Exploring better strategies for EGFR antibodies in colon cancer
Authors: Andrés Cervantes
Journal: The Lancet Oncology (2014)

Treatment of advanced colon cancer has improved over the past 15 years. Until the late 1990s, colorectal cancer was considered a chemoresistant disease, for which only fluorouracil could be offered as a palliative treatment. However, many options are available today. The combination of chemotherapy and biological drugs—including anti-EGFR or anti-VEGF antibodies—for first-line treatment, as well as the sequencing of different active drugs as disease progresses, can significantly improve outcomes.1Schmoll HJ van Cutsem E Stein A et al.ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making.Ann Oncol. 2012; 23: 2479-2515Summary Full Text Full Text PDF PubMed Scopus (1168) Google Scholar Median survival of patients included in clinical trials is often more than 2 years. Patients with initially unresectable metastatic disease limited to the liver can become resectable after treatment, with an opportunity for cure.2Adam R De Gramont A Figueras J et al.The oncosurgery approach to managing liver metastases from colorectal cancer: a multidisciplinary international consensus.Oncologist. 2012; 17: 1225-1239Crossref PubMed Scopus (424) Google Scholar Nevertheless, despite these advances, the optimal treatment for patients with advanced colorectal cancer in clinical practice is not yet defined. Present subjects of debate include how to sequence different schedules of chemotherapy and biological treatment, duration of treatment, and how to personalise treatment. Predictive biomarkers can help doctors to select patients for individualised treatment. The addition of mutations in NRAS and KRAS exons 3 and 4 to the conventional exon 2 KRAS mutations increases predictive value. Patients with all RAS wild-type tumours benefit greatly from treatment with the anti-EGFR antibodies cetuximab and panitumumab, whereas these drugs are harmful to patients with mutations in RAS.3Douillard JY Oliner KS Siena S et al.Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.N Eng J Med. 2013; 369: 1023-1034Crossref PubMed Scopus (1803) Google Scholar, 4Stintzing S, Jung A, Rossius L, et al. Analysis of KRAS/NRAS and BRAF mutations in FIRE-3: a randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients. European Cancer Congress 2013; Amsterdam, Netherlands; Sept 27–Oct 1, 2013.Google Scholar Moreover, no validated predictive biomarkers have been identified for anti-angiogenic drugs. In this setting, Harpreet Wasan and colleagues5Wasan H Meade A Adams R et al.Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trial.Lancet Oncol. 2014; (published online April 3.)http://dx.doi.org/10.1016/S1470-2045(14)70106-8Google Scholar assessed two cetuximab regimens in combination with intermittent chemotherapy with FOLFOX (folinic acid and oxaliplatin followed by bolus and infused fluorouracil) as the backbone in a randomised phase 2 trial. Only patients with KRAS exon 2 wild-type were eligible. Retrospectively, they also analysed NRAS, BRAF, and other KRAS mutations. Their results from the previous COIN trial6Adams RA Meade AM Seymour MT et al.Intermittent versus continuous and fluoropyrimidine combination chemotherapy for first-line treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.Lancet Oncol. 2011; 12: 642-653Summary Full Text Full Text PDF PubMed Scopus (205) Google Scholar show that intermittent oxaliplatin-based combinations are effective without causing any significant detrimental effect on survival. However, despite this evidence, clinicians do not always consider fully stopping chemotherapy after 12 weeks. Although oxaliplatin is halted when neurotoxicity occurs, or after 6 months of therapy, fluoropyrimidines and biological drugs are usually maintained until disease progression. In the COIN-B trial, the investigators challenged this strategy, assessing continuous and intermittent cetuximab when added to intermittent chemotherapy. In the intermittent cetuximab group, chemotherapy and cetuximab were only reintroduced on RECIST progression, which was assessed every 12 weeks after stopping treatment. In the maintenance cetuximab group, after 12 weeks of FOLFOX all patients continued with weekly cetuximab and only on RECIST progression was FOLFOX reintroduced. The outcomes in each group in COIN-B should not be compared, since each group was powered as a separate phase 2 trial. The primary outcome was failure-free survival at 10 months among patients who completed 12 weeks of treatment without progression, death, or leaving the trial for other reasons. The threshold that would lead to the regimens being tested in a conventional phase 3 design was a failure-free survival of 50% at 10 months. This measure was met for both groups (50% for the intermittent cetuximab group and 52% for the continuous cetuximab group) in patients who had wild-type KRAS. These results were even better—as expected—for patients who also had wild-type NRAS, and BRAF. These data show the need for proper molecular classification of colorectal cancer, which would enable clinicians to select the most effective treatment for patients. The ideal approach would be to select from all patients with wild-type genes those with tumours that are EGFR-driven and which would therefore benefit most from complete inhibition of EFGR. Some attempts at an effective classification have already been made, but further validation in clinical trials is needed.7Tian S Simon I Moreno V et al.A combined oncogenic pathway signature of BRAF, KRAS and PI3KCA mutation improves colorectal cancer classification and cetuximab treatment prediction.Gut. 2013; 62: 540-549Crossref PubMed Scopus (116) Google Scholar, 8Roepman P Schlicker A Tabernero J et al.Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition.Int J Cancer. 2014; 134: 552-562Crossref PubMed Scopus (256) Google Scholar, 9Sadanandam A Lyssiotis CA Homicsko K et al.A colorectal cancer classification system that associates cellular phenotype and responses to therapy.Nat Med. 2013; 19: 519-525Crossref PubMed Scopus (736) Google Scholar Another subject for further study is the dynamic process of clonal evolution in tumours. Under the selection pressure of continuous treatment, emerging RAS mutant clones could cause resistance to anti-EGFR antibodies.10Diaz Jr, LA Williams RT Wu J et al.The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancer.Nature. 2012; 486: 537-540Crossref PubMed Scopus (1384) Google Scholar Intermittent treatment might help to prevent the emergence of such clones. Liquid biopsies might identify the emergence of mutant clones and might also be useful for designing trials of biological treatments.11Diaz Jr, LA Bardelli A Liquid biopsies: genotyping circulating tumor DNA.J Clin Oncol. 2014; 32: 579-586Crossref PubMed Scopus (1659) Google Scholar We agree with the COIN-B investigators that their results cannot be translated into clinical practice without further validation in randomised phase 3 trials. However, COIN-B provides a clear hypothesis to test. Patients with EGFR-dependent tumours might need chemotherapy for only a short induction period followed by cetuximab maintenance or reintroduction on progression. MRC FOCUS 4, a molecularly stratified, multisite randomised trial of patients with colorectal cancer—which has already started accrual in the UK—might help to define the best strategy to use. I have received personal fees and non-financial support from Merck Serono and personal fees from Amgen. Intermittent chemotherapy plus either intermittent or continuous cetuximab for first-line treatment of patients with KRAS wild-type advanced colorectal cancer (COIN-B): a randomised phase 2 trialCetuximab was safely incorporated in two first-line intermittent chemotherapy strategies. Maintenance of biological monotherapy, with less cytotoxic chemotherapy within the first 6 months, in molecularly selected patients is promising and should be validated in phase 3 trials. Full-Text PDF Open Access