Cetuximab Alone or With Irinotecan for Resistant KRAS-, NRAS-, BRAF- and PIK3CA-wild-type Metastatic Colorectal Cancer: The AGITG Randomized Phase II ICECREAM Study

• Published in: Clinical colorectal cancer 2018-12, Vol.17 (4), p.313-319
• Main Authors: Shapiro, Jeremy D., Thavaneswaran, Subotheni, Underhill, Craig R., Robledo, Kristy P., Karapetis, Christos S., Day, Fiona L., Nott, Louise M., Jefford, Michael, Chantrill, Lorraine A., Pavlakis, Nick, Tebbutt, Niall C., Price, Timothy. J., Khasraw, Mustafa, Van Hazel, Guy A., Waring, Paul M., Tejpar, Sabine, Simes, John, Gebski, Val J., Desai, Jayesh, Segelov, Eva
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - genetics; Cetuximab; Cetuximab - administration & dosage; Chemotherapy colon cancer; Class I Phosphatidylinositol 3-Kinases - genetics; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Female; Follow-Up Studies; GTP Phosphohydrolases - genetics; Humans; Irinotecan; Irinotecan - administration & dosage; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Male; Membrane Proteins - genetics; Middle Aged; Mutation; Prognosis; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - genetics; RAS; Survival Rate
• ISSN: 1533-0028; 1938-0674
• DOI: 10.1016/j.clcc.2018.06.002

Most unresectable metastatic colon cancer remains incurable, with a median survival of less than 3 years. Molecularly targeted therapies have recently been developed; in particular, monoclonal antibodies against the epidermal growth factor receptor, which are efficacious in 40% to 60% of chemotherapy-resistant patients with wild-type KRAS. This study shows that cetuximab plus irinotecan, compared with cetuximab alone, increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation (ICECREAM) study assessed the efficacy of cetuximab monotherapy compared with cetuximab combined with chemotherapy for quadruple wild-type (KRAS, NRAS, BRAF, or P13KCA exon 20) metastatic colorectal cancer. Patients were enrolled in an open-label, multicenter, phase II trial and randomly assigned to cetuximab 400 mg/m2, then 250 mg/m2 cetuximab weekly, with or without irinotecan 180 mg/m2 every 2 weeks. The primary endpoint was 6-month progression-free survival; secondary endpoints were response rate, overall survival, toxicity, and quality of life. From 2012 to 2016, 48 patients were recruited. Two were ineligible, and 2 were not evaluable for response. Characteristics were balanced, except gender (male, 62% vs. 72%) and primary sidedness (left, 95% vs. 68%). For cetuximab compared with cetuximab-irinotecan, progression-free survival was 14% versus 41% (hazard ratio, 0.39; 95% confidence interval, 0.20-0.78; P = .008); response rate was 10% (2 partial responses) versus 38% (1 complete, 8 partial); P = .04. Grade 3 to 4 toxicities were less with cetuximab monotherapy (23% vs. 50%); global and specific quality of life scores did not differ. In comparison with cetuximab alone, cetuximab plus irinotecan increases the response rate and delays progression in irinotecan-resistant RAS wild-type colorectal cancer. This echoes data from molecularly unselected patients.