Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial

Abstract

SummaryBackgroundEGFR overexpression occurs in 27–55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma.MethodsIn this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m2 and oxaliplatin 130 mg/m2 on day 1 and capecitabine 1250 mg/m2 per day on days 1–21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m2 and oxaliplatin 100 mg/m2 on day 1, capecitabine 1000 mg/m2 per day on days 1–21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785.FindingsBetween June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11·3 months (95% CI 9·6–13·0) compared with 8·8 months (7·7–9·8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1·37, 95% CI 1·07–1·76; p=0·013). mEOC+P was associated with increased incidence of grade 3–4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥3 neutropenia 35 [13%] vs 74 [28%]).InterpretationAddition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma.FundingAmgen, UK National Institute for Health Research Biomedical Research Centre.

Optimal chemotherapy for advanced gastric cancer: is there a global consensus?

“…In contrast to the success obtained with trastuzumab in advanced GC, monoclonal antibodies that target HER1 (epidermal growth factor receptor, EGFR) have failed to improve outcome in biologically unselected GC patients [36,59]. It remains to be elucidated from tumor tissue analyses if a small proportion of GC patients may benefit from anti-EGFR targeted therapy, e.g., in the case of EGFR gene amplification [60].…”

“…3). Ramucirumab has also been shown to prolong the survival time with a very reasonable side-effect profile [59], but this anti-angiogenic antibody is not yet on the market.…”

Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma

“…The ToGA (Trastuzumab for Gastric Cancer) trial has shown that trastuzumab improves the survival of patients with HER2 protein-overexpressing and/or HER2 geneamplifying advanced gastric cancer [5]. Although the addition of cetuximab or panitumumab to chemotherapy in non-molecularly selected gastric cancer patients did not improve survival [6,7], a phase 2 study has shown a possible improvement in the survival of the patient subset with high EGFR expression who were treated with nimotuzumab, a humanized monoclonal antibody to EGFR [8]. At present, a phase 3 nimotuzumab trial (ENRICH study) in patients with EGFR-overexpressing advanced gastric and gastroesophageal junction cancer is ongoing.…”

Gene copy number gain of EGFR is a poor prognostic biomarker in gastric cancer: evaluation of 855 patients with bright-field dual in situ hybridization (DISH) method

“…EGFR overexpression and gene amplification serve as effective biomarkers for predicting the clinical benefit of anti-EGFR monoclonal antibodies for treating colorectal [17] and lung cancer [18]. The recent REAL3 (panitumumab) [19] and EXPAND (cetuximab) [20] randomized controlled phase III trials failed to demonstrate the efficacy of the anti-EGFR monoclonal antibodies for treating gastric cancer, presumably because precise patient inclusion criteria were not set for the trials. Several studies suggest that EGFR overexpression or gene amplification may serve as a potential biomarker for the efficacies of anti-EGFR therapies in gastric cancer [9,[21][22][23].…”