Biomarker analysis in oesophagogastric cancer: Results from the REAL3 and TransMAGIC trials
Introduction
Epidermal growth factor receptor (EGFR) is commonly over-expressed and/or amplified in human cancers, and capable of transforming cells in vitro.1 EGFR has been proven to be a clinically useful therapeutic target in EGFR-mutated lung cancer,2 head and neck3 and metastatic colorectal (mCRC) cancers.4 The efficacy of the anti-EGFR antibodies in mCRC is limited to patients without activating mutations in KRAS.4, 5 Mutations in BRAF and PIK3CA exon 20 are also predictive of resistance to cetuximab in chemotherapy-resistant mCRC.6
REAL3 was a phase II/III trial designed to evaluate the addition of panitumumab, a fully human IgG2 monoclonal antibody directed against EGFR, to EOC chemotherapy, initially in a molecularly unselected group of patients with advanced oesophagogastric cancer. Standard dose EOC combined with panitumumab resulted in unacceptable toxicity, leading to modification of the capecitabine and oxaliplatin doses, reported previously.7 The phase II analysis was conducted to exclude futility of the combination and assess potential predictive biomarkers for panitumumab efficacy for phase III.
In advanced gastric cancer, KRAS mutations are uncommon,8 and no association with response to cetuximab has been described.9, 10, 11, 12, 13 PIK3CA mutations have been reported in 16% of gastric cancers14 whereas BRAF mutations are rare, with a rate of 2·2% described in the largest series.8 Loss of expression of PTEN, is a further putative biomarker of resistance to anti-EGFR antibodies in mCRC,15 and is common in gastric cancer.16
Given the evidence available in support of the predictive role of KRAS, BRAF, PIK3CA and PTEN in mCRC, these were assessed in the phase II analysis of REAL3; to determine whether biomarkers used clinically for the selection of patients with mCRC to receive anti-EGFR therapies would be useful for the selection of patients to be enrolled in the phase III of REAL3. As survival was not an end-point of the phase II analysis, prognostic effect could not be assessed; therefore similar analyses were performed in patient-samples from the previously reported MAGIC trial,17 which compared surgery alone to surgery and peri-operative ECF in operable oesophagogastric cancer, to assess the prognostic impact of the biomarkers. It was hypothesised that biomarkers of poor prognosis would be more common in patients with advanced versus early disease, therefore comparison of frequencies in the MAGIC and REAL3 cohorts could theoretically provide information in support of their prognostic value.
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Patients
Full eligibility criteria for REAL3 (NCT00824785) and MAGIC have been reported elsewhere.7, 17 All REAL3 patients gave written informed consent to the study and were required to give additional consent to be included in the biomarker study. Patients gave written informed consent to the MAGIC study, which included pathological review of tissue. Both trials had approval by the required Research Ethics Committees (REC) (REAL3: North West REC 08/H1010/6, TransMAGIC: South East REC, 11/LO/0566).
Toxicity in REAL3
Two hundred patients from 40 UK oncology centres were randomised to mEOC + P (n = 100) or EOC (n = 100) between May 2009 and September 2010. Toxicity results are recorded in Supplementary Table 4.
Response rate
Eleven mEOC + P and 14 EOC patients who withdrew or died prior to radiological (or clinical) assessment of response are analysed as no response. Overall RR in 100 patients randomised to mEOC + P was 52% (95% confidence interval (CI) 42–62%), comprising complete response (CR) in three patients, partial response
Discussion
To our knowledge, this study is the largest prospective evaluation of potential biomarkers of resistance to an anti-EGFR antibody in oesophagogastric cancer, however no association was found between the evaluated biomarkers and RR to mEOC + P. RR was similar in KRAS wild-type and mutant patients; however mutations were infrequent, consistent with previous reports of gastric cancer patients treated with chemotherapy plus cetuximab.10, 13, 27, 28 This contrasts the effect of KRAS mutations in mCRC4
Grant support
REAL3 is sponsored by the Royal Marsden NHS Foundation Trust and supported by a research Grant and provision of panitumumab from Amgen Ltd. REAL3 is endorsed by CRUK (CRUKE/07/049). The study was designed by Investigators at the Royal Marsden Hospital and the protocol was approved by Amgen Ltd. prior to submission for regulatory and ethics approvals. TransMAGIC is funded by CRUK (Grant reference No. C20023/A7217), with support from the Medical Research Council through the MRC Clinical Trials
Financial support
J.S. Reis-Filho is funded in part by Breakthrough Breast Cancer. Ruth Langley, Lindsay Thompson and Sally Stenning are employed by the Medical Research Council.
Role of the funding source
Amgen Ltd. had no role in collecting or analysing data, writing the report or the decision to submit.
Conflict of interest statement
Dr. Okines has previously received an honorarium and travel support from Roche and travel support from Amgen and Bayer. Professor Cunningham has served on an advisory board for Roche and Amgen, acted as expert witness for Amgen (uncompensated) and received research funding from Amgen, Merck Serono, Roche and Sanofi Aventis. Dr. Coxon has received research funding from Roche, Professor Ferry has received an honorarium and research funding from Amgen, plus honoraria and travel support from Roche
Acknowledgements
The REAL3 and TransMAGIC study teams acknowledge the support of the National Institute for Health Research, through the National Cancer Research Network and NHS Funding to the NIHR Biomedical Research Centre.
We would like to thank all the REAL3 and MAGIC trial principal investigators, histopathologists, research nurses, trial coordinators and patients for their important contributions to this work.
We thank Clare Peckitt and Swaranali Gupta for providing additional statistical support for REAL3.
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On behalf of the NCRI Upper GI Clinical Studies Group.