DISCUSSION
tumor
TUMOR, HEPATOCELLULAR CARCINOMA
This multinational, multicenter, randomized phase II study showed that the addition of sorafenib to XP did not improve the response rates, PFS or OS, although the doses for this combination established in a previous phase I study were well tolerated. Moreover, only limited activity of sorafenib monotherapy in a second‐line setting was shown after failure of standard XP chemotherapy.Between the two treatment arms, the patient characteristics were well balanced except for the tumor location, which did not have a significant impact on the survival outcomes (Figure Efficacy outcomes, such as response rates, PFS, and OS, in both treatment groups were in line with previous pivotal phase III trials of first‐line chemotherapy for GC.Targeting angiogenesis has been widely investigated in GC and some novel anti‐angiogenic agents have proven their activity in randomized phase III trials.Aside from these monoclonal antibodies, VEGFR‐directed tyrosine kinase inhibitors (TKIs) have also proven their activity against GC. Apatinib, a small‐molecule VEGFR TKI, was significantly associated with improved survival compared with placebo in the third‐line setting.Currently, all positive trials targeting the VEGFR pathway in GC were in the second‐ or third‐line setting, not in the first‐line setting. Despite the success of ramucirumab as a second‐line treatment, ramucirumab in combination with modified FOLFOX as the first‐line treatment failed to show any benefit of adding ramucirumab.In the current study, sorafenib monotherapy showed only a limited efficacy after failure of XP in the XP arm, which seems inferior to standard second‐line cytotoxic regimens such as irinotecan, docetaxel, or paclitaxel. The lack of efficacy of sorafenib in the second‐line setting is interesting because regorafenib, which has a similar activity profile to sorafenib, showed significantly improved PFS compared to placebo in patients with GC after the failure of at least first‐line chemotherapy, although this needs further validation in an ongoing phase III trial (INTEGRATE‐II).Through biomarker analyses, the results of the current study suggest that patients with high pERK and VEGF expression by IHC can obtain a benefit from sorafenib. These results are consistent with previous studies of anti‐angiogenic agents. The pretreatment tumor tissue pERK expression level has been suggested as an important predictive marker of sorafenib response in advanced hepatocellular carcinoma.In conclusion, the combination of sorafenib and XP was feasible and well tolerated. However, it did not show any differences in efficacy outcomes compared with standard XP as the first‐line chemotherapy for patients with GC. Based on the results of the current study, further investigation of this combination regimen is not warranted in GC, at least in the first‐line setting, if patients are not selected by definite biomarkers. Novel anti‐angiogenic agents that have shown promising activity in the second or later lines of chemotherapy should be further investigated in the first‐line setting to improve the survival of patients with GC, especially in combination with ICIs.