Summary

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.

Methods

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Between June 2, 2008, and Oct 17, 2011, we enrolled 575 patients, three of whom were withdrawn because they did not fulfil eligibility criteria.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. Median follow-up in patients who were alive at the time of analysis was 4·6 months (IQR 1·8–10·1) in the EOC group and 5·3 months (2·6–9·5) in the mEOC+P group.

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Figure 1

Trial profile

EOC=epirubicin, oxaliplatin, and capecitabine. mEOC+P=modified EOC plus panitumumab.

Based on 251 events (EOC 110, mEOC+P 141) at the time of reporting, median overall survival was lower in the mEOC+P group than in the EOC group (HR 1·37, 95% CI 1·07–1·76, p=0·013; figure 2). Median overall survival was 8·8 months (95% CI 7·7–9·8) in the mEOC+P group compared with 11·3 months (9·6–13·0) in the EOC group (figure 2). 35 (13%) of 278 patients in the mEOC+P group and 54 (20%) of 275 patients in the EOC group were on treatment at the time of trial closure and were censored at this timepoint. 1-year overall survival was 33% (95% CI 26–41) in the mEOC+P group and 46% (38–54) in the EOC group. Subgroup analyses according to extent of disease, site of primary tumour, and KRAS mutation status were prespecified. Other subgroup analyses (age, sex, performance status, and number of metastatic sites) were exploratory. Figure 3 shows the forest plot analysis for subgroups tested, with a similar effect favouring EOC noted between all subgroups.

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Figure 2

Overall survival in 553 patients in the intention-to-treat population, by treatment group

Patients still on treatment at the time of trial closure and treatment crossover were censored. EOC=epirubicin, oxaliplatin, and capecitabine. mEOC+P=modified EOC plus panitumumab.

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Figure 3

Forest plot of hazard ratios (HR) for overall survival according to baseline characteristics

EOC=epirubicin, oxaliplatin, and capecitabine. mEOC+P=modified EOC plus panitumumab.

Based on 333 events (EOC 153, mEOC+P 180), PFS did not differ between treatment groups (HR 1·22, 95% CI 0·98–1·52, p=0·068; figure 4). Median PFS was 6·0 months (95% CI 5·5–6·5) in the mEOC+P group and 7·4 months (6·3–8·5) in the EOC group. 1-year PFS was 20% (95% CI 14–26) in the mEOC+P group compared with 21% (14–27) in the EOC group.

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Figure 4

Progression-free survival in 553 patients in the intention-to-treat population, by treatment group

Patients still on treatment at the time of trial closure and treatment crossover were censored. EOC=epirubicin, oxaliplatin, and capecitabine. mEOC+P=modified EOC plus panitumumab.

61 patients who were still on treatment (37 in the EOC group and 24 in the mEOC+P group) and had not reached their first response assessment at the time of data censoring were excluded from the response analysis. Patients who died, progressed, or withdrew before response assessment were classed as non-responders. 116 (46%) of 254 patients in the mEOC+P group had a complete or partial response compared with 100 (42%) of 238 patients in the EOC group (odds ratio 1·16, 95% CI 0·81–1·66, p=0·42; table 2).

542 patients received at least one cycle of chemotherapy and were assessed for toxicity (table 3). Addition of panitumumab was associated with increased rates of grade 3–4 diarrhoea, mucositis, rash, and hypomagnesaemia. Patients in the EOC group had increased rates of grade 3–4 peripheral neuropathy, neutropenia, febrile neutropenia, and thrombocytopenia compared with patients in the mEOC+P group. Overall, we noted no significant difference between the two groups in terms of grade 3–5 toxicity when all toxicities were combined (p=0·21). However, when we excluded haematological and biochemical toxicities, more patients had grade 3–5 toxicities in mEOC+P group (p=0·035, table 3).

Four patients died from toxicities regarded as related to mEOC+P: one each of septicaemia, neutropenic sepsis, pulmonary embolism, and upper gastrointestinal haemorrhage. Six patients died from toxicities regarded as related to EOC: one each of pneumonia, diarrhoea and dehydration, pneumonitis, and myocardial infarction, and two cases of neutropenic sepsis.

For 542 patients who started treatment, the median number of cycles delivered was five (IQR three to eight) in both trial groups. 80 (30%) of 266 patients who started EOC received all eight planned cycles of chemotherapy, as did 74 (27%) of 276 patients who started mEOC+P. These findings are restricted by data censoring for the 89 patients still on treatment at the time of trial closure. Excluding these patients, the median number of cycles delivered was six (IQR three to eight) with EOC (80 [38%] of 212 patients completed eight cycles) and five (IQR three to eight) with mEOC+P (74 [31%] of 241 patients completed eight cycles).

Overall, 1307 cycles of EOC were administered compared with 1375 cycles of mEOC+P. Table 4 shows the median relative dose intensity for each drug according to treatment group and the proportion of patients in each group achieving a relative intensity of at least 80%.

In exploratory biomarker analyses of 276 patients treated with mEOC+P, development of any grade of rash (219 patients) was associated with significantly longer overall survival compared with patients with no rash (57 patients; figure 5). Median overall survival was 10·3 months (95% CI 8·9–11·6) and median PFS was 6·8 months (5·9–7·8) in patients with grade 1–4 rash compared with median overall survival of 4·3 months (3·3–5·4) and a median PFS of 3·7 months (2·3–5·1) in patients with grade 0 rash (p<0·0001 for overall survival and PFS).

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Figure 5

Overall and progression-free survival in 276 assessable patients in the mEOC+P group, by skin rash grade (grade 0 vs grade 1–4)

mEOC+P=modified epirubicin, oxaliplatin, and capecitabine plus panitumumab.

However, outcomes in the grade 0 rash population might be negatively skewed by patients with rapid disease progression who received insufficient panitumumab to develop rash. A further exploratory analysis was therefore done including only 194 patients (177 with rash, 17 with no rash) who received at least four cycles of chemotherapy. Although possibly restricted by the smaller number of patients, in this analysis overall survival did not differ between patients who developed rash (median 10·6 months [95% CI 9·0–12·2]) and those who did not (8·5 months [7·1–9·9]; HR 0·64 [95% CI 0·37–1·11], p=0·11).

Few tissue biomarker analyses have been undertaken to date. Frequencies of tested biomarkers in the first 200 patients are shown in table 5 and have been reported elsewhere.¹⁴ For ten patients with known KRAS mutant tumours, we noted a potential association with benefit from mEOC+P, although this association was not significant (figure 3). In multivariate overall survival analysis incorporating performance status and disease stage, both KRAS mutation (HR 2·21, 95% CI 1·15–4·26; p=0·017) and PIK3CA mutation (HR 3·63, 95% CI 1·13–11·67, p=0·030) were negatively prognostic. No prognostic effect was associated with HER2 or PTEN status, and no BRAF mutations were noted (data not shown). These biomarker analyses are exploratory and were limited by the small numbers of mutations identified to date. Further biomarker analyses are ongoing in the full trial cohort.

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 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,¹² combination 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 OPUS¹⁶ and 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 series^23,24 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 KRAS oncogene 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.

Acknowledgments

Contributors

Conflicts of interest

References