ArticlesCapecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial
Introduction
In 2008, gastric cancer was the second most common cause of death related to cancer worldwide (9·7%).1 Although the overall incidence of gastric cancer is decreasing, the incidence of gastro-oesophageal junction tumours, which have an especially poor prognosis, is increasing. Complete surgical resection of early disease offers a chance for cure, although most patients (80–90%) in high-income non-Asian countries present with either advanced disease or develop a recurrence within 5 years of undergoing curative resection.2
Treatment with combination chemotherapy improves outcomes compared with single-drug chemotherapy or no chemotherapy in patients with advanced gastric cancer.3 With no international standard at present, first-line chemotherapy regimens commonly used in treatment include a platinum compound (typically cisplatin) in combination with either infusional fluorouracil or an oral fluoropyrimidine (typically capecitabine) or S-1, which is a preferred treatment in Asia.4, 5, 6 Despite the development of new chemotherapy regimens, the 5-year survival of patients in this setting is less than 10%, and therefore a high and unmet need exists for efficacious treatment.2
Introduction of biological drugs into treatment strategies has shown promise in this setting. Trastuzumab, a HER2 antibody, in combination with first-line cisplatin and fluoropyrimidine-based chemotherapy significantly improved overall survival in patients with HER2-overexpressing tumours compared with those receiving chemotherapy alone.7 EGFR, part of the family of receptor tyrosine kinases including HER2, is expressed in gastric and oesophageal tumours and is associated with poor prognosis.8, 9 Addition of cetuximab (an EGFR antibody) to standard first-line chemotherapy regimens improved clinical outcome in patients with KRAS wild-type metastatic colorectal cancer,10, 11 recurrent or metastatic squamous-cell carcinoma of the head and neck,12 and advanced non-small-cell lung cancer.13 Moreover, manageable and expected safety profiles with substantial activity (objective response rates of 41–65%) were reported in phase 2 studies of cetuximab plus various first-line chemotherapy regimens in patients with advanced gastric cancer.14, 15, 16, 17
In the randomised international Erbitux (cetuximab) in combination with Xeloda (capecitabine) and cisplatin in advanced esophago-gastric cancer (EXPAND) study, we aimed to assess efficacy and safety of addition of cetuximab to first-line capecitabine-cisplatin chemotherapy in patients with unresectable advanced or metastatic gastric adenocarcinoma.
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Study design and participants
In this open-label, randomised, controlled, phase 3 study, we enrolled adults (aged ≥18 years) with histologically confirmed adenocarcinoma of the stomach or gastro-oesophageal junction with locally advanced unresectable (M0) or metastatic (M1) disease. Patients were enrolled at 164 sites (teaching hospitals and clinics) in 25 countries worldwide (appendix). Other inclusion criteria were availability of tumour material for EGFR expression assessment; at least one radiographically documented
Results
Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients (table 1, figure 1). Recruitment was temporarily suspended in July 6, 2009, after 380 patients had been allocated treatment, because of an imbalance in cardiac events detected by the data and safety monitoring board. The study was restarted in Dec 11, 2009 after implementation of a cardiac monitoring programme (appendix). Baseline characteristics were generally well balanced (table 1). Only 16 (4%) of 455 patients in the
Discussion
In this randomised phase 3 study of patients with advanced or metastatic gastric or gastro-oesophageal junction cancer, addition of cetuximab to capecitabine and cisplatin did not improve PFS compared with chemotherapy alone. Therefore, the primary study endpoint was not met. The safety profiles of the treatment regimens were as expected (panel). PFS in the experimental group (median 4·4 months) was not generally improved compared with reported data from randomised studies of doublet and
References (41)
- et al.
S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial
Lancet Oncol
(2008) - et al.
Capecitabine/cisplatin versus 5-fluorouracil/cisplatin as first-line therapy in patients with advanced gastric cancer: a randomised phase III noninferiority trial
Ann Oncol
(2009) - et al.
Fluorouracil versus combination of irinotecan plus cisplatin versus S-1 in metastatic gastric cancer: a randomised phase 3 study
Lancet Oncol
(2009) - et al.
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial
Lancet
(2010) - et al.
Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study
Ann Oncol
(2011) - et al.
Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial
Lancet
(2009) - et al.
Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study
Ann Oncol
(2011) - et al.
EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study
Lancet Oncol
(2012) - et al.
Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction
Ann Oncol
(2008) - et al.
A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction
Ann Oncol
(2010)