Conde (Virgen de las Nieves Hospital, Granada), E. adverse events were diarrhoea and rash (18.0% each), hypomagnesaemia and asthenia (8.2% each). Conclusions The addition of panitumumab to irinotecan as salvage therapy is feasible but has limited activity in irinotecan-refractory metastatic colorectal EPSTI1 cancer. No biomarkers predictive of response were identified. mutational status, with the efficacy benefits of cetuximab treatment in metastatic CRC (mCRC) patients being confined to tumours wild-type for codons 12 and 13, while mutations predict adverse outcomes with panitumumab-FOLFOX treatment.5,6 Furthermore, benefit with anti-EGFR antibodies in combination with chemotherapy as front-line therapy in patients with wild-type mCRC, is greatest in patients with left-sided tumours,7 with similar effects in later lines.8,9 Few options exist for patients with irinotecan-refractory mCRC. Over a decade ago, the pivotal BOND study demonstrated that the addition of EGFR-targeted cetuximab to irinotecan restored chemotherapy sensitivity in a patient population previously treated with irinotecan, most of whom had received at least two prior therapy lines.10 A significantly higher response rate was Ro 61-8048 seen for the combination (22.9% versus 10.8% with irinotecan alone, exon-2 mCRC patients progressing on irinotecan-based therapy. Efficacy was analysed in terms of response rate, PFS and OS, along with evaluation of patient characteristics and genetic alterations as potential biomarkers predictive of benefit. Methods Patients Adult patients aged 18 years with histologically-confirmed metastatic adenocarcinoma of the colon or rectum and wild-type (codons 12 and 13; allelic discrimination, investigator-evaluated) were eligible. Patients had to have progressed (by radiographic imaging) during or within 3 months after irinotecan-based therapy, either 180?mg/m2 every 2 weeks (single-agent or FOLFIRI) or 350?mg/m2 every 3 weeks (single-agent), and have received irinotecan for at least 6 weeks, with no more than two dose reductions. In addition, one or more measurable lesion, a Karnofsky performance status of at least 70%, adequate haematological, hepatic and renal function, and serum magnesium and calcium levels within normal limits were required. Prior anti-EGFR therapy was not permitted. Patients provided written informed consent prior to enrolment. Study design This phase 2 single-arm, open-label study was performed in Ro 61-8048 12 Spanish centres. Patients received panitumumab (6?mg/kg, 60-min infusion) followed by irinotecan (180?mg/m2, 90-min infusion) every 2 weeks. For patients who had received a reduced dose with prior irinotecan therapy, this dose was maintained, Ro 61-8048 and for patients who had received 350?mg/m2 irinotecan every 3 weeks, the equivalent every-2-weeks dose was used. In the event of grade 3C4 related events or skin or nail toxicity requiring treatment or considered intolerable, panitumumab was withheld and the dose reduced (to 4.8 then 3.2?mg/kg), while irinotecan was maintained. If irinotecan was delayed, panitumumab was also delayed (maximum of 1 1 month). Panitumumab monotherapy was permitted after irinotecan discontinuation but not vice versa. Patients who underwent curative metastatic resection could continue in the study 4 weeks later. Patients continued treatment until progression or unacceptable toxicity. Efficacy and safety assessments Tumour response was evaluated by computerised tomography scan and/or magnetic resonance imaging according to the modified Response Evaluation Criteria in Solid Tumours (m-RECIST).11 Response was assessed every 6 weeks during the first 6 months and every 2 months thereafter until progression or withdrawal. Responses were confirmed at least 1 month after the criteria were first met. After discontinuation, patients without progression were followed-up every 6 weeks until progression, and progressing patients were followed-up every 3 months. Adverse events (AEs) were graded according to NCI-CTCAE v3.0. Biomarker analysis Tumour blocks were reviewed centrally. DNA and RNA were extracted using QIAamp? DNA FFPE Tissue and RNeasy? FFPE kits and analysed with a Nanodrop? ND1000. Mutations in codons 61, 117 and 146, and codons 12, 13, 61, 117 and 146 were detected by pyrosequencing. Mutations in (V600E) and (R88Q, N345k, C420R, E542K, E545D, E545K, M1043I, H1047R and H1047Y) were detected by real-time PCR cobas? Mutation Tests. and mRNA expression was evaluated by real-time PCR with TaqMan? Gene Expression assays. ROC curves were.