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

Zhu, Andrew X.; Park, Joon Oh; Ryoo, Baek Yeol; Yen, Chia Jui; Poon, Ronnie T. P.; Pastorelli, Davide; Blanc, Jean Frédéric; Chung, Hyun Cheol; Baron, Ari David; Pfiffer, Tatiana; Okusaka, Takuji; Kubáčková, Kateřina; Trojan, Jörg; Sastre, Javier; Chau, Ian; Chang, Shao Chun; Abada, Paolo; Yang, Lifen; Schwartz, Jonathan D.; Kudo, Masatoshi

doi:10.1016/s1470-2045(15)00050-9

Cited by 715 publications

(658 citation statements)

References 30 publications

Supporting

Mentioning

630

Contrasting

Unclassified

Order By: Relevance

“…In some cases, this 21 exploration can suggest the existence of interaction between treatment and a specific factor. This was the case for the subgroup analysis of the REACH trial, suggesting a significant effect of ramucirumab in patients with high baseline levels of alpha-fetoprotein [34]. Of course, subgroup analyses cannot provide definitive evidence (especially when they show a positive result in a subgroup within a globally negative trial), but the generated hypothesis can be worth to be tested in a prospective trial [47].…”

Section: Cabozantinibmentioning

confidence: 95%

“…Of note, in patients with Child-Pugh A cirrhosis, a median OS of 18 months was reported. Based on these preliminary, interesting results, a phase III trial (REACH) was designed to test the efficacy of ramucirumab [34]. However, although patients enrolled in the phase II trial were treatment-naïve, the phase III trial was designed to compare ramucirumab versus placebo in the second-line setting, after sorafenib failure.…”

Section: Ramucirumabmentioning

confidence: 99%

“…As described above, a recent phase III study (REACH) comparing ramucirumab to placebo in patients after failure to sorafenib missed its primary end point [34]. The overall survival in the intention to treat (ITT) population (n = 565) was not significant different between the ramucirumab and the placebo arm (HR 0.866, 95% confidence interval [CI] 0.717 -1.046; p = 0.1391; median overall survival 9.2 months for ramucirumab versus 7.6 months for placebo).…”

Section: Ramucirumabmentioning

confidence: 99%

See 2 more Smart Citations

Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?

Brizzi

Pignataro

Tampellini

et al. 2016

Expert Review of Anticancer Therapy

View full text Add to dashboard Cite

Section: Cabozantinibmentioning

confidence: 95%

Section: Ramucirumabmentioning

confidence: 99%

Section: Ramucirumabmentioning

confidence: 99%

See 1 more Smart Citation

Systemic treatment of hepatocellular carcinoma: why so many failures in the development of new drugs?

Brizzi

Pignataro

Tampellini

et al. 2016

Expert Review of Anticancer Therapy

View full text Add to dashboard Cite

“…While the REACH trial's primary endpoint of OS favored the ramucirumab arm, it was not statistically significant (Table 1) [92]. On the other hand, lenvatinib, an oral multi-targeted TKI of VEGFR, PDGFR, FLT3, and c-KIT, has shown highly promising response data in phase I/II clinical trials in HCC, although with some concerns regarding its toxicity profile [93].…”

Section: Anti-angiogenic Agentsmentioning

confidence: 99%

“…On the other hand, brivanib, which targets VEGFR, PDGFR and FGFR, also failed to prolong OS (Table 1) in a phase III trial conducted to investigate its efficacy as a first line therapy even though it had a more favorable toxicity profile than sorafenib [89,90]. Moreover, another phase III, randomized, placebo-controlled study investigated the efficacy of brivanib after sorafenib failure and the authors reported that, in comparison to placebo, brivanib resulted in a longer median TTP but insignificant increase in the OS (Table 1) [91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108].…”

Section: Anti-angiogenic Agentsmentioning

confidence: 99%

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

Mekuria¹,

Abdi²

2017

J Cancer Sci Ther

View full text Add to dashboard Cite

Hepatocellular Carcinoma (HCC) is a common type of primary liver cancer. According to the recent world cancer report, the disease ranked as the sixth most common cancer worldwide and the third largest cause of cancer-related death. Deregulation of numerous signaling pathways have been implicate in pathogenesis of HCC, including IGF, EGF/TGF, HGF/cMet, WNT, Hedgehog, notch, hippo, VEGF, PDGF, and FGF. Besides, intracellular mediators such as MAPK and PI3K/AKT/mTOR play a role in HCC development and progression. Currently sorafenib is the only molecularly targeted drug available to treat advanced HCC. It only extends survival by a matter of months. Moreover, there is no alternative agent for patients progressing under treatment with sorafenib. Thus, there remains a critical need for both continued molecular characterization and aggressive drug development. This review provided and updated appraisal of the deregulated signaling and epigenetic pathways, targeted therapeutics that is being investigated and possible challenges in drug development for HCC. Nevertheless, c-Met over-expression was reported to be related to increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition [26]. Pathways related to neo-angiogenesisHigh vascularization is a hallmark of human HCC [8]. This angiogenesis process relies on autocrine and paracrine interactions between tumor cells, vascular endothelial cells, and pericytes. Tumor cells release pro-angiogenic factors in response to hypoxic conditions and nutrient deprivation and thus activate endothelial cells [27]. Activated endothelial cells break down extracellular matrix and basement membrane which result in a release of angiogenic factors which includes VEGF, FGF, PDGF, and TGF β [16]. These angiogenic factors in turn activate endothelial cells through TKR and their intracellular mediator's MAPK and PI3K/Akt/mTOR pathways, which lead to proliferation and migration of endothelial cells to form a new tubular structure and lumen for new vessels and finally, pericytes are activated and recruited to stabilize the new blood vessels [27,28]. has become a potential investigating area of research to identify target(s) to inhibit proliferation of HCC and metastasis. IGF pathwayThe pathway consists of circulating ligands IGF-I, IGF-II, and the receptor IGF-IR. It has been known for its involvement in the regulation of cell growth and energy metabolism [17]. According to studies, overexpression of IGF-II and IGF-IR has been implicated in cell proliferation and inhibition of apoptosis [18]. In support of this, low expression of IGF I and progressive increase in the level of expression of IGF-IR, IGF-II, and IGF substrates during the hepatocarcinogenesis process was detected at mRNA and protein level, which was associated with cell increased proliferation and reduced apoptosis has been observed in HCC cell lines and rat models as well as in human HCC samples [18]. Other studies also indicated that the major tumorpromoting e...

show abstract