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Medline ® Abstract for Reference 42

of 'Systemic chemotherapy for nonoperable metastatic colorectal cancer: Treatment recommendations'

Response to Cetuximab With or Without Irinotecan in Patients With Refractory Metastatic Colorectal Cancer Harboring the KRAS G13D Mutation: Australasian Gastro-Intestinal Trials Group ICECREAM Study.
Segelov E, Thavaneswaran S, Waring PM, Desai J, Robledo KP, Gebski VJ, Elez E, Nott LM, Karapetis CS, Lunke S, Chantrill LA, Pavlakis N, Khasraw M, Underhill C, Ciardiello F, Jefford M, Wasan H, Haydon A, Price TJ, van Hazel G, Wilson K, Simes J, Shapiro JD
J Clin Oncol. 2016;34(19):2258.
PURPOSE: RAS mutations predict lack of response to epidermal growth factor receptor monoclonal antibody therapy in patients with metastatic colorectal cancer (mCRC), but preclinical studies and retrospective clinical data suggest that patients with tumors harboring the exon 2 KRAS G13D mutation may benefit from cetuximab. We aimed to assess cetuximab monotherapy and cetuximab plus irinotecan in patients with molecularly selected (G13D mutation) chemotherapy-refractory mCRC in a randomized phase II trial of this rare molecular subtype.
PATIENTS AND METHODS: Patients with chemotherapy-refractory KRAS G13D mutation-positive mCRC who had progressed within 6 months of irinotecan therapy were randomly assigned to cetuximab 400 mg/m(2) loading dose and then 250 mg/m(2) once per week with or without irinotecan 180 mg/m(2) once every 2 weeks. The primary end point was 6-month progression-free survival; secondary end points were response rate, overall survival, quality of life, and toxicity.
RESULTS: Fifty-one of 53 patients recruited over 2 years were eligible. The 6-month progression-free survival rate was 10% (95% CI, 2% to 26%) for cetuximab versus 23% (95% CI, 9% to 40%) for cetuximab plus irinotecan with a hazard ratio of 0.74 (95% CI, 0.42 to 1.32). Response and stable disease rates were 0% and 58% for monotherapy versus 9% and 70% for combination treatment, respectively. Overall survival and quality of life were similar; toxicities were higher with combination therapy.
CONCLUSION: In patients with G13D-mutated chemotherapy-refractory mCRC, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM (Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Among Patients with a G13D Mutation) study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.
Eva Segelov, St Vincent's Clinical School, University of New South Wales; Subotheni Thavaneswaran, Kristy P. Robledo, Val J. Gebski, Mustafa Khasraw, Kate Wilson, and John Simes, National Health and Medical Research Council Clinical Trials Centre (NHMRC), University of Sydney; Lorraine A. Chantrill, Macarthur Cancer Therapy Centre, Campbelltown Hospital and Kinghorn Cancer Centre; Nick Pavlakis and Mustafa Khasraw, Royal North Shore Hospital University of Sydney, Sydney; Paul M. Waring and Sebastian Lunke, Centre for Translational Pathology, University of Melbourne; Jayesh Desai, Royal Melbourne Hospital; Jayesh Desai and Michael Jefford, Peter MacCallum Cancer Centre; Andrew Haydon, Alfred Hospital; Jeremy D. Shapiro, Cabrini Hospital, Melbourne; Louise M. Nott, Royal Hobart Hospital, Hobart; Christos S. Karapetis, Flinders University and Flinders Medical Centre; Timothy J. Price, Queen Elizabeth Hospital and Lyell McEwin Hospital, Adelaide; Craig Underhill, Border Medical Oncology, Albury-Wodonga; Guy van Hazel, Sir Charles Gairdner Hospital, Perth, Australia; Elena Elez, Vall d'Hebron University Hospital, Barcelona, Spain; Fortunato Ciardiello, Seconda Universitàdegli Studi di Napoli, Naples, Italy; and Harpreet Wasan, Hammersmith Hospital, London,United Kingdom. e.segelov@unsw.edu.au.