REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib.

Zhu, Andrew X.; Kang, Yoon‐Koo; Yen, Chia-Jui; Finn, Richard S.; Galle, Peter R.; Llovet, Josep M.; Assenat, Éric; Brandi, Giovanni; Lim, Ho Yeong; Pracht, Marc; Rau, Kun‐Ming; Merle, Philippe; Motomura, Kenta; Ohno, Izumi; Daniele, Bruno; Shin, Donghyun; Gerken, Guido; Abada, Paolo; Hsu, Yanzhi; Kudo, Masatoshi

doi:10.1200/jco.2018.36.15_suppl.4003

Cited by 92 publications

(71 citation statements)

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“…Based on these data, another phase III randomised controlled trial (REACH‐2) has been conducted testing ramucirumab vs placebo in sorafenib‐experienced patients with AFP of 400 ng/mL or higher. As recently reported, ramucirumab moderately but significantly prolonged survival (median OS, 8.5 vs 7.3 months) with a HR of 0.71 (95% CI, 0.53‐0.95), making ramucirumab the first drug that showed a survival benefit in a biomarker‐selected population . Hence, ramucirumab—the first biomarker‐guided treatment in HCC—will likely become a preferred option in patients with AFP ≥400 ng/mL, and especially in those with poor tolerance to tyrosine kinase inhibitors.…”

Section: Targeted Therapiesmentioning

confidence: 82%

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Review article: systemic treatment of hepatocellular carcinoma

Pinter

Peck‐Radosavljevic

2018

Aliment Pharmacol Ther

140

122

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SummaryBackgroundThe approval of the tyrosine kinase inhibitor sorafenib in 2007 marked a milestone in the treatment of hepatocellular carcinoma, as sorafenib was the first systemic therapy to show a survival benefit in patients with advanced hepatocellular carcinoma. Since then many drugs failed in the first‐ and second‐line setting and it took almost another decade until further tyrosine kinase inhibitors succeeded in phase III trials.AimTo summarise the evolving field of systemic therapy of hepatocellular carcinoma.MethodsWe reviewed recently published studies identified from PubMed and data presented at recent meetings. Main search terms included hepatocellular carcinoma, tyrosine kinase inhibitors, immunotherapy, immune checkpoint inhibitors, sorafenib, regorafenib, lenvatinib, cabozantinib, ramucirumab, and nivolumab.ResultsWe discuss the evolution of targeted therapies since the approval of sorafenib including failures and recent advances. We also elaborate the unmet need of biomarkers to guide treatment decisions and discuss the emerging field of immunotherapy in hepatocellular carcinoma.ConclusionsThe tyrosine kinase inhibitors sorafenib (first line) and regorafenib (second line) have been approved for hepatocellular carcinoma, and the immune checkpoint inhibitor nivolumab obtained conditional approval for sorafenib‐experienced patients in the United States. With lenvatinib in the first line, and cabozantinib and ramucirumab in sorafenib‐experienced patients, three more targeted therapies reached their primary endpoint in phase III trials and may soon be added to the treatment armamentarium.

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Section: Targeted Therapiesmentioning

confidence: 82%

“…Some biomarkers (eg AFP, VEGF, hepatocyte growth factor) may have prognostic implications, but only serum AFP was so far successful as biomarker to guide treatment decisions in HCC …”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Review article: systemic treatment of hepatocellular carcinoma

Pinter

Peck‐Radosavljevic

2018

Aliment Pharmacol Ther

140

122

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“…The results of the REACH-2 trial were reported at the ASCO annual meeting in June 2018 [5]. OS was 8.5 months in the ramucirumab group and 7.3 months in the placebo group; the difference was significant (HR = 0.710, 95% CI 0.531–0.949, p = 0.0199) (Table 1).…”

Section: The Reach-2 Trialmentioning

confidence: 94%

“…ClinicalTrials.gov NCT02435433. Cited and modified from Zhu et al [5]. AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; BSC, best supportive care; ECOG PS, Eastern Cooperative Oncology Group performance status; FHSI-8, Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index-8; IV, intravenous; mOS, median overall survival; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PK, pharmacokinetics; Q2W, every 2 weeks; TTP, time to progression.…”

Section: The Reach-2 Trialmentioning

confidence: 99%

Ramucirumab as Second-Line Systemic Therapy in Hepatocellular Carcinoma

Kudo

2018

Liver Cancer

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“…A phase III trial (REACH) involving patients with advanced stage HCC after prior treatment with sorafenib showed negative results for its primary endpoint of OS, although a subgroup of patients with a baseline serum alpha‐fetoprotein (AFP) level ≥400 ng/mL demonstrated a significant improvement in median OS from 4.2 months with placebo to 7.8 months with ramucirumab. Based on this observation, a second phase III trial of ramucirumab in the second‐line setting (REACH‐2) was performed incorporating biomarker‐based enrichment for patients with baseline AFP concentrations ≥400 ng/dL. Results of this trial have demonstrated an improvement in OS of 8.5 months with ramucirumab versus 7.3 months for placebo (HR 0.710; 95% CI: 0.531‐0.949; P = 0.0199).…”

Section: Second‐line Therapiesmentioning

confidence: 99%

New Drugs Effective in the Systemic Treatment of Hepatocellular Carcinoma

Montironi

Montal

Llovet

2019

Clinical Liver Disease

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Liver cancer is a major health problem, being the second leading cause of cancer-related death worldwide, 1 with an annual incidence of more than 850,000 new cases globally. 2 Hepatocellular carcinoma (HCC) represents 85% to 90% of all primary liver cancers and occurs mainly in the setting of chronic inflammatory liver diseases. 2 Only 40% to 50% of patients with HCC are diagnosed at early stages (Barcelona Clinic Liver Cancer [BCLC] 0-A) amenable to potentially curative approaches. 2 However, up to 70% of patients present with disease recurrence within 5 years, 2 and no adjuvant therapies to prevent this complication are available to date. Patients diagnosed at an intermediate stage (BCLC B) are treated with transarterial chemoembolization, 2,3 whereas 40% Abbreviations: AE, adverse event; AFP, α-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; CCR4, chemokine receptor 4; CI, confidence interval; CTLA-4, cytotoxic T lymphocyte-associated antigen 4; DLTs, dose limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; EHS, extrahepatic spread; FDA, US Food and Drug Administration; FGFR, fibroblast growth factor receptor; FGFR4, fibroblast growth factor receptor 4; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HR, hazard ratio; Hsp90, heat shock protein 90; IDO1, indolamine2,3-dioxygenase 1; IHC, immunohistochemistry; mRECIST, modified response evaluation criteria in solid tumors; MTD, maximum tolerated dose; ORR, objective response rate; OS, overall survival; PD-1, programmed death-1; PDGFR, platelet-derived growth factor receptor; PDGFRB, platelet-derived growth factor receptor β; PD-L1, programmed death ligand 1; RP2D, recommended phase II dose; TGF-βR1, transforming growth factor-β receptor 1; VEGFA, vascular endothelial growth factor A; VEGFR, vascular endothelial growth factor receptor; VEGFR2, vascular endothelial growth factor receptor 2; VEGFR3, vascular endothelial growth factor receptor 3. From the

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REACH-2: A randomized, double-blind, placebo-controlled phase 3 study of ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma (HCC) and elevated baseline alpha-fetoprotein (AFP) following first-line sorafenib.

Cited by 92 publications

References 0 publications

Review article: systemic treatment of hepatocellular carcinoma

Review article: systemic treatment of hepatocellular carcinoma

Ramucirumab as Second-Line Systemic Therapy in Hepatocellular Carcinoma

New Drugs Effective in the Systemic Treatment of Hepatocellular Carcinoma

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