Effectiveness and safety of low‐dose apatinib in advanced gastric cancer: A real‐world study

Abstract Apatinib has been demonstrated to be effective and safe among patients with gastric cancer failing after at least two lines chemotherapy. This study aimed to evaluate its effectiveness and safety of low‐dose apatinib for the treatment of gastric cancer in real‐world practice. We performed a prospective, multicenter observation study in a real‐world setting. Patients with advanced gastric cancer more than 18 years old were eligible and received low‐dose apatinib (500 mg or 250mg per day) therapy. The median progression‐free survival (PFS), median overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Between September 2017 and April 2019, a total of 747 patients were enrolled. The mPFS was 5.56 months (95% CI 4.47‐6.28), and mOS was 7.5 months (95% CI 6.74‐8.88). Four patients achieved complete response, 47 achieved partial response, and 374 patients achieved stable disease. The ORR was 6.83% and DCR was 56.89%. In addition, multivariate Cox regression analysis indicated that hand‐foot syndrome was one independent predictor for PFS and OS. The most common adverse events (AEs) at any grade were hypertension (36.55%), proteinuria (10.26%), hand‐foot syndrome (33.53%), fatigue (24.9%), anemia (57.35%), leukopenia (44.49%), thrombocytopenia (34.21%), and neutropenia (53.33%). Grade 3‐4 AEs with incidences of 5% or greater were anemia (13.97%), thrombocytopenia (7.14%), and neutropenia (6.67%). No treatment‐related death was observed during the treatment of apatinib. The prospective study suggested that low‐dose apatinib was an effective regimen for the treatment of advanced gastric cancer with tolerable or controlled toxicity in real world. Trial registration: NCT03333967.


| INTRODUCTION
Gastric cancer is one of the most common digestive system malignancy, with high morbidity and mortality worldwide, which is next only to lung cancer and liver cancer. 1 For the early stage patients, surgery is the best treatment, however, approximately 80% of patients are initially diagnosed incurable due to locally advanced or metastatic gastric cancer. 2 With the development of chemotherapeutic drugs, targeted drugs, and immunotherapy, the median survival of advanced gastric cancer has been extended to more than 12 months. 3 However, the survival rate of 5 years remain poor with <10%. 2 Thus, exploring novel therapy strategies are necessary.
Angiogenesis has been investigated widely and known as its contribution to initial and development of tumor. 4 Vascular endothelial growth factor receptors (VEGFR), including VEGFR-1, VEGFR-2, VEGFR-3, and VEGFR-4, have been demonstrated to bind the vascular endothelial growth factor (VEGF) family to motivate angiogenesis signal pathway, and function important role as critical regulators of angiogenesis. 4 Apatinib, as a specifically targeting VEGFR-2 and oral receptor tyrosine kinase inhibitor, has been shown that it could inhibit the angiogenesis of tumor through prohibiting VEGFpromoted tumor development. Also, Li et al have reported that apatinib expressively advanced overall survival (OS) and PFS with tolerable toxicities in chemotherapy-refractory advanced gastric cancer after failing at least two lines chemotherapy in the randomized, double-blind, placebo-controlled phase III trial and a randomized, placebo-controlled, parallel-arm, phase II trial, 5,6 but the dose of 850 mg daily or 425 mg twice a day in the two trials resulted in many severe adverse events in clinical practice. Additionally, the dosage of 500 mg daily in clinical practice was commonly used mainly due to the concern of potential grade 3-4 adverse events such as hypertension, proteinuria, and hand-foot syndrome.
Preliminary data of this present have been released in ASCO 2019 (Abstract, 161) 7 and ESMO 2018 Congress (683P). 8 So, we further analyzed this prospective observation study in order to provide more clinical proof for the use of low-dose apatinib in patients with advanced gastric cancer.

Abstract
Apatinib has been demonstrated to be effective and safe among patients with gastric cancer failing after at least two lines chemotherapy. This study aimed to evaluate its effectiveness and safety of low-dose apatinib for the treatment of gastric cancer in real-world practice. We performed a prospective, multicenter observation study in a real-world setting. Patients with advanced gastric cancer more than 18 years old were eligible and received low-dose apatinib (500 mg or 250mg per day) therapy.
No treatment-related death was observed during the treatment of apatinib. The prospective study suggested that low-dose apatinib was an effective regimen for the treatment of advanced gastric cancer with tolerable or controlled toxicity in real world.

K E Y W O R D S
advanced gastric cancer, apatinib, real-world 5010 | DU et al.

| Patients
Patients receiving apatinib were included in this study from 23 centers in China. All men or women older than 18 years of age who pathologically or histologically confirmed advanced or metastatic adenocarcinoma of stomach were included. Patients with pregnancy or lactation, those with contraindications or allergy for apatinib, and those unsuitable to this study were excluded. All patients provided written informed consent before participating in the study. This study was approved by the local ethics committee of all hospitals.

| Study design and treatment
This was a prospective, multicenter observation study in a real-world setting. All patients received apatinib therapy by an oral administration once a day and the dose (500 mg or 250 mg) could be adjusted according to patient's performance status or adverse event.

| Efficacy and safety
Clinical responses were evaluated by computed tomography (CT) or magnetic resonance imaging (MRI) until disease progression. The responses were classified as complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. The objective response rate (ORR) or disease control rate (DCR) was computed as the addition of CRs plus PRs or CRs plus PRs plus SDs, respectively. Survival status was followed up every 3 months to analyze the PFS and OS. The PFS or OS was defined as time from the start of apatinib administration until disease progression or death of any cause death according to RECIST 1.1, respectively. All treatment-related adverse events (AEs) were defined and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

| Statistical analyses
The Kaplan-Meier method and log-rank test were used to analyze the PFS and OS. Multivariate analyses were performed with the Cox's proportional hazards regression model to explore the potential factors for PFS and OS. All the statistical analyses were performed using SAS 9.2 software (SAS Institute).

| Patient characteristics
Between September 1, 2017 and April 15, 2019, 747 patients with advanced gastric cancer who received the treatment of apatinib were included in the FAS population. The patients' characteristics were shown in Table 1
An exploratory univariate analysis was carried out by the Kaplan-Meier analysis and log-rank test. We found that there were significant association between the mPFS and combined therapy, apatinib suspension, number of metastases sites, and hand-foot syndrome (all P < .05). Also, there were also significant association of mOS with combined therapy, dose adjustment, clinical stage, previous surgery history, hypertension, proteinuria, and hand-foot syndrome (all P < .05). We also observed that apatinib treatment lines were not significantly associated with mPFS and mOS. Detailed results of univariate analysis were shown in Table 4.
In addition, as shown in Table 5, multivariate Cox regression analysis indicated that hand-foot syndrome was one independent predictor for PFS and OS. Also, combination regimen (apatinib plus taxol/docetaxel) was also one independent predictor for PFS.

| DISCUSSION
Patients with advanced gastric cancer generally showed dismal prognoses. Two-drug regimens or three-drug regimens from fluoropyrimidine-based and platinum-based chemotherapies have been used as the standard therapy of first line. [9][10][11] For HER2-positive advanced gastric or gastroesophageal junction (GEJ) cancer, trastuzumab in combination with chemotherapy dramatically extended the OS of the patients and might be a fresh standard therapy for this disease. 12 For second-line therapy for gastric cancer, chemotherapeutic agents such as paclitaxel and irinotecan and antiangiogenic targeted agents such as ramucirumab have been recommended by NCCN guideline. 13 The second-line chemotherapy achieved an mOS of 5.8-9.5 months and an mPFS of 2.2-3.6 months. 14 Ramucirumab monotherapy or combination with paclitaxel benefits patients with the mOS of 5.2-9.6 months. 15 Apatinib has been approved in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or GEJ as third-or furtherline treatment in China based on the results of a II and III trials, which showed the benefits of mPFS (2.6 months vs 1.8 months, P < .001) and mOS (6.5 months vs 4.7 months, P = .0149) compared with placebo control. 5,6 In this real-world study, our results showed that the mPFS was 5.56 months (95% CI 4.47-6.28), and mOS was 7.5 months (95% CI 6.74-8.88), the DCR and ORR was 56.89% and 6.83%, respectively. These data were better than the previous studies. For example, Li et al observed that apatinib achieved an mPFS of 2.6-3.67 months and mOS of 4.27-6.5 months in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or GEJ in a phase II trial and III trial. 5,6 In addition, in a real-world study, Zhang et al found that apatinib achieved an mPFS of 2.65 months, an mOS of 5.8 months, and ORR of 5.6% and DCR of 58.3% in 36 patients with advanced gastric adenocarcinoma or adenocarcinoma of GEJ after failing at least two lines of systemic therapy. 16

Variable
Number mPFS (m) P mOS (m) P In addition, univariate analysis found that mPFS and mOS were significantly associated with combined therapy and handfoot syndrome. Combination with chemotherapy included apatinib plus taxol/docetaxel, XELOX, 5-FU, DCF, and EOX regimen, which would improve the survival of patients.
To exclude the effect of the confounders for survival outcome, we further performed the Cox regression analysis and found that apatinib plus taxol/docetaxel and handfoot syndrome were independent significant factors to affect the PFS and hand-foot syndrome was only one independent significant factor to influence the OS. Li et al reported that apatinib treatment prolonged progression-free survival and lead to improved OS. 17 Interestingly, we did not observe the apatinib plus taxol/docetaxel affect the OS by Cox regression analysis. Hand-foot syndrome has been recognized as a viable biomarker of antitumor efficacy and was associated with prolonged mOS and prolonged mPFS in previous study, 18 consistently with our data.
In this study, apatinib was prescribed at a low dose of 500 mg or 250mg a day initially, which was lower than the previous reported dose in gastric cancer (850 mg daily or 425 mg twice a day) 5,6 ; and a large number of studies have also demonstrated that the dose of apatinib 500 mg per day is effective in other solid tumors, such as thyroid cancer, breast cancer, sarcoma, lung cancer, hepatocellular carcinoma. Thus, this real-world study further provided the clinical implication for the use of low-dose apatinib in gastric cancer.

| CONCLUSION
Taken together, the prospective study suggested that low-dose apatinib was an effective regimen for advanced gastric cancer with manageable toxicity in the real-world study.