1398 Brivanib Versus Placebo in Patients With Advanced Hepatocellular Carcinoma (Hcc) Who Failed or Were Intolerant to Sorafenib: Results From the Phase 3 Brisk-Ps Study

Llovet, J.M.; Decaens, Thomas; Raoul, Jean-Luc; Boucher, Éveline; Kudo, Mineo; Chang, Cheng-Chen; Kang, Yang; Assenat, Éric; Lim, Ho-Yeong; Boige, Valérie; Mathurin, Philippe; Fartoux, Lætitia; Lin, Derek; Bruix, Jordi; Poon, Rtp; Sherman, Morris; Blanc, Jean Frédéric; Finn, Richard S.; Tak, Won Young; Chao, YC; Ezzeddine, Rana; Liu, D.; Walters, Ian; Park, J.-W.

doi:10.1016/s0168-8278(12)61409-3

Cited by 83 publications

(21 citation statements)

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“…It showed a higher overall response rate (ORR) (11.5 vs 1.9%) and a longer median TTP (4.3 vs 2.7 months; p = 0.0001), but did not significantly improve OS (9.4 vs 8.2 months; p = 0.33) [58].…”

Section: The Improvement Of Previous Treatmentsmentioning

confidence: 97%

“…In this Asiatic study, lapatinib has been evaluated in combination with paclitaxel versus paclitaxel alone in pretreated HER2 amplified aGCs. OS improvement was not statistically significant in the intention-to-treat population (11.0 vs 8.9 months; HR: 0.84; p = 0.2088) Sorafenib [53] VEGFR Tivozanib [54] Gastric cancer HER2 Lapatinib [66,67] EGFR Erlotinib [61,62] Gefitinib c-MET Foretinib [86] Rilotumumab [87,93] Onartuzumab [88] Hepatocellular carcinoma VEGFR, BRAF, KIT, RET, PDGFR Sunitinib Linifanib [55,56] FGFR Brivanib [57,58] EGFR Erlotinib [59] mTOR Temsirolimus [60] c-MET Foretinib [82] Tivantinib [83] Cabozantinib [84] MEK Selumetinib [89,90] IGF/IGFR Cixutumumab [91] The role of targeted therapy for GI tumors Review informahealthcare.com while in the Chinese subgroup of HER2-positive patients, this improvement was higher [67]. In many Phase II trials, the association of cetuximab with chemotherapy has been shown to have some efficacy [68,69] and based on the increase of RR in previous studies, Richards et al evaluated in a Phase II trial the combination of cetuximab and chemotherapy with docetaxel plus oxaliplatin (DOCOX) versus chemotherapy alone in patients affected with metastatic gastric and GEJ adenocarcinoma.…”

Section: The Improvement Of Previous Treatmentsmentioning

confidence: 99%

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The role of targeted therapy for gastrointestinal tumors

Rolfo

Bronte

Sortino

et al. 2014

Expert Review of Gastroenterology & Hepatology

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Section: The Improvement Of Previous Treatmentsmentioning

confidence: 97%

Section: The Improvement Of Previous Treatmentsmentioning

confidence: 99%

The role of targeted therapy for gastrointestinal tumors

Rolfo

Bronte

Sortino

et al. 2014

Expert Review of Gastroenterology & Hepatology

View full text Add to dashboard Cite

“…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

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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...

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“…The SUN trial was discontinued in 2010 after early data showed sunitinib was inferior to sorafenib in terms of OS and was more toxic [Cheng et al 2011]. In December 2011, the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor targeted agent, brivanib, was reported to show no improvement in OS over placebo when given as second-line therapy in the Brivanib Study in HCC Patients at Risk Post Sorafenib (BRISK-PS) trial [Llovet et al 2012], and in 2012 the Brivanib Study in HCC Patients at Risk First Line (BRISK-FL) trial of brivanib as first-line therapy also failed to meet its primary OS endpoint [BMS, 2012].…”

Section: Search: Adding Erlotinib To Sorafenib Provides No Benefitmentioning

confidence: 99%