D Koeberle1, J-F Dufour2, G Demeter3, Q Li4, K Ribi5, P Samaras6, P Saletti7, A D Roth8, D Horber9, M Buehlmann10, A D Wagner11, M Montemurro11, G Lakatos3, J Feilchenfeldt12, M Peck-Radosavljevic13, D Rauch14, B Tschanz4, G Bodoky3. 1. Department of Medical Oncology, Kantonsspital St Gallen, St Gallen dieter.koeberle@claraspital.ch. 2. Department of Hepatology, University Hospital Bern, Bern, Switzerland. 3. Department of Medical Oncology, St László Teaching Hospital, Budapest, Hungary. 4. SAKK Coordinating Center, Berne. 5. Quality of life Office, International Breast Cancer Study Group, Bern. 6. Department of Medical Oncology, University Hospital Zurich, Zürich. 7. Department of Medical Oncology, Istituto Oncologico della Svizzera Italiana, Bellinzona. 8. Department of Medical Oncology, University Hospital of Geneva, Geneva. 9. Department of Medical Oncology, Kantonsspital St Gallen, St Gallen. 10. Department of Medical Oncology, University Hospital Bern, Bern. 11. Department of Medical Oncology, University Hospital Lausanne, Lausanne. 12. Department of Medical Oncology, Hôpital du Valais (RSV)-CHCVs, Lausanne, Switzerland. 13. Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria. 14. Department of Medical Oncology, Spital STS AG, Bern, Switzerland.
Abstract
BACKGROUND:Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S. PATIENTS AND METHODS: Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments. RESULTS: A total of 106 patients were randomized: 46 patients received S and 60 patients receivedS + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E. CONCLUSIONS: No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted. CLINICALTRIALSGOV: NCT01005199.
RCT Entities:
BACKGROUND:Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S. PATIENTS AND METHODS: Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments. RESULTS: A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E. CONCLUSIONS: No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted. CLINICALTRIALSGOV: NCT01005199.
Authors: Raymond Wu; Ramachandran Murali; Yasuaki Kabe; Samuel W French; Yi-Ming Chiang; Siyu Liu; Linda Sher; Clay C Wang; Stan Louie; Hidekazu Tsukamoto Journal: Hepatology Date: 2018-10-09 Impact factor: 17.425
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