Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial

• Published in: The lancet oncology 2013-07, Vol.14 (8), p.749-759
• Main Authors: Seymour, Matthew T, Prof, Brown, Sarah R, PhD, Middleton, Gary, Prof, Maughan, Timothy, Prof, Richman, Susan, PhD, Gwyther, Stephen, FRCR, Lowe, Catherine, MA, Seligmann, Jennifer F, MBChB, Wadsley, Jonathan, MBBChir, Maisey, Nick, MD, Chau, Ian, MD, Hill, Mark, MD, Dawson, Lesley, MBChB, Falk, Stephen, MD, O'Callaghan, Ann, MBB Ch BAO, Benstead, Kim, MD, Chambers, Philip, PhD, Oliver, Alfred, LLB, Marshall, Helen, MSc, Napp, Vicky, BSc, Quirke, Phil, Prof
• Format: Article
• Language: English
• Subjects: Aged; Antibodies, Monoclonal - administration & dosage; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Cancer therapies; Chi-Square Distribution; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Disease-Free Survival; DNA Mutational Analysis; Drug Administration Schedule; Drug Resistance, Neoplasm - genetics; Female; Fluorouracil - therapeutic use; Hematology, Oncology and Palliative Medicine; Humans; Male; Medical research; Middle Aged; Mutation; Proportional Hazards Models; Prospective Studies; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Time Factors; Toxicity; Treatment Outcome; Tumors; United Kingdom
• ISSN: 1470-2045; 1474-5488
• DOI: 10.1016/S1470-2045(13)70163-3

Summary Background Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. Methods In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m2 intravenous irinotecan every 3 weeks (300 mg/m2 if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146 , BRAF, NRAS , and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. Results Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12–13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83–1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64–0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p