Apatinib demonstrated an improvement in overall survival by 1.8 months and an acceptable toxicity profile compared to placebo as treatment for advanced gastric cancer.
Apatinib demonstrated an improvement in overall survival (OS) by 1.8 months and an acceptable toxicity profile compared to placebo as treatment for advanced gastric cancer, according to findings published in theJournal of Clinical Oncology.1
The randomized, double-blind, phase III trial, which was conducted at 32 centers in China, assessed the safety and efficacy of apatinib, a VEGFR-2 tyrosine kinase inhibitor (TKI), in patients with advanced metastatic gastric cancer who have experienced progression after receiving two or more lines of chemotherapy.
Between January 2011 and November 2012, a total of 273 patients ages 18-70 were randomly assigned at a 2:1 ratio to receive either 850 mg of oral apatinib or apatinib-matching placebo tablets.
Due to some patient attrition, 267 randomly assigned patients who received at least 1 dose of study medication were ultimately included in the full analysis set. The primary end points were overall survival (OS) and progression-free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), and quality of life (QoL).
In the apatinib arm of the study, patients received an average of 2.9 cycles of their medication. Patients in the placebo arm received 1.89 cycles of medication on average.
Mean OS was 6.5 months (95% CI, 4.8 to 7.6) for patients in the apatinib group and 4.7 months (95% CI, 3.6 to 5.4) for patients in the placebo group (P = .0149). The mean PFS was 2.6 months (95% CI, 2.0 to 2.9) for patients treated with apatinib and 1.8 months (95% CI, 1.4 to 1.9) for patients that received the placebo treatment (HR, 0.455; 95% CI, 0.332 to 0.624; P < .001).
At the time of data cutoff, 224 patients had died, which included 146 (83%) in the apatinib group and 78 (85.7%) in the placeo group. This represents 83.9% of the total number of events for the final analysis of OS.
The number of metastatic sites was the strongest predictor of survival, according to a multivariate analysis using the Cox model with inclusion of pre-specified factors.
In terms of results related to the secondary endpoints, the ORR was 2.84% with apatinib versus 0% with placebo. The DCR was significantly higher in the apatinib group (42.05%) than in the placebo group (8.79%, P < .001).
At the initial stage of the study, 14 patients in the placebo group crossed over to the apatinib group for further treatment after disease progression.
These results are consistent with those found in the preceding phase II study, which demonstrated a mean OS of 4.8 months for apatinib, which was 2.3 months longer than that of patients in the placebo arm.
In terms of safety results, dose modifications resulting from toxicity were more common with apatinib than with placebo (21% versus 3.3%). Dose reduction was largely attributed to hand-foot skin reaction (HFSR), proteinuria, and hypertension.
Results showed that grade 3 to 4 HFSR occurred more often in patients treated with apatinib than in patients who received the placebo treatment (8.5% versus 0%; P = .0032). Grade 3 to 4 hypertension and proteinuria occurred in 4.5% and 2.3% of patients in the apatinib group, respectively.
On the basis of this phase III study, apatinib was approved in October 2014 by the China Food and Drug Administration as a treatment for metastatic gastric or gastroesophageal junction adenocarcinoma after second-line chemotherapy.
As the third leading cause of cancer-related death worldwide, gastric cancer is commonly characterized by a very short overall survival, thus underscoring a critical need for new treatment options.
First-, second-, and even third-line chemotherapy treatments have been shown to provide survival benefit to patients with advanced or metastatic gastric cancer, but currently, these are not widely accepted standard treatments.
While several recent lines of research have assessed the effectiveness of various antiangiogenic agents in advanced or metastatic gastric or gastroespohageal junction carcinoma, apatinib appears to be the most promising monotherapy agent. Moreover, apatinib remains active as a type of rescue therapy in heavily treated patients who have failed 2 or more lines of chemotherapy.
Beyond the current research, biomarkers could be used to identify patients who are most likely to benefit from these angiogenesis inhibitors, said study authors. A biomarker study of apatinib in patients with breast cancer demonstrated that both hypertension and high expression of phosphorylated VEGFR-2 could serve as possible biomarkers for treatment efficacy.