could define HPD-high-risk cluster (n=37) and HPD-lower-risk cluster (n=80). Higher CA 19-9-to-lymphocyte ratio ( P =0.0004) or higher platelet-to-PD-L1 CPS (combined positivity score) ratio ( P =0.002) predicted HPD-high-risk-cluster. HPD pts (n=41) tend to have progression due to liver (73.2% vs 45.6%, P =0.0026) or peritoneum (53.7% vs 21.4%, P=<0.0001) metastases, compared to non-HPD pts (n=182). Conclusions: This study for the first time describe the clinicopathologic features of HPD among pembrolizumab treated BTC pts. Baseline pathology and laboratory tests may help optimal patient selection for immunotherapy to avoid HPD in BTC pts. Further validation of BTC-specific HPD predictive features and definition (TGK or TGR ratio cut-off) will be presented after comparison with clinicopathologic features among second line 5FU-based chemotherapy treated BTC pts.
Whole-genome sequencing of cholangiocarcinoma to reveal distinct profiles of patients with underlying cirrhosis or inflammatory disorders.
Authors: Holzapfel Nicholas Timothy , Zhang Amy , Denroche Robert Edward , Lam Bernard , Wilson Julie , Fischer Sandra , Notta Faiyaz , Gallinger Steven , Knox Jennifer J. , O'Kane Grainne M. 
Published: January 2021

340 Background: Cholangiocarcinoma (CCA) is a lethal malignancy with limited treatment options. Molecular profiling of these tumours has revealed a number of actionable mutations and four clusters have been defined through integrative genomic analysis. We sought to explore whole genome sequencing (WGS) data in 20 patients enriched for CCA arising in the setting of cirrhosis or inflammatory disorders. Methods: A previously established Biliary Tract Cancer (BTC) database at the Princess Margaret Cancer Centre (PMCC)/University Health Network (UHN) was used to identify patients of clinical interest including long-term survivors, those with germ-line mutations, and those with chronic inflammatory disorders. WGS and bioinformatic analyses were performed at the Ontario Institute for Cancer Research. Results: The 20 resected samples included 12 patients (pts) with intrahepatic CCA, 7 perihilar CCA, and 1 distal CCA. 8 pts were alive > 8 years post resection and one patient harboured a germline MLH1 pathogenic variant (MLH1 G67R). 3 pts had documented cirrhosis (hepatitis B n = 2, haemochromatosis n = 1); other inflammatory disorders (n = 4) included ulcerative colitis (UC) without documented PSC (n = 1), PSC alone (n = 1), UC with PSC (n = 1), and ankylosing spondylitis (n = 1). The remaining cases were randomly selected. The predominant COSMIC single base substitution (SBS) mutational signatures were 1, 8 and 5, and the median TMB was 1.75 mutations per MB (0.73-33.23). The pt with an MLH1 mutation exhibited a TMB of 33.23 with predominance of SBS26. Actionable variants were enriched in the 8 pts who are alive and disease free including 2 predicted FGFR fusions and mutations in IDH1 (n = 1), BRAF V600E (n = 1), and BAP1 (n = 1). TP53 mutations (n = 7) were present exclusively in patients with cirrhosis or inflammatory disorders and the median survival in the group was 12 months (3 -21 months). Although SBS signatures were similar in this group, in the two cases of UC, SBS17 (unknown etiology) was evident. SBS17 was also dominant in one case where the TMB was 13 mutations per MB and the patient died within 3 months of diagnosis. A somatic case of homologous recombination deficiency, with no causative genetic alteration identified, was evident in a further patient receiving maintenance rituximab for a coexisting stage 4 mantle cell lymphoma. Conclusions: WGS may provide additional biological information in CCA particularly in patients with underlying inflammatory disorders, where TP53 mutations are prevalent and mutational signatures are distinct.