Discussion
ascites, gastroesophageal junction adenocarcinoma, tumor, toxicity, proteinuria, hepatotoxicity, Bleeding, deaths, gastric cancer
ASCITES, TUMOR, BRAIN METASTASIS, CENTRAL NERVOUS SYSTEM BLEEDING, ADVERSE EVENTS, BRAIN METASTASES, CENTRAL NERVOUS SYSTEM METASTASES, HYPERTENSION, GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA, HAND-FOOT SYNDROME, BLEEDING, EVENTS, HEPATOBILIARY DISEASE, METASTASES, GASTRIC CANCER
The AHEAD study aimed to verify the safety and efficacy of third- or later-line apatinib in a broad population of patients with advanced gastric or gastroesophageal junction adenocarcinoma in China. Final data from this phase IV study demonstrated the well-established safety profile of apatinib and further confirmed the results of the phase III study.The results of the double-blind, randomized, placebo-controlled phase III study supported apatinib's approval as a third- and later-line treatment for gastric or gastroesophageal junction adenocarcinomas in China. The study included patients between the ages of 18 and 70, with an ECOG PS of 0 to 1, with at least one measurable lesion per RECIST, and who had previously undergone two lines of chemotherapy. There was a significant improvement in OS and PFS with apatinib compared to placebo (median OS, 6.5 vs 4.7 months, hazard ratio = 0.709; median PFS, 2.6 vs 1.8 months, hazard ratio = 0.444). Apatinib showed an ORR of 2.84% and a DCR of 42.05% [The AHEAD study set broad eligibility criteria that allowed enrollment of patients excluded from phase III studies, including elderly patients, patients with ECOG PS of 2, and patients with asymptomatic ascites and asymptomatic central nervous system metastases. Additionally, enrolled patients had a higher tumor burden than those in the phase III study of apatinib [The overall toxicity profile in the AHEAD study was consistent with that in previous studies of apatinib [Hypertension, proteinuria, and hand-foot syndrome are known adverse events associated with VEGF/VEGFR inhibition, frequently reported in studies of angiogenesis inhibitors such as bevacizumab [Bleeding is considered a major safety concern for anti-VEGF/VEGFR agents [Patients with symptomatic brain metastases were excluded from this study. However, those with asymptomatic metastases could have been enrolled since brain imaging was not mandated before enrollment. In the AHEAD study, few central nervous system bleeding events were reported, suggesting that the advanced gastric cancer patients with asymptomatic brain metastasis treated with apatinib were well-tolerated.Most hepatotoxicity events were grade 1 to 2 laboratory abnormalities. However, 3% of patients reported grade ≥ 3 hepatobiliary diseases, resulting in five deaths. Although the incidence of grade ≥ 3 hepatotoxicity was not high in the AHEAD study, changes in hepatic aminotransferase or serum bilirubin require regular monitoring in patients treated with apatinib to identify hepatic events early. Once physicians recognize hepatic events, in addition to immediate symptomatic therapy, they should take necessary procedures, including temporary interruption, dose reduction, or even discontinuation of apatinib, to prevent the development and deterioration of these events following the product introduction.We also explored the effectiveness of apatinib in treating advanced gastric cancer in the AHEAD study. The median OS was 5.8 months, slightly shorter than that reported in a previous study (6.5 months) [Our data also allowed for the identification of patients with a better prognosis. OS was shorter in patients with ECOG PS of 2–3 versus 0–1 and patients with > 2 versus ≤ 2 metastatic sites, whereas gender, age, clinical stage, and prior lines of chemotherapy were not associated with clinical outcome. The number of metastatic sites was a predictor of OS, consistent with the phase III study of apatinib [Apatinib was dosed at 850 mg once daily in the phase III study. Therefore, in the AHEAD study, apatinib was recommended at an initial dose of 850 mg, while the starting dose was decided by the investigator’s choice. A total of 98% of patients initiated apatinib at 500 mg, and subgroup analysis found the initial dose of apatinib did not affect OS or PFS. Notably, patients treated with an initial dose of ≤ 500 mg of apatinib had similar OS and PFS outcomes to those treated with an initial dose of 850 mg of apatinib in the phase III study [The strength of the AHEAD study was its large sample size and inclusion of patients excluded from phase III trials, providing a true presentation of the safety and efficacy of apatinib in treating advanced gastric cancer. Meanwhile, there were several limitations of this study. Firstly, AHEAD was a single-arm phase IV study lack of control group. Additionally, subgroup analyses were not prespecified and should be considered during the interpretation of the data.