Randomized phase II trial of intravenous RO5137382/GC33 at 1600 mg every other week and placebo in previously treated patients with unresectable advanced hepatocellular carcinoma (HCC; NCT01507168).
Chia‐Jui YenBruno DanieleMasatoshi KudoPhilippe MerleJoong‐Won ParkPaul J. RossJean‐Marie PéronOliver EbertStephen L. ChanRonnie T.P. PoonM. ColomboTakuji OkusakaBaek‐Yeol RyooBeatriz MínguezTakayoshi TanakaToshihiko OhtomoOlga RutmanYa‐Chi ChenReuy-min LeeGhassan K. Abou‐Alfa
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4102 Background: RO5137382/GC33 (GC33) is a humanized monoclonal antibody against GPC3 that is frequently expressed in HCC. GC33 interacts with CD16/FcγR3 and triggers antibody-dependent cytotoxicity. GC33 was compared with placebo in a randomized phase II study in advanced HCC patients (pts) who had failed prior systemic therapy. Methods: Pts with advanced HCC who had failed prior systemic therapy, ≥18 years, ECOG 0-1, Child-Pugh A were randomized in a 2:1 ratio to GC33 1600 mg Q2W after two weekly doses versus placebo. Prior to randomization, pts were assigned into 3 cohorts based degree of GPC3 immunohistochemical expression: A (GPC3 2-3+), B (GPC3 1+) and C (GPC3 no expression). Primary endpoint was progression free survival (PFS). Secondary endpoints include overall survival (OS), time to progression (TTP), tolerability, and pharmacokinetics (PK). Tumor assessment was based on RECIST1.0 criteria and safety on CTCAE 4.0. Results: Between February 2012 to March 2013, 185 pts were enrolled: 121 received GC33 and 64 placebo: Median age 64/63, 85/75% male, 46/42% Asian, ECOG 0 65/63%, 74/77% having vascular invasion and/or extra-hepatic metastasis. 49/41% had prior single agent sorafenib. Drug exposure was 98.6% of planned dose, with an identical adverse events profile between the 2 groups. The median PFS, OS, and TTP in the GC33 vs placebo groups in months were: 2.6 vs 1.5 (HR 0.97, p=0.87), 6.8 vs 6.7 (HR 0.99, p=0.97), and 2.9 vs 1.7 (HR 0.96, p=0.85). A subsequent exposure-efficacy analysis showed that increased exposure based on projected Ctroughat cycle 3 day 1 was associated with prolonged PFS and OS. Median PFS for high GC33 exposure group (n=60) was 4 vs 1.5 months for placebo (n=60), and OS 9.7 vs 6.7 months, respectively. Combining higher exposure with FcγR3A-158V polymorphism or CD16 expression intensity may correlate with improved PFS and OS. Conclusions: GC33 did not show a clinical benefit in this advanced, previously treated HCC population, potentially due to suboptimal dosing. Further studies are needed to investigate whether higher GC33 drug exposure and a favored CD16/FcgR3 immune environment may help. Clinical trial information: NCT01507168.Keywords:
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<div>AbstractPurpose:<p>To identify a predictive biomarker of sorafenib for hepatocellular carcinoma personalized therapy.</p>Experimental Design:<p>The patients treated with or without sorafenib after hepatocellular carcinoma recurrence from multicenters were matched with propensity score matching analysis. The expression levels of Fms-like tyrosine kinase 3 (FLT3) in hepatocellular carcinoma specimens of the matched patients (<i>n</i> = 276) were analyzed by IHC. The optimal cut-off point of FLT3 levels for overall survival (OS) was defined via Cutoff Finder. Subgroup analysis of OS was employed to investigate the association between FLT3 levels and sorafenib benefit. The predictive value was assessed via Cox regression models with an interaction term. Hepatocellular carcinoma and paratumoral normal tissues were used to investigate the expression and copy-number variation of FLT3. Patient-derived xenograft (PDX) models were used to confirm the association between FLT3 levels and sorafenib response.</p>Results:<p>Patients with FLT3-high hepatocellular carcinoma exhibited a superior OS upon sorafenib treatment. High FLT3 levels were predictive of sorafenib benefit in terms of OS (<i>P</i><sub>interaction</sub> = 0.00006). Copy-number losses and decreased expression of FLT3 in hepatocellular carcinoma were detected in about 64% of patients. Moreover, the PDXs derived from tumors with high FLT3 levels also displayed a better response to sorafenib.</p>Conclusions:<p>Sorafenib may be able to delay tumor progression in patients with FLT3-high hepatocellular carcinoma. This potential biomarker needs to be further validated in independent cohorts prior to helping stratify patients for precision therapy in advanced hepatocellular carcinoma.</p></div>
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Second line therapy after failure of sorafenib continues to be under study. Prognosis of hepatocellular carcinoma is measured in months, with median overall survival reaching 10.7 months with sorafenib. Because of the modest net benefit sorafenib has contributed, and rising incidence of hepatocellular carcinoma in the world, continued efforts are ongoing to look for efficient upfront, second line, or combination therapies. Herein we review the most relevant to date published literature on treatment options beyond sorafenib, reported studies, ongoing investigational efforts, and possibilities for future studies in advanced hepatocellular carcinoma. Keywords: Hepatocellular carcinoma; Antiangiogenic therapy; MET-inhibitors; Immunotherapy
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Sorafenib, a small molecule multikinase inhibitor, is the standard of care in the USA and Europe for the treatment of advanced hepatocellular carcinoma. This article reviews its development from the basis of molecular hepatocarcinogenesis to phase III trials and discusses the future for sorafenib in hepatocellular carcinoma.
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In hepatocellular carcinoma, sorafenib is the only active medical treatment validated to date. Sorafenib is a targeted therapy mainly blocking tumor vascularisation. Sorafenib is currently used for inoperable or advanced stages of hepatocellular carcinoma, as well for hepatocellular carcinoma recurrence when the disease is diffuse or multifocal. Current clinical trials are designed to identify new antitumor molecules active in hepatocellular carcinoma that could enrich the therapeutic armamentarium in addition to sorafenib.
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Hepatocellular carcinoma is one of the most common malignances worldwide. Sorafenib, a multikinase inhibitor, is the standard therapy for patients with advanced-stage hepatocellular carcinoma. Therefore, it is essential to develop more effective therapeutic strategies to overcome resistance and improve the efficacy of sorafenib in treating hepatocellular carcinoma patients. In this study, we demonstrate that sorafenib chemotherapy combined with gene therapy, which expressed short hairpin ribonucleic acid against heat shock protein 27, effectively overcomes the sorafenib resistance of hepatocellular carcinoma cells and improves the anti-tumor effect of sorafenib. This combinational therapy will be a new hope for hepatocellular carcinoma patients who have sorafenib resistance, can be a better therapeutic strategy to control the malignant liver cancer. Our study provides a new therapeutic strategy for hepatocellular carcinoma that not only overcomes the resistance of hepatocellular carcinoma to sorafenib, but also utilizes cutting edge of gene therapies.
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We investigated changes in tumor markers before and after sorafenib therapy for advanced hepatocellular carcinoma (HCC). Subjects were 28 patients who began sorafenib therapy. HCC stage was III (n=5), IVA (n=10) and IVB (n=13). AFP, AFP-L3 and PIVKA-II were compared before and at one month after sorafenib administration. While no significant changes were observed for AFP and AFP-L3, PIVKA-II increased significantly following treatment (p<0.001). Similar results were observed for investigation of outcomes based on RECIST criteria (PR, n=1; SD, n=18; PD, n=9), with increases also observed for PR or SD patients. PIVKA-II increased following sorafenib administration regardless of therapeutic effects based on imaging findings. The present results are very interesting from the perspective of the clinical effects of sorafenib.
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To identify a predictive biomarker of sorafenib for hepatocellular carcinoma personalized therapy.The patients treated with or without sorafenib after hepatocellular carcinoma recurrence from multicenters were matched with propensity score matching analysis. The expression levels of Fms-like tyrosine kinase 3 (FLT3) in hepatocellular carcinoma specimens of the matched patients (n = 276) were analyzed by IHC. The optimal cut-off point of FLT3 levels for overall survival (OS) was defined via Cutoff Finder. Subgroup analysis of OS was employed to investigate the association between FLT3 levels and sorafenib benefit. The predictive value was assessed via Cox regression models with an interaction term. Hepatocellular carcinoma and paratumoral normal tissues were used to investigate the expression and copy-number variation of FLT3. Patient-derived xenograft (PDX) models were used to confirm the association between FLT3 levels and sorafenib response.Patients with FLT3-high hepatocellular carcinoma exhibited a superior OS upon sorafenib treatment. High FLT3 levels were predictive of sorafenib benefit in terms of OS (Pinteraction = 0.00006). Copy-number losses and decreased expression of FLT3 in hepatocellular carcinoma were detected in about 64% of patients. Moreover, the PDXs derived from tumors with high FLT3 levels also displayed a better response to sorafenib.Sorafenib may be able to delay tumor progression in patients with FLT3-high hepatocellular carcinoma. This potential biomarker needs to be further validated in independent cohorts prior to helping stratify patients for precision therapy in advanced hepatocellular carcinoma.
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