Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial

Gebhart, Geraldine; Lamberts, Laetitia E.; Wimana, Zéna; Garcia, Camilo; Emonts, Patrick; Ameye, Lieveke; Stroobants, Sigrid; Huizing, Manon; Aftimos, P.; Tol, Jolien; Oyen, Wim J.G.; Vugts, Daniëlle J.; Hoekstra, Otto S.; Schröder, Carolina P.; Oordt, C. Willemien Menke-van der Houven van; Guiot, Thomas; Brouwers, Adrienne H.; Awada, Ahmad; Vries, Elisabeth G.E. de; Flamen, P

doi:10.1093/annonc/mdv577

Cited by 292 publications

(287 citation statements)

References 19 publications

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“…Similar results on heterogeneity of tumor tracer uptake were reported for the ZEPHIR trial, where one third of HER2-positive metastatic breast cancer patients were considered 89 Zrtrastuzumab PET-negative before start of treatment with trastuzumab-emtansine (39). Another trial assessing the biodistribution and PD of the Indium-111-labeled, anti-human death receptor 5 (DR5) monoclonal antibody tigatuzumab, seven out of 19 patients (37%) with metastatic colorectal cancer also had no SPECT-positive lesions and tumor tracer uptake did not correlate with DR5 expression or tumor response (40).…”

Section: Discussionsupporting

confidence: 72%

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Bensch

Lamberts

Smeenk

et al. 2017

Clinical Cancer Research

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# These authors contributed equally to this work. AbstractPurpose-We evaluated biodistribution and tumor targeting of 89 Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody.Experimental design-20 patients with histologically confirmed HER3-expressing tumors received 89 Zr-lumretuzumab and underwent Positron Emission Tomography (PET). In Part A, 89 Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab and scans were performed 2, 4 and 7 days postinjection to determine optimal imaging conditions. In Part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).Results-Optimal PET conditions were found to be 4 and 7 days after administration of 89 Zrlumretuzumab with 100 mg unlabeled lumretuzumab. At baseline using 100 mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days postinjection. SUVmean for normal blood, liver, lung and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n=7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5) and 24.6% (±20.9) at PD-active doses of 400, 800 and 1600 mg, respectively, when compared to baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400 mg lumretuzumab.Conclusions-PET imaging showed biodistribution and tumor specific 89 Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89 Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses.

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Section: Discussionsupporting

confidence: 72%

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Bensch

Lamberts

Smeenk

et al. 2017

Clinical Cancer Research

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“…That study showed the relevance of an adequate naked antibody dose for sufficient accumulation of a radiolabeled antibody in the tumor. Fourth, another study showed the value of adding 89 Zr-trastuzumab PET imaging to biopsies for the assessment of intrapatient tumor heterogeneity and for prediction of the treatment outcome in HER2-positive breast cancer patients treated with trastuzumab emtansine (T-DM1) (18). One third of the patients who had HER2-positive breast cancer showed little or no 89 Zr-trastuzumab uptake across their metastases and experienced a shorter median time to treatment failure than patients who had more homogeneous HER2-positive PET scan results.…”

Section: Use Of Theranostics In Clinical Decision Makingmentioning

confidence: 99%

“…The ZEPHIR trial is designed to prospectively investigate the role of pretreatment 89 Zrtrastuzumab PET combined with early response assessment using 18 F-FDG PET in the selection of patients who have metastatic HER2-positive tumors and are unlikely to benefit from T-DM1 treatment (18). An analysis of the data from the first 56 patients showed that negative 89 Zr-trastuzumab PET findings and the absence of a response in early 18 F-FDG PET resulted in a negative predictive value of 100% for a response according to RECIST 1.1 criteria. Substantial inter-and intrapatient heterogeneity of tracer uptake was observed.…”

Section: Use Of Molecular Imaging To Study Antibodies With Payloadmentioning

confidence: 99%

Theranostics Using Antibodies and Antibody-Related Therapeutics

et al. 2017

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In theranostics, radiolabeled compounds are used to determine a treatment strategy by combining therapeutics and diagnostics in the same agent. Monoclonal antibodies (mAbs) and antibody-related therapeutics represent a rapidly expanding group of cancer medicines. Theranostic approaches using these drugs in oncology are particularly interesting because antibodies are designed against specific targets on the tumor cell membrane and immune cells as well as targets in the tumor microenvironment. In addition, these drugs are relatively easy to radiolabel. Noninvasive molecular imaging techniques, such as SPECT and PET, provide information on the whole-body distribution of radiolabeled mAbs and antibodyrelated therapeutics. Molecular antibody imaging can potentially elucidate drug target expression, tracer uptake in the tumor, tumor saturation, and heterogeneity for these parameters within the tumor. These data can support drug development and may aid in patient stratification and monitoring of the treatment response. Selecting a radionuclide for theranostic purposes generally starts by matching the serum half-life of the mAb or antibody-related therapeutic and the physical half-life of the radionuclide. Furthermore, PET imaging allows better quantification than the SPECT technique. This information has increased interest in theranostics using PET radionuclides with a relatively long physical half-life, such as 89 Zr. In this review, we provide an overview of ongoing research on mAbs and antibodyrelated theranostics in preclinical and clinical oncologic settings. We identified 24 antibodies or antibody-related therapeutics labeled with PET radionuclides for theranostic purposes in patients. For this approach to become integrated in standard care, further standardization with respect to the procedures involved is required.

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“…Furthermore, it is well known that for ado-trastuzumab emtansine to be active, the presence of an intact HER2 receptor is of pivotal importance since internalization of the cytotoxic moiety of the drug depends on binding of trastuzumab to the external domain of HER2. Gebhart et al, at the 2014 American Society of Clinical Oncology meeting, presented data showing that the presence or absence of HER2, as indicated by 89 Zr-trastuzumab uptake, and response, as indicated by a decrease in 18 F-FDG uptake, provided an essentially 100% accurate prediction of later clinical response to HER2-directed therapy with ado-trastuzumab emtansine administration in metastatic HER2-positive breast cancer (NCT01565200 clinical trial) (9). This trial is a great example indicating that 89 Zr-trastuzumab is an accurate noninvasive test capable of identifying nonresponding patients before ado-trastuzumab emtansine administration.…”

Section: Role Of Imaging Her Receptors In Patient Stratification and mentioning

confidence: 99%

Targeting the Human Epidermal Growth Factor Receptors with Immuno-PET: Imaging Biomarkers from Bench to Bedside

Kramer‐Marek

Oyen

2016

J Nucl Med

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Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial

Abstract: NCT01565200.

Cited by 292 publications

References 19 publications

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors

Theranostics Using Antibodies and Antibody-Related Therapeutics

Targeting the Human Epidermal Growth Factor Receptors with Immuno-PET: Imaging Biomarkers from Bench to Bedside

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