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.
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preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn.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.
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%]).
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.
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 experimental group was not predicted by the phase 2 endpoint of response rate (overall response rate 52% with mEOC+P). This trial does, however, confirm the efficacy of the EOC control group in this setting, with median overall survival and PFS results that are consistent with those previously reported in REAL2 (11·2 months for overall survival and 7·0 months for PFS).3
The poor outcome associated with mEOC+P in this trial did not seem to be attributable to increased treatment-related deaths, and therefore other potential explanations for our findings need to be considered. First, as reported previously,12combination of panitumumab with full-dose EOC in the initial stages of the trial was associated with unacceptably high rates of grade 3 diarrhoea (four of the first five patients by cycle four). Therefore, we had to reduce the starting doses of oxaliplatin (by 23%) and capecitabine (by 20%) in the experimental group. Although these changes undoubtedly reduced the frequency of grade 3—4 diarrhoea with mEOC+P (17% in phase 3 population), they also served to reduce the dose intensity of chemotherapy, which is reflected in the reduced incidence of grade 3—4 neutropenia and peripheral neuropathy noted in the mEOC+P group. Additionally, the dose intensity data show a reduced proportion of patients achieving at least 80% of the planned capecitabine dose in the experimental group, suggesting that mEOC+P was still slightly more difficult to deliver than standard EOC.
Second, a negative interaction might have occurred between panitumumab and one or more of the EOC components. Evidence in the setting of colorectal cancer suggests that the chemotherapy partner for anti-EGFR therapy might be an important determinant of treatment efficacy, with oxaliplatin-containing regimens yielding inconsistent results. The OPUS16and PRIME11 studies provide evidence of improved outcomes with the addition of cetuximab and panitumumab respectively, whereas no benefit was associated with the addition of cetuximab in the COIN17 and NORDIC VII18 studies in the same setting. Recent cell-line data also suggest that greater synergy might exist between anti-EGFR therapy and irinotecan than with oxaliplatin.19 Additionally, the COIN trial17 results suggest that there might be a differential benefit from cetuximab dependent on the fluoropyrimidine partner, with patients receiving oxaliplatin plus fluorouracil seemingly deriving increased benefit compared with those treated with oxaliplatin plus capecitabine. At present, the significance of these potential interactions is unknown, and has not been assessed in the setting of oesophagogastric cancer.
Third, our findings might have been affected because we assessed panitumumab therapy in a molecularly unselected population. During the years since the inception of the REAL3 trial, several studies have advanced our understanding of the EGFR signalling pathway and its role in oesophagogastric adenocarcinoma. Hot-spot mutations in key oncogenic drivers such as KRAS (common in colorectal cancer) and BRAF (common in malignant melanoma) are now known to be infrequent molecular events in oesophagogastric adenocarcinoma. Indeed, the 5·7% frequency of KRAS mutation in our population is in keeping with the 3—10% reported in other studies,20—22 and we did not note any BRAF mutations in 167 tumour samples tested. By contrast, gene copy number alterations (amplifications and deletions) seem to be a relatively frequent finding in oesophagogastric adenocarcinoma and are more likely to represent the key molecular alterations driving carcinogenesis. Two recent series23, 24 of detailed genomic analyses in oesophagogastric adenocarcinoma reported that about 37% of tumours harbour copy number aberrations in genes that are deemed to be targetable, including KRAS, EGFR, HER2, and MET. Randomised clinical trials are therefore needed to establish whether targeting of these oncogenic signal transduction pathways can meaningfully improve outcomes for patients.
In preclinical studies, cetuximab can decrease EGFR pathway signalling via reduced phosphorylation of EGFR and AKT in oesophagogastric cancer cell lines.25 In combination with chemotherapy, cetuximab results in synergistic inhibition of cell proliferation and enhanced apoptosis.25—27 In hypoxic gastric cancer cell lines the addition of anti-EGFR therapy reversed oxaliplatin resistance.26 Additionally, a synergistic antitumour effect of combined cetuximab and S-1 was apparent in gastric cancer cell lines overexpressing EGFR.25, 27 In colorectal cancer, somatic mutations in codon 12, 13, or 61 of the KRASoncogene confer resistance to panitumumab therapy.11, 28 MET amplification with or without KRAS mutations might be associated with resistance to cetuximab therapy in gastric cancer cell lines;29 however, no validated predictive biomarkers for this setting exist.
Unfortunately, despite preclinical data suggesting a role for anti-EGFR therapy in the treatment of oesophagogastric adenocarcinoma, the REAL3 trial findings are supported by two other phase 3 trials assessing anti-EGFR therapy in this disease setting. The EXPAND trial15 assessed the addition of cetuximab to a cisplatin-capecitabine doublet in 904 patients with previously untreated adenocarcinoma of the stomach and gastro-oesophageal junction, and did not meet its primary endpoint of improved PFS (HR 1·09, 95% CI 0·92—1·29, p=0·32).15 EXPAND also noted no improvement with the addition of cetuximab in either overall survival (HR 1·00, 95% CI 0·87—1·17, p=0·95) or overall response rate (30% in the experimental group vs 29% for controls). The COG trial30 assessed the anti-EGFR tyrosine-kinase inhibitor gefitinib compared with placebo in the second-line treatment of 450 patients with oesophageal and type I—II gastro-oesophageal junction cancers. This trial also did not meet its primary endpoint, with no improvement in overall survival (HR 0·90, p=0·285). However, improvements in PFS (HR 0·795, p=0·017) and disease control at 8 weeks (25·5% in the experimental group vs 16·0% in controls, p=0·014) were noted, suggesting some activity of gefitinib in a small undefined subset of patients.
Taken together, these relatively consistent findings suggest that the EGFR pathway is unlikely to represent an important therapeutic target in most patients with oesophagogastric cancer (panel). The presented biomarker analyses accompanying the REAL3 trial are restricted by small patient numbers and low rates of tested mutations. However, this work is ongoing in the full trial dataset and these translational analyses represent a unique opportunity to further assess the molecular biology of advanced oesophagogastric adenocarcinoma within a randomised trial setting. Techniques such as gene-expression profiling and next-generation sequencing might help to provide further information regarding the driver genetic events in this complex disease. Furthermore, the evaluation of genetic aberrations in pathways linked to EGFR signalling could still offer the prospect of identification of a low-frequency biomarker that identifies a subpopulation of patients benefiting from anti-EGFR targeted therapy in this setting.