An open-label, multicentre biomarker-oriented AIO phase II trial of sunitinib for patients with chemo-refractory advanced gastric cancer
Introduction
Worldwide gastric cancer (GC) is the fourth most common malignancy and annually the second most common cause of cancer death. In Europe the incidence of GC in 2008 was approximately 150,000 cases.1, 2 Although GC mortality has markedly declined, the 5-year survival rate for patients with locally advanced disease is <20%, and approximately 30% for those undergoing surgery. Many chemotherapeutic agents demonstrate activity in advanced GC (AGC) with combination therapies reported to prolong survival and improve quality of life over single-agent therapy.3 Currently cisplatin/5-fluorouracil (5-FU)-based chemotherapeutic regimens are the mainstay of treatment for metastatic disease.3 In recent phase III trials, oxaliplatin, docetaxel, capecitabine and irinotecan demonstrated activity, increasing first-line treatment options,4, 5, 6, 7 with irinotecan also improving patient quality of life8 for AGC patients. Median survival currently ranges from 8 to 11 months.4, 7 However, the efficacy data reported from a number of phase II and III studies are disappointing for AGC patients receiving second-line treatment with median survival ranging from 5 to 6 months.9, 10 The identification of less toxic and more effective treatment strategies is needed to improve the survival of AGC patients, particularly those whose disease has progressed during or after chemotherapy.
Tumour angiogenesis, growth and metastasis can be inhibited by blocking receptor tyrosine kinases (RTKs) overexpressed in GC, including vascular endothelial growth factor receptors (VEGFRs), epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptors (PDGFRs).11, 12, 13 VEGF, EGFR and PDGF-A tumour expression is reportedly associated with progression and poor survival in GC patients.14, 15, 16 Therapies that specifically target RTK signalling through a single receptor pathway have been investigated in phase II studies in AGC including gefitinib17 and erlotinib18 as single-agents, and bevacizumab19 and cetuximab,20, 21 both in combination with chemotherapy. However, many tumours co-express several RTKs11 and drugs targeting multiple RTKs involved in angiogenesis growth and metastasis may provide additional benefits relative to single receptor targeted inhibition.
Sunitinib malate (SUTENT®; Pfizer Inc., New York, NY) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR1, -2 and -3, PDGFR-α and -β, and several other related RTKs.22, 23, 24 In a murine xenograft model of GC, sunitinib exhibited antiangiogenic and antitumour activity at 40 mg/day (Pfizer Inc., Data on file). Single agent sunitinib (50 mg/day) for 4 weeks followed by 2 weeks off treatment, demonstrated superior efficacy to standard treatment with acceptable toxicity in patients with gastrointestinal stromal tumours (refractory or intolerant to imatinib), and in patients with advanced renal cell carcinoma.25, 26
In this trial we investigated single agent sunitinib for objective response, safety and survival in patients with previously treated AGC. Pre-planned exploratory analyses of the influence of selected molecular biomarkers on trial end-points were also performed.
Section snippets
Patient population
Inclusion criteria were: male or female patients aged ⩾18 years old with histologically proven metastatic adenocarcinoma of stomach or 0esophagogastric junction or lower oesophagus (Barrett carcinoma); measurable metastatic disease according to Response Evaluation Criteria in Solid Tumours (RECIST-criteria, version 1.0); failure of at least one prior irinotecan- or cisplatin-based palliative chemotherapy (progression of disease or unacceptable toxicity). Further inclusion criteria included:
Patients
Fifty-two patients were enrolled and treated with sunitinib and comprised the SP. The ITT population contained 51 patients as tumour diagnosis could not be confirmed in one patient. Fourteen patients were excluded (because no tumour assessment under study treatment had been documented), giving rise to the EPP (n = 38). Non-evaluable patients terminated study treatment before tumour staging in cycle 1 could be assessed, this was due to death, clinical/symptomatic deterioration, toxicity related to
Discussion
In this study, sunitinib monotherapy in heavily pretreated patients with AGC led to RECIST defined PRs in 4% of patients and SD was recorded in 16% of patients. In support similar ORR were recorded in the EPP (5.3%) and PPP (6.7%) compared with the ITT population, therefore classifying patients without any tumour assessment as non-responders had no impact on ORR. These data are comparable to a recent phase II study of sunitinib monotherapy in 78 Korean patients with AGC, the ORR rate was 2.6%
Funding
The trial was conducted in cooperation with IZKS Mainz. IZKS Mainz is the central clinical trial management of the University Medical Center (UMC) Mainz supported by grant “Clinical Trial Centers, funding number FKN 01KN1103, IZKS Mainz” of German Federal Ministry of Education and Research.
Conflict of interest statement
M. Moehler has received research funding from company Pfizer. M. Moehler and T.Trarbach have reported honoraria or a consultancy role with Pfizer. All other authors have declared no conflict of interest.
Acknowledgements
The authors are grateful to all investigators and patients who participated in the trial. The trial was co-ordinated by the Interdisciplinary Center for Clinical Trials (IZKS) of the University Medical Center Mainz. The authors would like to thank Annette Weissmann (IZKS Mainz) for study coordination and Anne Ehrlich (IZKS Mainz) for pharmacovigilance. Additional financial support was provided by Pfizer. Editorial services were provided by Cancer Communications and Consultancy Ltd. funded by
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