Phase III trial confirms efficacy and safety of new second-line agent
BARCELONA-LUGANO, 30 June 2016 – Oral multikinase inhibitor regorafenib achieves significantly improved survival rates compared to placebo in patients with hepatocellular carcinoma, according to data from the phase III RESORCE trial (1), presented at the ESMO 18th World Congress of Gastrointestinal Cancer in Barcelona, Spain.
“Systemic treatment for hepatocellular carcinoma has long consisted of just one agent - sorafenib –which was shown to provide a significant improvement in life expectancy almost 10 years ago, but no other agent has surpassed its benefits,” said the study’s principal investigator Dr Jordi Bruix, Head of the BCLC group at the Hospital Clínic and Scientific Director of the Network for Biomedical Research for Hepatic and Digestive Diseases (CIBEREHD).
While the last decade has seen many potential new agents for hepatocellular carcinoma fail in clinical trials, phase I and II data from early regorafenib trials were promising, and led to the initiation of this international, multi-center phase III trial.
Researchers enrolled 573 patients with intermediate or advanced stage hepatocellular carcinoma, who had all been previously treated with sorafenib, and randomized them 2:1 to 160mg oral regorafenib or placebo once daily for 1-3 of each four week cycle, in addition to best supportive care.
After a median of 3.6 months of treatment, patients on regorafenib showed a 38% reduction in the risk of death and a 54% reduction in the risk of progression or death compared to placebo.
Mean progression-free survival was 3.1 months with regorafenib and 1.5 months with placebo, while median overall survival was 10.6 months for regorafenib and 7.8 months with placebo.
Overall, 65.2% of patients on regorafenib showed complete or partial response or stable disease, compared to 36.1% of the placebo group.
Regorafenib had a similar safety and side effect profile to sorafenib, with hypertension, hand-foot skin reaction, fatigue and diarrhea all being significantly more common in patients taking the drug.
Dr Bruix said that the benefits of the drug were evident regardless of the cause or stage of the tumor, but analysis of biomarkers would reveal whether there might be certain sub-groups of patients likely to derive even greater benefit from this treatment.
“This is a very difficult to treat cancer but now we have an effective second-line agent, which is good news for the patients and also for the field as interest in further developments will be stimulated,” Dr Bruix said.
Notes to Editors
References
1 LBA-03: Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international, randomized phase 3 RESORCE trial will be presented by Jordi Bruix during Session VIII: Liver Malignancies on Thursday, 30 June 2016, 17:40 (CEST).
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LBA-03
Efficacy and safety of regorafenib versus placebo in patients with hepatocellular carcinoma (HCC) progressing on sorafenib: Results of the international, randomized phase 3 RESORCE trial
Jordi Bruix1, Philippe Merle2, Alessandro Granito3, Yi-Hsiang Huang4, Gyorgy Bodoky5, Osamu Yokosuka6, Olivier Rosmorduc7, Valeriy Breder8, Rene Gerolami9, Gianluca Masi10, Paul J Ross11, Shukui Qin12, Tianqiang Song13, Jean-Pierre Bronowicki14, Isabelle Ollivier-Hourmand15, Masatoshi Kudo16, Marie-Aude LeBerre17, Annette Baumhauer18, Gerold Meinhardt19, Guohong Han20, on behalf of the RESORCE Investigators
- BCLC Group, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain;
- Groupement Hospitalier Lyon Nord, Hepatology Unit, Lyon, France;
- Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy;
- Division of Gastroenterology and Hepatology, Taipei Veterans General Hospital; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan;
- St Laszlo Teaching Hospital, Budapest, Hungary;
- Department of Gastroenterology and Nephrology, Chiba University, Chiba, Japan;
- Department of Hepatology, Hôpital de la Pitié-Salpétrière, Assistance Publique-Hôpitaux de Paris and Université Pierre et Marie Curie, Sorbonne Universités, Paris, France;
- Russian Cancer Research Center n.a.N.Blokhin, Moscow, Russian Federation;
- CHU Timone, Université de la Méditerranée, Marseille, France;
- Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy;
- King's College Hospital NHS Foundation Trust, London, UK;
- Chinese People’s Liberation Army Cancer Center of Nanjing Bayi Hospital, Nanjing, China;
- Tianjin Medical University Cancer Hospital, Tianjin, China;
- INSERM 954, CHU de Nancy, Université de Lorraine, Nancy, France;
- Service d’Hépatogastroentérologie, CHU, Caen, France;
- Kindai University Faculty of Medicine, Osaka, Japan;
- Bayer HealthCare SAS, Loos, France;
- Bayer Pharmaceuticals, Bayer Vital GmbH, Leverkusen, Germany;
- Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA;
- The First Affiliated Hospital of the Fourth Military Medical University, Xi’an, China
Background: There are no proven or approved second-line treatment options for patients with advanced HCC. Based on promising activity in a second-line phase 2 study (Bruix, Eur J Cancer 2013), we evaluated regorafenib, an oral multikinase inhibitor, in patients with intermediate or advanced HCC who had disease progression on sorafenib.
Methods: In this double-blind, placebo-controlled trial, adults with HCC Barcelona Clinic Liver Cancer (BCLC) stage B or C who received sorafenib for ≥20 days at ≥400 mg/day and had documented radiological progression on sorafenib, Child-Pugh A liver function, and ECOG performance status 0-1 were randomized 2:1 (stratification by geographic region Asia vs rest of the world, performance status, alpha-fetoprotein, extrahepatic spread, macroscopic vascular invasion) to regorafenib 160 mg or placebo once daily during weeks 1–3 of each 4-week cycle. All received best supportive care. Treatment continued until disease progression, death, or unacceptable toxicity. The primary endpoint of overall survival (OS) was analyzed by intent-to-treat. Secondary endpoints were progression-free survival (PFS), time-to-progression (TTP), response rate (RR), and disease control rate (DCR).
Results: The trial was conducted in 21 countries and a total of 573 patients were randomized (regorafenib=379; placebo=194). Baseline demographic and disease characteristics were balanced between arms. For all patients, median age was 63 years, 88% were male, and 87% were BCLC stage C. Median (range) treatment duration was 3.6 months (0.03‒29.4) for regorafenib and 1.9 months (0.2‒27.4) for placebo. The regorafenib group had a 38% reduction in the risk of death (HR 0.62; 95%CI 0.50‒0.78; p <0.001); median OS (regorafenib vs placebo) was 10.6 vs 7.8 months. There was a 54% reduction in the risk of progression or death with regorafenib (HR 0.46; 95%CI 0.37‒0.56; p <0.001); median PFS (regorafenib vs placebo) was 3.1 vs 1.5 months. Median TTP (regorafenib vs placebo) was 3.2 vs 1.5 months (HR 0.44; 95%CI 0.36–0.55; p<0.001). DCR (complete and partial responses + stable disease by mRECIST) for regorafenib vs placebo was 65.2% vs 36.1% (p<0.001). Overall RRs (complete and partial responses) were 10.6% vs 4.1% (p=0.005), respectively. Rates of grade ≥3 adverse events were 79.7% with regorafenib and 58.5% with placebo. Most common grade ≥3 adverse events occurring more frequently in the regorafenib group included (regorafenib vs placebo) hypertension (15.2% vs 4.7%), hand-foot skin reaction (12.6% vs 0.5%), fatigue (9.1% vs 4.7%), and diarrhea (3.2% vs 0%). Rates of dose modifications due to adverse events were 68.2% with regorafenib and 31.1% with placebo. Deaths occurring up to 30 days after last dose of study drug were higher in the placebo group (13.4% regorafenib, 19.7% placebo).
Conclusions: Regorafenib significantly improved OS in patients with HCC who progressed during treatment with sorafenib. Adverse events were consistent with the known safety profile of regorafenib.