Dalotuzumab in chemorefractory KRAS exon 2 mutant colorectal cancer: Results from a randomised phase II/III trial.

Abstract

Limited data are available on the efficacy of anti-IGF-1R agents in KRAS mutant colorectal cancer (CRC). We analysed the outcome of 69 chemorefractory, KRAS exon 2 mutant CRC patients who were enrolled in a double-blind, randomised, phase II/III study of irinotecan and cetuximab plus dalotuzumab 10 mg/kg once weekly (arm A), dalotuzumab 7.5 mg/kg every second week (arm B) or placebo (arm C). Objective response rate (5.6% vs. 3.1% vs. 4.8%), median progression-free survival (2.7 vs. 2.6 vs. 1.4 months) and overall survival (7.8 vs. 10.3 vs. 7.8 months) were not statistically significantly different between treatment groups. Most common grade ≥3 treatment-related toxicities included neutropenia, diarrhoea, hyperglycaemia, fatigue and dermatitis acneiform. Expression of IGF-1R, IGF-1, IGF-2 and EREG by quantitative real-time polymerase chain reaction was assessed in 351 patients from the same study with available data on KRAS exon 2 mutational status. Median cycle threshold values for all biomarkers were significantly lower (i.e., higher expression, p < 0.05) among patients with KRAS wild-type compared to those with KRAS exon 2 mutant tumours. No significant changes were found according to location of the primary tumour with only a trend towards lower expression of IGF-1 in colon compared to rectal cancers (p = 0.06). Albeit limited by the small sample size, this study does not appear to support a potential role for anti-IGF-1R agents in KRAS exon 2 mutant CRC. Data on IGF-1R, IGF-1 and IGF-2 expression here reported may be useful for patient stratification in future trials with inhibitors of the IGF pathway.

• Authors: Francesco Sclafani, Tae Y Kim, David Cunningham, Tae W Kim, Josep Tabernero, Hans J Schmoll, Jae K Roh, Sun Y Kim, Young S Park, Tormod K Guren, Eliza Hawkes, Stephen J Clarke, David Ferry, Jan-Erik Frodin, Mark Ayers, Michael Nebozhyn, Clare Peckitt, Andrey Loboda, David J Watkins
• Journal: International journal of cancer (Int J Cancer) Vol. 140 Issue 2 Pg. 431-439 (Jan 15 2017) ISSN: 1097-0215 [Electronic] United States
• PMID: 27681944 (Publication Type: Clinical Trial, Phase II, Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial)
• Copyright: © 2016 UICC.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• KRAS protein, human
• Insulin-Like Growth Factor I
• Insulin-Like Growth Factor II
• dalotuzumab
• Irinotecan
• Receptor, IGF Type 1
• Proto-Oncogene Proteins p21(ras)
• Cetuximab
• Camptothecin

Topics

• Adult
• Aged
• Antibodies, Monoclonal (therapeutic use)
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives)
• Cetuximab (administration & dosage)
• Colorectal Neoplasms (drug therapy, genetics)
• Disease-Free Survival
• Double-Blind Method
• Exons (genetics)
• Female
• Humans
• Insulin-Like Growth Factor I (genetics)
• Insulin-Like Growth Factor II (genetics)
• Irinotecan
• Male
• Middle Aged
• Mutation (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Receptor, IGF Type 1 (genetics)