[Zr-89]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer

E J van Helden; S G Elias; S L Gerritse; S C van Es; E Boon; M C Huisman; N C T van Grieken; H Dekker; G A M S van Dongen; D J Vugts; R Boellaard; C M L van Herpen; E G E de Vries; W J G Oyen; A H Brouwers; H M W Verheul; O S Hoekstra; C W Menke-van der Houven van Oordt

doi:10.1007/s00259-019-04555-6

[Zr-89]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer

E J van Helden
, S G Elias
, S L Gerritse
, S C van Es
, E Boon
, M C Huisman
, N C T van Grieken
, H Dekker
, G A M S van Dongen
, D J Vugts
, R Boellaard
, C M L van Herpen
, E G E de Vries
, W J G Oyen
, A H Brouwers
, H M W Verheul
, O S Hoekstra
, C W Menke-van der Houven van Oordt

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Abstract

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy.

PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks.

RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab.

CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

Original language	English
Pages (from-to)	849-859
Number of pages	11
Journal	European Journal of Nuclear Medicine and Molecular Imaging
Volume	47
Issue number	4
DOIs	https://doi.org/10.1007/s00259-019-04555-6
Publication status	Published - Apr 2020

Keywords

CT
Cetuximab
Colorectal cancer
Imaging biomarker
PET
Targeted therapy
PET/CT

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Helden2020_Article_[89Zr]Zr-cetuximabPETCTAsBiomaFinal published version, 1.14 MB

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van Helden, E. J., Elias, S. G., Gerritse, S. L., van Es, S. C., Boon, E., Huisman, M. C., van Grieken, N. C. T., Dekker, H., van Dongen, G. A. M. S., Vugts, D. J., Boellaard, R., van Herpen, C. M. L., de Vries, E. G. E., Oyen, W. J. G., Brouwers, A. H., Verheul, H. M. W., Hoekstra, O. S., & Menke-van der Houven van Oordt, C. W. (2020). [Zr-89]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer. European Journal of Nuclear Medicine and Molecular Imaging, 47(4), 849-859. https://doi.org/10.1007/s00259-019-04555-6

@article{0751780281864fb2a8e85b6fc498c51e,

title = "[Zr-89]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer",

abstract = "PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy.PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks.RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66\% of 35 patients. There was no relationship between PET positivity and treatment benefit (52\% versus 80\% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67\% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab.CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.",

keywords = "CT, Cetuximab, Colorectal cancer, Imaging biomarker, PET, Targeted therapy, PET/CT",

author = "\{van Helden\}, \{E J\} and Elias, \{S G\} and Gerritse, \{S L\} and \{van Es\}, \{S C\} and E Boon and Huisman, \{M C\} and \{van Grieken\}, \{N C T\} and H Dekker and \{van Dongen\}, \{G A M S\} and Vugts, \{D J\} and R Boellaard and \{van Herpen\}, \{C M L\} and \{de Vries\}, \{E G E\} and Oyen, \{W J G\} and Brouwers, \{A H\} and Verheul, \{H M W\} and Hoekstra, \{O S\} and \{Menke-van der Houven van Oordt\}, \{C W\}",

note = "Funding Information: This study was funded by Alpe d{\textquoteright}HuZes, Dutch Cancer Society (KWF 2012-5565). Funding Information: Evaluation of study (imaging) data was supported by online data analysis software from an IT research infrastructure project, CTMM-TraIT, to allow multicenter blinded PET reviewing []. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2020",

month = apr,

doi = "10.1007/s00259-019-04555-6",

language = "English",

volume = "47",

pages = "849--859",

journal = "European Journal of Nuclear Medicine and Molecular Imaging",

issn = "1619-7070",

publisher = "Springer",

number = "4",

}

van Helden, EJ, Elias, SG, Gerritse, SL, van Es, SC, Boon, E, Huisman, MC, van Grieken, NCT, Dekker, H, van Dongen, GAMS, Vugts, DJ, Boellaard, R, van Herpen, CML, de Vries, EGE, Oyen, WJG, Brouwers, AH, Verheul, HMW, Hoekstra, OS & Menke-van der Houven van Oordt, CW 2020, '[Zr-89]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer', European Journal of Nuclear Medicine and Molecular Imaging, vol. 47, no. 4, pp. 849-859. https://doi.org/10.1007/s00259-019-04555-6

TY - JOUR

T1 - [Zr-89]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer

AU - van Helden, E J

AU - Elias, S G

AU - Gerritse, S L

AU - van Es, S C

AU - Boon, E

AU - Huisman, M C

AU - van Grieken, N C T

AU - Dekker, H

AU - van Dongen, G A M S

AU - Vugts, D J

AU - Boellaard, R

AU - van Herpen, C M L

AU - de Vries, E G E

AU - Oyen, W J G

AU - Brouwers, A H

AU - Verheul, H M W

AU - Hoekstra, O S

AU - Menke-van der Houven van Oordt, C W

N1 - Funding Information: This study was funded by Alpe d’HuZes, Dutch Cancer Society (KWF 2012-5565). Funding Information: Evaluation of study (imaging) data was supported by online data analysis software from an IT research infrastructure project, CTMM-TraIT, to allow multicenter blinded PET reviewing []. Publisher Copyright: © 2019, The Author(s).

PY - 2020/4

Y1 - 2020/4

N2 - PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy.PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks.RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab.CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

AB - PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy.PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks.RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab.CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

KW - CT

KW - Cetuximab

KW - Colorectal cancer

KW - Imaging biomarker

KW - PET

KW - Targeted therapy

KW - PET/CT

UR - https://www.scopus.com/pages/publications/85074927208

U2 - 10.1007/s00259-019-04555-6

DO - 10.1007/s00259-019-04555-6

M3 - Article

C2 - 31705176

SN - 1619-7070

VL - 47

SP - 849

EP - 859

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

IS - 4

ER -

[Zr-89]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer

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