Effect of Everolimus on Survival in Advanced Hepatocellular Carcinoma After Failure of Sorafenib

Zhu, Andrew X.; Kudo, Masatoshi; Assenat, Éric; Cattan, Stéphane; Kang, Yoon Koo; Lim, Ho Yeong; Poon, Ronnie Tung‐Ping; Blanc, Jean Frédéric; Vogel, Arndt; Chen, Chao Long; Dorval, Étienne; Peck‐Radosavljevic, Markus; Santoro, Armando; Daniele, Bruno; Furuse, Junji; Jappe, Annette; Perraud, Kevin; Anak, Oezlem; Sellami, Dalila; Chen, Li Tzong

doi:10.1001/jama.2014.7189

Cited by 531 publications

(425 citation statements)

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“…Understanding the molecular factors that may predict patient benefits derived from novel targeted therapies will be crucial for the successful development of HCC treatments. Despite the high frequency of mTOR activation in HCC, the EVOLVE-1 phase III trial showed essentially no OS benefit by everolimus in unselected HCC patients (15). The fact that mTOR inhibition was not sufficient to suppress tumor growth in many HCC patients suggests that mTOR dependence cannot solely be predicted by general mTOR activation.…”

Section: Discussionmentioning

confidence: 99%

“…The EVOLVE-1 (clinicaltrial.gov # NCT01035229) clinical trial design, patient inclusion, and exclusion criteria have been published (15). Briefly, 546 patients aged !18 years with BCLC stage B or C HCC whose disease progressed during or after sorafenib or who were intolerant to sorafenib were randomized 2:1 to everolimus 7.5 mg/day group or placebo group.…”

Section: Clinical Studymentioning

confidence: 99%

“…The median OS for the everolimus group and placebo group were 7.56 months and 7.33 months, respectively (HR: 1.05; 95% CI: 0.86-1.27; P ¼ 0.675; ref. 15). To test whether patients with no or low TSC2 expression in their tumors had an OS benefit from everolimus treatment, we quantified TSC2 expression in tumor samples from the EVOLVE-1 patients using our IHC assay and an H-score scoring system as described in the Materials and Methods.…”

Section: Tsc2 Immunohistochemistry Assay Identified Tsc2 Loss In Primmentioning

confidence: 99%

“…The allosteric mTORC1 inhibitor RAD001/everolimus has been tested in a randomized, placebo-controlled phase III clinical trial in patients with advanced HCC who failed sorafenib (EVOLVE-1; ref. 15). Overall survival (OS), the primary endpoint, showed nonsignificant improvement with everolimus treatment versus placebo.…”

Section: Introductionmentioning

confidence: 99%

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Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV þ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224-35. Ó2015 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Clinical Studymentioning

confidence: 99%

Section: Tsc2 Immunohistochemistry Assay Identified Tsc2 Loss In Primmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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“…In a phase I/II trial, everolimus demonstrated a disease control rate for at least 12 week of 44%, a median time-to-progression of 3.9 months and a median overall survival of 8.4 months, with a 10 mg/die schedule [29]. Based on these preliminary results, the phase III trial (EVOLVE-1) randomized 546 patients, in a 2:1 ratio, to receive everolimus (at the dose of 7.5 mg/die) or placebo as second-line treatment after sorafenib failure ( Table 2) [30]. No significant difference in overall survival was described between the two treatment arms: median overall survival was 7.6 months for patients assigned to everolimus and 7.3 months for patients assigned to placebo (Hazard Ratio 1.05, 95% confidence interval 0.86 -1.27; p=0.68).…”

Section: Everolimusmentioning

confidence: 99%