Pattern of progression in advanced HCC treated with ramucirumab/placebo: Results from two randomized phase III trials (REACH/REACH-2).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 544-544
Author(s):  
Maria Reig ◽  
Peter R. Galle ◽  
Masatoshi Kudo ◽  
Richard S. Finn ◽  
Josep M. Llovet ◽  
...  
Keyword(s):  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Cox Models ◽  
Poor Prognostic Factor ◽  
Advanced Hcc ◽  
Pooled Data ◽  
Phase Iii Trials ◽  
Ecog Ps ◽  
Post Hoc ◽  
The Impact

544 Background: REACH (NCT01140347) and REACH-2 (NCT02435433) studied ramucirumab (RAM) in pts with advanced hepatocellular carcinoma (HCC) following sorafenib; REACH-2 enrolled pts with baseline alpha-fetoprotein (AFP) ≥400 ng/mL, and met its primary endpoint of overall survival (OS) for RAM vs placebo. This post-hoc analysis examined radiological progression patterns (RPP) incidence every 6 weeks per RECIST v1.1, and if RPP were related to OS and post-progression survival (PPS). Methods: Pts with advanced HCC, Child-Pugh A, and ECOG PS 0-1 with prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to receive RAM 8 mg/kg or placebo Q2W. Among pts with ≥1 RPP (new extrahepatic lesion [NEH], new intrahepatic lesion [NIH], extrahepatic growth [EHG], or intrahepatic growth [IHG]), results were analyzed by trial and for pooled individual patient data of REACH-2 and REACH (AFP ≥400 ng/mL). Cox models evaluated treatment effect of RPP on OS, and prognostic implications of RPP on OS (adjusting baseline ECOG PS, AFP, macrovascular invasion, arm) and on PPS (adjusting ECOG PS, AFP at progression). Results: RPP incidence in the pooled population was: NEH 39%; NIH 24%; EHG 39%; IHG 37%. When examining NEH vs other RPP, PPS was worse among those with NEH in REACH (HR 2.33, 95% CI 1.51, 3.60), REACH-2 (HR 1.49, 95% CI 0.72, 3.08), and the pooled data (HR 1.75, 95% CI 1.12, 2.74). Use of post-discontinuation therapy may have influenced results. OS was also significantly reduced in those with NEH across studies (Table). RAM provided OS benefit in the pooled population, including pts with NEH (HR 0.56, 95% CI 0.39, 0.80). Conclusions: Acknowledging limitations of post-randomization RPP analysis, the emergence of NEH on RAM or placebo may be an independent poor prognostic factor for PPS. The impact of RAM on OS was consistent across all RPP subgroups. Clinical trial information: NCT01140347 and NCT02435433. [Table: see text]

Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5037-5037 ◽  
Author(s):  
Fred Saad ◽  
Karim Fizazi ◽  
Matthew R. Smith ◽  
Thomas W. Griffin ◽  
Anil Londhe ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Cox Regression ◽  
Performance Status ◽  
Phase Iii ◽  
End Points ◽  
Opiate Use ◽  
Potential Clinical Benefit ◽  
Ecog Ps ◽  
Post Hoc ◽  
The Impact

5037 Background: BTT can delay symptomatic progression in cancer pts with bone metastases. In a post hoc analysis, we assessed the impact of concomitant BTT on outcomes in a recent large, multinational study in mCRPC pts without prior ctx. Methods: COU-AA-302 was a phase III trial in asymptomatic/mildly symptomatic pts with progressive mCRPC and no prior ctx. 1,088 pts were stratified by ECOG performance status (ECOG-PS, 0 vs 1) and randomized 1:1 to AA 1 g or placebo QD, plus prednisone 5 mg BID. Radiographic progression-free survival (rPFS) and overall survival (OS) were primary end points; secondary end points were times to opiate use, ctx, ECOG-PS deterioration, and PSA progression. The effect of concomitant use of BTT on all end points was assessed retrospectively using a stratified Cox regression model with factors for treatment, concomitant BTT, interaction of treatment and BTT, and baseline covariates. All data were obtained from a prespecified interim analysis at 55% OS events. Results: Median follow-up at the time of analysis was 27.1 mos. Among intent-to-treat (ITT) pts, 184/546 AA and 169/542 P pts received concomitant BTT for treatment of bone metastases, either zoledronic acid (n = 330), other bisphosphonates (n = 16), denosumab (n = 22), and/or other BTT (n = 5). In these pts, concomitant BTT use was associated with improved OS, time to opiate use for cancer pain, and time to ECOG-PS deterioration (Table). Results were similar in a sensitivity analysis including only ITT pts with bone metastases at baseline. Conclusions: In this post hoc, exploratory analysis, concomitant BTT use was associated with delayed symptomatic progression in asymptomatic/mildly symptomatic mCRPC pts. This potential clinical benefit should be investigated in prospective studies. Clinical trial information: NCT00887198. [Table: see text]

A phase II (PhII) trial of sorafenib (S) in combination with 5-fluorouracil (5FU) continuous infusion (c.i.) in patients (pts) with advanced hepatocellular carcinoma (HCC): Preliminary data

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4592-4592
Author(s):  
I. Petrini ◽  
M. Lencioni ◽  
M. Ricasoli ◽  
M. Iannopollo ◽  
C. Orlandini ◽  
...  
Keyword(s):  
Disease Control ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Tumour Response ◽  
Pharmacokinetic Interaction ◽  
Disease Control Rate ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Ecog Ps

4592 Background: S, an oral multi-kinase inhibitor that targets Raf-kinase and receptor tyrosine kinases, improved overall survival (OS) and time to progression (TTP) versus placebo in a randomized phase III study in HCC (SHARP study). The safety of S in association with infusional and bolus 5FU regimens was established in a previous PhI study, with no clinically relevant pharmacokinetic interaction between S and 5FU. The present trial was designed to evaluate the safety and efficacy of S with infusional 5FU in HCC pts. Methods: Patients with advanced HCC (not eligible to surgical or locoregional therapies), age≥18 years, Child-Pugh Class A or B, ECOG PS 0–1, without prior systemic treatment for HCC and adequate bone marrow, liver and renal function, were eligible for the study. The primary endpoint is the Disease Control Rate (DCR). Secondary endpoints included response rate, TTP, OS and safety. According to a two-step Simon's model 46 pts were to be accrued. Pts were treated with oral S 400 mg bid continuously and c.i. 5FU 200 mg/sqm/day day 1–14 every 3 weeks. Tumour response was assessed according to RECIST criteria every 9 weeks. Results: Between October 2006 and October 2008 38 pts were enrolled: M-F: 32–6, median age (range): 68(47–83) years, ECOG-PS 0–1: 28–10, Child-Pugh A-B: 35–3, extrahepatic spread: 14 pts, macroscopic vascular invasion: 6 pts. Grade 3/4 (%) toxicities (NCI CTC v 3.0 criteria) included diarrhoea 5/0, stomatitis 21/3, hand foot syndrome 21/0, skin rash 11/0, hypertension 11/0; hyperbilirubinemia 5/3, AST 11/0, ALT 8/0, cardiac toxicity (one cardiac failure, one atrial fibrillation) 5/0 and bleeding (melena) in 3/0. One partial response was observed. Stable disease was obtained in 45% of pts with a median duration of 9.6 months (range 5–18+). Median TTP was 7.6 months (CI 95%=5.3–9.9) and median OS 12.2 months (CI 95%=4.45–19.8). Conclusions: Preliminary results of this PhII study show encouraging disease control rate, TTP and OS in pts with advanced HCC. The S+5FU association is feasible, well tolerated and AEs were predictable and manageable. [Table: see text]

Prognostic and predictive factors in patients treated with ramucirumab (RAM) with advanced hepatocellular carcinoma (aHCC) and elevated alpha-fetoprotein (AFP): Results from two phase III trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4146-4146
Author(s):  
Josep M. Llovet ◽  
Amit G. Singal ◽  
Augusto Villanueva ◽  
Richard S. Finn ◽  
Masatoshi Kudo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Meta Analysis ◽  
Performance Status ◽  
Phase Iii ◽  
P Value ◽  
Vegf Receptor ◽  
Advanced Hepatocellular Carcinoma ◽  
Poor Prognostic Factor ◽  
Molecular Features ◽  
Phase Iii Trials

4146 Background: Elevated AFP in patients with aHCC is a poor prognostic factor with distinct molecular features, including high vascular endothelial growth factor (VEGF) signalling and increased angiogenesis. RAM, a human IgG1 monoclonal antibody, VEGF receptor 2 (VEGFR2) inhibitor, demonstrated improved survival vs placebo among patients with elevated AFP in the REACH-2 trial and is accepted as a standard of care for management of aHCC. We analyzed prognostic factors in patients with AFP ≥400 ng/mL and predictors of clinical benefit to RAM in an individual participant data (IPD) meta-analysis of the REACH and REACH-2 Phase III trials. Methods: Patients with aHCC, Child-Pugh A, ECOG performance status (PS) ≤1, and prior sorafenib were randomized (REACH 1:1; REACH-2 2:1) to RAM 8 mg/kg or Placebo Q2W. Meta-analysis was conducted in patients with AFP ≥400 ng/mL (n = 542). Univariate (UV) and multivariate (MV) analyses were performed using a Cox proportional hazard regression model. MV used the cut-off p-value < 0.1 from UV, irrespective of treatment arm. Overall survival (OS) was evaluated by Kaplan-Meier estimator and Cox models. To define predictors of RAM benefit, treatment-by-covariate interactions terms were evaluated. Results: In terms of prognosis assessed by MV analysis in patients with AFP ≥400 ng/mL, 6 variables among demographic and baseline disease characteristics were associated with poor OS in the RAM cohort (ECOG PS 1, AFP > 1000 ng/mL, Child-Pugh > A5, Extrahepatic site > 1, neutrophil-to-lymphocyte ratio > 3.2 and aspartate aminotransferase > 57 U/L) with an additional 3 factors identified within the whole cohort (macrovascular invasion presence, etiology HCV vs. Other and alkaline phosphatase ≥146). RAM benefit was present across all subgroups, including patients with very aggressive HCCs (AFP > 4000 ng/mL; HR: 0.64; 95% CI: 0.49-0.84) and those with nonalcoholic steatohepatitis /alcohol related aHCC (HR: 0.56; 95% CI: 0.40-0.79). Of note, two treatment-emergent (TE) events were the only factors that were significantly associated with improved RAM-related survival: TE-hypertension (p interaction = 0.0392) and TE-ascites (p interaction = 0.0001). However, these results should be interpreted with caution given that TE events are factors only observed after randomization. Conclusions: Several poor prognostic factors for OS were identified in patients with aHCC and elevated AFP. RAM provided an OS benefit irrespective of baseline prognostic covariates, with greater benefit observed in patients with aggressive HCC and those who experienced TE-hypertension or TE-ascites. Clinical trial information: NCT01140347; NCT02435433.

Comparison of lenalidomide in combination with dexamethasone to dexamethasone alone in patients who have received prior thalidomide in relapsed or refractory multiple myeloma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7522-7522 ◽  
Author(s):  
M. Wang ◽  
R. Knight ◽  
M. Dimopoulos ◽  
D. Siegel ◽  
S. V. Rajkumar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Subgroup Analysis ◽  
Phase Iii ◽  
Significant Variable ◽  
Refractory Multiple Myeloma ◽  
Prior Therapy ◽  
Pooled Data ◽  
Phase Iii Trials ◽  
Previously Treated ◽  
The Impact

7522 Background: Lenalidomide (len), an analog of thalidomide (thal) is a novel, oral immunomodulatory agent that is effective against multiple myeloma (MM). Two randomized, Phase III trials (MM009 and MM010) have recently demonstrated superior responses and overall survival (OS) for patients (pts) treated with len and dexamethasone (dex) in comparison with dex-placebo. This is a prospective subgroup analysis to assess the impact of prior therapy with thal on the sensitivity of MM to subsequent lenalidomide. Methods: We evaluated 692 pts from both trials (MM009 and MM010). The pts had relapsed/refractory MM, were not refractory to dex and were randomized to receive either len (25 mg daily for 3 weeks (wks) every 4 wks) plus dex (40 mg on days 1–4, 9–12, 17–20 every 4 wks for 4 cycles, then 40 mg on days 1–4 every subsequent cycle) or placebo plus dex. Standard criteria were used to evaluate response and TTP. Results: Pooled data from 692 pts showed superior median TTP (48.1 vs 20.1 wks) and OR (59.2% vs 22.5%) in pts treated with len/dex compared to dex-placebo (p <0.001). Although subgroup analysis of pts with prior thal therapy revealed that pts who received len/dex had significantly improved OR, PR CR and median TTP than pts who received dex-placebo, OR, CR and TTP were highest in len/dex pts not previously treated with thal. Multivariate analysis indicates that after controlling for the treatment factor and baseline disease characteristics, whether or not pt had prior exposure to thal is a marginally significant variable to predict TTP. The risk of deep venous thrombosis and pulmonary embolism in these subgroups will be updated on further analysis. Conclusions: Lenalidomide in combination with dexamethasone is more effective than dexamethasone-placebo regardless of prior thalidomide in relapsed/refractory multiple myeloma. [Table: see text] [Table: see text]

Effect of macroscopic vascular invasion (MVI), extrahepatic spread (EHS), and ECOG performance status (ECOG PS) on outcome in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib: Analysis of two phase III, randomized, double-blind trials

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4580-4580 ◽  
Author(s):  
J. Bruix ◽  
A. Cheng ◽  
Y. Kang ◽  
C. Tsao ◽  
S. Qin ◽  
...  
Keyword(s):  
Clin Oncol ◽  
Annual Meeting ◽  
Conflict Of Interest ◽  
Principal Investigator ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Interest Policy ◽  
Grade 3 ◽  
Ecog Ps

4580^ Background: The landmark phase III SHARP trial (Llovet et al, N Engl J Med, 2008) showed that sorafenib is effective and safe for the treatment of advanced HCC. These results were confirmed in an Asian population in the phase III Asia-Pacific (AP) study (Cheng et al, Lancet Oncol, 2009). We compared outcomes of sorafenib treatment in patients enrolled in the SHARP and AP trials with known baseline predictors of poor prognosis. Methods: Patients with advanced, unresectable, measurable HCC, ECOG PS 0–2, Child-Pugh A, and no prior systemic therapy for HCC were randomized to sorafenib 400 mg BID or placebo (SHARP: N=602; AP: N=226). Patients in the AP study had more evolved disease and a predominance of hepatitis B infection. Endpoints included overall survival (OS), disease-control rate (DCR; defined as complete/partial response or stable disease by RECIST, maintained for ≥28 days from first demonstration of response), and safety. Results: Efficacy results are shown in the table . The incidence of grade 3/4 drug-related adverse events (AEs) across subgroups in each study was consistent with the overall population for each study. The most common grade 3/4 AEs in all sorafenib populations were hand-foot skin reaction and diarrhea. Conclusions: Sorafenib is effective and safe for the treatment of advanced HCC in patients globally, irrespective of baseline ECOG PS and presence or absence of MVI and/or EHS. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

Alpha fetoprotein (AFP) response and efficacy outcomes in the phase III CELESTIAL trial of cabozantinib (C) versus placebo (P) in advanced hepatocellular carcinoma (HCC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 423-423 ◽  
Author(s):  
Robin Kate Kelley ◽  
Lorenza Rimassa ◽  
Baek-Yeol Ryoo ◽  
Joong-Won Park ◽  
Jean-Frédéric Blanc ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Progression Free Survival ◽  
Serum Levels ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Best Response ◽  
Previously Treated ◽  
Definition Of ◽  
Ecog Ps

423 Background: AFP response, defined as a decrease in serum levels of the tumor marker AFP after therapy, may be associated with improved survival of patients (pts) with HCC treated with locoregional or systemic therapy, and high baseline AFP levels may be associated with poor prognosis. In the phase III CELESTIAL trial (NCT01908426), C, an inhibitor of MET, VEGFR, and AXL, significantly improved overall survival (OS) and progression-free survival (PFS) versus P in pts with previously treated advanced HCC. Here we evaluate clinical outcomes with C in CELESTIAL based on AFP response or progression on treatment. Methods: 707 pts were randomized 2:1 to receive C (60 mg daily) or P. Eligible patients had a pathologic diagnosis of HCC, Child-Pugh score A, and ECOG PS ≤ 1. Pts received prior sorafenib and ≤ 2 lines of prior systemic therapy for HCC. Serum AFP levels were measured centrally at baseline and every 8 weeks thereafter. Outcomes were evaluated for pts with baseline AFP ≥ 20 ng/mL based on AFP response ( ≥ 20% decrease from baseline) or progression ( ≥ 20% increase from baseline) at Week 8. This definition of AFP response has been used in previous studies but requires further validation in large prospective studies. Results: Overall, 331 pts (70%) in the C arm and 160 (68%) in the P arm had baseline AFP ≥ 20 ng/mL; among these pts, 236 (71%) and 111 (69%), respectively, were evaluable for AFP response at week 8. Among evaluable pts, 117 pts (50%) in the C arm vs 14 (13%) in the P arm had an AFP response, and 72 (31%) vs 75 (68%) had AFP progression. Median OS with C was 16.1 mo for pts with an AFP response versus 9.1 mo for pts without a response (HR 0.61, 95% CI 0.45-0.84), and median PFS with C was 7.3 mo versus 4.0 mo (HR 0.55, 95% CI 0.41-0.74). For pts with AFP progression, median OS with C was 8.1 mo, and median PFS with C was 3.6 mo. Hazard ratios for OS and PFS with C also favored AFP responders over non-responders when analyzed using best response through week 24. Conclusions: The AFP response rate was higher with C versus P, and AFP response was associated with longer OS and PFS with C for pts with previously treated advanced HCC. On-treatment AFP changes warrant further evaluation as a biomarker of response. Clinical trial information: NCT01908426.

scholarly journals Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
Ziyu Liu ◽  
Yan Lin ◽  
Jinyan Zhang ◽  
Yumei Zhang ◽  
Yongqiang Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Line Treatment ◽  
Phase Ii Trials ◽  
Advanced Hcc ◽  
Phase Iii Trials ◽  
Asian Pacific

Abstract Molecular targeted therapy for advanced hepatocellular carcinoma (HCC) has changed markedly. Although sorafenib was used in clinical practice as the first molecular targeted agent in 2007, the SHARPE and Asian-Pacific trials demonstrated that sorafenib only improved overall survival (OS) by approximately 3 months in patients with advanced HCC compared with placebo. Molecular targeted agents were developed during the 10-year period from 2007 to 2016, but every test of these agents from phase II or phase III clinical trial failed due to a low response rate and high toxicity. In the 2 years after, 2017 through 2018, four successful novel drugs emerged from clinical trials for clinical use. As recommended by updated Barcelona Clinical Liver cancer (BCLC) treatment algorithms, lenvatinib is now feasible as an alternative to sorafenib as a first-line treatment for advanced HCC. Regorafenib, cabozantinib, and ramucirumab are appropriate supplements for sorafenib as second-line treatment for patients with advanced HCC who are resistant, show progression or do not tolerate sorafenib. In addition, with promising outcomes in phase II trials, immune PD-1/PD-L1 checkpoint inhibitors nivolumab and pembrolizumab have been applied for HCC treatment. Despite phase III trials for nivolumab and pembrolizumab, the primary endpoints of improved OS were not statistically significant, immune PD-1/PD-L1 checkpoint therapy remains to be further investigated. This review summarizes the development and progression of molecular targeted and immune-based checkpoint therapies in HCC.

The outcome of patients with advanced hepatocellular carcinoma (HCC) in pre- and post-sorafenib eras using the SEER database.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 276-276
Author(s):  
Jiahuai Tan ◽  
Minsig Choi ◽  
Philip Agop Philip ◽  
Gregory Dyson ◽  
Anthony Frank Shields ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Survival ◽  
Cox Regression ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment ◽  
Advanced Hcc ◽  
Number Of Patients ◽  
The Impact

276 Background: HCC is the third most common cause of cancer-related death globally. Prognosis for advanced HCC is dismal due to lack of effective treatment options for the majority of patients who present with advanced disease. Sorafenib was the first agent reported to improve overall survival in patients with good liver function enrolled in phase III clinical trials. However, survival impact of sorafenib on the general population with advanced HCC has not been studied to date. Methods: Sorafenib was approved for patients with advanced HCC and Child-Pugh A liver disease in 2007. We analyzed 2005-2006 and 2008-2009 clinical outcome data from the SEER to compare the impact of this targeted therapy in the population based setting. The Kaplan-Meier method was used to estimate the median survival and 95% confidence intervals (CI). The log-rank test was used to test the difference in survival curves. Cox regression analyses were utilized for the estimation of hazard ratios. Results: We identified 2297 and 2808 stage III and IV HCC cases diagnosed in [2005, 2006] and [2008, 2009], respectively. Seventy-seven percent of the patients were male and the median age was 61 years old for males and 66 for females. The median survival estimates (95% CIs) are 3 (3, 4) months and 4 (4, 4) months for patients diagnosed in [2005, 2006] and [2008, 2009], respectively. The hazard ratio (95% CI) for overall survival comparing [2008, 2009] to [2005, 2006] was 0.92 (0.87, 0.98, p-value = 0.01). We performed multivariable Cox regression modeling and African American patients have a hazard ratio of death [1.14 (1.06, 1.23)] as compared to European American patients. Younger females have a decreased hazard of dying relative to younger men, while older females have an increase hazard of dying relative to older men. Conclusions: The approval of sorafenib treatment produced very modest median survival gain in advanced HCC patients based on SEER population study. However, the small benefit in hazard ratio may have been impacted by small number of patients with advanced HCC who are being treated or are able to be treated with sorafenib in this era.

Randomized phase III trial of sorafenib versus placebo in patients with advanced hepatocellular carcinoma (HCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. LBA1-LBA1 ◽  
Author(s):  
J. Llovet ◽  
S. Ricci ◽  
V. Mazzaferro ◽  
P. Hilgard ◽  
J. Raoul ◽  
...  
Keyword(s):  
Phase Iii ◽  
Rank Test ◽  
Clinical Activity ◽  
Advanced Hepatocellular Carcinoma ◽  
Early Stopping ◽  
Serious Adverse Events ◽  
Phase Iii Trial ◽  
Advanced Hcc ◽  
Significant Difference ◽  
Ecog Ps

LBA1 Background: HCC is the 3rd cause of cancer death globally with most deaths occurring within 1 year of diagnosis. No standard therapy exists for advanced HCC. Sorafenib (Sor) is a multikinase inhibitor with anti-angiogenic, pro-apoptotic and Raf kinase inhibitory activity, with clinical activity in a phase II HCC trial. This large, multicenter, randomized, placebo-controlled phase III trial evaluated the efficacy and safety of Sor vs placebo (P) in pts with HCC. Methods: Patients with advanced measurable HCC, no prior systemic treatment, ECOG PS 0–2 and Child-Pugh status A received Sor 400 mg bid or P. Primary efficacy endpoints were overall survival (OS) and time to symptomatic progression (TTSP). Time to progression (TTP) and disease control rate (DCR; CR+PR+SD for at least 2 cycles) were secondary endpoints.Treatment arms were compared for OS and TTSP using a 1-sided log-rank test [overall a of 0.02 (OS) and 0.005 (TTSP)] stratified by region, ECOG PS and tumor burden. An O’Brien-Fleming-type error spending function determined criteria for early stopping for efficacy. Results: 602 pts (Sor n=299; P n=303) were randomized. Baseline characteristics were similar for Sor vs P: median age (67 vs 68 y), male (87% vs 87%), ECOG PS 0 (54% vs 54%), Child-Pugh A (95% vs 98%), and BCLC stage C (82% vs 83%). Based on 321 deaths (Sor n=143; P n=178), the hazard ratio (HR) for OS (Sor/P) was 0.69 (95% CI: 0.55, 0.87; p=0.0006), representing a 44% improvement in OS vs P which met early stopping criteria. Median OS was 10.7 vs 7.9 mos (Sor vs P). Primary TTSP analysis demonstrated no statistically significant difference for Sor vs P. HR for TTP (independent assessment) was 0.58 (95% CI: 0.45, 0.74; p=0.000007). Median TTP was longer (5.5 vs 2.8 mos) and DCR was higher (43% vs 32%) with Sor vs P. Incidence of serious adverse events was similar for Sor vs P (52% vs 54%). The most frequent grade 3/4 events were diarrhea (11% vs 2%), hand-foot skin reaction (8% vs 1%), fatigue (10% vs 15%), and bleeding (6% vs 9%) for Sor vs P. Conclusions: Sorafenib was well tolerated and is the first agent to demonstrate a statistically significant improvement in OS for pts with advanced HCC. This effect is clinically meaningful and establishes sorafenib as first-line treatment for these pts. [Table: see text]

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