Supplementary Material for: Regional Differences in Efficacy, Safety, and Biomarkers for Second-Line Axitinib in Patients with Advanced Hepatocellular Carcinoma: From a Randomized Phase II Study

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.