FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study

Ravit Geva, Loredana Vecchione, Konstantinos T Kalogeras, Benny Vittrup Jensen, Heinz-Josef Lenz, Takayuki Yoshino, David Paez, Clara Montagut, John Souglakos, Federico Cappuzzo, Andrés Cervantes, Milo Frattini, George Fountzilas, Julia S Johansen, Estrid Vilma Høgdall, Wu Zhang, Dongyun Yang, Kentaro Yamazaki, Tomohiro Nishina, Demetris Papamichael & 9 andre Bruno Vincenzi, Teresa Macarulla, Fotios Loupakis, Jef De Schutter, Karen-Lise Garm Spindler, Per Pfeiffer, Fortunato Ciardiello, Hubert Piessevaux, Sabine Tejpar

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.

DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.

RESULTS: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.

CONCLUSIONS: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.

OriginalsprogEngelsk
TidsskriftGut
Vol/bind64
Sider (fra-til)921-928
ISSN0017-5749
DOI
StatusUdgivet - 2015

Fingeraftryk

IgG Receptors
Colorectal Neoplasms
oxaliplatin
irinotecan
Disease-Free Survival
Fluorouracil
Sarcoma
Sample Size
Cetuximab
Survival Rate
Incidence

Citer dette

Geva, R., Vecchione, L., Kalogeras, K. T., Vittrup Jensen, B., Lenz, H-J., Yoshino, T., ... Tejpar, S. (2015). FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study. Gut, 64, 921-928. https://doi.org/10.1136/gutjnl-2014-307234
Geva, Ravit ; Vecchione, Loredana ; Kalogeras, Konstantinos T ; Vittrup Jensen, Benny ; Lenz, Heinz-Josef ; Yoshino, Takayuki ; Paez, David ; Montagut, Clara ; Souglakos, John ; Cappuzzo, Federico ; Cervantes, Andrés ; Frattini, Milo ; Fountzilas, George ; Johansen, Julia S ; Høgdall, Estrid Vilma ; Zhang, Wu ; Yang, Dongyun ; Yamazaki, Kentaro ; Nishina, Tomohiro ; Papamichael, Demetris ; Vincenzi, Bruno ; Macarulla, Teresa ; Loupakis, Fotios ; De Schutter, Jef ; Spindler, Karen-Lise Garm ; Pfeiffer, Per ; Ciardiello, Fortunato ; Piessevaux, Hubert ; Tejpar, Sabine. / FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study. I: Gut. 2015 ; Bind 64. s. 921-928.
@article{2197a31ca5014196ac59db6257b436e3,
title = "FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study",
abstract = "OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80{\%} power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.RESULTS: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33{\%}) and 109/676 (16.1{\%}) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95{\%} CI18.8 to 25.2) versus non-HH (22.0 weeks; 95{\%} CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95{\%} CI 13.0 to 19.8) versus non-VV (23 weeks; 95{\%} CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.CONCLUSIONS: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.",
author = "Ravit Geva and Loredana Vecchione and Kalogeras, {Konstantinos T} and {Vittrup Jensen}, Benny and Heinz-Josef Lenz and Takayuki Yoshino and David Paez and Clara Montagut and John Souglakos and Federico Cappuzzo and Andr{\'e}s Cervantes and Milo Frattini and George Fountzilas and Johansen, {Julia S} and H{\o}gdall, {Estrid Vilma} and Wu Zhang and Dongyun Yang and Kentaro Yamazaki and Tomohiro Nishina and Demetris Papamichael and Bruno Vincenzi and Teresa Macarulla and Fotios Loupakis and {De Schutter}, Jef and Spindler, {Karen-Lise Garm} and Per Pfeiffer and Fortunato Ciardiello and Hubert Piessevaux and Sabine Tejpar",
note = "Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.",
year = "2015",
doi = "10.1136/gutjnl-2014-307234",
language = "English",
volume = "64",
pages = "921--928",
journal = "Gut",
issn = "0017-5749",
publisher = "B M J Group",

}

Geva, R, Vecchione, L, Kalogeras, KT, Vittrup Jensen, B, Lenz, H-J, Yoshino, T, Paez, D, Montagut, C, Souglakos, J, Cappuzzo, F, Cervantes, A, Frattini, M, Fountzilas, G, Johansen, JS, Høgdall, EV, Zhang, W, Yang, D, Yamazaki, K, Nishina, T, Papamichael, D, Vincenzi, B, Macarulla, T, Loupakis, F, De Schutter, J, Spindler, K-LG, Pfeiffer, P, Ciardiello, F, Piessevaux, H & Tejpar, S 2015, 'FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study', Gut, bind 64, s. 921-928. https://doi.org/10.1136/gutjnl-2014-307234

FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study. / Geva, Ravit; Vecchione, Loredana; Kalogeras, Konstantinos T; Vittrup Jensen, Benny; Lenz, Heinz-Josef; Yoshino, Takayuki; Paez, David; Montagut, Clara; Souglakos, John; Cappuzzo, Federico; Cervantes, Andrés; Frattini, Milo; Fountzilas, George; Johansen, Julia S; Høgdall, Estrid Vilma; Zhang, Wu; Yang, Dongyun; Yamazaki, Kentaro; Nishina, Tomohiro; Papamichael, Demetris; Vincenzi, Bruno; Macarulla, Teresa; Loupakis, Fotios; De Schutter, Jef; Spindler, Karen-Lise Garm; Pfeiffer, Per; Ciardiello, Fortunato; Piessevaux, Hubert; Tejpar, Sabine.

I: Gut, Bind 64, 2015, s. 921-928.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - FCGR polymorphisms and cetuximab efficacy in chemorefractory metastatic colorectal cancer: an international consortium study

AU - Geva, Ravit

AU - Vecchione, Loredana

AU - Kalogeras, Konstantinos T

AU - Vittrup Jensen, Benny

AU - Lenz, Heinz-Josef

AU - Yoshino, Takayuki

AU - Paez, David

AU - Montagut, Clara

AU - Souglakos, John

AU - Cappuzzo, Federico

AU - Cervantes, Andrés

AU - Frattini, Milo

AU - Fountzilas, George

AU - Johansen, Julia S

AU - Høgdall, Estrid Vilma

AU - Zhang, Wu

AU - Yang, Dongyun

AU - Yamazaki, Kentaro

AU - Nishina, Tomohiro

AU - Papamichael, Demetris

AU - Vincenzi, Bruno

AU - Macarulla, Teresa

AU - Loupakis, Fotios

AU - De Schutter, Jef

AU - Spindler, Karen-Lise Garm

AU - Pfeiffer, Per

AU - Ciardiello, Fortunato

AU - Piessevaux, Hubert

AU - Tejpar, Sabine

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

PY - 2015

Y1 - 2015

N2 - OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.RESULTS: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.CONCLUSIONS: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.

AB - OBJECTIVE: We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.DESIGN: To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.RESULTS: Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.CONCLUSIONS: No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.

U2 - 10.1136/gutjnl-2014-307234

DO - 10.1136/gutjnl-2014-307234

M3 - Journal article

VL - 64

SP - 921

EP - 928

JO - Gut

JF - Gut

SN - 0017-5749

ER -