Won Young Tak

Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

BACKGROUND Most cases of hepatocellular carcinoma occur in the Asia-Pacific region, where chronic hepatitis B infection is an important aetiological factor. Assessing the efficacy and safety of new therapeutic options in an Asia-Pacific population is thus important. We did a multinational phase III, randomised, double-blind, placebo-controlled trial to assess the efficacy and safety of sorafenib in patients from the Asia-Pacific region with advanced (unresectable or metastatic) hepatocellular carcinoma. METHODS Between Sept 20, 2005, and Jan 31, 2007, patients with hepatocellular carcinoma who had not received previous systemic therapy and had Child-Pugh liver function class A, were randomly assigned to receive either oral sorafenib (400 mg) or placebo twice daily in 6-week cycles, with efficacy measured at the end of each 6-week period. Eligible patients were stratified by the presence or absence of macroscopic vascular invasion or extrahepatic spread (or both), Eastern Cooperative Oncology Group performance status, and geographical region. Randomisation was done centrally and in a 2:1 ratio by means of an interactive voice-response system. There was no predefined primary endpoint; overall survival, time to progression (TTP), time to symptomatic progression (TTSP), disease control rate (DCR), and safety were assessed. Efficacy analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00492752. FINDINGS 271 patients from 23 centres in China, South Korea, and Taiwan were enrolled in the study. Of these, 226 patients were randomly assigned to the experimental group (n=150) or to the placebo group (n=76). Median overall survival was 6.5 months (95% CI 5.56-7.56) in patients treated with sorafenib, compared with 4.2 months (3.75-5.46) in those who received placebo (hazard ratio [HR] 0.68 [95% CI 0.50-0.93]; p=0.014). Median TTP was 2.8 months (2.63-3.58) in the sorafenib group compared with 1.4 months (1.35-1.55) in the placebo group (HR 0.57 [0.42-0.79]; p=0.0005). The most frequently reported grade 3/4 drug-related adverse events in the 149 assessable patients treated with sorafenib were hand-foot skin reaction (HFSR; 16 patients [10.7%]), diarrhoea (nine patients [6.0%]), and fatigue (five patients [3.4%]). The most common adverse events resulting in dose reductions were HFSR (17 patients [11.4%]) and diarrhoea (11 patients [7.4%]); these adverse events rarely led to discontinuation. INTERPRETATION Sorafenib is effective for the treatment of advanced hepatocellular carcinoma in patients from the Asia-Pacific region, and is well tolerated. Taken together with data from the Sorafenib Hepatocellular Carcinoma Assessment Randomised Protocol (SHARP) trial, sorafenib seems to be an appropriate option for the treatment of advanced hepatocellular carcinoma.

Brivanib Versus Sorafenib As First-Line Therapy in Patients With Unresectable, Advanced Hepatocellular Carcinoma: Results From the Randomized Phase III BRISK-FL Study

PURPOSE Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. PATIENTS AND METHODS Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. RESULTS The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. CONCLUSION Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.

Brivanib in Patients With Advanced Hepatocellular Carcinoma Who Were Intolerant to Sorafenib or for Whom Sorafenib Failed: Results From the Randomized Phase III BRISK-PS Study

PURPOSE Brivanib is a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor receptors implicated in tumorigenesis and angiogenesis in hepatocellular carcinoma (HCC). An unmet medical need persists for patients with HCC whose tumors do not respond to sorafenib or who cannot tolerate it. This multicenter, double-blind, randomized, placebo-controlled trial assessed brivanib in patients with HCC who had been treated with sorafenib. PATIENTS AND METHODS In all, 395 patients with advanced HCC who progressed on/after or were intolerant to sorafenib were randomly assigned (2:1) to receive brivanib 800 mg orally once per day plus best supportive care (BSC) or placebo plus BSC. The primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), and disease control rate based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and safety. RESULTS Median OS was 9.4 months for brivanib and 8.2 months for placebo (hazard ratio [HR], 0.89; 95.8% CI, 0.69 to 1.15; P = .3307). Adjusting treatment effect for baseline prognostic factors yielded an OS HR of 0.81 (95% CI, 0.63 to 1.04; P = .1044). Exploratory analyses showed a median time to progression of 4.2 months for brivanib and 2.7 months for placebo (HR, 0.56; 95% CI, 0.42 to 0.76; P < .001), and an mRECIST ORR of 10% for brivanib and 2% for placebo (odds ratio, 5.72). Study discontinuation due to treatment-related adverse events (AEs) occurred in 61 brivanib patients (23%) and nine placebo patients (7%). The most frequent treatment-related grade 3 to 4 AEs for brivanib included hypertension (17%), fatigue (13%), hyponatremia (11%), and decreased appetite (10%). CONCLUSION In patients with HCC who had been treated with sorafenib, brivanib did not significantly improve OS. The observed benefit in the secondary outcomes of TTP and ORR warrants further investigation.

Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma

BACKGROUND In Japan and South Korea, transarterial chemoembolisation (TACE) is an important locoregional treatment for patients with unresectable hepatocellular carcinoma (HCC). Sorafenib, a multikinase inhibitor, has been shown effective and safe in patients with advanced HCC. This phase III trial assessed the efficacy and safety of sorafenib in Japanese and Korean patients with unresectable HCC who responded to TACE. METHODS Patients (n=458) with unresectable HCC, Child-Pugh class A cirrhosis and ≥25% tumour necrosis/shrinkage 1-3 months after 1 or 2 TACE sessions were randomised 1:1 to sorafenib 400mg bid or placebo and treated until progression/recurrence or unacceptable toxicity. Primary end-point was time to progression/recurrence (TTP). Secondary end-point was overall survival (OS). FINDINGS Baseline characteristics in the two groups were similar; >50% of patients started sorafenib>9 weeks after TACE. Median TTP in the sorafenib and placebo groups was 5.4 and 3.7 months, respectively (hazard ratio (HR), 0.87; 95% confidence interval (CI), 0.70-1.09; P=0.252). HR (sorafenib/placebo) for OS was 1.06 (95% CI, 0.69-1.64; P=0.790). Median daily dose of sorafenib was 386 mg, with 73% of patients having dose reductions and 91% having dose interruptions. Median administration of sorafenib and placebo was 17.1 and 20.1 weeks, respectively. No unexpected adverse events were observed. INTERPRETATION This trial, conducted prior to the reporting of registrational phase III trials, found that sorafenib did not significantly prolong TTP in patients who responded to TACE. This may have been due to delays in starting sorafenib after TACE and/or low daily sorafenib doses.

Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial.

BACKGROUND There is no standard of care for adjuvant therapy for patients with hepatocellular carcinoma. This trial was designed to assess the efficacy and safety of sorafenib versus placebo as adjuvant therapy in patients with hepatocellular carcinoma after surgical resection or local ablation. METHODS We undertook this phase 3, double-blind, placebo-controlled study of patients with hepatocellular carcinoma with a complete radiological response after surgical resection (n=900) or local ablation (n=214) in 202 sites (hospitals and research centres) in 28 countries. Patients were randomly assigned (1:1) to receive 400 mg oral sorafenib or placebo twice a day, for a maximum of 4 years, according to a block randomisation scheme (block size of four) using an interactive voice-response system. Patients were stratified by curative treatment, geography, Child-Pugh status, and recurrence risk. The primary outcome was recurrence-free survival assessed after database cut-off on Nov 29, 2013. We analysed efficacy in the intention-to-treat population and safety in randomly assigned patients receiving at least one study dose. The final analysis is reported. This study is registered with ClinicalTrials.gov, number NCT00692770. FINDINGS We screened 1602 patients between Aug 15, 2008, and Nov 17, 2010, and randomly assigned 1114 patients. Of 556 patients in the sorafenib group, 553 (>99%) received the study treatment and 471 (85%) terminated treatment. Of 558 patients in the placebo group, 554 (99%) received the study treatment and 447 (80%) terminated treatment. Median duration of treatment and mean daily dose were 12·5 months (IQR 2·6-35·8) and 577 mg per day (SD 212·8) for sorafenib, compared with 22·2 months (8·1-38·8) and 778·0 mg per day (79·8) for placebo. Dose modification was reported for 497 (89%) of 559 patients in the sorafenib group and 206 (38%) of 548 patients in the placebo group. At final analysis, 464 recurrence-free survival events had occurred (270 in the placebo group and 194 in the sorafenib group). Median follow-up for recurrence-free survival was 8·5 months (IQR 2·9-19·5) in the sorafenib group and 8·4 months (2·9-19·8) in the placebo group. We noted no difference in median recurrence-free survival between the two groups (33·3 months in the sorafenib group vs 33·7 months in the placebo group; hazard ratio [HR] 0·940; 95% CI 0·780-1·134; one-sided p=0·26). The most common grade 3 or 4 adverse events were hand-foot skin reaction (154 [28%] of 559 patients in the sorafenib group vs four [<1%] of 548 patients in the placebo group) and diarrhoea (36 [6%] vs five [<1%] in the placebo group). Sorafenib-related serious adverse events included hand-foot skin reaction (ten [2%]), abnormal hepatic function (four [<1%]), and fatigue (three [<1%]). There were four (<1%) drug-related deaths in the sorafenib group and two (<1%) in the placebo group. INTERPRETATION Our data indicate that sorafenib is not an effective intervention in the adjuvant setting for hepatocellular carcinoma following resection or ablation.

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III Sorafenib Asia–Pacific trial☆

BACKGROUND The phase III Sorafenib Asia-Pacific (AP) trial-conducted in China, Taiwan and South Korea - confirmed that sorafenib improves overall survival (OS) and is safe for patients with advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib. METHODS In the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 400mg bid or matching placebo. Subanalyses were based on aetiology (hepatitis B virus present/absent); tumour burden (macroscopic vascular invasion and/or extrahepatic spread present/absent); presence or absence of either lung or lymph node metastasis at baseline, Eastern Cooperative Oncology Group performance status (0, 1-2); serum concentrations of alanine aminotransferase/aspartate aminotransferase (normal, mildly elevated, moderately elevated), alpha-fetoprotein (normal/elevated) and total bilirubin (normal/elevated); and whether or not there was a history of hepatectomy or transarterial chemoembolisation/embolisation. Subgroup assessments included OS, time to progression (TTP), disease control rate and safety. FINDINGS Sorafenib consistently improved both median OS and median TTP, compared with placebo (range of hazard ratios (HR), 0.32-0.87 and 0.31-0.75, respectively). The most common grade 3/4 adverse events were hand-foot skin reaction, diarrhoea and fatigue, the incidence of which was similar between subgroups. INTERPRETATION The efficacy and safety profiles of sorafenib in the subpopulations described were comparable with those in the overall study population. These exploratory analyses suggest that sorafenib is effective for patients from the AP region with advanced HCC, irrespective of baseline status.

Sorafenib or placebo plus TACE with doxorubicin-eluting beads for intermediate stage HCC: The SPACE trial

BACKGROUND & AIMS Transarterial chemoembolization with doxorubicin-eluting beads (DC Bead®; DEB-TACE) is effective in patients with Barcelona clinic liver cancer stage B hepatocellular carcinoma (HCC). The multikinase inhibitor sorafenib enhances overall survival (OS) and time-to-tumor progression (TTP) in patients with advanced HCC. This exploratory phase II trial tested the efficacy and safety of DEB-TACE plus sorafenib in patients with intermediate stage HCC. METHODS Patients with intermediate stage multinodular HCC without macrovascular invasion (MVI) or extrahepatic spread (EHS) were randomized 1:1 to DEB-TACE (150 mg doxorubicin) plus sorafenib 400 mg twice daily or placebo. The primary endpoint was TTP by blinded central review. Secondary endpoints included time to MVI/EHS, OS, overall response rate (ORR) using modified response evaluation criteria in solid tumors, disease control rate (DCR), time to unTACEable progression (TTUP), and safety. RESULTS Of 307 patients randomized, 154 received sorafenib and 153 received placebo. Median TTP for subjects receiving sorafenib plus DEB-TACE or placebo plus DEB-TACE was similar (169 vs. 166 days, respectively; hazard ratio (HR) 0.797, p=0.072). Median time to MVI/EHS (HR 0.621, p=0.076) and OS (HR 0.898, p=0.29) had not been reached. The ORRs for patients in the sorafenib and placebo groups with post-baseline scans were 55.9% and 41.3%, respectively, and the DCRs were 89.2% and 76.1%, respectively. TTUP was lower with sorafenib than with placebo (HR 1.586; 95% confidence intervals, 1.200-2.096; median 95 vs. 224 days). No unexpected adverse events related to sorafenib were observed. CONCLUSION Sorafenib plus DEB-TACE was technically feasible, but the combination did not improve TTP in a clinically meaningful manner compared with DEB-TACE alone.

Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: multicentre, open-label, phase II safety study

PURPOSE We assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma (HCC) that had progressed following first-line sorafenib. PATIENTS AND METHODS Thirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function (Child-Pugh class A) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression, unacceptable toxicity, death or patient/physician decision to discontinue. The primary end-point was safety; secondary end-points included efficacy (including time to progression and overall survival). RESULTS The median treatment duration was 19.5 weeks (range 2-103). At data cutoff, three patients remained on treatment. Reasons for discontinuation were adverse events (n=20), disease progression (n=10), consent withdrawal (n=2) and death (n=1). Seventeen patients required dose reductions (mostly for adverse events [n=15]); 35 patients had treatment interruption (mostly for adverse events [n=32] or patient error [n=11]). The most frequent treatment-related adverse events were hand-foot skin reaction (any grade n=19; grade ≥3 n=5), diarrhoea (n=19; n=2), fatigue (n=19; n=6), hypothyroidism (n=15; n=0), anorexia (n=13; n=0), hypertension (n=13; n=1), nausea (n=12; n=0) and voice changes (n=10; n=0). Disease control was achieved in 26 patients (partial response n=1; stable disease n=25). Median time to progression was 4.3 months. Median overall survival was 13.8 months. CONCLUSION Regorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib.

Factors related to lymph node metastasis and the feasibility of endoscopic mucosal resection for treating poorly differentiated adenocarcinoma of the stomach

BACKGROUND AND AIM Endoscopic mucosal resection (EMR) is currently not accepted as an alternative treatment to surgery in early gastric cancer (EGC) of the undifferentiated histologic type. The present retrospective analysis examined the correlation of various histologic factors with the presence of lymph node metastasis (LNM). PATIENTS AND METHODS A retrospective analysis on 234 patients with poorly differentiated EGC who underwent radical gastrectomy with D2 lymph node dissection was undertaken. Several clinicopathologic factors were investigated to identify predictive factors for LNM: age, sex, type of operation, tumor location, tumor size, gross type, ulceration, lymphatic invasion, and depth of invasion. RESULTS Of the 234 lesions with poorly differentiated EGC, half (n = 116) already showed submucosal invasion in the resection specimen; 25.9 % of those (30/116) were limited to the upper third (SM1). Of the lesions confined to the mucosa, LNM was found in 3.4 % (4/118). With minor submucosal infiltration (SM1), the LNM rate was lower (0/30) in our patient population. Only with SM2/3 infiltration did the LNM rate sharply rise to around 30 %. The cut-off for submucosal infiltration depth was 500 microm (0/32 LNM), above which LNM rates were substantial (31.2 %; 24/77). There was limited correlation between the SM1-3 classification and actual measurement of submucosal infiltration depth. In a multivariate analysis, tumor size ( P = 0.033), depth of invasion ( P = 0.004), and lymphatic invasion ( P < 0.001) were associated with LNM. CONCLUSION Poorly differentiated EGC confined to the mucosa or with minimal submucosal infiltration (<or= 500 microm) could be considered for curative EMR due to the low risk of LNM. Given the limited case number of subgroups, these findings should be confirmed by more data from other centers, which should also focus on local recurrence after EMR in poorly differentiated EGC.

Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial

Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate‐stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double‐blind, placebo‐controlled, phase III study, 870 patients with TACE‐eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once‐daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow‐up was approximately 16 months. Intention‐to‐treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0‐30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66‐1.23]; log‐rank P = 0.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45‐0.90]), TTP (0.61 [0.48‐0.77]), and rate of TACE (0.72 [0.61‐0.86]), but not TTDP (0.94 [0.72‐1.22]) versus placebo. Most frequent grade 3‐4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%). Conclusions: In this study, brivanib as adjuvant therapy to TACE did not improve OS. (Hepatology 2014;60:1697–1707)