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

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.

Avelumab in Combination with Axitinib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma: Results from the Phase 1b VEGF Liver 100 Trial

“…In a randomized phase 2 trial in advanced HCC, second-line treatment with axitinib plus best supportive care resulted in significantly longer PFS and time to progression and a higher clinical benefit rate versus placebo plus best supportive care, with an acceptable safety profile [32]. Although the primary OS endpoint had not been met in this study, a subset of Japanese patients showed favorable OS outcomes compared with patients from other countries [33].…”

Towards a tailored systemic therapy for liver cancer

“…In this series of 202 patients, 78 non-Asian and 124 Asian, no significant differences in OS were found according to location of enrollment. However, in an exploratory analysis excluding patients intolerant to prior antiangiogenic therapy, axitinib showed favorable OS in Asians, especially Japanese patients (18). No difference in safety profile was observed on regional basis.…”

“…Therefore, the authors concluded that axitinib may represent a valuable option in a subgroup of Japanese patients that excludes sorafenib-intolerant subjects; moreover, several potential biomarkers might help the clinician in selecting a subgroup of patients more likely to benefit from axitinib therapy (18).…”

“…No difference in safety profile was observed on regional basis. Four circulating microRNAs, including miR-5684 and miR-1224-5p, and stromal cellderived factor 1 were found to play a predictive role in both Asians and non-Asians (18).…”

“…In an interesting manuscript recently published in Liver Cancer, Kudo et al analyzed data from the aforementioned trial (17) with the aim to explore the efficacy and safety of axitinib based on location of recruitment (Asia versus non-Asia versus Asian subgroups) and to investigate the potential predictive and/or prognostic value of baseline levels of circulating microRNAs (miRNAs) and serum soluble proteins thus attempting to explore the predictive role of several molecular biomarkers (18).…”