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

Sclafani, Francesco; Kim, Tae Y; Cunningham, David; Kim, Tae W; Tabernero, Josep; Schmoll, Hans J; Roh, Jae K; Kim, Sun Y; Park, Young S; Guren, Tormod K; Hawkes, Eliza; Clarke, Steven J; Ferry, David; Frodin, Jan-Erik; Ayers, Mark; Nebozhyn, Michael; Peckitt, Clare; Loboda, Andrey; Mauro, David J; Watkins, David J
Journal of the National Cancer Institute
2015Dec ; 107 ( 12 ) :djv258.
저자 상세정보
Sclafani, Francesco -
Kim, Tae Y -
Cunningham, David -
Kim, Tae W -
Tabernero, Josep -
Schmoll, Hans J -
Roh, Jae K -
Kim, Sun Y -
Park, Young S -
Guren, Tormod K -
Hawkes, Eliza -
Clarke, Steven J -
Ferry, David -
Frodin, Jan-Erik -
Ayers, Mark -
Nebozhyn, Michael -
Peckitt, Clare -
Loboda, Andrey -
Mauro, David J -
Watkins, David J -
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. CI - ??The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
Adult, Aged, Antibodies, Monoclonal/administration & dosage/adverse effects, Antineoplastic Combined Chemotherapy Protocols/*therapeutic use, Asthenia/chemically induced, Camptothecin/administration & dosage/adverse effects/analogs & derivatives, Cetuximab/administration & dosage/adverse effects, Colorectal Neoplasms/*drug therapy/genetics/pathology, Disease-Free Survival, Double-Blind Method, Drug Administration Schedule, Feasibility Studies, Female, Gene Expression Regulation, Neoplastic, Humans, Hyperglycemia/chemically induced, Kaplan-Meier Estimate, Male, Middle Aged, Proto-Oncogene Proteins/*genetics, Receptor, Epidermal Growth Factor/*antagonists & inhibitors, Receptor, IGF Type 1/*metabolism, Up-Regulation/drug effects, ras Proteins/*genetics

주제명(Target field)
연구참여(Sample size)
질병특성(Condition Category)
연구설계(Study Design)
중재방법(Intervention Type)
중재명칭(Intervention Name)
This study showed that adding dalotuzumab to cetuximab and irinotecan in chemo-refractory, KRAS exon 2 wild-type, mCRC patients was associated with an acceptable safety profile. However, no benefit over standard therapy was observed.
연구비지원(Fund Source)
근거수준평가(Evidence Hierarchy)
ICD 03