Phase II study of necitumumab plus modified FOLFOX6 as first-line treatment in patients with locally advanced or metastatic colorectal cancer

Colorectal cancer (CRC) is the third most common form of cancer in men and the second most common form of cancer in women worldwide (Ferlay et al, 2013). An estimated annual total of 1.4 million cases will be diagnosed, leading to ∼694 000 deaths per year (∼8.5% of all cancer-related deaths). Approximately, 25% of CRC cases are overtly metastatic at diagnosis, and ∼50% of patients will ultimately develop recurrent or metastatic disease (Van Cutsem et al, 2014). Many phase II–III trials have investigated the addition of an epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) to a first-line FOLFOX (oxaliplatin, folinic acid and 5-fluorouracil (5-FU)) combination in patients with KRAS exon 2 wild-type metastatic CRC (mCRC). The phase III PRIME study (Douillard et al, 2010, 2014) and the randomised phase II OPUS study (Bokemeyer et al, 2011) evaluated the FOLFOX4 regimen in combination with panitumumab and cetuximab, respectively. In these studies, objective response rate (ORR) and progression-free survival (PFS) were significantly improved with the addition of an EGFR mAb to FOLFOX4 among patients with tumours assessed as wild type at codons 12 and 13 of KRAS exon 2; in the PRIME study, a significant improvement in overall survival (OS) was also observed. Extended mutation analyses of additional tumour RAS loci (KRAS exons 3 and 4, and NRAS exons 2, 3 and 4) suggested that the efficacy benefit was further restricted to patients with tumours wild type at all screened loci (Douillard et al, 2013; Bokemeyer et al, 2015). In both the PRIME and OPUS studies, a negative effect on efficacy was reported from combining an EGFR mAb with FOLFOX4 among patients whose tumours harboured a RAS mutation (Douillard et al, 2010, 2013; Bokemeyer et al, 2011, 2015). On the basis of additional evidence showing anti-EGFR antibodies were unlikely to benefit patients with this disease whose tumours carry KRAS mutations (Amado et al, 2008; Karapetis et al, 2008), the phase III COIN trial evaluated the addition of cetuximab to oxaliplatin-based chemotherapy (oxaliplatin plus capecitabine or oxaliplatin plus fluorouracil and folinic acid) in first-line treatment of patients with advanced CRC with KRAS wild-type tumours (Maughan et al, 2011). In this trial, cetuximab increased the response rate; no evidence of benefit in PFS or OS was seen. On the basis of these data, FOLFOX4 in combination with either panitumumab or cetuximab is recommended in Europe and the United States for the first-line treatment of patients with RAS wild-type mCRC only (NCCN). Necitumumab (LY3012211; IMC-11F8) is a second-generation recombinant human EGFR mAb of the immunoglobulin G1 class, which demonstrates a high affinity for EGFR and blocks ligand-induced receptor phosphorylation and downstream signalling (Liu et al, 2004). In vitro studies further demonstrate that necitumumab inhibits EGFR-dependent tumour cell proliferation, and can exert cytotoxic effects in tumour cells through antibody-dependent cell-mediated cytotoxicity. Necitumumab has also been shown to block tumour growth in CRC xenograft models in combination with chemotherapy (Prewett et al, 2004). The dose and treatment schedule used for necitumumab in the current study was based on safety and pharmacokinetic data from a phase I study in 60 heavily pretreated patients with advanced solid tumours (Kuenen et al, 2010). This study established the maximum tolerated dose of necitumumab and the recommended dose for further clinical development to be 800 mg, administered intravenously (i.v.), either weekly or every second week. The major dose-limiting toxicity was grade 3 headache. The most common drug-related adverse events (AEs) were typical for this class of agent and consisted predominantly of skin reactions, headache, nausea/vomiting, and fatigue (mostly grade 1 or 2). Importantly, no hypersensitivity or infusion reactions associated with necitumumab were reported in this trial. The present phase II study was designed to investigate necitumumab in combination with a modified version of the FOLFOX6 regimen (mFOLFOX6) and was initiated following preliminary reports (later reported in full) of encouraging activity and safety associated with cetuximab in combination with oxaliplatin-based chemotherapy (Tabernero et al, 2007; Boccia et al, 2010). Evidence at that time from small single-arm studies in chemorefractory mCRC suggested that responses to treatment with cetuximab were confined to patients whose tumours did not harbour KRAS codon 12 or 13 (exon 2) mutations (Di Fiore et al, 2007; De Roock et al, 2008; Lievre et al, 2008). These findings were later confirmed in larger randomised studies conducted in the first-line setting (Bokemeyer et al, 2011; Van Cutsem et al, 2011; Douillard et al, 2014). Accordingly, in March 2008, the protocol for the present study was amended to include evaluation of tumour mutation status at KRAS codons 12 and 13 among enrolled patients.