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Purpose Transarterial chemoembolization (TACE) is the standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC). Lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, have shown efficacy and tolerability in patients with HCC, and adding this combination to TACE may enhance clinical benefit. Protocol LEAP-012 is a prospective, double-blind randomized phase 3 study. Adults with confirmed HCC localized to the liver without portal vein thrombosis and not amenable to curative treatment, ≥ 1 measurable tumor per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), Eastern Cooperative Oncology Group performance status 0 or 1, Child–Pugh class A and no previous systemic treatment for HCC are eligible. Patients will be randomly assigned to lenvatinib once daily plus pembrolizumab every 6 weeks plus TACE or placebos plus TACE. Dual primary endpoints are overall survival and progression-free survival per RECIST 1.1 by blinded independent central review (BICR). Secondary endpoints are progression-free survival, objective response rate, disease control rate, duration of response and time to progression per modified RECIST by BICR; objective response rate, disease control rate, duration of response and time to progression per RECIST 1.1 by BICR; and safety. Statistics The planned sample size, 950 patients, was calculated to permit accumulation of sufficient overall survival events in 5 years to achieve 90% power for the overall survival primary endpoint. Discussion LEAP-012 will evaluate the clinical benefit of adding lenvatinib plus pembrolizumab to TACE in patients with intermediate-stage HCC not amenable to curative treatment. ClinicalTrials.gov NCT04246177.

Background: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. Methods: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. Findings: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7–30·4). Median overall survival was 12·7 months (95% CI 11·5–13·6) in the pembrolizumab group versus 10·9 months (9·9–11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72–0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. Interpretation: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Supplementary Data from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial

Editorial from Serum Antioxidant Nutrients, Vitamin A, and Mortality in U.S. Adults

Supplementary Table from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial

Background: Observational studies have suggested that antioxidant nutrients may reduce cancer and overall mortality risks. However, most randomized trials have failed to show survival benefits. Examining nonlinear associations between antioxidant levels and health outcomes may help to explain these discrepant findings.Methods: We evaluated all-cause, cancer, and cardiovascular mortality risks associated with quintiles (Q1–Q5) of serum antioxidant (vitamins C and E, β-carotene, and selenium) and vitamin A levels, in 16,008 adult participants of The Third National Health and Nutrition Examination Survey (NHANES III; 1988–1994).Results: Over a median follow-up period of 14.2 years, there were 4,225 deaths, including 891 from cancer and 1,891 from cardiovascular disease. We observed a dose–response decrease in cancer and overall mortality risks with higher vitamin C levels. In contrast, for vitamin A, risk of cancer death decreased from Q1–Q2, with no further decline in risk at higher levels. For vitamin E, having levels in Q4 was associated with the lowest cancer mortality risk. Both vitamin A and E had U-shaped associations with all-cause mortality. Cancer mortality risks decreased from Q1–Q2 for β-carotene and from Q1–Q4 for selenium. However, for β-carotene and selenium, overall mortality risks decreased from Q1–Q2 but then did not change significantly with higher levels.Conclusions: Antioxidant supplement use should be studied in the context of overall mortality and other competing mortality risks.Impact: These data suggest the need for novel intervention studies where doses of these agents are individualized based on their serum levels, and possibly, markers of oxidative stress and systemic inflammatory response. Cancer Epidemiol Biomarkers Prev; 22(12); 2202–11. ©2013 AACR.

PDF - 304 KB, Table S1. Hazard Ratios Additionally Adjusted for Serum C-reactive Protein Levels Table S2. Hazard Ratios Additionally Adjusted for Serum Levels of Other Micronutrients in the study Table S3. Hazard Ratios after Excluding NHANES III Participants who are Current Smokers Table S4. Hazard Ratios after Excluding NHANES III Participants with History of Heart Attack, Congestive Heart Failure, Stroke or Cancer Table S5. Hazard Ratios after excluding Deaths within the First Three Years of the Survey Table S6. Hazard Ratios for All-Cause Mortality for 5- and 10-years of Follow-up Table S7. Hazard Ratios for All-Cause Mortality Stratified by Age, Gender, Race-Ethnicity, BMI and Supplement Use Table S8. Hazard Ratios for Gastrointestinal and Respiratory Tract Cancer Mortality Table S9. Hazard Ratios for Ischemic Heart Disease and Stroke Mortality Figure S1. Restricted Cubic Splines for All-Cause Mortality Figure S2. Restricted Cubic Splines for Cancer Mortality Figure S3. Restricted Cubic Splines for Cardiovascular Mortality

Supplementary Figure from Pembrolizumab Monotherapy for Previously Untreated Advanced Hepatocellular Carcinoma: Data from the Open-Label, Phase II KEYNOTE-224 Trial

Purpose:KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy.Patients and Methods:KEYNOTE-224 was an open-label, multicountry phase II trial. Eligible patients in cohort 2 had advanced HCC not amenable or refractory to locoregional therapy and not previously treated with systemic therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤2 years. Primary endpoint was objective response rate (ORR) by central imaging review per RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety/tolerability.Results:Between September 4, 2018, and February 20, 2019, 51 patients were allocated in cohort 2. The median time from the first dose to data cutoff (January 19, 2021) was 27 months (range, 23–29). ORR was 16% [95% confidence interval (CI), 7–29] and was similar across key subgroups. Median DOR was 16 months (range, 3–24+), and DCR was 57%. The median PFS was 4 months (95% CI, 2–8), and median TTP was 4 months (95% CI, 3–9). Median OS was 17 months (95% CI, 8–23). Grade ≥3 treatment-related adverse events occurred in 16% of patients.Conclusions:In patients with advanced HCC with no prior systemic therapy, pembrolizumab provided durable antitumor activity, promising OS, and had a safety profile consistent with previous observations. These findings support further evaluation of pembrolizumab-based regimens for HCC.

In the U.S., Hepatocellular carcinoma (HCC) incidence rates have increased. We aimed to determine whether environmental exposure plays a role in the high incidence of HCC observed in New York City. We conducted a hospital-based case only study to examine the prevalence of aflatoxin B1 (AFB1)- and polycyclic aromatic hydrocarbon (PAH)-albumin adducts and the distribution of adducts by different characteristics of HCC patients. Blood samples were collected from 155 HCC patients for biomarker analyses. We observed that about 46% and 49% of cases had detectable AFB1- and PAH-albumin adducts, respectively. There were significant differences between AFB1-albumin adducts and selected factors such as HCV infection status (p = 0.04), diabetes (p = 0.03) and Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.02). Cases with detectable PAH-albumin adducts had a smoking history compared with those with nondetectable levels (p = 0.04). The level of AFB1-albumin adducts was positively correlated with plasma bilirubin (rs=0.32, p s=0.28, p = 0.0005). The level of aflatoxin B1-albumin adducts was negatively associated with blood albumin concentration (rs=-0.28, p = 0.0009) and plasma DNA LINE-1 methylation (rs=-0.16, p = 0.04). Our study provides additional evidence that environmental exposures including to aflatoxin might partially explain the increase in the incidence of HCC in the US.

Introduction: KEYNOTE-240 investigated the efficacy and safety of pembrolizumab plus best supportive care (BSC) in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC). Results for the subgroup of patients from Asia are described. Methods: Adults with advanced HCC previously treated with sorafenib were randomized 2:1 to pembrolizumab or placebo plus BSC. Here, the Asian subgroup comprised patients enrolled in Hong Kong, Japan, Korea, the Philippines, Taiwan, and Thailand. Primary endpoints were progression-free survival (PFS) per blinded central imaging review and overall survival (OS). Secondary endpoints included objective response rate (ORR) per blinded central imaging review, duration of response (DOR), and safety. Results: The Asian subgroup included 157 patients. As of January 2, 2019, the median follow-up in this subgroup was 13.8 months for pembrolizumab and 8.3 months for placebo. The median PFS was 2.8 months for pembrolizumab (95% confidence interval [CI] 2.6–4.1) versus 1.4 months (95% CI 1.4–2.4) for placebo (hazard ratio [HR] 0.48; 95% CI 0.32–0.70). The median OS was 13.8 months (95% CI 10.1–16.9) for pembrolizumab versus 8.3 months (95% CI 6.3–11.8) for placebo (HR 0.55; 95% CI 0.37–0.80). ORR was 20.6% (95% CI 13.4–29.5) for pembrolizumab versus 2.0% (95% CI 0.1–10.6) for placebo (difference: 18.5%; 95% CI 8.3–27.6). The median DOR was 8.6 and 2.8 months for pembrolizumab and placebo, respectively. Any grade treatment-related adverse events (TRAEs) occurred in 63 patients (58.9%) receiving pembrolizumab and 24 patients (48.0%) receiving placebo; 14 (13.1%) and 2 (4.0%) patients experienced grade 3–5 TRAEs, respectively. No treatment-related deaths occurred. Conclusion: Pembrolizumab demonstrated antitumor activity and was well tolerated in the Asian subgroup of KEYNOTE-240. A trend toward greater benefit with pembrolizumab in the Asian subgroup was observed compared with the overall cohort, supporting further evaluation of pembrolizumab treatment in this population.

Purpose: KEYNOTE-224 cohort 1 demonstrated that pembrolizumab was efficacious and tolerable in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib. We report results from KEYNOTE-224 (NCT02702414) cohort 2, which enrolled patients with advanced HCC and no prior systemic therapy. Patients and Methods: KEYNOTE-224 was an open-label, multicountry phase II trial. Eligible patients in cohort 2 had advanced HCC not amenable or refractory to locoregional therapy and not previously treated with systemic therapy. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤2 years. Primary endpoint was objective response rate (ORR) by central imaging review per RECIST v1.1. Secondary endpoints included duration of response (DOR), disease control rate (DCR), time to progression (TTP), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Results: Between September 4, 2018, and February 20, 2019, 51 patients were allocated in cohort 2. The median time from the first dose to data cutoff (January 19, 2021) was 27 months (range, 23–29). ORR was 16% [95% confidence interval (CI), 7–29] and was similar across key subgroups. Median DOR was 16 months (range, 3–24+), and DCR was 57%. The median PFS was 4 months (95% CI, 2–8), and median TTP was 4 months (95% CI, 3–9). Median OS was 17 months (95% CI, 8–23). Grade ≥3 treatment-related adverse events occurred in 16% of patients. Conclusions: In patients with advanced HCC with no prior systemic therapy, pembrolizumab provided durable antitumor activity, promising OS, and had a safety profile consistent with previous observations. These findings support further evaluation of pembrolizumab-based regimens for HCC.

Background The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC. Methods Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm. Results The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%–19%) in arm 1 versus 10% (95% CI 0%–23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2. Conclusions This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.

Aims: This post hoc analysis evaluated albumin/bilirubin (ALBI) score, an objective measure of liver function, in patients receiving pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC in the KEYNOTE-240 study. Methods: Patients with confirmed hepatocellular carcinoma (HCC) and progression after/intolerance to sorafenib, Child–Pugh class A liver function, and Eastern Cooperative Oncology Group performance status of 0–1 were randomly assigned 2:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks plus BSC for ⩽35 cycles or until confirmed progression/unacceptable toxicity. Outcomes were assessed by ALBI grade. Results: Of 413 patients, at baseline 116 had an ALBI grade 1 score (pembrolizumab, n = 74; placebo, n = 42) and 279 had an ALBI grade 2 score ( n = 193; n = 86). Change from baseline in ALBI score to the end of treatment was similar in both arms [difference in least squares mean, −0.039; 95% confidence interval (CI): −0.169 to 0.091]. Time to ALBI grade increase was similar in both arms [median for pembrolizumab versus placebo: 7.8 versus 6.9 months; hazard ratio (HR) = 0.863 (95% CI: 0.625–1.192)]. Regardless of baseline ALBI grade, a trend toward improved overall survival was observed with pembrolizumab [grade 1: HR = 0.725 (95% CI: 0.454–1.158); grade 2: HR = 0.827 (95% CI: 0.612–1.119)]. Conclusion: Pembrolizumab did not adversely impact liver function compared with placebo in patients with HCC, as measured by changes in ALBI scores. A trend toward improved overall survival was observed with pembrolizumab in both ALBI grade groups. ClinicalTrials.gov identifier: NCT02702401.

OBJECTIVE: Pembrolizumab, a PD-1 inhibitor, demonstrated anti-tumour activity and tolerability in patients treated with sorafenib and with advanced hepatocellular carcinoma in KEYNOTE-224. Longer-term efficacy and safety after ∼2.5 years of additional follow-up are reported. PATIENTS AND METHODS: Adults with confirmed hepatocellular carcinoma who experienced progression after or intolerance to sorafenib treatment received pembrolizumab 200 mg every 3 weeks for ≤35 cycles or until confirmed progression, unacceptable toxicity, withdrawal of consent or investigator decision. The primary end-point was objective response rate assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours v1.1. The secondary end-points included duration of response, disease control rate, time to progression, progression-free survival, overall survival and adverse events. RESULTS: Efficacy and safety were assessed in 104 patients. The median time from first dose to data cutoff was 45.1 months (range, 41.3-49.3). Objective response rate was 18.3% (95% CI: 11.4-27.1), and median duration of response was 21.0 months (range, 3.1 to 39.5+). Disease control rate was 61.5%, and median time to progression was 4.8 months (95% CI: 3.9-7.0). Median progression-free survival was 4.9 months (95% CI: 3.5-6.7) and median overall survival was 13.2 months (95% CI: 9.7-15.3). Of 104 patients, 76 (73.1%) patients reported treatment-related adverse events; most were low grade in severity (grade 3-4, n = 26 [25.0%]; grade 5, n = 1 [1.0%]). Immune-mediated hepatitis occurred in 3 patients (all grade 3). No viral-induced hepatitis flares occurred. CONCLUSIONS: After ∼2.5 years of additional follow-up, pembrolizumab continued to provide durable anti-tumour activity and no new safety concerns were identified. GOV IDENTIFIER: NCT02702414. ispartof: EUROPEAN JOURNAL OF CANCER vol:167 pages:1-12 ispartof: location:England status: published

Background: In patients (pts) with previously treated aHCC, pembro demonstrated comparable efficacy and safety vs placebo (pbo) in the phase 3 KEYNOTE-240 (NCT02702401) and KEYNOTE-394 (NCT03062358) studies in global and Asian populations, respectively. The hazard ratio ([HR]; 95% confidence interval [CI]) for OS was 0.781 (0.611-0.998) in KEYNOTE-240 and 0.79 (0.63-0.99) in KEYNOTE-394; HR (95% CI) for PFS was 0.78 (0.61-0.99) and 0.74 (0.60-0.92), respectively. ORR differences with pembro vs pbo were similar in KEYNOTE-240 (13.8% [95% CI, 7.7-19.5]) and KEYNOTE-394 (11.4% [95% CI, 6.7-16.0]). We performed a prespecified meta-analysis of KEYNOTE-240 and KEYNOTE-394 to obtain a more precise estimate of the pembro treatment effect. Methods: In KEYNOTE-240 and KEYNOTE-394, pts with confirmed aHCC and progression or intolerance to sorafenib or oxaliplatin-based chemotherapy (KEYNOTE-394 only) were randomized 2:1 to pembro (200 mg IV Q3W) or pbo for ≤35 cycles, both with best supportive care. Inclusion/exclusion criteria were similar. Meta-analysis of pt data pooled from the ITT population of the pembro and pbo arms of each study was completed. OS, PFS (blinded independent central review [BICR] per RECIST 1.1), and ORR (BICR per RECIST 1.1) were assessed. Results: In total, 578 pts who received pembro and 288 who received pbo were included. The HR for OS and PFS and the difference in ORR for pembro vs pbo in all pts was 0.79 (95% CI, 0.67-0.93), 0.76 (0.64-0.89), and 12.5 (8.8-16.2), respectively (Table). Results were consistent across subgroups, including viral etiology, BCLC stage, and age. Conclusions: This meta-analysis of two studies with similar design, inclusion/exclusion criteria, and endpoints, showed improvement in OS, PFS, and ORR with pembro vs pbo across studies. These data also show consistent outcomes between the studies, providing further evidence for the benefit of second-line pembro for aHCC globally. All Patients Patients With Sorafenib-Treated aHCC Pembrolizumab(n = 578) Placebo(n = 288) Pembrolizumab(n = 550) Placebo (n = 274) OS, median (95% CI), mo 14.2 (12.8-16.2) 12.5 (10.2-13.6) 14.2 (12.8-16.0) 12.5 (10.4-13.6) HR (95% CI)a,b 0.79 (0.67-0.93) 0.78 (0.66-0.92) PFS, median (95% CI), mo 2.8 (2.7-2.9) 2.7 (1.6-2.8) 2.8 (2.7-2.9) 2.7 (1.6-2.8) HR (95% CI)a,b 0.76 (0.64-0.89) 0.76 (0.64-0.90) ORR, % (95% CI) 15.4 (12.6-18.6) 2.8 (1.2-5.4) 15.6 (12.7-18.9) 2.9 (1.3-5.7) Estimated treatment difference, (95% CI)b,c 12.5 (8.8-16.2) 12.6 (8.8-16.4) aHCC, advanced hepatocellular carcinoma; CI, confidence interval; HR, hazard ratio.aStratified Cox proportional hazard model with treatment as a single covariate and Efron’s method of tie handling was used to estimate the OS and PFS HR and its 95% CI.bStratification was performed per protocol and within each protocol, by strata used in the analysis of the respective protocol.cMiettinen & Nurminen method was used to estimate the difference in ORR and its 95% CI. Citation Format: Richard S. Finn, Kangsheng Gu, Xi Chen, Philippe Merle, Kyung-Hun Lee, Mohamed Bouattour, Peiguo Cao, Wei Wang, Ann-Lii Cheng, Liangjun Zhu, Ho Yeong Lim, Masatoshi Kudo, Yueyin Pan, Ting-Tsung Chang, Julien Edeline, Wei Li, Ping Yang, Chen Li, Jianfeng Li, Abby B. Siegel, Shukui Qin. Pembrolizumab (pembro) for previously treated advanced hepatocellular carcinoma (aHCC): Meta-analysis of the phase 3 KEYNOTE-240 and KEYNOTE-394 studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT222.

The impact of folate deficiency on global DNA methylation is uncertain. It also is unclear whether global DNA methylation is associated with outcome in HCC. LINE-1 methylation levels, as a surrogate marker of global methylation, may be influenced by folate deficiency. However, the interaction between LINE-1 methylation and folate level on overall survival (OS) in hepatocellular carcinoma (HCC) patients is unknown. We evaluated whether LINE-1 hypomethylation and folate deficiency are associated with HCC prognosis. We prospectively recruited 172 HCC patients between 2008 and 2012. LINE-1 methylation levels in plasma and white blood cells (WBC) were measured by pyrosequencing, and plasma folate levels by a radioprotein-binding assay. Patients with plasma LINE-1 methylation

PURPOSE The immunomodulatory effect of lenvatinib (a multikinase inhibitor) on tumor microenvironments may contribute to antitumor activity when combined with programmed death receptor-1 (PD-1) signaling inhibitors in hepatocellular carcinoma (HCC). We report results from a phase Ib study of lenvatinib plus pembrolizumab (an anti–PD-1 antibody) in unresectable HCC (uHCC). PATIENTS AND METHODS In this open-label multicenter study, patients with uHCC received lenvatinib (bodyweight ≥ 60 kg, 12 mg; < 60 kg, 8 mg) orally daily and pembrolizumab 200 mg intravenously on day 1 of a 21-day cycle. The study included a dose-limiting toxicity (DLT) phase and an expansion phase (first-line patients). Primary objectives were safety/tolerability (DLT phase), and objective response rate (ORR) and duration of response (DOR) by modified RECIST (mRECIST) and RECIST version 1.1 (v1.1) per independent imaging review (IIR; expansion phase). RESULTS A total of 104 patients were enrolled. No DLTs were reported (n = 6) in the DLT phase; 100 patients (expansion phase; included n = 2 from DLT phase) had received no prior systemic therapy and had Barcelona Clinic Liver Cancer stage B (n = 29) or C disease (n = 71). At data cutoff, 37% of patients remained on treatment. Median duration of follow-up was 10.6 months (95% CI, 9.2 to 11.5 months). Confirmed ORRs by IIR were 46.0% (95% CI, 36.0% to 56.3%) per mRECIST and 36.0% (95% CI, 26.6% to 46.2%) per RECIST v1.1. Median DORs by IIR were 8.6 months (95% CI, 6.9 months to not estimable [NE]) per mRECIST and 12.6 months (95% CI, 6.9 months to NE) per RECIST v1.1. Median progression-free survival by IIR was 9.3 months per mRECIST and 8.6 months per RECIST v1.1. Median overall survival was 22 months. Grade ≥ 3 treatment-related adverse events occurred in 67% (grade 5, 3%) of patients. No new safety signals were identified. CONCLUSION Lenvatinib plus pembrolizumab has promising antitumor activity in uHCC. Toxicities were manageable, with no unexpected safety signals.

Background: SWOG initiated a cancer care delivery research study of virus infection rates among newly diagnosed cancer patients. This study will inform viral screening guidelines in oncology clinics. Methods: In a first step ‘vanguard’ phase, we evaluated the feasibility of multiple study procedures. Site investigators were surveyed to obtain feedback on study implementation. Results: Much higher enrollment occurred at sites where all physicians participated and viral testing was performed as routine practice. These procedures will be required going forward. Additional protocol changes based on site investigator input were implemented. Conclusion: This multistep protocol design process illustrates how cancer care delivery research studies can adapt to real-world strategies and procedures that exist at community clinics where the predominance of cancer patients are treated.

Background: Biliary tract cancer (BTC), including intra- or extrahepatic cholangiocarcinoma (CCA) and gallbladder cancer, is an aggressive malignancy with limited treatment options. Most patients (pts) present with advanced or unresectable disease, for which the current first-line standard of care is gemcitabine with cisplatin. Prognosis for these pts is poor, with median survival of approximately 12 months. Pembrolizumab (pembro) has improved outcomes when combined with platinum-based chemotherapy in other tumor types (eg, gastric/GEJ, NSCLC). The randomized, placebo-controlled, double-blind, phase 3 KEYNOTE-966 trial (NCT04003636) will be conducted to evaluate pembro plus gemcitabine and cisplatin compared with placebo plus gemcitabine and cisplatin in pts with metastatic or unresectable locally advanced BTC. Methods: Pts will be randomly assigned 1:1 to receive pembro 200 mg or placebo IV every 3 weeks plus gemcitabine 1000 mg/m2 IV and cisplatin 25 mg/m2 IV on days 1 and 8 of every 3-week cycle. Cisplatin will be given for a maximum of 8 cycles. Treatment with pembro/placebo will continue for up to 35 administrations or until disease progression, unacceptable toxicity, or withdrawal from the study. Gemcitabine will be continued until disease progression, unacceptable toxicity, or withdrawal from the study. Pts will be stratified by region (Asia, non-Asia), stage (locally advanced, metastatic), and site of origin (gallbladder, intrahepatic CCA, or extrahepatic CCA). Key eligibility criteria are age ≥18 years; histologically confirmed metastatic or unresectable locally advanced BTC, measurable by RECIST v1.1; no prior systemic therapy for advanced BTC; Eastern Cooperative Oncology Group performance status of 0 or 1; and tumor sample adequate for biomarker analyses. Pts with past or ongoing hepatitis C or controlled hepatitis B virus infection are eligible per protocol-defined criteria. During the initial stage, response will be assessed by imaging every 6 weeks until week 54 and every 12 weeks thereafter. Safety, assessed by CTCAE v.5.0, will be monitored throughout the study and for 30 days after treatment end or 90 days for serious adverse events. The primary end points are progression-free survival (as assessed by blinded independent central review) and overall survival (OS). Secondary end points are objective response rate, duration of response, and safety. Additional analyses will include disease control rate, health-related quality of life (by EORTC QLQ-C30, EuroQol EQ-5D, and EORTC QLQ-BIL21), and molecular and genetic biomarkers. The study opened to recruitment on September 24, 2019. Recruitment is underway in 17 countries and will continue until approximately 788 pts are enrolled. Citation Format: Richard S. Finn, Robin K. Kelley, Junji Furuse, Julien Edeline, Zhenggang Ren, Shu-Chih Su, Usha Malhotra, Abby B. Siegel, Juan W. Valle. KEYNOTE-966: A randomized, double-blind, placebo-controlled, phase 3 study of pembrolizumab in combination with gemcitabine and cisplatin for the treatment of advanced biliary tract carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT283.

Background: For patients with hepatocellular carcinoma (HCC) who are undergoing potentially curative surgical resection or local ablation, 5-year recurrence rates are up to 50%-80%; there is no standard of care for adjuvant treatment. The programmed death 1 inhibitor pembrolizumab is approved for the treatment of patients with HCC previously treated with sorafenib. There is no direct evidence of benefit with pembrolizumab in the HCC adjuvant setting, but a favorable benefit/risk profile is anticipated based on data from other indications. KEYNOTE-937 (NCT03867084) is a randomized, double-blind, phase 3 trial to examine the safety and efficacy of adjuvant pembrolizumab versus placebo in patients with complete radiologic response after surgical resection or local ablation of HCC. Methods: Eligible patients are aged ≥18 years and have confirmed HCC, complete radiologic response after complete resection or local ablation, Eastern Cooperative Oncology Group performance status of 0, and class A Child-Pugh score. Patients with past or ongoing HCV or controlled HBV are eligible if they meet certain criteria. Patients (N~950) will be randomly assigned 1:1 to receive pembrolizumab 200 mg or placebo every 3 weeks and stratified by geographic region, prior local therapy (resection vs ablation), recurrence risk, and alpha-fetoprotein level at diagnosis. Treatment will continue for up to 17 cycles (~1 year) or until documented disease recurrence, unacceptable toxicity, or investigator/patient decision to withdraw. Dual primary end points are recurrence free survival (RFS) and overall survival. Secondary end points are safety, tolerability, and quality of life. Exploratory end points include distant metastases-free survival (DMFS); time to recurrence (TTR); and genomic, metabolic, and/or proteomic biomarkers. RFS, DMFS, and TTR will be assessed radiographically by the investigator and/or by subsequent biopsy and confirmed by blinded independent central review. Adverse events (AEs), graded per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0, will be recorded up to 30 days after last dose (90 days for serious AEs). Citation Format: Andrew Zhu, Masatoshi Kudo, Arndt Vogel, Thomas Yau, Jian Zhou, Eunhee Kim, Usha Malhotra, Abby B. Siegel, Ann-Lii Cheng. Phase 3 KEYNOTE-937: Adjuvant pembrolizumab versus placebo in patients with hepatocellular carcinoma and complete radiologic response after surgical resection or local ablation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT284.

Background LEN is a multikinase inhibitor of VEGFR 1–3, FGFR 1–4, PDGFRα, RET, and KIT. PEMBRO is an anti-PD-1 monoclonal antibody. LEN monotherapy is approved for first-line treatment of uHCC. PEMBRO monotherapy has shown significant efficacy in the second-line treatment of HCC. We report updated results from a phase 1b trial of LEN + PEMBRO in uHCC. Methods In this open-label, phase 1b study of LEN + PEMBRO in uHCC, 104 patients (pts) with BCLC stage B (not amenable for transarterial chemoembolization) or C, Child-Pugh class A, and ECOG PS≤1 received LEN (body wt≥60kg: 12mg/day; Results Pts received LEN + PEMBRO (DLT-evaluation part, n=6; expansion part, n=61). At data cutoff (June 30, 2019), 34 (50.7%) pts remained on study treatment; median duration of follow-up was 11.7 months (95% CI, 7.8-17.6). Serious adverse events occurred in 42 (62.7%) pts; no new safety signals emerged. Updated safety data will be provided. ORR (including unconfirmed responses) was 44.8% (Table) and compared favorably with LEN arm of REFLECT trial (24.1%; Kudo M. Lancet. 2018). Median DOR was 18.7 months (95% CI, 6.9-NE). Conclusions LEN + PEMBRO showed promising antitumor activity and an acceptable safety profile in pts with uHCC. Blinded independent central review is in progress. A phase 3 trial (LEAP-002; NCT03713593) is ongoing to assess LEN + PEMBRO vs LEN alone as first-line therapy for pts with uHCC.Table747PTableResponse Parameter, n (%)LEN + PEMBRO (n=67)mRECIST Per Investigator ORR (CR + PR + unconfirmed PR or CR)a Best Overall Response CR. PRa Stable disease Progressive disease Unknown/not evaluable 30 (44.8) 4 (6.0) 26 (38.8) 25 (37.3) 6 (9.0) 6 (9.0) aIncludes unconfirmed partial responses (2 patients). CR, complete response; (m)RECIST, (modified) Response Evaluation Criteria In Solid Tumors [Lencioni et al. Semin Liver Dis. 2010;30:52-60]; ORR, objective response rate; PR, partial response. Clinical trial identification NCT03006926; Release date: December 30, 2016. Editorial acknowledgement Medical writing support was provided by April Suriano, PhD, of Oxford PharmaGenesis, Newtown, PA, USA and was funded by Eisai Inc. Legal entity responsible for the study Eisai Inc. Funding Eisai Inc. and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure J. Llovet: Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Ipsen; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Celsion Corporation; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Merck; Advisory / Consultancy: Glycotest; Advisory / Consultancy: Navigant; Advisory / Consultancy: Leerink Swann LLC; Advisory / Consultancy: Midatech Ltd; Advisory / Consultancy: Fortess Biotech; Advisory / Consultancy: Sprink Pharmaceuticals; Advisory / Consultancy: Nucleix; Advisory / Consultancy: Can-Fite Biopharma. K.V. Shepard: Full / Part-time employment: Eisai Inc. R.S. Finn: Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer. M. Ikeda: Honoraria (self): Abbott, Bayer, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Eisai, Lilly, Nobelpharma, Novartis, Otsuka, Taiho Pharmaceutical, Teijin Pharma, Yakult Honsha; Advisory / Consultancy: Bayer, Daiichi Sankyo, Eisai, Kyowa Hakko Kirin, MSD, NanoCarrier, Novartis, Shire, Teijin Pharma, Lilly; Research grant / Funding (self): ASLAN Pharmaceuticals, AstraZeneca, Baxalta/Shire, Bayer, Bristol-Myers Squibb, Chugai Pharma, Eisai, Kowa, Kyowa Hakko Kirin, Lilly, Merck Serono, MSD, NanoCarrier, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Takara Bio, Yakult Honsha. M. Sung: Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis. A.D. Baron: Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Genentech/Roche; Speaker Bureau / Expert testimony: Lilly; Speaker Bureau / Expert testimony: Merck. M. Kudo: Honoraria (self), Research grant / Funding (self): AbbVie; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self): EA Pharma; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self): Gilead Sciences; Honoraria (self): Merck Serono; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (self): Taiho Pharmaceutical; Research grant / Funding (self): Astellas Pharma; Research grant / Funding (self): Chugai Pharma; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Otsuka. T. Okusaka: Honoraria (self): AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Chugai Pharma, Daiichi Sankyo, EA Pharma, Eisai, Fujifilm, Lilly Japan, Nippon Chemiphar, Nobelpharma, Novartis, Ono Pharmaceutical, Pfizer, Sumitomo Dainippon, Taiho Pharmaceutical, Teijin Pharma, Yakult; Advisory / Consultancy: Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Zeria Pharmaceutical; research funding from AstraZeneca, Baxter, Bayer, Chugai Pharma, Dainippon Sumitomo Pharma, Eisai, Kowa, Kyowa Hakko Kirin, Lilly Japan, Merck Serono, NanoCarrier, Nippon Boeh. M. Kobayashi: Speaker Bureau / Expert testimony: Eisai Inc. H. Kumada: Honoraria (self): AbbVie; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Gilead Sciences; Honoraria (self): MSD; Honoraria (self): Sumitomo; Honoraria (self): Dainippon. S. Kaneko: Honoraria (self): EA Pharma, MSD, Aska Pharma, Astellas Pharma, AbbVie, Eisai, Eidia, Otsuka, Gilead Sciences, Sysmex Corporation, Daiichi Sankyo, Taisho Toyama, Sumitomo Dainippon, Taiho, Takeda, Chugai, Bayer, Bristol-Myers, Mylan EPD, Miyarisan, Mochida, Kowa, Mitsubis; Research grant / Funding (self): Gilead Sciences, AbbVie, Daiichi Sankyo, Astellas Pharma, Takeda, Nippon Boehringer Ingelheim, MSD, Ono Pharma, Pfizer, Shionogi, Teijin Pharma, Mitsubishi Tanabe, Zeria, Abbott Vascular Japan, Taisho Toyama, Novartis, Terumo Corporation, Taiho, Novo Nord. K. Mamontov: Honoraria (self): Bayer; Honoraria (self): Eisai; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Medtronic; Honoraria (self): Roche. T. Meyer: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai; Advisory / Consultancy: BTG; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: BeiGene; Advisory / Consultancy: Tarveda; Advisory / Consultancy: MSD. K. Mody: Full / Part-time employment: Eisai Inc. T. Kubota: Full / Part-time employment: Eisai Co., Ltd. K. Saito: Full / Part-time employment: Eisai Inc. A.B. Siegel: Full / Part-time employment: Merck. L. Dubrovsky: Full / Part-time employment: Merck. A.X. Zhu: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Sanofi. All other authors have declared no conflicts of interest.

Long non-coding RNAs (lncRNAs) are larger than 200 nucleotides in length and pervasively expressed across the genome. An increasing number of studies indicate that lncRNA transcripts play integral regulatory roles in cellular growth, division, differentiation and apoptosis. Deregulated lncRNAs have been observed in a variety of human cancers, including hepatocellular carcinoma (HCC). We determined the expression profiles of 90 lncRNAs for 65 paired HCC tumor and adjacent non-tumor tissues, and 55 lncRNAs were expressed in over 90% of samples. Eight lncRNAs were significantly down-regulated in HCC tumor compared to non-tumor tissues (p &lt, 0.05), but no lncRNA achieved statistical significance after Bonferroni correction for multiple comparisons. Within tumor tissues, carrying more aberrant lncRNAs (6–7) was associated with a borderline significant reduction Cancers 2015, 7 1848 in survival (HR = 8.5, 95% CI: 1.0–72.5). The predictive accuracy depicted by the AUC was 0.93 for HCC survival when using seven deregulated lncRNAs (likelihood ratio test p = 0.001), which was similar to that combining the seven lncRNAs with tumor size and treatment (AUC = 0.96, sensitivity = 87%, specificity = 87%). These data suggest the potential association of deregulated lncRNAs with hepatocarcinogenesis and HCC survival.

Objectives: To investigate the clinical efficacy and tolerability of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Methods: A total of 90 patients with advanced HCC, Child-Pugh class A–B7 cirrhosis, and no prior systemic therapy were randomly assigned (1: 1) to receive either 10 mg/kg B intravenously every 14 days and 150 mg E orally daily (n = 47) (B+E) or 400 mg S orally twice daily (n = 43). The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), time to progression, and safety and tolerability. Results: The median OS was 8.55 months (95% CI: 7.00–13.9) for patients treated with B+E and 8.55 months (95% CI: 5.69–12.2) for patients receiving S. The hazard ratio (HR) for OS was 0.92 (95% CI: 0.57–1.47). The median EFS was 4.37 months (95% CI: 2.99–7.36) for patients receiving B+E and 2.76 months (95% CI: 1.84–4.80) for patients receiving S. The HR for EFS was 0.67 (95% CI: 0.42–1.07; p = 0.09), favoring B+E over S. When OS was assessed among patients who were Child-Pugh class A, the median OS was 11.4 months (95% CI: 7.5–15.7) for patients treated with B+E (n = 39) and 10.26 months (95% CI: 5.9–13.0) for patients treated with S (n = 38) (HR = 0.88; 95% CI: 0.53–1.46). Conclusions: There was no difference in efficacy between the B+E and S arms, although the safety and tolerability profile tended to favor B+E over S based on competing risk analysis.

Aim Deregulation of microRNAs (miRNAs) expression has been identified in hepatocellular carcinoma (HCC), but few results are consistent. The objective of this study is to investigate "HCC tumor type specific" and "tumor common" miRNA panels. Methods The authors integrate and analyze clinical, etiologic and miRNA profiles data from 9 types of solid tumors in The Cancer Genome Atlas (TCGA) and HCC data from Columbia University Medical Center (CUMC). Results Levels of 33 miRNAs were significant different between HCC tumor and paired non-tumor tissues (over 2-fold changes) after Bonferroni correction for multiple comparisons, and most (28 miRNAs) were down-regulated in HCC tumors. Using this panel, the authors well classified HCC tumor tissues with 4 misclassifications among 48 paired tissues. Validating this panel in an additional 302 HCC tumor tissues, the authors almost perfectly distinguished tumor from non-tumor tissues with only two misclassifications (99% of HCC tissues correctly classified). Evaluating miRNA profiles in 32 independent HCC paired tissues from CUMC, the authors observed 40 miRNAs significantly deregulated in HCC with over 2-fold changes; 14 overlapped with those identified in TCGA. Subgroup analyses by HCC etiology found that 4 upregulated and 8 downregulated miRNAs were significantly associated with alcohol-related HCC. There were 7 and 4 miRNAs significantly associated with hepatitis B virus- and hepatitis C virus-related HCC, respectively. Data for the first time revealed that miR-24-1, miR-130a and miR-505 were significantly down-regulated only in HCC tumors; miR-142 and miR-455 were significantly down-regulated in HCC, but up-regulated in 5 other solid tumors; suggesting their HCC "tumor type specific" characteristics. A panel of 8 miRNAs was significant in at least 5 tumor types, including HCC, and was identified as "tumor common" marker. Conclusion The authors concluded that aberrant miRNA panels have HCC "tumor type specificity" and may be affected by etiologic factors.

Background. More than 50% of US adults, and an even larger proportion of cancer patients, use dietary supplements. Since many supplements require hepatic metabolism, they may be particularly likely to cause toxicities in patients with hepatocellular carcinoma (HCC). However, little is known about supplement use in patients with HCC. Methods. From 2008 to 2012, we gave newly diagnosed HCC patients at our institution a standardized questionnaire about dietary supplement use, demographic factors, and clinical characteristics. We then followed patients for four years or until time to death to examine the relationship with supplement use. Results. Of 146 patients, 71% had used vitamins and 45% herbal supplements. Most commonly used supplements were antioxidants (51%), multivitamins (46%), vitamin D (25%), and milk thistle (23%). People in mid-higher income brackets were more likely to use herbal supplements (19% of those earning $60 000 used supplements). Hepatitis C (HCV) patients were more likely to use milk thistle than those without HCV (30% vs 13%, P = .03), and patients with hepatitis B (HBV) were more likely than non-HBV patients to use vitamin C (32% vs 14%, P = .01). Supplement use was not associated with overall survival. Conclusions. Like cancer patients in other studies, the majority of our HCC patients used dietary supplements. Supplement use was not associated with overall survival but should be studied in larger patient samples.

There is conflicting literature regarding the superiority of transarterial chemoembolization (TACE) versus bland transarterial embolization (TAE), and this has not been well studied before transplantation. Twenty-five TAE patients were matched in a 1:2 ratio with TACE patients by the initial radiographic tumor size and number in a retrospective, case-controlled study. The patients were otherwise treated according to the same protocols. The method of embolization was chosen on the basis of interventionalist practices at 2 sites within the program. Kaplan-Meier survival analyses at 1 and 3 years were the primary endpoints. There were no significant demographic differences between the groups. The mean adjusted Model for End-Stage Liver Disease scores at transplantation and waiting times were not significantly different between the TAE and TACE patients (MELD scores: 26 ± 3 versus 24 ± 3 points, P = 0.12; waiting times: 13 ± 8 versus 11 ± 10 months, P = 0.43). TAE patients (16%) were less likely than TACE patients (40%) to require 2 procedures (P = 0.04). Explant tumors were completely necrotic for 36% of the TAE patients and for 26% of the TACE patients. The 3-year overall survival rates were 78% for the TAE patients and 74% for the TACE patients (P = 0.66), and the 3-year recurrence-free survival rates were 72% for the TAE patients and 68% for the TACE patients (P = 0.67). On an intention-to-treat basis, there was no significant risk of wait-list dropout associated with TAE or TACE (P = 0.83). In conclusion, there were no significant differences in wait-list dropout or in overall or recurrence-free survival between HCC patients undergoing TAE and HCC patients undergoing TACE before transplantation.

Background KEYNOTE-240 (ClinicalTrials.gov: NCT02702401) is a double-blind, randomized, placebo-controlled, phase 3 trial that evaluated pembro 200 mg every 3 weeks compared with BSC in pts with advanced HCC who were previously systemically treated. Pembro reduced the risk of death by 22% and improved progression-free survival over BSC in pts with advanced HCC, although significance was not reached per prespecified statistical criteria. Here we present the results of prespecified exploratory HRQoL analyses. Methods The EORTC QLQ-C30 and EORTC QLQ-HCC18 questionnaires were administered electronically at baseline; weeks 3, 6, 9, 12, and 18; every 9 weeks thereafter up to 1 year or end of treatment; and at the 30-day safety follow-up visit. Least squares mean (LSM) score changes from baseline to week 12 (prespecified) were compared using constrained longitudinal data analysis model including treatment by study visit interaction and stratification factors as covariates. Time to deterioration (TTD) (≥10-point decline from baseline) was estimated by Kaplan-Meier method, and the magnitude of the treatment difference (hazard ratio) between treatment arms was assessed by a stratified Cox proportional hazards model. Results Pts receiving ≥1 dose of study treatment and completing ≥1 HRQoL assessment were included in the analysis. The HRQoL population included 398 pts (271 pembro; 127 BSC). HRQoL compliance at week 12 was 90.0% for pembro and 89.3% for BSC. From baseline to week 12, there was no statistically significant difference in LSM between the 2 arms for global health status (GHS)/QoL score (-1.19; 95% CI, -5.35, 2.97; P = 0.573). The GHS/QOL scores remained stable over time for both arms. TTD for prespecified symptoms of abdominal swelling (HR, 1.08; 95% CI, 0.76, 1.54; P = 0.6552), fatigue (HR, 0.98; 95% CI, 0.71, 1.20; P = 0.2795), and pain (HR, 0.97; 95% CI, 0.74, 1.27; P = 0.4078) from EORTC QLQ-HCC18 were similar between the 2 arms. Conclusions Over 12 weeks, pts treated with pembro had similar HRQoL compared to pts receiving BSC. Along with efficacy and safety results from KN240, these data support the benefit of pembrolizumab in HCC pts. Clinical trial identification NCT02702401; Release date: March 8, 2016. Editorial acknowledgement Harleigh E. Willmott, CMPP (ApotheCom, Yardley, PA, USA, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure P. Merle: Advisory / Consultancy, Leadership role, Research grant / Funding (institution): Onxeo; Advisory / Consultancy: Bayer; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Ipsen; Advisory / Consultancy: Eisai; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: BMS. A.S. Kulkarni: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme Corp. A. Cheng: Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eisai; Honoraria (self): MSD; Honoraria (self), Advisory / Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: IQVIA; Advisory / Consultancy: Bayer Schering Pharma; Advisory / Consultancy: BMS; Advisory / Consultancy: Exilixis; Advisory / Consultancy: Nucleix Ltd; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer Yakuhin, Ltd.; Speaker Bureau / Expert testimony: Amgen Taiwan. M. Kudo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self): Bayer; Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Ono; Advisory / Consultancy: BMS; Advisory / Consultancy: Eli Lilly; Research grant / Funding (institution): EA Pharma; Research grant / Funding (institution): Gilead; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Otsuka; Research grant / Funding (institution): Taiho. M. Bouattour: Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer Pharma; Advisory / Consultancy, Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Sirtex Medical; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen. H.Y. Lim: Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eisai. V. Breder: Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Eisai; Travel / Accommodation / Expenses: BioCad. J. Edeline: Honoraria (self), Honoraria (institution), Research grant / Funding (self): BTG; Honoraria (self): Eisai; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Novartis; Honoraria (self): Bayer; Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Servier; Travel / Accommodation / Expenses: Roche. S. Ogasawara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Merck Sharp & Dohme Corp.; Advisory / Consultancy: Chugai Pharma; Advisory / Consultancy: AstraZeneca. T. Yau: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: BMS. M. Garrido: Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony: MSD; Research grant / Funding (institution): Pfizer. B. Daniele: Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self): Lilly; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self): MSD; Advisory / Consultancy: Eisai; Advisory / Consultancy: Incyte; Travel / Accommodation / Expenses: Sanofi. J. Norquist: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme Corp. E. Chen: Full / Part-time employment: Merck Sharp & Dohme Corp. A.B. Siegel: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck Sharp & Dohme Corp. A.X. Zhu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly; Advisory / Consultancy: Eisai; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme Corp.; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Bayer; Advisory / Consultancy: Exelixis. R.S. Finn: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Eisai; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Merck Sharp & Dohme Corp.; Advisory / Consultancy: Roche/Genentech; Speaker Bureau / Expert testimony: Novartis. All other authors have declared no conflicts of interest.

BackgroundLEN is a multikinase inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRα, RET, and KIT. In a Phase III trial (REFLECT), LEN demonstrated a treatment effect on overall survival (OS) by statistical confirmation of noninferiority vs sorafenib for first-line treatment of uHCC. PEMBRO is an anti-PD-1 monoclonal antibody. LEN and PEMBRO monotherapies are approved for unresectable first- and second-line treatment of HCC, respectively. We report updated results from a Phase Ib trial of LEN + PEMBRO in uHCC. Methods In this open-label, multicenter phase 1b study of tolerability and safety of LEN + PEMBRO, patients (pts) with uHCC, BCLC stage C or B (not amenable for transarterial chemoembolization), Child-Pugh class A, and ECOG PS ≤ 1 received LEN (body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day, QD) and PEMBRO (200 mg IV Q3W). No dose-limiting toxicities were reported in Part 1 (n=6); thus, pts with no prior systemic therapy for uHCC (n=24) were enrolled in Part 2 (Expansion). Primary endpoint was safety. Tumor assessments were by investigators per modified Response Evaluation Criteria In Solid Tumors (mRECIST) for HCC, and independent imaging review (IIR) per mRECIST and RECIST 1.1. Results 30 pts were enrolled and received LEN + PEMBRO (Part 1, n=6; Part 2, n=24). Pts had BCLC stage B (n=9) or C (n=21), Child-Pugh scores of 5 (n=26) or 6 (n=4). At data cutoff (Aug 23, 2018), 18 (60%) pts were still on study treatment; median duration of follow-up was 9.7 months (95% CI 7.6-12.2). Any-grade treatment-emergent adverse events (TEAEs) occurred in 28 pts (93%); the most common any-grade TEAEs were decreased appetite (63%) and hypertension (60%). 7 (23%) pts discontinued treatment due to TEAEs, and no new safety signals were identified. Efficacy outcomes reported in the Table. Conclusions The LEN + PEMBRO combination showed promising antitumor activity and an acceptable safety profile in pts with uHCC. The trial protocol has been amended to enroll up to a total of 100 pts to part 2 of the study. LEN + PEMBRO (N=30)mRECIST per investigatormRECIST per IIRRECIST 1.1 per IIRObjective Response Rate, n (%)*11 (36.7)15 (50.0)11 (36.7)Best Overall Response, n (%)Complete Response*1 (3.3)3 (10.0)0Partial Response*10 (33.3)12 (40.0)11 (36.7)Stable Disease18 (60.0)13 (43.3)16 (53.3)Progressive Disease01 (3.3)2 (6.7)Unknown/Not Evaluable1 (3.3)1 (3.3)1 (3.3)IIR, independent imaging review; (m)RECIST, (modified) Response Evaluation Criteria in Solid Tumors (Lencioni et al. Semin Liver Dis. 2010 Feb;30(1):52-60). *Confirmed responses only Citation Format: Masafumi Ikeda, Max W. Sung, Masatoshi Kudo, Masahiro Kobayashi, Ari D. Baron, Richard S. Finn, Shuichi Kaneko, Andrew X. Zhu, Tomoki Kubota, Silvija Kralijevic, Hiroki Ikezawa, Abby B. Siegel, Hiromitsu Kumada, Takuji Okusaka. A Phase Ib trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC): Updated results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT061.

Background: MicroRNAs (miRNA) are abundant in the circulation and play a central role in diverse biologic processes; they may be useful for early diagnosis of hepatocellular carcinoma. Methods: We conducted a two-phase, case–control study (20 pairs for the discovery set and 49 pairs for the validation set) to test the hypothesis that genome-wide dysregulation of circulating miRNAs differentiates hepatocellular carcinoma cases from controls. Taqman low-density arrays were used to examine genome-wide miRNA expression for the discovery set, and quantitative real-time PCR was used to validate candidate miRNAs for both discovery and validation sets. Results: Sixty-six miRNAs were found to be significantly overexpressed in plasma of hepatocellular carcinoma cases compared with controls after adjusting for false discovery rate (P < 0.05). A volcano plot indicated that seven miRNAs had greater than 2-fold case–control differences with P < 0.01. Four significant miRNAs (miR-150, miR-30c, miR-483-5p, and miR-520b) detectable in all samples with varied expression levels were further validated in a validation set. MiR-483-5p was statistically significantly overexpressed in hepatocellular carcinoma cases compared with controls (3.20 vs. 0.82, P < 0.0001). Hepatocellular carcinoma risk factors and clinic-pathological characteristics did not influence miR-483-5p expression. The combination of plasma miR-483-5p level and hepatitis C virus status can significantly differentiate hepatocellular carcinoma cases from controls with an area under the curve of 0.908 (P < 0.0001). The sensitivity and specificity were, respectively, 75.5% and 89.8%. Conclusions: These preliminary results suggest the importance of dysregulated circulating miR-483-5p as a potential hepatocellular carcinoma biomarker. Impact: Confirmation of aberrant expression of miR-483-5p in a large prospective hepatocellular carcinoma study will provide support for its application to hepatocellular carcinoma detection. Cancer Epidemiol Biomarkers Prev; 22(12); 2364–73. ©2013 AACR.

Hepatocellular carcinoma (HCC) incidence has increased in the US and also has one of the fastest growing death rates of any cancer. The purpose of the current study was to discover novel genome-wide aberrant DNA methylation patterns in HCC tumors that are predominantly HCV-related. Infinium HumanMethylation 450K BeadChip arrays were used to examine genome-wide DNA methylation profiles in 66 pairs of HCC tumor and adjacent non-tumor tissues. After Bonferroni adjustment, a total of 130,512 CpG sites significantly differed in methylation level in tumor compared with non-tumor tissues, with 28,017 CpG sites hypermethylated and 102,495 hypomethylated in tumor tissues. Absolute tumor/non-tumor methylation differences ≥ 20% were found in 24.9% of the hypermethylated and 43.1% of the hypomethylated CpG sites; almost 10,000 CpG sites have ≥ 30% DNA methylation differences. Most (60.1%) significantly hypermethylated CpG sites are located in CpG islands, with 21.6% in CpG shores and 3.6% in shelves. In contrast, only a small proportion (8.2%) of significantly hypomethylated CpG sites are situated in islands, while most are found in open sea (60.2%), shore (17.3%) or shelf (14.3%) regions. A total of 2,568 significant CpG sites (2,441 hypermethylated and 127 hypomethylated) covering 589 genes are located within 684 differentially methylated regions defined as regions with at least two significant CpG sites displaying > 20% methylation differences in the same direction within 250-bp. The top 500 significant CpG sites can significantly distinguish HCC tumor from adjacent tissues with one misclassification. Within adjacent non-tumor tissues, we also identified 75 CpG sites significantly associated with gender, 228 with HCV infection, 17,207 with cirrhosis, and 56 with both HCV infection and cirrhosis after multiple comparisons adjustment. Aberrant DNA methylation profiles across the genome were identified in tumor tissues from US HCC cases that are predominantly related to HCV infection. These results demonstrate the significance of aberrant DNA methylation in HCC tumorigenesis.

AIM To investigate the levels of leptin and adiponectin in prediction of hepatocellular carcinoma (HCC) survival among patients without liver transplantation. MATERIALS AND METHODS We measured pretreatment plasma leptin and adiponectin in 172 HCC cases who were prospectively followed-up over 7 years. RESULTS Gender, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, high body mass index (BMI), diabetes mellitus (DM) history and Child-Pugh (CP) class were associated with leptin and adiponectin levels, while α-fetoprotein (AFP) and presence of metastasis, being outside the Milan criteria and Barcelona clinic liver cancer (BCLC) stage, were significantly associated with liver transplantation and HCC survival. No significant association was observed for leptin or adiponectin and HCC survival in the overall group. In subgroup analyses among those without liver transplantation, we found significant associations between metastasis, Milan criteria, BCLC stage, hepatitis B surface antigen (HBsAg) and HCC survival. When separately determining the Cox proportional hazard models and Kaplan-Meier survival curves by liver transplantation status, higher adiponectin was significantly associated with an increased hazard ratio (HR) of death of 1.72 (95% confidence interval (CI)=1.12-2.64), i.e. poor survival among patients without liver transplantation. A multivariate Cox proportional hazard model, including adiponectin, CP class, presence of metastasis, tumor outside of Milan criteria, AFP and BCLC stage B/C parameters, also showed significant association with poor HCC survival (likelihood ratio test p

The association between cigarette smoking and mortality from hepatocellular carcinoma (HCC) is ambiguous. We analyzed the association between smoking and mortality in HCC patients seen at our center. We collected data retrospectively on patients diagnosed with HCC between 2002 and 2009. We estimated the association of smoking history with demographic, clinical and treatment factors. We then modeled these factors as predictors of mortality. Among smokers, we analyzed the effects of pack-year history and cessation times on survival. Two hundred and twenty-three out of 444 patients with HCC had a history of smoking. Smokers were more likely to be younger at diagnosis, to have α fetoprotein (AFP) values less than the median, and to have had surgery (p=0.04) compared to non-smokers. In a Cox model, younger age, lower AFP and Child's Class were all independently predictive of survival, but smoking was not. Smokers with over 20 pack-years did not have worse survival than lighter smokers, and cessation times also did not affect survival after controlling for age. We found a significant interaction between smoking and drinking. In our data, smoking was not independently associated with HCC survival in a multivariable model. Smoking was associated with favorable prognostic features which likely outweighed any independent effect of smoking.