A Randomized Phase II/III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory, KRAS Wild-Type, Metastatic Colorectal Cancer

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; Steven J Clarke; David Ferry; Jan-Erik Frödin; Mark Ayers; Michael Nebozhyn; Clare Peckitt; Andrey Loboda; David J Mauro; David J Watkins

doi:10.1093/jnci/djv258

A Randomized Phase II/III Study of Dalotuzumab in Combination With Cetuximab and Irinotecan in Chemorefractory, KRAS Wild-Type, Metastatic Colorectal Cancer

J Natl Cancer Inst. 2015 Sep 23;107(12):djv258. doi: 10.1093/jnci/djv258. Print 2015 Dec.

Authors

Francesco Sclafani¹, Tae Y Kim¹, David Cunningham², Tae W Kim¹, Josep Tabernero¹, Hans J Schmoll¹, Jae K Roh¹, Sun Y Kim¹, Young S Park¹, Tormod K Guren¹, Eliza Hawkes¹, Steven J Clarke¹, David Ferry¹, Jan-Erik Frödin¹, Mark Ayers¹, Michael Nebozhyn¹, Clare Peckitt¹, Andrey Loboda¹, David J Mauro¹, David J Watkins¹

Affiliations

¹ The Royal Marsden NHS Foundation Trust, London and Surrey, UK (FS, DC, EH, CP, DJW); Seoul National University College of Medicine, Seoul, Korea (TYK); Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (TWK); Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain (JT); University Clinic Halle (Saale), Martin Luther University Halle-Wittenberg, Halle, Germany (HJS); Yonsey Cancer Center, Yonsey University, College of Medicine, Seoul, Korea (JKR); Center for Colorectal Cancer, National Cancer Center, Seoul, Korea (SYK); Samsung Medical Center, Seoul, Korea (YSP); Oslo University Hospital, Oslo, Norway (TKG); Concord Repatriation General Hospital, Concord, Sydney, Australia (SJC); New Cross Hospital, Wolverhamptom, UK (DF); Karolinska University Hospital, Stockholm, Sweden (JEF); Merck & Co., Inc., Whitehouse Station, NJ (MA, MN, AL, DJM).
² The Royal Marsden NHS Foundation Trust, London and Surrey, UK (FS, DC, EH, CP, DJW); Seoul National University College of Medicine, Seoul, Korea (TYK); Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (TWK); Vall d'Hebron University Hospital, Universitat Autònoma de Barcelona, Barcelona, Spain (JT); University Clinic Halle (Saale), Martin Luther University Halle-Wittenberg, Halle, Germany (HJS); Yonsey Cancer Center, Yonsey University, College of Medicine, Seoul, Korea (JKR); Center for Colorectal Cancer, National Cancer Center, Seoul, Korea (SYK); Samsung Medical Center, Seoul, Korea (YSP); Oslo University Hospital, Oslo, Norway (TKG); Concord Repatriation General Hospital, Concord, Sydney, Australia (SJC); New Cross Hospital, Wolverhamptom, UK (DF); Karolinska University Hospital, Stockholm, Sweden (JEF); Merck & Co., Inc., Whitehouse Station, NJ (MA, MN, AL, DJM). david.cunningham@rmh.nhs.uk.

PMID: 26405092
DOI: 10.1093/jnci/djv258

Abstract

Background: Insulin-like growth factor type 1 receptor (IGF-1R) mediates resistance to epidermal growth factor receptor (EGFR) inhibition and may represent a therapeutic target. We conducted a multicenter, randomized, double blind, phase II/III trial of dalotuzumab, an anti-IGF-1R monoclonal antibody, with standard therapy in chemo-refractory, KRAS wild-type metastatic colorectal cancer.

Methods: Eligible patients were randomly assigned to dalotuzumab 10mg/kg weekly (arm A), dalotuzumab 7.5mg/kg every alternate week (arm B), or placebo (arm C) in combination with cetuximab and irinotecan. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints included exploratory biomarker analyses. All statistical tests were two-sided.

Results: The trial was prematurely discontinued for futility after 344 eligible KRAS wild-type patients were included in the primary efficacy population (arm A = 116, arm B = 117, arm C = 111). Median PFS was 3.9 months in arm A (hazard ratio [HR] = 1.33, 95% confidence interval [CI] = 0.98 to 1.83, P = .07) and 5.4 months in arm B (HR = 1.13, 95% CI = 0.83 to 1.55, P = .44) compared with 5.6 months in arm C. Median OS was 10.8 months in arm A (HR = 1.41, 95% CI = 0.99 to 2.00, P = .06) and 11.6 months in arm B (HR = 1.26, 95% CI = 0.89 to 1.79, P = .18) compared with 14.0 months in arm C. Grade 3 or higher asthenia and hyperglycaemia occurred more frequently with dalotuzumab compared with placebo. In exploratory biomarker analyses, patients with high IGF-1 mRNA tumors in arm A had numerically better PFS (5.6 vs 3.6 months, HR = 0.59, 95% CI = 0.28 to 1.23, P = .16) and OS (17.9 vs 9.4 months, HR = 0.67, 95% CI = 0.31 to 1.45, P = .31) compared with those with high IGF-1 mRNA tumors in arm C. In contrast, in arm C high IGF-1 mRNA expression predicted lower response rate (17.6% vs 37.3%, P = .04), shorter PFS (3.6 vs 6.6 months, HR = 2.15, 95% CI = 1.15 to 4.02, P = .02), and shorter OS (9.4 vs 15.5 months, HR = 2.42, 95% CI = 1.21 to 4.82, P = .01).

Conclusions: Adding dalotuzumab to irinotecan and cetuximab was feasible but did not improve survival outcome. IGF-1R ligands are promising biomarkers for differential response to anti-EGFR and anti-IGF-1R therapies.

Trial registration: ClinicalTrials.gov NCT00614393.

Publication types

Clinical Trial, Phase II
Clinical Trial, Phase III
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal / adverse effects
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Asthenia / chemically induced
Camptothecin / administration & dosage
Camptothecin / adverse effects
Camptothecin / analogs & derivatives
Cetuximab / administration & dosage
Cetuximab / adverse effects
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology
Disease-Free Survival
Double-Blind Method
Drug Administration Schedule
ErbB Receptors / antagonists & inhibitors*
Feasibility Studies
Female
Gene Expression Regulation, Neoplastic
Humans
Hyperglycemia / chemically induced
Irinotecan
Kaplan-Meier Estimate
Male
Middle Aged
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins p21(ras)
Receptor, IGF Type 1 / metabolism*
Up-Regulation / drug effects
ras Proteins / genetics*

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
KRAS protein, human
Proto-Oncogene Proteins
dalotuzumab
Irinotecan
EGFR protein, human
ErbB Receptors
Receptor, IGF Type 1
Proto-Oncogene Proteins p21(ras)
ras Proteins
Cetuximab
Camptothecin

Associated data

ClinicalTrials.gov/NCT00614393