Abstract
The epidermal growth factor receptor (EGFR)–targeted antibodies cetuximab, a chimeric monoclonal antibody (MoAb), and panitumumab, a fully humanized MoAb, are approved for metastatic colorectal cancer (mCRC) in the chemotherapy-refractory disease setting. 1 Gallagher DJ Kemeny N Second-line management of metastatic colorectal cancer. Clin Colorectal Cancer. 2008; 7: 25-32 Abstract Full Text PDF PubMed Scopus (5) Google Scholar In the first-line setting, 2 recent large randomized trials evaluated cetuximab combined with either FOLFOX (5-fluorouracil [5-FU]/leucovorin [LV]/oxaliplatin; OPUS; Oxaliplatin and Cetuximab in First-Line Treatment of mCRC) or FOLFIRI (5-FU/LV/irinotecan; CRYSTAL; Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer). Based on the intent-to-treat analyses of these trials, the survival benefit in an unselected patient population was modest with cetuximab plus FOLFIRI and absent with cetuximab plus FOLFOX. 2 Bokemeyer C Bondarenko I Makhson A et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009; 27: 663-671 Crossref PubMed Scopus (1458) Google Scholar , 3 Van Cutsem E Kohne CH Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360: 1408-1417 Crossref PubMed Scopus (3287) Google Scholar However, based on retrospective analyses of clinical trials that evaluated cetuximab or panitumumab, either as monotherapy or in combination regimens, in patients with mCRC in both the first-line and refractory settings, activating mutations in KRAS, a downstream target of EGFR and other cell receptors, were identified as a predictive biomarker for resistance to EGFR-targeted therapy. 2 Bokemeyer C Bondarenko I Makhson A et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009; 27: 663-671 Crossref PubMed Scopus (1458) Google Scholar , 3 Van Cutsem E Kohne CH Hitre E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360: 1408-1417 Crossref PubMed Scopus (3287) Google Scholar , 4 Amado RG Wolf M Peeters M et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008; 26: 1626-1634 Crossref PubMed Scopus (2775) Google Scholar , 5 Chu E Clinical colorectal cancer: “2008 - the year in review.”. Clin Colorectal Cancer. 2009; 8: 9-10 Abstract Full Text PDF PubMed Scopus (3) Google Scholar In these analyses, the addition of EGFR-targeted antibodies did not enhance progression-free survival (PFS) in patients whose tumors expressed mutant KRAS but significantly improved PFS in patients with wild-type KRAS tumors. Importantly, however, it should be noted that not all patients whose tumors express wild-type KRAS derive clinical benefit. In fact, up to 70%-80% of patients with wild-type KRAS will be resistant to anti-EGFR therapy. Thus, additional biomarkers involved in EGFR signaling such as B-Raf, which is downstream of KRAS, are being investigated. 6 Walther A Johnstone E Swanton C et al. Genetic prognostic and predictive markers in colorectal cancer. Nat Rev Cancer. 2009; 9: 489-499 Crossref PubMed Scopus (539) Google Scholar Recently, updated efficacy and biomarker analysis results from 2 phase III trials evaluating panitumumab or cetuximab in the first-line treatment of patients with metastatic KRAS wild-type colorectal tumors were presented at the American Society of Clinical Oncology (ASCO) 2010 Gastrointestinal Cancers Symposium held January 22-24, 2010, in Orlando, FL. 7 Siena S, Cassidy J, Tabernero J, et al. Randomized phase III study of panitumumab (pmab) with FOLFOX4 compared to FOLFOX4 alone as first-line treatment (tx) for metastatic colorectal cancer (mCRC): PRIME trial. Presented at: the 2010 ASCO Gastrointestinal Cancers Symposium; January 22-24, 2010; Orlando, FL. Abstract 283. Google Scholar , 8 Van Cutsem E, Lang I, Folprecht G, et al. Cetuximab plus FOLFIRI in the treatment of metastatic colorectal cancer (mCRC): The influence of KRAS and BRAF biomarkers on outcome: Updated data from the CRYSTAL trial. Presented at: the 2010 ASCO Gastrointestinal Cancers Symposium; January 22-24, 2010; Orlando, FL. Abstract 281. Google Scholar
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