Dalotuzumab in Chemorefractory KRAS Exon 2 Mutant Colorectal Cancer: Results From a Randomised Phase II/III Trial

Int J Cancer. 2017 Jan 15;140(2):431-439. doi: 10.1002/ijc.30453. Epub 2016 Oct 17.

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.

Keywords: EREG; IGF-1; IGF-1R; IGF-2; KRAS exon 2 mutation; cetuximab; chemorefractory colorectal cancer; dalotuzumab.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Cetuximab / administration & dosage
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / 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

Substances

  • 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