Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer

Andrew J Weickhardt, Tim J Price, Geoff Chong, Val Gebski, Nick Pavlakis, Terrance Grant Johns, Arun Azad, Effie Skrinos, Kate Fluck, Alex Dobrovic, Renato Salemi, Andrew M Scott, John M Mariadason, Nial C Tebbutt

Research output: Contribution to journalArticleResearchpeer-review

72 Citations (Scopus)

Abstract

This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design. Results Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31 (95 CI, 26 to 57 ), with a median PFS of 4.6 months (95 CI, 2.8 to 5.6 months). RR was 41 (95 CI, 26 to 57 ) in KRAS WT tumors, with a median PFS of 5.6 months (95 CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48 ), hypomagnesaemia (18 ), and fatigue (10 ). CONCLUSION The combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.
Original languageEnglish
Pages (from-to)1505 - 1512
Number of pages8
JournalJournal of Clinical Oncology
Volume30
Issue number13
DOIs
Publication statusPublished - 2012

Cite this

Weickhardt, Andrew J ; Price, Tim J ; Chong, Geoff ; Gebski, Val ; Pavlakis, Nick ; Johns, Terrance Grant ; Azad, Arun ; Skrinos, Effie ; Fluck, Kate ; Dobrovic, Alex ; Salemi, Renato ; Scott, Andrew M ; Mariadason, John M ; Tebbutt, Nial C. / Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. In: Journal of Clinical Oncology. 2012 ; Vol. 30, No. 13. pp. 1505 - 1512.
@article{2be94db4c497409aadd79f5be7ba5b41,
title = "Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer",
abstract = "This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design. Results Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31 (95 CI, 26 to 57 ), with a median PFS of 4.6 months (95 CI, 2.8 to 5.6 months). RR was 41 (95 CI, 26 to 57 ) in KRAS WT tumors, with a median PFS of 5.6 months (95 CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48 ), hypomagnesaemia (18 ), and fatigue (10 ). CONCLUSION The combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.",
author = "Weickhardt, {Andrew J} and Price, {Tim J} and Geoff Chong and Val Gebski and Nick Pavlakis and Johns, {Terrance Grant} and Arun Azad and Effie Skrinos and Kate Fluck and Alex Dobrovic and Renato Salemi and Scott, {Andrew M} and Mariadason, {John M} and Tebbutt, {Nial C}",
year = "2012",
doi = "10.1200/JCO.2011.38.6599",
language = "English",
volume = "30",
pages = "1505 -- 1512",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "AMER SOC CLINICAL ONCOLOGY",
number = "13",

}

Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer. / Weickhardt, Andrew J; Price, Tim J; Chong, Geoff; Gebski, Val; Pavlakis, Nick; Johns, Terrance Grant; Azad, Arun; Skrinos, Effie; Fluck, Kate; Dobrovic, Alex; Salemi, Renato; Scott, Andrew M; Mariadason, John M; Tebbutt, Nial C.

In: Journal of Clinical Oncology, Vol. 30, No. 13, 2012, p. 1505 - 1512.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer

AU - Weickhardt, Andrew J

AU - Price, Tim J

AU - Chong, Geoff

AU - Gebski, Val

AU - Pavlakis, Nick

AU - Johns, Terrance Grant

AU - Azad, Arun

AU - Skrinos, Effie

AU - Fluck, Kate

AU - Dobrovic, Alex

AU - Salemi, Renato

AU - Scott, Andrew M

AU - Mariadason, John M

AU - Tebbutt, Nial C

PY - 2012

Y1 - 2012

N2 - This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design. Results Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31 (95 CI, 26 to 57 ), with a median PFS of 4.6 months (95 CI, 2.8 to 5.6 months). RR was 41 (95 CI, 26 to 57 ) in KRAS WT tumors, with a median PFS of 5.6 months (95 CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48 ), hypomagnesaemia (18 ), and fatigue (10 ). CONCLUSION The combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.

AB - This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design. Results Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31 (95 CI, 26 to 57 ), with a median PFS of 4.6 months (95 CI, 2.8 to 5.6 months). RR was 41 (95 CI, 26 to 57 ) in KRAS WT tumors, with a median PFS of 5.6 months (95 CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48 ), hypomagnesaemia (18 ), and fatigue (10 ). CONCLUSION The combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.

UR - http://jco.ascopubs.org/content/30/13/1505.full.pdf

U2 - 10.1200/JCO.2011.38.6599

DO - 10.1200/JCO.2011.38.6599

M3 - Article

VL - 30

SP - 1505

EP - 1512

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 13

ER -