Safety and efficacy of apatinib in patients with advanced gastric or … – BMC Medicine

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 4.7months, hazard ratio=0.709; median PFS, 2.6 vs 1.8months, hazard ratio=0.444). Apatinib showed an ORR of 2.84% and a DCR of 42.05% [6].

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 [6], such as 96% of patients with clinical IV staging and 34% of patients with metastatic lesions involving more than two organs. The study findings support that apatinib can bring clinical benefits to such patients without an increased risk of drug-related adverse events.

The overall toxicity profile in the AHEAD study was consistent with that in previous studies of apatinib [5, 6], with no new safety signals identified. The incidence of TRAEs and grade3 TRAEs in the AHEAD study was similar to that reported in the phase III study of apatinib [6]. Furthermore, the incidence and severity of grade3 TRAEs and TRSAEs did not vary broadly between patients with ECOG PS of 23 and those of 01, suggesting that apatinib was also tolerable in patients with poor ECOG PS.

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 [11], ramucirumab [12, 13], sorafenib [13], lenvatinib [14], and apatinib [6]. Interestingly, a previous study of post-hoc analyses of the phase III trial of apatinib in advanced gastric cancer demonstrated that the presence of hypertension, proteinuria, or hand-foot syndrome correlated with statistically significant and clinically meaningful outcomes [15]. Hypertension was the most common TRAEs in the AHEAD study. The grade3 hypertension incidence was relatively higher in the AHEAD study than in the phase III study of apatinib (25% vs 5%). However, only 15 (1%) of hypertension events necessitated permanent discontinuation of apatinib, indicating that apatinib-related hypertension was well-controlled. Proteinuria may be caused by inhibiting the VEGF signaling pathway in pedal cells and mesangial cells in glomerular [16, 17] and represented the second most common TRAEs in the AHEAD study, with a low incidence of grade3 proteinuria (4%). In 17% of patients, hand-foot syndrome occurred, but 3% reported grade3 events. A low incidence of dose reduction or permanent discontinuation of apatinib was required to manage hand-foot syndrome in the AHEAD study. Furthermore, most hypertension events, proteinuria events, and hand-foot syndrome events recovered or improved, and none of the death occurred due to these events. The AHEAD data provide up-to-date evidence that the presence and development of hypertension, proteinuria, and hand-foot syndrome should not be considered barriers for patients with advanced gastric cancer when treated with apatinib.

Bleeding is considered a major safety concern for anti-VEGF/VEGFR agents [12, 18, 19]. In this trial, the majority of bleeding events were grade 1 to 2 laboratory abnormalities (15%). Clinically significant (grade3) bleeding events occurred in 5% of patients, which was slightly higher than that reported in the previous trial of apatinib in advanced gastric cancer (3%) [6]. Among these bleeding events, 4% of patients had grade3 gastrointestinal hemorrhage, and 23 (1%) patients reported grade 5 gastrointestinal hemorrhage. Apatinib was temporarily interrupted in 10% of bleeding events and permanently discontinued for 11%, suggesting most bleeding events were managed with the standard clinical procedure. Gastrointestinal hemorrhage is not unusually occurring in patients with advanced gastric cancer and may represent the progression of the disease. But these data remind us that a more cautious assessment for the risk of gastrointestinal hemorrhage should be performed in patients planning to receive apatinib, and more careful monitoring and immediate management are needed during apatinib treatment.

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 grade3 hepatobiliary diseases, resulting in five deaths. Although the incidence of grade3 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 5.8months, slightly shorter than that reported in a previous study (6.5months) [6]. The efficacy in the AHEAD study might be potentially underestimated due to the inclusion of patients with ECOG PS of 2 and a higher rate of patients with more than two metastatic sites. The median OS in the AHEAD study was consistent with that of the TAGS study. A median OS of 5.7months was achieved with trifluridine/tipiracil over 3.6months with placebo (hazard ratio 0.69, 95% CI 0.560.85, p=0.00058) [9]. Notably, the median OS of apatinib in the AHEAD study was slightly higher than that of nivolumab for advanced gastric cancer as a third-line treatment [20]. At the same time, the results should be interpreted cautiously since the head-to-head comparison was not performed.

Our data also allowed for the identification of patients with a better prognosis. OS was shorter in patients with ECOG PS of 23 versus 01 and patients with>2 versus2 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 [6]. Furthermore, the results of subgroup analyses according to baseline characteristics supported the interpretation of the lower OS observed in this study compared to the phase III study.

Apatinib was dosed at 850mg once daily in the phase III study. Therefore, in the AHEAD study, apatinib was recommended at an initial dose of 850mg, while the starting dose was decided by the investigators choice. A total of 98% of patients initiated apatinib at 500mg, and subgroup analysis found the initial dose of apatinib did not affect OS or PFS. Notably, patients treated with an initial dose of500mg of apatinib had similar OS and PFS outcomes to those treated with an initial dose of 850mg of apatinib in the phase III study [6]. In the phase III trial of apatinib in the treatment of advanced hepatocellular carcinoma (AHLEP) [21], the initial dose was recommended at 750mg, while 45% of patients reduced apatinib to 500mg due to adverse events. We analyzed the daily exposure of apatinib in the AHEAD study. The median daily exposure of apatinib was also 500mg, without obvious implication on OS or PFS. The AHEAD study showed comparable toxicity results with the phase III study of apatinib [6]. These results suggested that a starting dose of 500mg in clinical practice had an acceptable toxicity profile and had no impact on efficacy compared with 850mg. A starting dose of 500mg of apatinib is recommended in clinical settings for patients with gastric or gastroesophageal junction adenocarcinoma.

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.

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Safety and efficacy of apatinib in patients with advanced gastric or ... - BMC Medicine