Masatoshi Kudo1, Yoon-Koo Kang2, Joong-Won Park3, Shukui Qin4, Yoshitaka Inaba5, Eric Assenat6, Yoshiko Umeyama7, Maria José Lechuga8, Olga Valota8, Yosuke Fujii7, Jean-Francois Martini9, J Andrew Williams9, Shuntaro Obi10. 1. Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. 2. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 3. Center for Liver Cancer, National Cancer Center, Goyang, Republic of Korea. 4. Department of Medical Oncology, Nanjing Bayi Hospital, Nanjing, China. 5. Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan. 6. Department of Medical Oncology, Hôpital Saint Eloi, Montpellier, France. 7. Pfizer Japan Inc., Tokyo, Japan. 8. Pfizer Srl, Milan, Italy. 9. Pfizer Inc., San Diego, CA, USA. 10. Department of Hepatology, Sasaki Foundation Kyoundo Hospital, Tokyo, Japan.
Abstract
BACKGROUND: An unmet need exists for treatment of patients with advanced hepatocellular carcinoma (HCC) who progress on or are intolerant to sorafenib. A global randomized phase II trial (ClinicalTrial.gov No. NCT01210495) of axitinib, a vascular endothelial growth factor receptor 1-3 inhibitor, in combination with best supportive care (BSC) did not prolong overall survival (OS) over placebo/BSC, but showed improved progression-free survival in some patients. Subgroup analyses were conducted to identify potential predictive/prognostic factors. METHODS: The data from this phase II study were analyzed for the efficacy and safety of axitinib/BSC in patients from Asia versus non-Asia versus Asian subgroups (Japan, Korea, or mainland China/Hong Kong/Taiwan) and predictive/prognostic values of baseline microRNAs and serum soluble proteins, using the Cox proportional hazards model. RESULTS: Of 202 patients, 78 were from non-Asia and 124 from Asia (37 Japanese, 36 Korean, and 51 Chinese). No significant differences in OS were found between axitinib/BSC and placebo/BSC in non-Asians, Asians, or Asian subgroups. However, in an exploratory analysis, axitinib/BSC showed favorable OS in Asians, especially Japanese, when patients intolerant to prior antiangiogenic therapy were excluded from the data set. Axitinib/BSC was well tolerated by non-Asians and Asians alike. The presence of 4 circulating microRNAs, including miR-5684 and miR-1224-5p, or a level lower than or equal to the median protein level of stromal cell-derived factor 1 at baseline was significantly associated with longer OS in axitinib/BSC-treated Asians or non-Asians. CONCLUSIONS: Axitinib/BSC did not prolong survival over placebo/BSC in non-Asians, Asians, or Asian subgroups, but favorable OS with axitinib/BSC was observed in a subset of Japanese patients. A patient population that excludes sorafenib-intolerant patients might potentially be more suitable for clinical trials of new agents in advanced HCC. Since these results are very preliminary, further investigation is warranted. The potential predictive/prognostic value of several baseline microRNAs and soluble proteins identified in this study would require validation in prospective studies on a large cohort of patients.
BACKGROUND: An unmet need exists for treatment of patients with advanced hepatocellular carcinoma (HCC) who progress on or are intolerant to sorafenib. A global randomized phase II trial (ClinicalTrial.gov No. NCT01210495) of axitinib, a vascular endothelial growth factor receptor 1-3 inhibitor, in combination with best supportive care (BSC) did not prolong overall survival (OS) over placebo/BSC, but showed improved progression-free survival in some patients. Subgroup analyses were conducted to identify potential predictive/prognostic factors. METHODS: The data from this phase II study were analyzed for the efficacy and safety of axitinib/BSC in patients from Asia versus non-Asia versus Asian subgroups (Japan, Korea, or mainland China/Hong Kong/Taiwan) and predictive/prognostic values of baseline microRNAs and serum soluble proteins, using the Cox proportional hazards model. RESULTS: Of 202 patients, 78 were from non-Asia and 124 from Asia (37 Japanese, 36 Korean, and 51 Chinese). No significant differences in OS were found between axitinib/BSC and placebo/BSC in non-Asians, Asians, or Asian subgroups. However, in an exploratory analysis, axitinib/BSC showed favorable OS in Asians, especially Japanese, when patients intolerant to prior antiangiogenic therapy were excluded from the data set. Axitinib/BSC was well tolerated by non-Asians and Asians alike. The presence of 4 circulating microRNAs, including miR-5684 and miR-1224-5p, or a level lower than or equal to the median protein level of stromal cell-derived factor 1 at baseline was significantly associated with longer OS in axitinib/BSC-treated Asians or non-Asians. CONCLUSIONS: Axitinib/BSC did not prolong survival over placebo/BSC in non-Asians, Asians, or Asian subgroups, but favorable OS with axitinib/BSC was observed in a subset of Japanese patients. A patient population that excludes sorafenib-intolerant patients might potentially be more suitable for clinical trials of new agents in advanced HCC. Since these results are very preliminary, further investigation is warranted. The potential predictive/prognostic value of several baseline microRNAs and soluble proteins identified in this study would require validation in prospective studies on a large cohort of patients.
Authors: Ying Chen; Akiyuki Suzuki; Michael A Tortorici; May Garrett; Robert R LaBadie; Yoshiko Umeyama; Yazdi K Pithavala Journal: Invest New Drugs Date: 2015-02-08 Impact factor: 3.850
Authors: Massimo Iavarone; Giuseppe Cabibbo; Marco Biolato; Cristina Della Corte; Marcello Maida; Marco Barbara; Michele Basso; Sara Vavassori; Antonio Craxì; Antonio Grieco; Carlo Cammà; Massimo Colombo Journal: Hepatology Date: 2015-03-20 Impact factor: 17.425
Authors: Andrew X Zhu; Masatoshi Kudo; Eric Assenat; Stéphane Cattan; Yoon-Koo Kang; Ho Yeong Lim; Ronnie T P Poon; Jean-Frederic Blanc; Arndt Vogel; Chao-Long Chen; Etienne Dorval; Markus Peck-Radosavljevic; Armando Santoro; Bruno Daniele; Junji Furuse; Annette Jappe; Kevin Perraud; Oezlem Anak; Dalila B Sellami; Li-Tzong Chen Journal: JAMA Date: 2014-07-02 Impact factor: 56.272
Authors: Brian I Rini; May Garrett; Bill Poland; Janice P Dutcher; Olivier Rixe; George Wilding; Walter M Stadler; Yazdi K Pithavala; Sinil Kim; Jamal Tarazi; Robert J Motzer Journal: J Clin Pharmacol Date: 2013-03-28 Impact factor: 3.126