Explaining the Unexplainable: EGFR Antibodies in Colorectal Cancer

Abstract

Cetuximab and panitumumab, monoclonal antibodies (mAbs) against the epidermal growth factor receptor (EGFR), have demonstrated efficacy in the treatment of advanced colorectal cancer as single agents and in combination with conventional chemotherapy. Since the US Food and Drug Administration approval of cetuximab in 2004 and panitumumab in 2006, EGFR mAbs have become standard components of treatment algorithms for this disease. The discovery of KRAS mutations as a negative predictive marker for this class of agents in colorectal cancer has rapidly been integrated into clinical practice and has opened the door for a new era in translational and clinical research. In KRAS wild-type colorectal cancer, EGFR mAbs have documented activity in various therapeutic settings and have been successfully combined with different chemotherapy backbones in randomized trials, including irinotecanand oxaliplatin-based regimens. Until recently, the body of evidence from randomized trials suggested that (1) EGFR mAbs as single agents or in combination with chemotherapy showed activity only in KRAS wild-type colorectal cancer; (2) the observed improvement of progression-free survival (PFS) was independent of the line of therapy in which the EGFR mAb was used; (3) the increased response rate with EGFR mAbs in patients with KRAS wild-type tumors was observed even in trials that did not meet their time-related end points of PFS or overall survival (OS); and (4) cetuximab and panitumumab had interchangeable activity. Several questions remained, however, despite extensive clinical experience with EGFR antibodies. The negative data of the large COIN (Continuous Chemotherapy Plus Cetuximab, or Intermittent Chemotherapy With Standard Continuous Palliative Combination Chemotherapy With Oxaliplatin and a Fluoropyrimidine in First-Line Treatment of Metastatic Colorectal Cancer) trial, which investigated cetuximab added to an oxaliplatin-based chemotherapy backbone, seemed to contrast with the positive data of the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial, which used an irinotecan-based regimen. These findings suggested that there may be a preferred chemotherapy partner for EGFR antibodies. In addition, the randomized phase II trial, OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer), demonstrated that the use of cetuximab in combination with oxaliplatin-based treatment for KRAS-mutated colorectal cancer appeared to have a detrimental effect. Eventually, the well-conducted first-line phase III PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) trial, which investigated the addition of panitumumab to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX), appeared to clarify the situation by demonstrating that in KRAS wild-type cancers, an EGFR mAb can indeed add efficacy to a FOLFOX backbone. In addition, PRIME also confirmed that, in KRAS-mutated colorectal cancers, the use of an EGFR mAb added to chemotherapy can decrease efficacy. Although this detrimental effect in KRAS-mutated cancers was initially thought to be linked only to an oxaliplatin-based chemotherapy backbone, recently presented data from the second-line phase III trial PICCOLO (Panitumumab, Irinotecan & Ciclosporin in Colorectal Cancer Therapy; irinotecan with or without panitumumab) demonstrated a similar negative effect on PFS and response rate in this group of patients. In the adjuvant setting, the addition of cetuximab to FOLFOX did not improve outcomes in stage III colon cancer, not even in patients with KRASwild-typetumors. InKRAS-mutatedstageIIIcancers, cetuximab was associated with inferior outcome, mirroring the detrimental effect observed in some trials in the metastatic setting. The most recent National Comprehensive Cancer Network guidelines suggest that cetuximab should be not combined with oxaliplatin. The guidelines, however, somewhat inconsistently do allow the use of panitumumab in combination with FOLFOX, on the basis of results from the PRIME trial. The NORDIC (5-Fluorouracil/Folinate/Oxaliplatin [Eloxatin] [FLOX Regimen] Given Continuously or Intermittently, in Combination With Cetuximab [Erbitux] in First-Line Treatment of Metastatic Colorectal Cancer) trial published in this issue of Journal of Clinical Oncology now adds another layer of confusion to the already complex and somewhat inconsistent results on the use of EGFR mAbs in colorectal cancer. In this first-line phase III study, cetuximab was added to bolus fluorouracil (FU)/leucovorin plus oxaliplatin (FLOX), a combination regimen commonly used in Scandinavia, but not in other parts of the world. The primary end point of the trial was PFS, with secondary end points of OS, response rate, R0-resection rate of metastases, and safety. During the conduct of the trial, KRAS mutation emerged as a negative predictive marker for EGFR mAbs, and a prospective KRAS status–based outcomes analysis was integrated into the trial, but no adjustment of the sample size was performed. In the end, the number of patients in the two main comparison arms, FLOX with JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 15 MAY 2