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 -
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. CI - ??The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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MESH
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
링크

주제코드
주제명(Target field)
연구대상(Population)
연구참여(Sample size)
대상성별(Gender)
질병특성(Condition Category)
연구환경(Setting)
연구설계(Study Design)
연구기간(Period)
중재방법(Intervention Type)
중재명칭(Intervention Name)
키워드(Keyword)
유효성결과(Recomendation)
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)
출판년도(Year)
참여저자수(Authors)
대표저자
DOI
https://doi.org/10.1093/jnci/djv258
KCD코드
ICD 03
건강보험코드