Dalotuzumab in chemorefractory KRAS exon 2 mutant colorectal cancer: Results from a randomised phase II/III trial.
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.
The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
Francesco
F
Sclafani
Seoul National University College of Medicine, Seoul, Korea.
Tae Y
TY
Kim
The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
David
D
Cunningham
Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
Tae W
TW
Kim
Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
Josep
J
Tabernero
Department of Internal Medicine, University Clinic Halle (Saale), Martin Luther University Halle-Wittenberg, Halle, Germany.
Hans J
HJ
Schmoll
College of Medicine, Yonsey Cancer Center, Yonsey University, Seoul, Korea.
Jae K
JK
Roh
Center for Colorectal Cancer, National Cancer Center, Seoul, Korea.
Sun Y
SY
Kim
Department of Medicine, Division of Hematology/Oncology, Samsung Medical Center, Seoul, Korea.
Young S
YS
Park
Department of Oncology and K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
Tormod K
TK
Guren
The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
Eliza
E
Hawkes
Concord Repatriation General Hospital, Concord, Sydney, Australia.
Stephen J
SJ
Clarke
New Cross Hospital, Wolverhamptom, United Kingdom.
David
D
Ferry
Karolinska University Hospital, Stockholm, Sweden.
Jan-Erik
JE
Frodin
Merck & Co, Inc, Whitehouse Station, NJ.
Mark
M
Ayers
Merck & Co, Inc, Whitehouse Station, NJ.
Michael
M
Nebozhyn
The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
Clare
C
Peckitt
Merck & Co, Inc, Whitehouse Station, NJ.
Andrey
A
Loboda
The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
David J
DJ
Watkins
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C569480:dalotuzumab; D000077146:Irinotecan; D017526:Receptor, IGF Type 1; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002166:Camptothecin
EREG; IGF-1; IGF-1R; IGF-2; KRAS exon 2 mutation; cetuximab; chemorefractory colorectal cancer; dalotuzumab