Ramucirumab in patients with advanced hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): An exposure-response analysis

Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond.

The hepatocellular carcinoma (HCC) treatment landscape changed a decade ago, with sorafenib demonstrating survival benefit in the first-line setting and becoming the first systemic therapy to be approved for HCC. More recently, regorafenib and nivolumab have received approval in the second-line setting after sorafenib, with further positive phase 3 studies emerging in the first line (lenvatinib non-inferior to sorafenib) and second line versus placebo (cabozantinib and ramucirumab). A key recommendation in the management of patients receiving sorafenib is to promote close communication between the patient and the physician so that adverse events (AEs) are detected early and severe AEs can b…

Efficacy and safety of ramucirumab (RAM) for advanced hepatocellular carcinoma (HCC) with elevated alpha-fetoprotein (AFP) following first-line sorafenib across age subgroups in two global phase III trials (REACH and REACH-2)

Abstract Background REACH (NCT01140347) and REACH-2 (NCT02435433) were two global, randomized, double-blind, placebo (PL)-controlled multicenter, phase 3 studies of RAM vs PL in patients with HCC after prior sorafenib. REACH-2 confirmed overall survival (OS) benefit of RAM for patients with baseline AFP ≥400ng/mL, consistent with results in a prespecified subgroup of patients in REACH with AFP ≥400ng/mL. Methods Post-hoc pooled analyses were performed to examine efficacy and safety in three age subgroups ( Results Both intention-to-treat populations were pooled (542 patients in total). Within each age subgroup, baseline characteristics between treatment arms were similar. Patients of Conclu…

Lenvatinib (len) plus pembrolizumab (pembro) for the first-line treatment of patients (pts) with advanced hepatocellular carcinoma (HCC): Phase 3 LEAP-002 study.

TPS4152 Background: Len, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, is approved for first-line treatment of unresectable HCC (uHCC) based on the open-label phase 3 REFLECT study in which len showed noninferior overall survival (OS) and significantly improved objective response rate (ORR), progression-free survival (PFS), and time-to-progression (TTP) vs sorafenib. In the phase 2 KEYNOTE-224 study of pembro (a PD-1 inhibitor) as second-line treatment of advanced HCC, pembro showed meaningful clinical efficacy in pts previously treated with sorafenib, with median PFS 4.9 mo, median OS 12.9 mo, and a manageable safety profile. In results from the pha…

Validation of the easy-to-use lenvatinib prognostic index to predict prognosis in advanced hepatocellular carcinoma patients treated with lenvatinib

Aim The identification of new prognostic factors able to stratify hepatocellular carcinoma patients candidate to first-line therapy is urgent. In the present work we validated the prognostic value of the lenvatinib prognostic index. Methods Data of Eastern and Western patients treated with lenvatinib as first-line for Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma were recollected. The lenvatinib prognostic index was composed by three classes of risk according with our previous study. The "low risk" group includes patients with prognostic nutritional index (PNI) >43.3 and with previous transarterial chemoembolization. The "medium risk" group includes patients with PN…

Clinical outcomes with atezolizumab plus bevacizumab or lenvatinib in patients with hepatocellular carcinoma: a multicenter real-world study

Purpose: The purpose of this study is to compare response rates of lenvatinib and atezolizumab plus bevacizumab, in first-line real-world setting. Methods: Overall cohort included Western and Eastern hepatocellular carcinoma (HCC) patient populations from 46 centres in 4 countries (Italy, Germany, Japan, and Republic of Korea). Results: 1312 patients were treated with lenvatinib, and 823 patients were treated with atezolizumab plus bevacizumab. Objective response rate (ORR) was 38.6% for patients receiving lenvatinib, and 27.3% for patients receiving atezolizumab plus bevacizumab (p < 0.01; odds ratio 0.60). For patients who achieved complete response (CR), overall survival (OS) was not …

TH-302 + Gemcitabine (G + T) vs Gemcitabine (G) in Patients with Previously Untreated advanced Pancreatic Cancer (PAC)

ABSTRACT Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G…

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

Background: VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. Methods: In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy…

Trial Design and Endpoints in Hepatocellular Carcinoma: AASLD Consensus Conference

Proper trial design is critical for the success of clinical investigations. Hepatocellular carcinoma (HCC) is a complex disease that has several unique properties. In 2008, after the approval of sorafenib, a panel of experts proposed guidelines for trial design and endpoints in HCC that have been instrumental during the last decade and provided a framework to allow an homogeneous analysis of reported investigations. Since then, several phase III studies have been reported and novel challenges have emerged. A panel of experts conveyed by AASLD organized a Special Topic Conference on trial design and endpoints to address those emerging challenges. This review summarizes the analysis and concl…

Ramucirumab in patients with previously treated advanced hepatocellular carcinoma: Impact of liver disease aetiology.

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying aetiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease aetiology and baseline serum viral load. METHODS Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N = 542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by aetiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pre-treatment serum HBV DNA and HCV RNA were quantified using Roche CO…

Prognostic and predictive factors in patients treated with ramucirumab (RAM) with advanced hepatocellular carcinoma (aHCC) and elevated alpha-fetoprotein (AFP): Results from two phase III trials.

4146 Background: Elevated AFP in patients with aHCC is a poor prognostic factor with distinct molecular features, including high vascular endothelial growth factor (VEGF) signalling and increased angiogenesis. RAM, a human IgG1 monoclonal antibody, VEGF receptor 2 (VEGFR2) inhibitor, demonstrated improved survival vs placebo among patients with elevated AFP in the REACH-2 trial and is accepted as a standard of care for management of aHCC. We analyzed prognostic factors in patients with AFP ≥400 ng/mL and predictors of clinical benefit to RAM in an individual participant data (IPD) meta-analysis of the REACH and REACH-2 Phase III trials. Methods: Patients with aHCC, Child-Pugh A, ECOG perfo…

Real Life Study of Lenvatinib Therapy for Hepatocellular Carcinoma: RELEVANT Study

<b><i>Introduction:</i></b> In the REFLECT trial, lenvatinib was found to be noninferior compared to sorafenib in terms of overall survival. Here, we analyze the effects of lenvatinib in the real-life experience of several centers across the world and identify clinical factors that could be significantly associated with survival outcomes. <b><i>Methods:</i></b> The study population was derived from retrospectively collected data of HCC patients treated with lenvatinib. The overall cohort included western and eastern populations from 23 center in five countries. <b><i>Results:</i></b> We included 1,325 patients with HCC …

Ramucirumab for patients with intermediate-stage hepatocellular carcinoma (HCC) and elevated alpha fetoprotein (AFP): Pooled results from two phase III studies (REACH and REACH-2).

549 Background: Intermediate-stage HCC, as defined as Barcelona Clinic Liver Cancer (BCLC) Stage B, is a heterogeneous disease in terms of liver function and tumor load. REACH (NCT01140347) and REACH-2 (NCT02435433) investigated ramucirumab (RAM) in patients (pts) with HCC after prior sorafenib (SOR), with REACH-2 enrolling only pts with baseline AFP ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: All pts had HCC (BCLC stage C or B disease refractory/not amenable to locoregional therapy), Child-Pugh A, ECOG PS 0-1, and prior SOR. Pts were randomized to RAM 8 mg/kg or Placebo (P) Q2W. A pooled meta-analysis of independent pt data (stratified by study) f…

Ramucirumab in elderly patients with hepatocellular carcinoma and elevated alpha-fetoprotein after sorafenib in REACH and REACH-2.

Background & Aims: Limited data on treatment of elderly patients with hepatocellular carcinoma (HCC) increase the unmet need. REACH and REACH-2 were global phase III studies of ramucirumab in patients with HCC after prior sorafenib, where patients with alpha-fetoprotein (AFP) ≥400 ng/mL showed an overall ssurvival (OS) benefit for ramucirumab. These post-hoc analyses examined efficacy and safety of ramucirumab in patients with HCC and baseline AFP ≥ 400 ng/mL by three prespecified age subgroups (<65, ≥65 to <75 and ≥75 years). Methods: Individual patient data were pooled from REACH (baseline AFP ≥400 ng/mL) and REACH-2. Kaplan-Meier and Cox proportional hazards regression methods …

Consensus report from the 9th International Forum for Liver Magnetic Resonance Imaging: applications of gadoxetic acid-enhanced imaging

Abstract Objectives The 9th International Forum for Liver Magnetic Resonance Imaging (MRI) was held in Singapore in September 2019, bringing together radiologists and allied specialists to discuss the latest developments in and formulate consensus statements for liver MRI, including the applications of gadoxetic acid–enhanced imaging. Methods As at previous Liver Forums, the meeting was held over 2 days. Presentations by the faculty on days 1 and 2 and breakout group discussions on day 1 were followed by delegate voting on consensus statements presented on day 2. Presentations and discussions centered on two main meeting themes relating to the use of gadoxetic acid–enhanced MRI in primary l…

Biology and significance of alpha‐fetoprotein in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths globally due, in part, to the majority of patients being diagnosed with intermediate or advanced stage disease. Our increased understanding of the heterogeneous molecular pathogenesis of HCC has led to significant developments in novel targeted therapies. Despite these advances, there remains a high unmet need for new treatment options. HCC is a complex disease with multiple pathogenic mechanisms caused by a variety of risk factors, making it difficult to characterize with a single biomarker. In fact, numerous biomarkers have been studied in HCC, but alpha-fetoprotein (AFP) remains the most widely used …

Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab

Abstract Background & Aims Radiological progression patterns to first‐line sorafenib have been associated with post‐progression and overall survival in advanced hepatocellular carcinoma, but these associations remain unknown for therapies in second‐ and later‐line settings. This post hoc analysis of REACH and REACH‐2 examined outcomes by radiological progression patterns in the second‐line setting of patients with advanced hepatocellular carcinoma treated with ramucirumab or placebo. Methods Patients with advanced hepatocellular carcinoma, Child‐Pugh A and Eastern Cooperative Oncology Group Performance Status 0 or 1 with prior sorafenib were randomized to receive ramucirumab 8mg/kg or place…