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

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Date
2017-01
ICR Author
Cunningham, David
Marsden,
Author
Sclafani, F
Kim, TY
Cunningham, D
Kim, TW
Tabernero, J
Schmoll, HJ
Roh, JK
Kim, SY
Park, YS
Guren, TK
Hawkes, E
Clarke, SJ
Ferry, D
Frodin, J-E
Ayers, M
Nebozhyn, M
Peckitt, C
Loboda, A
Watkins, DJ
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Type
Journal Article
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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.
URI
https://repository.icr.ac.uk/handle/internal/785
DOI
https://doi.org/10.1002/ijc.30453
Collections
  • Clinical Studies
Subject
Humans
Colorectal Neoplasms
Camptothecin
Receptor, IGF Type 1
Insulin-Like Growth Factor I
Insulin-Like Growth Factor II
Antineoplastic Combined Chemotherapy Protocols
Antibodies, Monoclonal
Disease-Free Survival
Double-Blind Method
Mutation
Exons
Adult
Aged
Middle Aged
Female
Male
Proto-Oncogene Proteins p21(ras)
Antibodies, Monoclonal, Humanized
Cetuximab
Irinotecan
Research team
Medicine (RMH Smith Cunningham)
Language
eng
Date accepted
2016-08-19
License start date
2017-01
Citation
International journal of cancer, 2017, 140 (2), pp. 431 - 439

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