Managing advanced colorectal cancer: have we reached the PEAK with current therapies?

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During the past 20 years, median overall survival (OS) for patients with metastatic colorectal cancer (CRC) has steadily improved from 10 to 12 months to greater than 24 months, due in large part to approval of eight new therapeutic agents. Yet, as we have observed in other diseases, the benefits of empiric therapies without regard to molecular subtype has limits, and CRC remains a leading cause of cancer-related death in the United States. In the article that accompanies this editorial, results of the PEAK (Panitumumab Efficacy in Combination With mFOLFOX6 Against Bevacizumab Plus mFOLOFOX6 in Metastatic CRC Subjects With Wild-Type KRAS Tumors) trial are reported. In this phase II study, 285 patients with previously untreated, KRAS exon 2 wild-type, metastatic CRC were randomly assigned to receive FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) plus panitumumab versus FOLFOX plus bevacizumab. The specified primary objective was to estimate progression-free survival (PFS) for panitumumab relative to bevacizumab in combination with FOLFOX. In this regard, PFS was similar between the panitumumab and bevacizumab arms, with median PFS times of 10.9 and 10.1 months, respectively. Thus, the primary result of this trial does not suggest a difference in controlling disease progression for one regimen versus the other in the primary analysis population. However, further results of interest are provided in secondary analyses, including evaluation of additional end points and examination of patient subgroups stratified by extended RAS testing (KRAS and NRAS exons 2-4, but not BRAF exon 15). In the first-line treatment of metastatic CRC, studies have demonstrated similar efficacy for FOLFIRI (infusional fluorouracil, leucovorin, irinotecan), FOLFOX, and CAPOX (capecitabine and oxaliplatin). However, whether to add an inhibitor of angiogenesis, such as bevacizumab, or a monoclonal antibody to the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, to first-line treatment programs has remained unclear. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor A that has demonstrated improved PFS and OS when added to IFL (bolus fluorouracil, leucovorin, irinotecan) and improved PFS with a trend toward improved OS when added to FOLFOX or CAPOX in the first-line treatment of metastatic CRC. Given that validated predictive biomarkers are not available for antiangiogenic therapy, bevacizumab-containing treatment programs have been widely adopted for patients with metastatic CRC, independent of tumor mutations identified by genomic profiling. The efficacy of anti-EGFR monoclonal antibodies first emerged in the setting of previously treated metastatic CRC, and two randomized trials demonstrated modest improvements in survival for cetuximab or panitumumab as monotherapy compared with placebo. Soon after these results became available, mutations in exon 2 (codons 12 and 13) of the KRAS oncogene emerged as predictive biomarkers for intrinsic resistance to anti-EGFR therapy. KRAS encodes a small GTPase protein that integrates signals from cell surface receptors such as EGFR to regulate cell growth and division. Mutations in KRAS lead to persistent binding of GTP and constitutive activation of the protein. In a multitude of studies, the presence of these mutations was noted to confer resistance to anti-EGFR therapy, rapidly leading to a change in practice whereby these agents were limited to patients without KRAS exon 2 mutations. Nevertheless, clinical trials have not consistently demonstrated benefit to anti-EGFR antibodies in the first-line setting, even among patients with KRAS exon 2 wild-type tumors. The CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) trial evaluated the addition of cetuximab to FOLFIRI, demonstrating improved PFS and OS among patients with KRAS exon 2 wild-type tumors receiving cetuximab. The PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) study randomly assigned patients to FOLFOX with or without panitumumab, demonstrating improved PFS and a trend toward improved OS for the panitumumab arm among patients with KRAS exon 2 wild-type tumors. However, the NORDIC-VII and MRC COIN studies demonstrated no improvements in outcome measures for the addition of cetuximab to a fluoropyrimidine and oxaliplatin in this same molecularly defined patient subgroup (NORDIC-VII: 5-Fluorouracil/Folinate/Oxaliplatin [FLOX Regimen], Given Continuously or Intermittently, in Combination With Cetuximab, in First-Line Treatment of Metastatic Colorectal Cancer; and MRC COIN: Medical Research Council 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). Given that anti-EGFR monoclonal antibodies clearly have activity against CRC, the mixed results from these studies have left us to ponder whether more comprehensive analysis of the CRC genome JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 21 JULY 2