scholarly journals Trends of Clinical Outcomes of Patients with Advanced Hepatocellular Carcinoma Treated with First-line Sorafenib in Randomized Controlled Trials

2021 ◽  
Author(s):  
Timothy J. Brown ◽  
Arjun Gupta ◽  
Ramy Sedhom ◽  
Muhammad S. Beg ◽  
Thomas B. Karasic ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Outcomes ◽  
Median Duration ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Duration Of Therapy ◽  
Recist 1.1 ◽  
Significant Change ◽  
Over Time

Background: Sorafenib has consistently served as the control arm in multiple RCTs evaluating novel therapies for advanced HCC for more than a decade. Analyzing trends in clinical outcomes of patients treated with sorafenib for the same indication over time offers the opportunity for unique insight into the evolution of clinical trial conduct and potential non-drug factors impacting outcomes. Methods: We identified RCTs in patients with treatment-naïve advanced HCC where sorafenib was compared to another systemic therapy or placebo. We extracted trial-level demographic, clinicopathologic, and outcome data (OS, progression-free survival (PFS), objective response rate (ORR) and duration of therapy). Sample-weighted linear regression was used to identify temporal trends with significance set at p0.05. Results: Sixteen RCTs (9 phase III and 7 phase II) enrolling 4086 patients treated with sorafenib were included in the analysis. Included trials enrolled patients from 2005-2019. OS has significantly improved by 4.5 months from 2005-2019 (p=0.048) over time. Thirteen studies provided data on PFS using RECIST 1.1, with no significant change over time (p=0.69). ORR assessed by RECIST 1.1 has significantly improved by 6.0% over time (p=0.003). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p=0.0037). There was no significant change in patient demographics were identified over time to explain the OS findings. Conclusion: The median OS of patients with advanced HCC treated with sorafenib has improved significantly over 15 years. At the same time, the median duration of therapy with sorafenib has decreased. The reason for these findings was not explained by changing demographics of patients enrolled in these trials and has implications for ongoing clinical trials.

Trends of clinical outcomes with sorafenib in randomized controlled trials for patients with treatment-naïve advanced hepatocellular carcinoma.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 327-327
Author(s):  
Timothy J Brown ◽  
Arjun Gupta ◽  
Ramy Sedhom ◽  
Thomas Benjamin Karasic ◽  
Mark Yarchoan
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Median Duration ◽  
Systemic Therapy ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Duration Of Therapy ◽  
Recist 1.1 ◽  
Over Time

327 Background: Sorafenib was first approved by the US FDA to treat patients with advanced hepatocellular carcinoma (HCC) after two landmark trials (SHARP and Asia-Pacific) showed improved overall survival (OS). Since those two landmark trials, median OS has increased in the sorafenib arms in several recent phase III trials in HCC. We analyzed trends in OS, progression-free survival (PFS), and objective response rates (ORR) in published randomized clinical trials of sorafenib in HCC to better understand factors underlying the improvements. Methods: We searched PubMed for all published trials of sorafenib in advanced HCC. Trials were included if the patients were naïve to systemic therapy and had a comparison arm that was active systemic therapy or placebo. We extracted demographic and trial-level outcome data to correlate outcomes such as OS, PFS, ORR, and duration of therapy. T-tests were used to compare outcomes and linear regression was used to identify temporal trends with significance set at p£0.05. Results: The PubMed search returned 100 studies. A total of 15 studies met inclusion criteria with a total of 3755 patients treated with sorafenib (9 phase III and 6 phase II). Included trials enrolled patients from 2005-2019. The median OS in all trials was 10.0 mos (range: 6.5-14.8 mos). OS has significantly improved since the first trial began accruing (p = 0.04). A total of 12 studies provided data on PFS using RECIST 1.1, with a median PFS of 4.0 months (range: 2.7-6.6 mos). PFS has not changed over time (p = 0.99). However, ORR assessed by RECIST 1.1 have trended toward improvement over time (p = 0.08). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p = 0.02). Despite this, no significant correlations were observed with the interaction of duration of therapy and OS (p = 0.92). Further, there was no significant change in the age of patients included, proportion of patients with Childs-Pugh A, Barcelona Clinic Liver Cancer (BCLC) B, BCLC C, ECOG performance status 0, HBV or HCV, proportion of patients with extrahepatic spread or vascular invasion at time of enrollment, or proportion of patients who have undergone prior locoregional therapies to explain the OS findings. Conclusions: The OS of patients with advanced HCC on the sorafenib arm in published trials has been increasing, however the reasons for this increase are not apparent from data available in the published literature. At the same time, the median duration of treatment with sorafenib has been decreasing over time and PFS is unchanged, suggesting improvements in sorafenib delivery may not be the primary factor. It is possible these trends represent heretofore unquantified changes in patient selection for systemic therapy, improvements in supportive care, or post-progression treatment for patients on HCC clinical trials.

Clinical trial in progress: Pivotal study of VB-111 combined with paclitaxel versus paclitaxel for treatment of platinum-resistant ovarian cancer (OVAL, VB-111-701/GOG-3018).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5599-TPS5599
Author(s):  
Rebecca Christian Arend ◽  
Bradley J. Monk ◽  
Thomas J. Herzog ◽  
Jonathan A. Ledermann ◽  
Kathleen N. Moore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Phase Iii ◽  
Weekly Paclitaxel ◽  
Ca 125 ◽  
Recist 1.1 ◽  
Platinum Resistant ◽  
Phase Iii Study

TPS5599 Background: Ofranergene obadenovec (VB-111) is a targeted anti-cancer gene therapy with a dual mechanism of action that includes a broad antiangiogenic effect and induction of a tumor directed immune response. A phase II trial in patients with platinum resistant ovarian cancer showed that VB-111 in combination with weekly paclitaxel was well tolerated and associated with a CA-125 Objective Response Rate (ORR) of 58% with a trend for improved survival. The favorable outcomes were associated with induction of an immunotherapeutic effect of tumor infiltration with CD-8 T cells. Based on these observations, a phase III study was initiated in collaboration with the GOG Foundation, Inc. Methods: Study NCT03398655 is an international, randomized, double-blind, placebo-controlled, phase III study. Eligible patients have recurrent platinum-resistant epithelial ovarian cancer with measurable disease (RECIST 1.1), and may have been previously treated with up to 5 prior lines of therapy. Patient are randomized 1:1 to receive VB-111 (1x1013 VPs) with weekly paclitaxel (80mg/m2), or weekly paclitaxel with placebo. Randomization is stratified by number of prior treatment lines, prior antiangiogenic therapy and platinum refractory disease status. The efficacy endpoints are OS, PFS and ORR by RECIST 1.1 and by CA-125 (GCIG criteria). A pre-planned interim analysis was performed by the DSMC in the first 60 patients evaluable for CA-125 response. The analysis met the pre-defined criteria of a CA-125 ORR (GCIG) in the treatment arm at least 10% higher than in the control arm. Study enrolment is ongoing and over 220 patients were enrolled in the US, EU, and Israel. Enrolment of the full sample size of 400 patients is expected to complete by the end of 2021. Clinical trial information: NCT03398655.

A review of the patterns of docetaxel use for hormone refractory prostate cancer (HRPC) at the Princess Margaret Hospital

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16161-e16161
Author(s):  
S. N. Chin ◽  
L. Wang ◽  
A. Lau ◽  
M. Moore ◽  
S. S. Sridhar
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Practice ◽  
Median Duration ◽  
Response Rates ◽  
Routine Clinical Practice ◽  
Phase Iii ◽  
Line Treatment ◽  
Second Line ◽  
First Line

e16161 Background: Docetaxel is standard of care for the treatment of HRPC, based on two large randomized clinical trials. The aim of this study was to determine if docetaxel use and effectiveness in routine clinical practice was similar to that seen in the TAX 327 randomized phase III clinical trial. Methods: A retrospective chart review was undertaken to assess patterns of docetaxel use for HRPC at our institution for the 2-year period since its approval for the first-line treatment of HRPC in 2005. Results: Eighty-eight patients, median age 71 and baseline PSA 107, received docetaxel in the first line setting. Main reasons for initiating docetaxel were rising PSA (90%) and progressive symptoms (71%). Eighteen percent of patients received docetaxel for rising PSA alone. A median of 7 cycles was administered. PSA response rates were 61%, time to response 1.5 months, and response duration 6.8 months. Disease progression was the most common reason for treatment discontinuation (36%). Main toxicities were fatigue (32%) and neuropathy (22%). Kaplan Meier survival analysis showed median duration of survival was 15.9 months (95% CI 12.4–20.5) from first drug use. 1-year survival was 0.63 (95% CI 0.52–0.72). Post-docetaxel, 36 patients received second-line treatment, mostly with mitoxantrone (89%). Second-line response rates were 22%, and median duration of response was 4 months. Conclusions: In routine clinical practice, docetaxel is a well-tolerated regimen for the treatment of HRPC. Response rates and toxicity profiles were comparable to the randomized trials. However, compared with the TAX 327 clinical trial, survival was slightly shorter than expected (15.9 vs. 18.9 months), possibly due to inclusion of patients with poorer performance status and comorbidities, who may be excluded from clinical trials. Second-line response rates were also comparable with previous reports. No significant financial relationships to disclose.

Analyzing changes in oncology trial records over time using automated semantic web-mining.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13073-e13073
Author(s):  
David J Cocker ◽  
Johanna Caroline Lievens ◽  
Kristof Geentjens ◽  
Piet Van Remortel ◽  
Mireille De Cre ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Semantic Web ◽  
Language Processing ◽  
Web Mining ◽  
Semantic Analysis ◽  
Phase Iii ◽  
Differential Analysis ◽  
Clinical Trial Registries ◽  
The Uk ◽  
Over Time

e13073 Background: Incorrect assumptions and poor feasibility are often cited as the major cause of study delay and outcome resolution. Trial placement and recruitment can be optimized by monitoring and regular assessment of trial registries. However, just a snapshot analysis does not take into account retrospective editing of records. This paper evaluates the effectiveness of a robotic, semantic analysis of registered oncology trials to assess individual changes in trial records over time. Methods: Evaluating individual trial records from 2008 to 2012 with state-of-the art natural language processing and semantic linking of data fields within clinical trial registries and literature databases to add increased resolution to erroneous or inadequate registry fields. Results: Substantial modifications are made to registration records over the life cycle of a clinical trial. Quantifiable fields as recruitment, site numbers and end dates all deviate significantly from the study roll-out. Analysis of oncology trials recruiting over 200 patients between 2008 and 2012 shows two thirds of trials deviate from the initial record. Most frequently study end date is delayed (about 50% of all trials) or enrollment targets are amended (at least 25%). Over all oncology indications, enrollment increases are twice more frequent as decreases. However, there are notable exceptions such as lung cancer, where enrollment is frequently decreased. A differential analysis of countries and sites in commercial oncology phase III trials over the period revealed a marked shift of research to sites in France, Spain, the UK and China. However, when sites were added to ongoing trials this general trend was not entirely followed as Poland, Japan, Belgium, Argentina and Switzerland were frequently chosen as additional countries above the normal distribution, suggesting these are preferred countries for trial “rescue”. Conclusions: This paper demonstrates the effectiveness of automated semantic web-mining to identify incorrect clinical trial assumptions and subsequent remediation.

Phase IIb randomized trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), a targeted oncolytic vaccinia virus, plus best supportive care (BSC) versus BSC alone in patients with advanced hepatocellular carcinoma who have failed sorafenib treatment (TRAVERSE).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS4161-TPS4161
Author(s):  
Jeong Heo ◽  
Yee Chao ◽  
Derek J. Jonker ◽  
Ari David Baron ◽  
Francois Habersetzer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Vaccinia Virus ◽  
Median Survival ◽  
Hazard Ratio ◽  
High Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment ◽  
Advanced Hcc ◽  
Gm Csf

TPS4161^ Background: Pexa-Vec is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony stimulating factor (GM-CSF). Direct oncolysis plus GM-CSF expression stimulates tumor vascular disruption and anti-tumor immunity (Nature Rev Cancer, 2009). Pexa-Vec was well-tolerated in Phase 1 trials and was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol, 2008 and Nature, 2011). A randomized high vs low dose Phase 2 trial in 30 patients with advanced HCC, demonstrated prolonged survival in the high-dose Pexa-Vec arm (median survival 14.1 mo vs. 6.7 mo; Hazard Ratio 0.39, p=0.02) (AASLD Annual Meeting, 2011, LB1). Methods: TRAVERSE is a Phase 2b randomized, open-label, multi-center trial in patients with advanced HCC who have failed sorafenib treatment. Approximately 120 patients will be randomized 2:1 to Pexa-Vec plus BSC versus BSC, respectively. Randomization will be stratified by region (Asian vs. non-Asian); sorafenib intolerant vs refractory; and presence vs absence of extra-hepatic disease. The primary objective is to determine overall survival. Main inclusion criteria are advanced HCC having failed sorafenib (intolerance or radiographic progression during or < 3 months following last sorafenib), Child-Pugh A-B7 (no ascites), acceptable hematologic function. Assuming a median overall survival of 4.0 months with BSC and a target hazard ratio of 0.57 (corresponding to an experimental arm median survival of 7.0 months), 73 events (deaths) will provide 70% power at 1-sided alpha = 0.05 to detect a difference in overall survival between the treatment groups using a stratified logrank test. Patients randomized to Pexa-Vec will receive a dose of 109 plaque forming units (pfu) IV on Day 1 followed by five IT treatments between Day 8 and Week 18. Enrollment has begun on this study with clinical trial registry number of NCT01387555. Clinical trial information: NCT01387555.

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]

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma (HCC): Asia-Pacific (AP) trial subgroup analyses by baseline transaminase (ALT/AST)/α-fetoprotein (AFP) levels

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4590-4590 ◽  
Author(s):  
S. Qin ◽  
T. Yang ◽  
W. Tak ◽  
S. Yu ◽  
C. Tsao ◽  
...  
Keyword(s):  
Clin Oncol ◽  
Annual Meeting ◽  
Conflict Of Interest ◽  
Hepatic Function ◽  
Principal Investigator ◽  
Phase Iii ◽  
Asia Pacific ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Interest Policy

4590^ Background: Results of the phase III, randomized, double blind, placebo-controlled AP trial demonstrated that sorafenib is effective and safe for the treatment of advanced HCC in patients from the AP region (Cheng et al, Lancet Oncol, 2009). Hepatic function influences treatment as a measure of organ damage and tumor stage. We performed subset analyses of the AP study dataset according to baseline hepatic function, as indicated by levels of ALT/AST and AFP. Methods: Patients (N=226) with advanced HCC, ECOG PS 0–2, Child-Pugh class A, and no prior systemic therapy were randomized 2:1 to receive sorafenib 400 mg BID or placebo. 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), time to progression (TTP) and safety. Patients were grouped by baseline levels of ALT/AST (normal, mild, or moderate) and AFP (normal or abnormal). Results: Median TTP, OS and DCR by subset are shown in the table . The most common grade 3/4 adverse events in the sorafenib populations were hand-foot skin reaction and diarrhea. Conclusions: Sorafenib was effective and safe in patients from the AP region with advanced HCC within a broad range of baseline hepatic enzyme and AFP levels. These results suggest that sorafenib is an effective treatment for HCC, irrespective of baseline ALT/AST or AFP levels. [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 .

Surrogate endpoint in advanced hepatocellular carcinoma treated with molecular targeted therapy: Meta-analysis of randomized controlled trials.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 454-454
Author(s):  
Kyung-Hun Lee ◽  
Dae-Won Lee ◽  
Myoung-Jin Jang ◽  
Tae-Yong Kim ◽  
Sae-Won Han ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Targeted Therapy ◽  
Molecular Targeted Therapy ◽  
Treatment Effects ◽  
Phase Iii ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Incremental Benefit ◽  
Randomized Controlled

454 Background: Time to progression (TTP) is suggested as a reliable endpoint compared to progression free survival (PFS) in the clinical trials of hepatocellular carcinoma (HCC). However, the correlation between TTP and overall survival (OS) has never been studied. Methods: We searched Pubmed and Embase data to obtain data source. Eligible studies were randomized controlled phase III trials which evaluated the efficacy of systemic chemotherapy or molecular targeted therapy in advanced HCC. The association of treatment effects as shown by the hazard ratio (HR) of TTP and OS in each trial was assessed by Spearman rank correlation coefficient ( rs) and linear regression analysis. The association between median TTP and OS was also investigated. Results: Nine studies with a total of 18 treatment arms and 6318 patients were included. Incremental benefit from the study treatment in TTP from each trial was correlated with incremental benefit in OS. The rs value and R2 value between log (HRTTP) and log (HROS) was 0.73 (95% CI 0.12 – 0.94, p = 0.024) and 0.57. The minimum TTP effect to predict a treatment effect on OS was 0.63. Median TTP was associated with median OS. The rs value between TTP and OS was 0.73 (95% confidence interval (CI) 0.40 – 0.89, p < 0.001) and the corresponding R2 was 0.42. Conclusions: Our study results suggest that TTP could be used as a surrogate marker for OS in the clinical trials of advanced HCC. However, the results suggest modest correlation between treatment effects on TTP and OS. Along with individual-level analysis more evidences are needed to confirm our finding.

A phase 2 and biomarker study of sorafenib combined with FOLFOX in patients with advanced hepatocellular carcinoma (HCC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 270-270
Author(s):  
Lipika Goyal ◽  
Hui Zheng ◽  
Thomas Adam Abrams ◽  
Rebecca A. Miksad ◽  
Andrea J. Bullock ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Phase Iii ◽  
Disease Rate ◽  
Advanced Hepatocellular Carcinoma ◽  
Line Treatment ◽  
Phase 2 ◽  
First Line ◽  
Advanced Hcc ◽  
Biomarker Analysis ◽  
First Line Treatment

270 Background: Sorafenib is the standard first line treatment for advanced HCC and showed a median time to progression (TTP) of 5.5 months and an overall response rate (ORR) of 2% in the phase III SHARP trial. FOLFOX has shown modest activity in HCC with a progression free survival (PFS) of 2.9 months and ORR of 8% in a phase III trial. In this single-arm, multicenter phase 2 and biomarker study, sorafenib plus FOLFOX was evaluated in the first line treatment of advanced HCC. Methods: Patients with histologically proven advanced HCC, Child Pugh A liver function, and no prior systemic therapies received sorafenib 400mg orally twice daily during a 2-week lead-in, followed by concurrent modified FOLFOX (5-FUCI 1200mg/m2/day for 46 hours and LV 400mg/m2 bolus, Oxaliplatin 85mg/m2) on day 1 and 15 of each 28-day cycle. The primary endpoint was TTP, calculated from date of study entry to date of radiological or clinical disease progression. Serial plasma anti-angiogenic and anti-inflammatory biomarkers were evaluated. Results: The study enrolled 40 patients with advanced HCC: median age, 65 years; male 85%; Child Pugh A5, 70%; BCLC stage C, 95%; HCC etiology, HCV 40%, HBV 13%, alcohol 13%. Grade 3/4 adverse events were notable for AST (23%), ALT (15%), bilirubin (10%), diarrhea (10%), anemia (10%), hypertension (5%), hand-foot syndrome (5%), and thrombocytopenia (5%). Dose reductions for sorafenib and FOLFOX were done in 73% and 65% of patients, respectively. The median TTP was 8.8 months (95%CI, 6.5-11.2). The ORR was 18%, and the stable disease rate was 55%. Among 36 patients with a baseline AFP ≥ 5 ng/mL, 10 (28%) had a ≥ 50% drop in AFP. Low baseline plasma levels of sVEGFR1, VEGF-C, and bFGF and high levels of s-cMET and IL-12 tended to associate with longer TTP (p < 0.10). Decreased s-cMET at day 15 and decreased s-cMET and IL-2 at day 43 were associated with longer TTP (p < 0.05). Conclusions: Sorafenib+FOLFOX demonstrated encouraging clinical efficacy with moderate toxicity in the first line treatment of advanced HCC. Initial biomarker evaluation suggested a correlation between TTP and baseline angiogenic markers as well as changes in IL-2 and s-cMET. Complete biomarker analysis will be presented at the meeting. Clinical trial information: NCT01775501.

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]

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