Drug Evaluation
Apatinib for the treatment of gastric cancer
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Queen's University on 01/05/15 For personal use only.
Ruixuan Geng & Jin Li† †
1.
Introduction
2.
Introduction to apatinib
3.
Clinical efficacy
4.
Safety and tolerability
5.
Regulatory affairs
6.
Conclusion
7.
Expert opinion
Fudan University Shanghai Cancer Center, Shanghai Medical College, Department of Medical Oncology, Shanghai, China
Introduction: Antiangiogenesis therapy plays an important role in cancer treatment. Apatinib mesylate, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has been recommended as third-line treatment for metastatic gastric cancer patients. Areas covered: The current review summarizes the publications and conference reports relating to apatinib from preclinical and clinical research in gastric cancer. Apatinib showed good safety, tolerance and treatment efficacy in Phase I/II studies. In a Phase III study, apatinib prolonged the median overall survival of patients with chemotherapy-refractory metastatic gastric cancer by 55 days and the median progression-free survival by 25 days compared with placebo. Expert opinion: Apatinib is a new treatment option for advanced gastric cancer. Apatinib is expected to have a broader application when it has been evaluated worldwide. The key issues are to find biomarkers and overcome drug resistance. Keywords: apatinib, stomach neoplasms, tyrosine kinase inhibitor, VEGF receptor-2 Expert Opin. Pharmacother. (2015) 16(1):117-122
1.
Introduction
Angiogenesis plays an important role in the growth and metastasis of malignant tumors. Ever since Folkman et al. raised the concept of antiangiogenic therapy in the 1970s [1], this treatment has been widely accepted as an effective anticancer strategy. Antiangiogenic therapy mainly targets VEGF or its receptor VEGFR. The VEGF family includes VEGF-A to E and placenta growth factor 1 and 2, whereas the VEGFR family includes VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), VEGFR-3 (Flt-4), and VEGFR co-receptors neuropilin 1 and 2 [2]. Many VEGF/ VEGFR inhibitors, including bevacizumab, ramucirumab, aflibercept, sunitinib, sorafenib, regorafenib and axitinib, have proven activity against different solid tumors. Gastric cancer is one of the indications for VEGF/VEGFR-targeted therapy based on the angiogenic evidence [3,4]. Gastric cancer is the fourth most common malignant tumor and ranks as the second leading cause of cancer-related mortality, with a survival time of 3 -- 5 months if left untreated [5-7]. Although first-line chemotherapy provided a 6-month survival benefit for patients with advanced gastric cancer, second-line chemotherapy with irinotecan or docetaxel added only ~ 1.5 months to the overall survival (OS) compared with best supportive care [8-11]. There is no standard third-line treatment if second-line chemotherapy fails. The need for treatments providing extended survival led to the investigation of targeted therapy, including antiangiogenic strategies. Indeed, antiangiogenesis treatment has shown efficacy and safety in advanced gastric cancer in several Phase III trials. In the past decade, many clinical studies have been performed to investigate targeted therapy for advanced gastric cancer. However, most of the therapies failed to provide efficacy. Although trastuzumab achieved 2.7 months improvement in OS 10.1517/14656566.2015.981526 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description/mechanism of action Route of administration Chemical structure
Apatinib mesylate (YN968D1) Approved Advanced gastric cancer after failure of second-line chemotherapy A selective small molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor Oral
CN
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O
N H N
NH -CH3SO3H
N
Pivotal trials
[24-26]
when added to chemotherapy in patients with tumors overexpressing human epidermal growth factor receptor-2 (HER-2), other novel agents, including cetuximab, panitumumab, and everolimus, failed to show superiority compared with a control regimen for metastatic gastric cancer [12-17]. However, antiangiogenic therapies may signal a new era for the treatment of advanced gastric cancer, with attractive data from several Phase III studies [18,19]. The anti-VEGFR-2 monoclonal antibody ramucirumab has been shown to be effective in treating chemotherapyrefractory advanced gastric or gastroesophageal junction adenocarcinoma [18]. A further Phase III clinical trial, RAINBOW, found that patients in the ramucirumab plus paclitaxel arm lived 2.2 months longer than those in the placebo plus paclitaxel arm [19]. Recently, oral apatinib has shown good safety and efficacy results for heavily treated patients in a Phase III clinical trial. Apatinib is the first oral VEGFR tyrosine kinase inhibitor to show active control of tumor growth in gastric cancer. The Phase II/III studies of apatinib suggest that apatinib could be a new option for the treatment of advanced metastatic gastric cancer. 2.
Introduction to apatinib
Chemistry Apatinib mesylate is a small molecule tyrosine kinase inhibitor targeting VEGFR-2. The structure of apatinib is similar to that of vatalanib (PTK787), on which its synthesis is based. The main hexatomic ring has remained intact, whereas the benzene ring has been changed to a pyridine group to increase the hydrophilicity of the molecule and, consequently, increase the water solubility and permeability of the drug. The picolyl 2.1
118
and the para-substituents in the benzene ring have been retained and multiple fatty acid rings have been introduced to increase the lipophilicity and improve the interaction and binding of the drug to receptors (Box 1). Pre-clinical studies In vitro, apatinib inhibited proliferation and migration of human umbilical vein endothelial cells and tube formation induced by VEGF, and the budding of rat aortic rings [20]. In vivo, apatinib showed good inhibitory effects on various tumors implanted into nude mice, including colon and gastric cancer. Moreover, apatinib significantly improved the efficacy of traditional chemotherapy drugs such as oxaliplatin, 5-fluorouracil, docetaxel, and doxorubicin in vivo [20]. Apatinib also reversed multidrug resistance through the inhibition of ABCB-1 and ABCG-2 excretion [21] and improved the killing effect of doxorubicin on leukemia cells and side population cells with ABCB-1 overexpression [22]. 2.2
Pharmacodynamics and pharmacokinetics Apatinib selectively inhibits VEGFR-2 with a 50% median inhibitory concentration (IC50) of 0.001 µM. When VEGFR-2 is inhibited, downstream p-erk is also blocked. Moreover, apatinib also has selective inhibition effects on Ret, c-kit, and c-SRC with IC50 of 0.013, 0.429, and 0.53 µM, respectively. However, apatinib has little effect on inhibiting EGFR, HER-2, or FGFR1 [20]. The bioavailability of apatinib through oral intake is between 10 and 20% (Dr. Liguang Lou; Unpublished data; 2008). Ninety-six hours after oral intake of apatinib, excretion of the drug was 76.8%, with 69.8% in feces and 7.0% in urine. The excreted drug in feces was mainly intact and had not been metabolized, whereas that in the urine had been 2.3
Expert Opin. Pharmacother. (2015) 16(1)
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Apatinib
almost completely metabolized [23]. The binding efficiencies of apatinib to multiple plasma proteins (in rats, canines, monkeys and humans) range from 86 -- 93% (Dr. Liguang Lou; Unpublished data; 2008). Under treatment with the enzymes CYP3A4/5, CYP2C9, CYP2D6, CYP2E1, or UGT2B7, apatinib has four types of metabolites: cis-3-hydroxy-apatinib (M1-1), trans-3-hydroxy-apatinib (M1-2), apatinib-25-Noxide (M1-6), and cis-3-hydroxy-apatinib-O-glucuronide (M9-2), with M9-2 as the main metabolite [23]. A Phase I clinical trial investigated the pharmacokinetics of apatinib in single and multiple dose evaluations. In the singledose evaluation, 28 patients were divided into three groups according to drug doses of 500 mg (n = 8), 750 mg (n = 12), and 850 mg (n = 8). 3 -- 4h after oral apatinib intake, the plasma drug concentration reached the peak. The mean maximum plasma drug concentration (Cmax) of the three groups were 1521, 2379 and 2833 ng/ml, respectively, and the areas under the concentration-time curve 0--24 h (AUC0-24h) were 11295, 18172, and 21975 ng·h/ml, respectively. The Cmax and AUC0 -- 24h both showed dosedependent increases with significant individual differences. The elimination half-life of apatinib was 9 h, which was consistent among the three groups. In the 750 mg group, 11 patients enrolled in the multiple dosing study and received apatinib 750 mg daily. Plasma drug concentrations were titrated at days 1, 6, 28, and 56. The results showed that both Cmax and AUC0 -- 24h at day 6 were higher than those at day 1, but there were no further increases after day 6, indicating that apatinib has little accumulation in patients [24]. 3.
Clinical efficacy
Phase I and II studies The Phase I study of apatinib recruited 46 patients with advanced solid tumors for whom no standard treatment was available. Among the 46 patients, 34 had gastrointestinal cancer, 3 had lung cancer, 3 had breast cancer, and 6 had other types of cancer. Apatinib 250, 500, 750, 850 or 1000 mg per day was given using the standard 3 + 3 doseescalation method. The study found that the maximum tolerated dose of apatinib was 850 mg/day and a dose of 750 mg/ day was chosen for the anti-tumor study [24]. Of 37 evaluable patients, 7 achieved partial response (PR), including 3 with colon cancer, 1 with gastric cancer, 1 with gastrointestinal stromal tumor, 1 with kidney cancer and 1 with an unknown primary cancer. Twenty-four patients were defined as having stable disease and the disease control rate (DCR) was 83.8% [24]. Li et al. conducted a multi-center, Phase II, clinical study of apatinib and recruited 144 patients with advanced metastatic gastric cancer in whom second-line or above chemotherapy had failed. Patients were randomly assigned to receive placebo (group A, n = 48), oral apatinib 850 mg once daily (q.d.; group B, n = 47), or oral apatinib 425 mg twice daily (b.i.d.; group C, n = 46). The primary end point was 3.1
progression-free survival (PFS). The median age of the patients was 54, 55, and 53 years, respectively, and male patients were 75, 83, and 74%, respectively. The Eastern Cooperative Oncology Group performance status scores of all patients were 0 -- 1. Metastatic sites were the liver (48, 60, 43% for groups A, B, and C, respectively), lung (19, 11, and 24%, respectively), and retroperitoneal lymph nodes (23, 19, and 24%, respectively). The median PFS (mPFS) for groups A, B, and C were 1.4 months (95% confidence interval [CI], 1.20 -- 1.83 months), 3.7 months (95% CI, 2.17 -- 6.80 months) and 3.2 months (95% CI, 2.37 -- 4.53 months), respectively. The median OS (mOS) for groups A, B and C were 2.5 months (95% CI, 1.87 -- 3.70 months), 4.83 months (95% CI, 4.03 -5.97 months) and 4.27 months (95% CI, 3.83 -4.77 months), respectively. Compared with group A, the mPFS and mOS of groups B and C were significantly prolonged (mPFS: group B vs group A, p < 0.001, group C vs group A, p < 0.001; mOS: group B vs group A, p < 0.001, group C vs group A, p = 0.0017). In the objective response rate (ORR) assessment, 9 patients (3 from group B and 6 from group C) achieved PR. In the DCR assessment, intent-to-treat analysis found that groups B and C had higher DCRs than group A: group A, 5 patients (10.42%); group B, 24 patients (51.06%); and group C, 16 patients (34.78%) [25]. Phase III studies A multi-center, randomized, double-blind, placebocontrolled Phase III study of apatinib has recently been completed. A total of 273 patients were randomly assigned to oral apatinib 850 mg q.d. (28-day treatment cycles) or placebo at a ratio of 2:1. The primary end point was OS. Patients receiving apatinib had significantly prolonged mOS (195 vs 140 days; hazard ratio [HR] = 0.71; 95% CI, 0.54 -- 0.94; p < 0.016) and mPFS (78 vs 53 days; HR = 0.44; 95% CI, 0.33 -- 0.61; p < 0.0001) compared with those receiving placebo. The ORRs for the apatinib and placebo groups were 2.84 and 0.00%, respectively [26]. 3.2
4.
Safety and tolerability
Apatinib is an oral drug with a good safety profile. During the Phase I clinical trial of 37 evaluable patients, the three most common adverse events (AEs) were hypertension (69.5%, n = 3 for grade 3 -- 4), proteinuria (47.8%, n = 6 for grade 3 -- 4), and hand-foot syndrome (45.6%, n = 6 for grade 3 -- 4). After the treatment stopped, these reactions were alleviated to some degree. Other minor AEs included pain, thrombocytopenia, fatigue and hyperbilirubinemia. In the group receiving apatinib 1000 mg q.d., two patients demonstrated dose-limiting toxicity; namely, grade 4 hematologic AEs or grade 3 -- 4 non-hematologic AEs. Among the 37 patients, 15 completed at least 1 week of apatinib treatment at the original doses, 1 from the apatinib 250 mg q.d. group withdrew due to disease progression, and 3 from the
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apatinib 1000 mg q.d. group withdrew because of AEs, whereas the remaining 18 patients completed the study with decreased dosing [24]. Apatinib also showed acceptable tolerability in a Phase II study. Grade 3 -- 4 AEs occurring in > 5% of patients included hand--foot syndrome, hypertension, thrombocytopenia, anemia, liver function impairment (elevated aminotransferase and bilirubin) and diarrhea. Grade 3 -- 4 AEs reported in > 10% of patients were hand--foot syndrome and high blood pressure. Fatigue, a common symptom among patients with advanced tumors, was present for 10.4, 17.0, and 15.2% of patients in the placebo, apatinib 850 mg q.d., and apatinib 425 mg b.i.d. groups, respectively. Severe fatigue (grade 3 -- 4) was present at a rate of ~ 2% in each of the 3 groups [25]. A Phase III clinical study further reinforced the general tolerability of apatinib. About 60% of patients experienced grade 3 -- 4 AEs, which included hypertension, hand--foot syndrome, proteinuria, fatigue, anorexia and elevated aminotransferase. The rate of grade 3 -- 4 AEs in the apatinib arm was significantly higher than that in the placebo arm (41%, p = 0.0045), whereas no significant difference in severe AEs was observed between the two groups. The AEs were manageable and reversible, and patients were treated with symptomatic therapy and dose interruptions or reductions [26]. 5.
Regulatory affairs
Based on the results of a Phase III clinical trial in China, apatinib has been approved by the Chinese Food and Drug Administration recently. 6.
Conclusion
To date, there has been no standard treatment strategy for patients with advanced metastatic gastric cancer who have failed at least two chemotherapeutic regimens. The development of apatinib has shown the potential of the antiVEGFR-2 strategy in the treatment of patients with advanced metastatic gastric cancer. As a novel oral small molecule VEGFR-2 inhibitor, apatinib has demonstrated good safety, tolerability and efficacy in these patients. Given the positive results obtained in the Phase III clinical study, apatinib offers a new option for patients with advanced metastatic gastric cancer. 7.
Expert opinion
The results for apatinib in the Phase III study are definitely exciting. For patients with advanced metastatic gastric cancer, the total OS is about 1 year, and treatment with apatinib could prolong survival by nearly 2 months when patients have previously failed with second-line chemotherapy. As anti-VEGFR-2 drugs, ramucirumab and apatinib share some 120
similarities. In the REGARD and the Phase III apatinib studies of patients with previously treated gastric cancer, both drugs achieved > 1 month mOS (1.8 and 1.4 months for ramucirumab and apatinib, respectively) and mPFS of 0.8 months (for both drugs). The difference between the two studies is that apatinib was given as third-line treatment and ramucirumab was given as second-line therapy. Heavily treated patients receiving apatinib seemed to experience more AEs than those receiving ramucirumab. It has been reported that the only AE in the ramucirumab group that occurred more commonly than in the placebo group was hypertension, whereas apatinib is associated with proteinuria, hypertension, and hand--foot syndrome. All toxicities occurring in apatinib-treated patients are related to antiangiogenesis, as reported previously for other VEGF/VEGFR inhibitors. There have been no new toxicities found for apatinib. In terms of patient populations, REGARD is a worldwide study that enrolled patients from 29 countries, including Caucasians and Asians. However, in the RAINBOW study, ramucirumab did not show additional survival benefit in the Asian population when compared with the control [27]. The Phase III clinical trial of apatinib was conducted in China. Its global significance is limited until it has been tested and proven to be effective in other populations. A Phase I clinical trial has therefore been started in the US and South Korea (NCT01726101) [28], which is recruiting participants currently. As bevacizumab failed to benefit survival in first-line treatment of gastric cancer [13,29], researchers are not optimistic about an anti-VEGF/VEGFR strategy in the first-line setting. It is widely accepted that any following treatment will dilute the marginal benefit of first-line treatment if OS is designated as a primary end point. This may be why there is no plan to conduct clinical trials in patients with previously untreated advanced gastric cancer. However, other indications for apatinib could be other previously treated solid tumors. Current clinical studies of apatinib in lung [30,31], breast [32] and liver [33] cancers have all been in the chemotherapy-refractory setting. A challenge to the use of apatinib is the need to find biomarkers to predict drug efficacy. A study of biomarkers for apatinib in breast cancer patients showed that both hypertension and high expression of p-VEGFR2 could be biomarkers for good treatment efficacy [34]. Moreover, in the biomarker analysis of the Avastin in Gastric Cancer trial, bevacizumab response was positively correlated with the levels of VEGF-A in plasma and neuropilin-1 in tumor tissue [35]. However, there has been no final outcome on finding biomarkers for antiangiogenesis drugs, although reliable biomarkers are of great importance, both for individualized treatment and for improving efficacy. Drug resistance is a problem encountered with every targeted therapy, and this does occur with apatinib. Drug resistance is especially important for patients who proceed to
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Apatinib
second-line or above chemotherapy because there are no further drugs available once resistance to apatinib occurs. Many studies of resistance of antiangiogenic agents have shown that resistance is mainly related to activation of cell adhesion-associated or other growth-associated signaling pathways [36,37], implying that blockage of these pathways may solve the problem. Solving the drug resistance issue would be a major benefit to antiangiogenic therapy.
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Mi YJ, Liang YJ, Huang HB, et al. Apatinib (YN968D1) reverses multidrug resistance by inhibiting the efflux function of multiple ATP-binding cassette transporters. Cancer Res 2010;70:7981-91
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Tong XZ, Wang F, Liang S, et al. Apatinib (YN968D1) enhances the efficacy of conventional chemotherapeutical drugs in side population cells and ABCB1overexpressing leukemia cells. Biochem Pharmacol 2012;83:586-97 Ding J, Chen X, Gao Z, et al. Metabolism and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor apatinib in humans. Drug Metab Dispos 2013;41:1195-210 Li J, Zhao X, Chen L, et al. Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies. BMC Cancer 2010;10:529 Phase I study of apatinib in advanced solid tumors. Li J, Qin S, Xu J, et al. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallelarm, phase II trial. J Clin Oncol 2013;31:3219-25 Phase II study of apatinib demonstrating benefit in chemotherapy-refractory advanced metastatic gastric cancer. Qin S. Phase III study of apatinib in advanced gastric cancer: A randomized, double-blind, placebo-controlled trial. J Clin Oncol 2014;32(15 Suppl):abstract 4003 Phase III study of apatinib demonstrating effectiveness in thirdline chemotherapy for advanced gastric cancer. Hironaka S, Shimada Y, Sugimoto N, et al. RAINBOW: a global, phase III, randomized, double-blind study of
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Affiliation
Ruixuan Geng1 MD & Jin Li†2 MD PhD † Author for correspondence 1 Fudan University Shanghai Cancer Center, Shanghai Medical College, Department of Medical Oncology, Shanghai 200032, China 2 Professor and Dean, Fudan University Shanghai Cancer Center, Shanghai Medical College, Department of Medical Oncology, Shanghai 200032, China Tel: +86 21 64433755; Fax: +86 21 64170366; E-mail: [email protected]
Apatinib for the treatment of gastric cancer
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Queen's University on 01/05/15 For personal use only.
Ruixuan Geng & Jin Li† †
1.
Introduction
2.
Introduction to apatinib
3.
Clinical efficacy
4.
Safety and tolerability
5.
Regulatory affairs
6.
Conclusion
7.
Expert opinion
Fudan University Shanghai Cancer Center, Shanghai Medical College, Department of Medical Oncology, Shanghai, China
Introduction: Antiangiogenesis therapy plays an important role in cancer treatment. Apatinib mesylate, a small molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2, has been recommended as third-line treatment for metastatic gastric cancer patients. Areas covered: The current review summarizes the publications and conference reports relating to apatinib from preclinical and clinical research in gastric cancer. Apatinib showed good safety, tolerance and treatment efficacy in Phase I/II studies. In a Phase III study, apatinib prolonged the median overall survival of patients with chemotherapy-refractory metastatic gastric cancer by 55 days and the median progression-free survival by 25 days compared with placebo. Expert opinion: Apatinib is a new treatment option for advanced gastric cancer. Apatinib is expected to have a broader application when it has been evaluated worldwide. The key issues are to find biomarkers and overcome drug resistance. Keywords: apatinib, stomach neoplasms, tyrosine kinase inhibitor, VEGF receptor-2 Expert Opin. Pharmacother. (2015) 16(1):117-122
1.
Introduction
Angiogenesis plays an important role in the growth and metastasis of malignant tumors. Ever since Folkman et al. raised the concept of antiangiogenic therapy in the 1970s [1], this treatment has been widely accepted as an effective anticancer strategy. Antiangiogenic therapy mainly targets VEGF or its receptor VEGFR. The VEGF family includes VEGF-A to E and placenta growth factor 1 and 2, whereas the VEGFR family includes VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), VEGFR-3 (Flt-4), and VEGFR co-receptors neuropilin 1 and 2 [2]. Many VEGF/ VEGFR inhibitors, including bevacizumab, ramucirumab, aflibercept, sunitinib, sorafenib, regorafenib and axitinib, have proven activity against different solid tumors. Gastric cancer is one of the indications for VEGF/VEGFR-targeted therapy based on the angiogenic evidence [3,4]. Gastric cancer is the fourth most common malignant tumor and ranks as the second leading cause of cancer-related mortality, with a survival time of 3 -- 5 months if left untreated [5-7]. Although first-line chemotherapy provided a 6-month survival benefit for patients with advanced gastric cancer, second-line chemotherapy with irinotecan or docetaxel added only ~ 1.5 months to the overall survival (OS) compared with best supportive care [8-11]. There is no standard third-line treatment if second-line chemotherapy fails. The need for treatments providing extended survival led to the investigation of targeted therapy, including antiangiogenic strategies. Indeed, antiangiogenesis treatment has shown efficacy and safety in advanced gastric cancer in several Phase III trials. In the past decade, many clinical studies have been performed to investigate targeted therapy for advanced gastric cancer. However, most of the therapies failed to provide efficacy. Although trastuzumab achieved 2.7 months improvement in OS 10.1517/14656566.2015.981526 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication Pharmacology description/mechanism of action Route of administration Chemical structure
Apatinib mesylate (YN968D1) Approved Advanced gastric cancer after failure of second-line chemotherapy A selective small molecule vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor Oral
CN
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O
N H N
NH -CH3SO3H
N
Pivotal trials
[24-26]
when added to chemotherapy in patients with tumors overexpressing human epidermal growth factor receptor-2 (HER-2), other novel agents, including cetuximab, panitumumab, and everolimus, failed to show superiority compared with a control regimen for metastatic gastric cancer [12-17]. However, antiangiogenic therapies may signal a new era for the treatment of advanced gastric cancer, with attractive data from several Phase III studies [18,19]. The anti-VEGFR-2 monoclonal antibody ramucirumab has been shown to be effective in treating chemotherapyrefractory advanced gastric or gastroesophageal junction adenocarcinoma [18]. A further Phase III clinical trial, RAINBOW, found that patients in the ramucirumab plus paclitaxel arm lived 2.2 months longer than those in the placebo plus paclitaxel arm [19]. Recently, oral apatinib has shown good safety and efficacy results for heavily treated patients in a Phase III clinical trial. Apatinib is the first oral VEGFR tyrosine kinase inhibitor to show active control of tumor growth in gastric cancer. The Phase II/III studies of apatinib suggest that apatinib could be a new option for the treatment of advanced metastatic gastric cancer. 2.
Introduction to apatinib
Chemistry Apatinib mesylate is a small molecule tyrosine kinase inhibitor targeting VEGFR-2. The structure of apatinib is similar to that of vatalanib (PTK787), on which its synthesis is based. The main hexatomic ring has remained intact, whereas the benzene ring has been changed to a pyridine group to increase the hydrophilicity of the molecule and, consequently, increase the water solubility and permeability of the drug. The picolyl 2.1
118
and the para-substituents in the benzene ring have been retained and multiple fatty acid rings have been introduced to increase the lipophilicity and improve the interaction and binding of the drug to receptors (Box 1). Pre-clinical studies In vitro, apatinib inhibited proliferation and migration of human umbilical vein endothelial cells and tube formation induced by VEGF, and the budding of rat aortic rings [20]. In vivo, apatinib showed good inhibitory effects on various tumors implanted into nude mice, including colon and gastric cancer. Moreover, apatinib significantly improved the efficacy of traditional chemotherapy drugs such as oxaliplatin, 5-fluorouracil, docetaxel, and doxorubicin in vivo [20]. Apatinib also reversed multidrug resistance through the inhibition of ABCB-1 and ABCG-2 excretion [21] and improved the killing effect of doxorubicin on leukemia cells and side population cells with ABCB-1 overexpression [22]. 2.2
Pharmacodynamics and pharmacokinetics Apatinib selectively inhibits VEGFR-2 with a 50% median inhibitory concentration (IC50) of 0.001 µM. When VEGFR-2 is inhibited, downstream p-erk is also blocked. Moreover, apatinib also has selective inhibition effects on Ret, c-kit, and c-SRC with IC50 of 0.013, 0.429, and 0.53 µM, respectively. However, apatinib has little effect on inhibiting EGFR, HER-2, or FGFR1 [20]. The bioavailability of apatinib through oral intake is between 10 and 20% (Dr. Liguang Lou; Unpublished data; 2008). Ninety-six hours after oral intake of apatinib, excretion of the drug was 76.8%, with 69.8% in feces and 7.0% in urine. The excreted drug in feces was mainly intact and had not been metabolized, whereas that in the urine had been 2.3
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Apatinib
almost completely metabolized [23]. The binding efficiencies of apatinib to multiple plasma proteins (in rats, canines, monkeys and humans) range from 86 -- 93% (Dr. Liguang Lou; Unpublished data; 2008). Under treatment with the enzymes CYP3A4/5, CYP2C9, CYP2D6, CYP2E1, or UGT2B7, apatinib has four types of metabolites: cis-3-hydroxy-apatinib (M1-1), trans-3-hydroxy-apatinib (M1-2), apatinib-25-Noxide (M1-6), and cis-3-hydroxy-apatinib-O-glucuronide (M9-2), with M9-2 as the main metabolite [23]. A Phase I clinical trial investigated the pharmacokinetics of apatinib in single and multiple dose evaluations. In the singledose evaluation, 28 patients were divided into three groups according to drug doses of 500 mg (n = 8), 750 mg (n = 12), and 850 mg (n = 8). 3 -- 4h after oral apatinib intake, the plasma drug concentration reached the peak. The mean maximum plasma drug concentration (Cmax) of the three groups were 1521, 2379 and 2833 ng/ml, respectively, and the areas under the concentration-time curve 0--24 h (AUC0-24h) were 11295, 18172, and 21975 ng·h/ml, respectively. The Cmax and AUC0 -- 24h both showed dosedependent increases with significant individual differences. The elimination half-life of apatinib was 9 h, which was consistent among the three groups. In the 750 mg group, 11 patients enrolled in the multiple dosing study and received apatinib 750 mg daily. Plasma drug concentrations were titrated at days 1, 6, 28, and 56. The results showed that both Cmax and AUC0 -- 24h at day 6 were higher than those at day 1, but there were no further increases after day 6, indicating that apatinib has little accumulation in patients [24]. 3.
Clinical efficacy
Phase I and II studies The Phase I study of apatinib recruited 46 patients with advanced solid tumors for whom no standard treatment was available. Among the 46 patients, 34 had gastrointestinal cancer, 3 had lung cancer, 3 had breast cancer, and 6 had other types of cancer. Apatinib 250, 500, 750, 850 or 1000 mg per day was given using the standard 3 + 3 doseescalation method. The study found that the maximum tolerated dose of apatinib was 850 mg/day and a dose of 750 mg/ day was chosen for the anti-tumor study [24]. Of 37 evaluable patients, 7 achieved partial response (PR), including 3 with colon cancer, 1 with gastric cancer, 1 with gastrointestinal stromal tumor, 1 with kidney cancer and 1 with an unknown primary cancer. Twenty-four patients were defined as having stable disease and the disease control rate (DCR) was 83.8% [24]. Li et al. conducted a multi-center, Phase II, clinical study of apatinib and recruited 144 patients with advanced metastatic gastric cancer in whom second-line or above chemotherapy had failed. Patients were randomly assigned to receive placebo (group A, n = 48), oral apatinib 850 mg once daily (q.d.; group B, n = 47), or oral apatinib 425 mg twice daily (b.i.d.; group C, n = 46). The primary end point was 3.1
progression-free survival (PFS). The median age of the patients was 54, 55, and 53 years, respectively, and male patients were 75, 83, and 74%, respectively. The Eastern Cooperative Oncology Group performance status scores of all patients were 0 -- 1. Metastatic sites were the liver (48, 60, 43% for groups A, B, and C, respectively), lung (19, 11, and 24%, respectively), and retroperitoneal lymph nodes (23, 19, and 24%, respectively). The median PFS (mPFS) for groups A, B, and C were 1.4 months (95% confidence interval [CI], 1.20 -- 1.83 months), 3.7 months (95% CI, 2.17 -- 6.80 months) and 3.2 months (95% CI, 2.37 -- 4.53 months), respectively. The median OS (mOS) for groups A, B and C were 2.5 months (95% CI, 1.87 -- 3.70 months), 4.83 months (95% CI, 4.03 -5.97 months) and 4.27 months (95% CI, 3.83 -4.77 months), respectively. Compared with group A, the mPFS and mOS of groups B and C were significantly prolonged (mPFS: group B vs group A, p < 0.001, group C vs group A, p < 0.001; mOS: group B vs group A, p < 0.001, group C vs group A, p = 0.0017). In the objective response rate (ORR) assessment, 9 patients (3 from group B and 6 from group C) achieved PR. In the DCR assessment, intent-to-treat analysis found that groups B and C had higher DCRs than group A: group A, 5 patients (10.42%); group B, 24 patients (51.06%); and group C, 16 patients (34.78%) [25]. Phase III studies A multi-center, randomized, double-blind, placebocontrolled Phase III study of apatinib has recently been completed. A total of 273 patients were randomly assigned to oral apatinib 850 mg q.d. (28-day treatment cycles) or placebo at a ratio of 2:1. The primary end point was OS. Patients receiving apatinib had significantly prolonged mOS (195 vs 140 days; hazard ratio [HR] = 0.71; 95% CI, 0.54 -- 0.94; p < 0.016) and mPFS (78 vs 53 days; HR = 0.44; 95% CI, 0.33 -- 0.61; p < 0.0001) compared with those receiving placebo. The ORRs for the apatinib and placebo groups were 2.84 and 0.00%, respectively [26]. 3.2
4.
Safety and tolerability
Apatinib is an oral drug with a good safety profile. During the Phase I clinical trial of 37 evaluable patients, the three most common adverse events (AEs) were hypertension (69.5%, n = 3 for grade 3 -- 4), proteinuria (47.8%, n = 6 for grade 3 -- 4), and hand-foot syndrome (45.6%, n = 6 for grade 3 -- 4). After the treatment stopped, these reactions were alleviated to some degree. Other minor AEs included pain, thrombocytopenia, fatigue and hyperbilirubinemia. In the group receiving apatinib 1000 mg q.d., two patients demonstrated dose-limiting toxicity; namely, grade 4 hematologic AEs or grade 3 -- 4 non-hematologic AEs. Among the 37 patients, 15 completed at least 1 week of apatinib treatment at the original doses, 1 from the apatinib 250 mg q.d. group withdrew due to disease progression, and 3 from the
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apatinib 1000 mg q.d. group withdrew because of AEs, whereas the remaining 18 patients completed the study with decreased dosing [24]. Apatinib also showed acceptable tolerability in a Phase II study. Grade 3 -- 4 AEs occurring in > 5% of patients included hand--foot syndrome, hypertension, thrombocytopenia, anemia, liver function impairment (elevated aminotransferase and bilirubin) and diarrhea. Grade 3 -- 4 AEs reported in > 10% of patients were hand--foot syndrome and high blood pressure. Fatigue, a common symptom among patients with advanced tumors, was present for 10.4, 17.0, and 15.2% of patients in the placebo, apatinib 850 mg q.d., and apatinib 425 mg b.i.d. groups, respectively. Severe fatigue (grade 3 -- 4) was present at a rate of ~ 2% in each of the 3 groups [25]. A Phase III clinical study further reinforced the general tolerability of apatinib. About 60% of patients experienced grade 3 -- 4 AEs, which included hypertension, hand--foot syndrome, proteinuria, fatigue, anorexia and elevated aminotransferase. The rate of grade 3 -- 4 AEs in the apatinib arm was significantly higher than that in the placebo arm (41%, p = 0.0045), whereas no significant difference in severe AEs was observed between the two groups. The AEs were manageable and reversible, and patients were treated with symptomatic therapy and dose interruptions or reductions [26]. 5.
Regulatory affairs
Based on the results of a Phase III clinical trial in China, apatinib has been approved by the Chinese Food and Drug Administration recently. 6.
Conclusion
To date, there has been no standard treatment strategy for patients with advanced metastatic gastric cancer who have failed at least two chemotherapeutic regimens. The development of apatinib has shown the potential of the antiVEGFR-2 strategy in the treatment of patients with advanced metastatic gastric cancer. As a novel oral small molecule VEGFR-2 inhibitor, apatinib has demonstrated good safety, tolerability and efficacy in these patients. Given the positive results obtained in the Phase III clinical study, apatinib offers a new option for patients with advanced metastatic gastric cancer. 7.
Expert opinion
The results for apatinib in the Phase III study are definitely exciting. For patients with advanced metastatic gastric cancer, the total OS is about 1 year, and treatment with apatinib could prolong survival by nearly 2 months when patients have previously failed with second-line chemotherapy. As anti-VEGFR-2 drugs, ramucirumab and apatinib share some 120
similarities. In the REGARD and the Phase III apatinib studies of patients with previously treated gastric cancer, both drugs achieved > 1 month mOS (1.8 and 1.4 months for ramucirumab and apatinib, respectively) and mPFS of 0.8 months (for both drugs). The difference between the two studies is that apatinib was given as third-line treatment and ramucirumab was given as second-line therapy. Heavily treated patients receiving apatinib seemed to experience more AEs than those receiving ramucirumab. It has been reported that the only AE in the ramucirumab group that occurred more commonly than in the placebo group was hypertension, whereas apatinib is associated with proteinuria, hypertension, and hand--foot syndrome. All toxicities occurring in apatinib-treated patients are related to antiangiogenesis, as reported previously for other VEGF/VEGFR inhibitors. There have been no new toxicities found for apatinib. In terms of patient populations, REGARD is a worldwide study that enrolled patients from 29 countries, including Caucasians and Asians. However, in the RAINBOW study, ramucirumab did not show additional survival benefit in the Asian population when compared with the control [27]. The Phase III clinical trial of apatinib was conducted in China. Its global significance is limited until it has been tested and proven to be effective in other populations. A Phase I clinical trial has therefore been started in the US and South Korea (NCT01726101) [28], which is recruiting participants currently. As bevacizumab failed to benefit survival in first-line treatment of gastric cancer [13,29], researchers are not optimistic about an anti-VEGF/VEGFR strategy in the first-line setting. It is widely accepted that any following treatment will dilute the marginal benefit of first-line treatment if OS is designated as a primary end point. This may be why there is no plan to conduct clinical trials in patients with previously untreated advanced gastric cancer. However, other indications for apatinib could be other previously treated solid tumors. Current clinical studies of apatinib in lung [30,31], breast [32] and liver [33] cancers have all been in the chemotherapy-refractory setting. A challenge to the use of apatinib is the need to find biomarkers to predict drug efficacy. A study of biomarkers for apatinib in breast cancer patients showed that both hypertension and high expression of p-VEGFR2 could be biomarkers for good treatment efficacy [34]. Moreover, in the biomarker analysis of the Avastin in Gastric Cancer trial, bevacizumab response was positively correlated with the levels of VEGF-A in plasma and neuropilin-1 in tumor tissue [35]. However, there has been no final outcome on finding biomarkers for antiangiogenesis drugs, although reliable biomarkers are of great importance, both for individualized treatment and for improving efficacy. Drug resistance is a problem encountered with every targeted therapy, and this does occur with apatinib. Drug resistance is especially important for patients who proceed to
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second-line or above chemotherapy because there are no further drugs available once resistance to apatinib occurs. Many studies of resistance of antiangiogenic agents have shown that resistance is mainly related to activation of cell adhesion-associated or other growth-associated signaling pathways [36,37], implying that blockage of these pathways may solve the problem. Solving the drug resistance issue would be a major benefit to antiangiogenic therapy.
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Affiliation
Ruixuan Geng1 MD & Jin Li†2 MD PhD † Author for correspondence 1 Fudan University Shanghai Cancer Center, Shanghai Medical College, Department of Medical Oncology, Shanghai 200032, China 2 Professor and Dean, Fudan University Shanghai Cancer Center, Shanghai Medical College, Department of Medical Oncology, Shanghai 200032, China Tel: +86 21 64433755; Fax: +86 21 64170366; E-mail: [email protected]
