89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

I C Kok; J S Hooiveld; P P van de Donk; D Giesen; E L van der Veen; M N Lub-de Hooge; A H Brouwers; T J N Hiltermann; A J van der Wekken; L B M Hijmering-Kappelle; W Timens; S G Elias; G A P Hospers; H J M Groen; W Uyterlinde; B van der Hiel; J B Haanen; D J A de Groot; M Jalving; E G E de Vries

doi:10.1016/j.annonc.2021.10.213

⁸⁹Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

I C Kok, J S Hooiveld, P P van de Donk, D Giesen, E L van der Veen, M N Lub-de Hooge, A H Brouwers, T J N Hiltermann, A J van der Wekken, L B M Hijmering-Kappelle, W Timens, S G Elias, G A P Hospers, H J M Groen, W Uyterlinde, B van der Hiel, J B Haanen, D J A de Groot, M Jalving, E G E de Vries

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Abstract

BACKGROUND: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment.

PATIENTS AND METHODS: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1.

RESULTS: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation.

CONCLUSION: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

Original language	English
Pages (from-to)	80-88
Number of pages	9
Journal	Annals of oncology : official journal of the European Society for Medical Oncology
Volume	33
Issue number	1
DOIs	https://doi.org/10.1016/j.annonc.2021.10.213
Publication status	Published - Jan 2022

Keywords

PD-1
PET
Zr
immunotherapy
pembrolizumab

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Kok, I. C., Hooiveld, J. S., van de Donk, P. P., Giesen, D., van der Veen, E. L., Lub-de Hooge, M. N., Brouwers, A. H., Hiltermann, T. J. N., van der Wekken, A. J., Hijmering-Kappelle, L. B. M., Timens, W., Elias, S. G., Hospers, G. A. P., Groen, H. J. M., Uyterlinde, W., van der Hiel, B., Haanen, J. B., de Groot, D. J. A., Jalving, M., & de Vries, E. G. E. (2022). ⁸⁹Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer. Annals of oncology : official journal of the European Society for Medical Oncology, 33(1), 80-88. https://doi.org/10.1016/j.annonc.2021.10.213

@article{fd590ec7733c4de8b2693d1ab77197f3,

title = "89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer",

abstract = "BACKGROUND: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment.PATIENTS AND METHODS: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1.RESULTS: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation.CONCLUSION: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.",

keywords = "PD-1, PET, Zr, immunotherapy, pembrolizumab",

author = "Kok, {I C} and Hooiveld, {J S} and {van de Donk}, {P P} and D Giesen and {van der Veen}, {E L} and {Lub-de Hooge}, {M N} and Brouwers, {A H} and Hiltermann, {T J N} and {van der Wekken}, {A J} and Hijmering-Kappelle, {L B M} and W Timens and Elias, {S G} and Hospers, {G A P} and Groen, {H J M} and W Uyterlinde and {van der Hiel}, B and Haanen, {J B} and {de Groot}, {D J A} and M Jalving and {de Vries}, {E G E}",

note = "Funding Information: This work was supported by the Dutch Cancer Society Grant POINTING [grant number RUG 2016-10034] and the Innovative Medicines Initiatives2 Joint Undertaking project TRISTAN [grant number GA no. 116106]. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EPFIA (no grant number). MJ reports consultancy fees from AstraZeneca (paid to UMCG). JBH reports consultancy roles for Achilles Therapeutics, BioNTech, BMS, GSK, Immunocore, Instil Bio, Molecular Partners, MSD, Merck Serono, Neogene Therapeutics, Novartis, Pfizer, PokeAcel, Roche/Genentech, Sanofi, T-Knife, and Third Rock Ventures and research grants from Amgen, Asher-Bio, BMS, BioNTech, MSD, Novartis, and Neogene Therapeutics (paid to the Netherlands Cancer Institute). WT reports fees from Merck, Sharp, Dohme, and Bristol-Myers-Squibb (paid to UMCG). EGEdV reports an advisory role at Daiichi Sankyo, NSABP, and Sanofi and research funding from Amgen, AstraZeneca, Bayer, Chugai Pharma, Crescendo, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon (paid to UMCG). GAPH reports consulting and advisory role at Amgen, Roche, MSD, BMS, Pfizer, Novartis, and Pierre Fabry and research funding from BMS and Seerave (paid to UMCG). TJNH reports consultancy fees (paid to UMCG) from BMS, MSD, Merck, Boehringer, AstraZeneca, and Roche. AJvdW reports an advisory role at Janssen, Takeda, and Boehringer-Ingelheim (paid to UMCG) and research funding from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, and Takeda. MNL-dH reports research funding from Merck, Bayer, and Amgen (paid to UMCG). HJMG reports an advisory role at Eli Lilly, MSD, BMS, and Novartis. All other authors have declared no conflicts of interest. Funding Information: This work was supported by the Dutch Cancer Society Grant POINTING [grant number RUG 2016-10034 ] and the Innovative Medicines Initiatives2 Joint Undertaking project TRISTAN [grant number GA no. 116106]. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EPFIA (no grant number). Publisher Copyright: {\textcopyright} 2021",

year = "2022",

month = jan,

doi = "10.1016/j.annonc.2021.10.213",

language = "English",

volume = "33",

pages = "80--88",

journal = "Annals of oncology : official journal of the European Society for Medical Oncology",

issn = "0923-7534",

publisher = "Oxford University Press",

number = "1",

}

Kok, IC, Hooiveld, JS, van de Donk, PP, Giesen, D, van der Veen, EL, Lub-de Hooge, MN, Brouwers, AH, Hiltermann, TJN, van der Wekken, AJ, Hijmering-Kappelle, LBM, Timens, W, Elias, SG, Hospers, GAP, Groen, HJM, Uyterlinde, W, van der Hiel, B, Haanen, JB, de Groot, DJA, Jalving, M & de Vries, EGE 2022, '⁸⁹Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer', Annals of oncology : official journal of the European Society for Medical Oncology, vol. 33, no. 1, pp. 80-88. https://doi.org/10.1016/j.annonc.2021.10.213

TY - JOUR

T1 - 89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

AU - Kok, I C

AU - Hooiveld, J S

AU - van de Donk, P P

AU - Giesen, D

AU - van der Veen, E L

AU - Lub-de Hooge, M N

AU - Brouwers, A H

AU - Hiltermann, T J N

AU - van der Wekken, A J

AU - Hijmering-Kappelle, L B M

AU - Timens, W

AU - Elias, S G

AU - Hospers, G A P

AU - Groen, H J M

AU - Uyterlinde, W

AU - van der Hiel, B

AU - Haanen, J B

AU - de Groot, D J A

AU - Jalving, M

AU - de Vries, E G E

N1 - Funding Information: This work was supported by the Dutch Cancer Society Grant POINTING [grant number RUG 2016-10034] and the Innovative Medicines Initiatives2 Joint Undertaking project TRISTAN [grant number GA no. 116106]. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EPFIA (no grant number). MJ reports consultancy fees from AstraZeneca (paid to UMCG). JBH reports consultancy roles for Achilles Therapeutics, BioNTech, BMS, GSK, Immunocore, Instil Bio, Molecular Partners, MSD, Merck Serono, Neogene Therapeutics, Novartis, Pfizer, PokeAcel, Roche/Genentech, Sanofi, T-Knife, and Third Rock Ventures and research grants from Amgen, Asher-Bio, BMS, BioNTech, MSD, Novartis, and Neogene Therapeutics (paid to the Netherlands Cancer Institute). WT reports fees from Merck, Sharp, Dohme, and Bristol-Myers-Squibb (paid to UMCG). EGEdV reports an advisory role at Daiichi Sankyo, NSABP, and Sanofi and research funding from Amgen, AstraZeneca, Bayer, Chugai Pharma, Crescendo, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon (paid to UMCG). GAPH reports consulting and advisory role at Amgen, Roche, MSD, BMS, Pfizer, Novartis, and Pierre Fabry and research funding from BMS and Seerave (paid to UMCG). TJNH reports consultancy fees (paid to UMCG) from BMS, MSD, Merck, Boehringer, AstraZeneca, and Roche. AJvdW reports an advisory role at Janssen, Takeda, and Boehringer-Ingelheim (paid to UMCG) and research funding from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche, and Takeda. MNL-dH reports research funding from Merck, Bayer, and Amgen (paid to UMCG). HJMG reports an advisory role at Eli Lilly, MSD, BMS, and Novartis. All other authors have declared no conflicts of interest. Funding Information: This work was supported by the Dutch Cancer Society Grant POINTING [grant number RUG 2016-10034 ] and the Innovative Medicines Initiatives2 Joint Undertaking project TRISTAN [grant number GA no. 116106]. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EPFIA (no grant number). Publisher Copyright: © 2021

PY - 2022/1

Y1 - 2022/1

N2 - BACKGROUND: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment.PATIENTS AND METHODS: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1.RESULTS: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation.CONCLUSION: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

AB - BACKGROUND: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment.PATIENTS AND METHODS: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1.RESULTS: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation.CONCLUSION: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

KW - PD-1

KW - PET

KW - Zr

KW - immunotherapy

KW - pembrolizumab

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DO - 10.1016/j.annonc.2021.10.213

M3 - Article

C2 - 34736925

SN - 0923-7534

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JO - Annals of oncology : official journal of the European Society for Medical Oncology

JF - Annals of oncology : official journal of the European Society for Medical Oncology

IS - 1

ER -

⁸⁹Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer

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