Elsevier

The Lancet Oncology

Volume 14, Issue 6, May 2013, Pages 490-499
The Lancet Oncology

Articles
Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial

https://doi.org/10.1016/S1470-2045(13)70102-5Get rights and content

Summary

Background

Patients with advanced gastric cancer have a poor prognosis and few efficacious treatment options. We aimed to assess the addition of cetuximab to capecitabine-cisplatin chemotherapy in patients with advanced gastric or gastro-oesophageal junction cancer.

Methods

In our open-label, randomised phase 3 trial (EXPAND), we enrolled adults aged 18 years or older with histologically confirmed locally advanced unresectable (M0) or metastatic (M1) adenocarcinoma of the stomach or gastro-oesophageal junction. We enrolled patients at 164 sites (teaching hospitals and clinics) in 25 countries, and randomly assigned eligible participants (1:1) to receive first-line chemotherapy with or without cetuximab. Randomisation was done with a permuted block randomisation procedure (variable block size), stratified by disease stage (M0 vs M1), previous oesophagectomy or gastrectomy (yes vs no), and previous (neo)adjuvant (radio)chemotherapy (yes vs no). Treatment consisted of 3-week cycles of twice-daily capecitabine 1000 mg/m2 (on days 1–14) and intravenous cisplatin 80 mg/m2 (on day 1), with or without weekly cetuximab (400 mg/m2 initial infusion on day 1 followed by 250 mg/m2 per week thereafter). The primary endpoint was progression-free survival (PFS), assessed by a masked independent review committee in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. This study is registered at EudraCT, number 2007-004219-75.

Findings

Between June 30, 2008, and Dec 15, 2010, we enrolled 904 patients. Median PFS for 455 patients allocated capecitabine-cisplatin plus cetuximab was 4·4 months (95% CI 4·2–5·5) compared with 5·6 months (5·1–5·7) for 449 patients who were allocated to receive capecitabine-cisplatin alone (hazard ratio 1·09, 95% CI 0·92–1·29; p=0·32). 369 (83%) of 446 patients in the chemotherapy plus cetuximab group and 337 (77%) of 436 patients in the chemotherapy group had grade 3–4 adverse events, including grade 3–4 diarrhoea, hypokalaemia, hypomagnesaemia, rash, and hand-foot syndrome. Grade 3–4 neutropenia was more common in controls than in patients who received cetuximab. Incidence of grade 3–4 skin reactions and acne-like rash was substantially higher in the cetuximab-containing regimen than in the control regimen. 239 (54%) of 446 in the cetuximab group and 194 (44%) of 436 in the control group had any grade of serious adverse event.

Interpretation

Addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced gastric cancer in our trial.

Funding

Merck KGaA.

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.

Section snippets

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)

  • AF Okines et al.

    Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy for the treatment of advanced oesophago-gastric cancer

    Ann Oncol

    (2009)
  • TS Maughan et al.

    Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial

    Lancet

    (2011)
  • C Gravalos et al.

    HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target

    Ann Oncol

    (2008)
  • J Ferlay et al.

    Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008

    Int J Cancer

    (2010)
  • TJ Price et al.

    Management of advanced gastric cancer

    Expert Rev Gastroenterol Hepatol

    (2012)
  • AD Wagner et al.

    Chemotherapy for advanced gastric cancer

    Cochrane Database Syst Rev

    (2010)
  • RI Nicholson et al.

    EGFR and cancer prognosis

    Eur J Cancer

    (2001)
  • MA Kim et al.

    EGFR in gastric carcinomas: prognostic significance of protein overexpression and high gene copy number

    Histopathology

    (2008)
  • E Van Cutsem et al.

    Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status

    J Clin Oncol

    (2011)
  • JB Vermorken et al.

    Platinum-based chemotherapy plus cetuximab in head and neck cancer

    N Engl J Med

    (2008)
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