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

doi:10.1016/S1470-2045(13)70096-2

The Lancet Oncology

Volume 14, Issue 6, May 2013, Pages 481-489

https://doi.org/10.1016/S1470-2045(13)70096-2 Get rights and content

Summary

Background

EGFR 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.

Methods

In 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preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn.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.

Findings

Between 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%]).

Interpretation

Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma.

Funding

Amgen, UK National Institute for Health Research Biomedical Research Centre.

Introduction

Gastric and oesophageal cancers are among the most common causes of cancer-related mortality, and were responsible for more than 1·1 million deaths worldwide in 2008.¹ Combination chemotherapy is beneficial in perioperative and advanced disease settings, although overall survival is poor. In patients with metastatic disease, median overall survival with best supportive care is about 3 months, which can be extended to about 10 months with chemotherapy.2, 3 No internationally accepted standard of care regimen exists for advanced oesophagogastric adenocarcinoma, although most centres use doublet or triplet chemotherapy combinations with a platinum-fluoropyrimidine backbone. The REAL2 non-inferiority study established epirubicin, oxaliplatin, and capecitabine (EOC) as a standard first-line regimen, and noted a median overall survival of 11·2 months.³ This result compared favourably with the alternative regimens assessed in REAL2, including a combination of epirubicin, cisplatin, and fluorouracil that had a median overall survival of 9·9 months.

In the past decade, the EGFR pathway has been recognised as one of the key proliferative pathways that is dysregulated during tumorigenesis. Preclinical data confirm that transfection of EGFR into human cancer cells is associated with an aggressive phenotype,⁴ and several molecular aberrations within this pathway can function as potent oncogenes. In oesophagogastric adenocarcinoma, EGFR overexpression is reported in 27–55% of cases in published literature,5, 6 and has been associated with reduced overall survival in some series.5, 7 Amplification of EGFR, measured by fluorescence in-situ hybridisation, is also reported in a smaller subset of oesophagogastric adenocarcinoma.5, 8 This pathway therefore represents a potential therapeutic target in this disease setting, and single-drug phase 2 trials have reported a small number of responses with monoclonal antibodies⁹ or tyrosine-kinase inhibitors¹⁰ targeting EGFR in advanced oesophagogastric adenocarcinoma.

Panitumumab is a fully human immunoglobulin G2 monoclonal antibody directed against EGFR that has confirmed survival benefits in advanced colorectal cancer.¹¹ We designed the REAL3 trial to assess the addition of panitumumab to EOC in molecularly unselected patients with advanced oesophagogastric adenocarcinoma.

Section snippets

Study design and participants

REAL3 was an open-label, multicentre, phase 3, randomised controlled trial, undertaken at 63 parti-cipating centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Safety, response, and survival outcomes were compared between standard EOC and modified EOC plus panitumumab (mEOC+P). The mEOC+P schedule was established in an unplanned dose-finding study,¹² which was done because excessive toxicity (primarily diarrhoea) was noted when the drugs were

Results

Between June 2, 2008, and Oct 17, 2011, we enrolled 575 patients, three of whom were withdrawn because they did not fulfil eligibility criteria. Additionally, 19 patients randomly allocated during the phase 1 dose-finding study were excluded from the intention-to-treat analysis.¹² We included 553 eligible patients in the phase 3 intention-to-treat population, representing 76% of the planned accrual at the time of trial closure (figure 1; table 1). 494 (89%) patients had metastatic disease.

Discussion

The REAL3 trial is one of two concurrent randomised phase 3 trials (the other being the EXPAND trial¹⁵) assessing the addition of anti-EGFR monoclonal antibodies to chemotherapy in first-line oesophagogastric cancer. Based on the findings of REAL3, use of panitumumab in combination with EOC cannot be recommended in an unselected population with advanced oesophagogastric adenocarcinoma, and was associated with inferior overall survival and PFS. Notably, this detrimental outcome in the

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

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Cell

Ann Oncol

Lancet

Ann Oncol

Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008

Int J Cancer

Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer

Cancer

Capecitabine and oxaliplatin for advanced esophagogastric cancer

N Engl J Med

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

Histopathology

Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study

J Clin Pathol

Expression of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) is an independent prognostic indicator of worse outcome in gastric cancer patients

Ann Surg Oncol

Gene amplification in esophageal adenocarcinomas and Barrett's with high-grade dysplasia

Clin Cancer Res

A phase II study of gefitinib monotherapy in advanced esophageal adenocarcinoma: evidence of gene expression, cellular, and clinical response

Clin Cancer Res

Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study

J Clin Oncol

Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for advanced esophagogastric cancer: dose-finding study for the prospective multicenter, randomized, phase II/III REAL-3 trial

J Clin Oncol

New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada

J Natl Cancer Inst

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