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Published on: September 20, 2020
Regional Differences in Efficacy, Safety, and Biomarkers for Second-Line Axitinib in Patients with Advanced
Masatoshi Kudo1, Yoon-Koo Kang2, Joong-Won Park3
1Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
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.
Insights
Axitinib plus best supportive care (BSC) did not improve overall survival in advanced hepatocellular carcinoma (HCC) patients compared to placebo/BSC. However, favorable outcomes were seen in some Japanese patients, suggesting potential predictive factors.
Area of Science:
- Oncology
- Hepatocellular Carcinoma Research
- Clinical Trials
Background:
- Advanced hepatocellular carcinoma (HCC) presents an unmet need for treatments post-sorafenib progression or intolerance.
- A global phase II trial evaluated axitinib, a VEGFR inhibitor, combined with best supportive care (BSC) versus placebo/BSC.
- The trial did not meet its primary endpoint of prolonged overall survival (OS) but indicated potential benefits in progression-free survival for some patients.
Purpose of the Study:
- To analyze subgroup efficacy and safety of axitinib/BSC in advanced HCC patients across Asian and non-Asian populations.
- To identify potential predictive and prognostic factors for axitinib/BSC treatment response.
- To explore the influence of prior antiangiogenic therapy intolerance on treatment outcomes.
Main Methods:
- Phase II clinical trial data from 202 advanced HCC patients (124 Asian, 78 non-Asian) were analyzed.
- Cox proportional hazards models were used to assess efficacy, safety, and biomarker associations.
- Subgroup analyses focused on geographic regions (Asia vs. non-Asia, specific Asian countries) and baseline biomarkers (microRNAs, soluble proteins).
Main Results:
- No significant OS differences were observed between axitinib/BSC and placebo/BSC in overall Asian or non-Asian groups.
- Exploratory analysis suggested improved OS with axitinib/BSC in Asian patients, particularly Japanese, when sorafenib-intolerant patients were excluded.
- Four circulating microRNAs and baseline stromal cell-derived factor 1 levels showed potential as predictive/prognostic biomarkers for OS in axitinib/BSC-treated patients.
Conclusions:
- Axitinib/BSC did not demonstrate improved OS over placebo/BSC in the overall study population.
- A subset of Japanese patients showed favorable OS, suggesting potential efficacy in specific populations.
- Excluding sorafenib-intolerant patients may be beneficial for future advanced HCC clinical trials; further validation of biomarkers is warranted.
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