Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials.
UNLABELLED: Two mitogen-activated protein kinase kinase (MAPK2, also known as MEK) inhibitors were assessed with (18)F-FDG PET in separate phase I clinical studies, clearly illustrating the potential of metabolic imaging for dose, dosing regimen, and compound selection in early-phase trials and uti...
| Автори: | , , , , , , , , , , , |
|---|---|
| Формат: | Journal article |
| Мова: | English |
| Опубліковано: |
2012
|
| _version_ | 1826271244096372736 |
|---|---|
| author | Kraeber-Bodéré, F Carlier, T Naegelen, V Shochat, E Lumbroso, J Trampal, C Nagarajah, J Chua, S Hugonnet, F Stokkel, M Gleeson, F Tessier, J |
| author_facet | Kraeber-Bodéré, F Carlier, T Naegelen, V Shochat, E Lumbroso, J Trampal, C Nagarajah, J Chua, S Hugonnet, F Stokkel, M Gleeson, F Tessier, J |
| author_sort | Kraeber-Bodéré, F |
| collection | OXFORD |
| description | UNLABELLED: Two mitogen-activated protein kinase kinase (MAPK2, also known as MEK) inhibitors were assessed with (18)F-FDG PET in separate phase I clinical studies, clearly illustrating the potential of metabolic imaging for dose, dosing regimen, and compound selection in early-phase trials and utility for predicting nonresponding patients. METHODS: (18)F-FDG PET data were collected during 2 independent, phase I, dose-escalation trials of 2 novel MEK inhibitors (RO5126766 and RO4987655). PET acquisition procedures were standardized between the 2 trials, and PET images were analyzed centrally. Imaging was performed at baseline; at cycle 1, day 15; and at cycle 3, day 1. A 10-mm-diameter region of interest was defined for up to 5 lesions, and peak standardized uptake values were determined for each lesion. The relationship between PET response and pharmacokinetic factors (dose and exposure), inhibition of extracellular-signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells, and anatomic tumor response as measured by Response Evaluation Criteria in Solid Tumors was investigated for both compounds. RESULTS: Seventy-six patients underwent PET, and 205 individual PET scans were analyzed. Strong evidence of biologic activity was seen as early as cycle 1, day 15, for both compounds. (18)F-FDG PET revealed striking differences between the 2 MEK inhibitors at their recommended dose for phase II investigation. The mean amplitude of the decrease in (18)F-FDG from baseline to cycle 1, day 15, was greater for patients receiving RO4987655 than for those receiving RO5126766 (47% vs. 16%, respectively; P = 0.052). Furthermore, a more pronounced relationship was seen between the change in (18)F-FDG uptake and dose or exposure and phosphorylated ERK inhibition in peripheral blood mononuclear cells in patients receiving RO4987655. For both investigational drugs, PET responses tended to be greatest in patients with melanoma tumors. (18)F-FDG was able to identify early nonresponding patients with a 97% negative predictive value. CONCLUSION: These data exemplify the role of (18)F-FDG PET for guiding the selection of novel investigational drugs, choosing dose in early-phase clinical development, and predicting nonresponding patients early in treatment. |
| first_indexed | 2024-03-06T21:53:36Z |
| format | Journal article |
| id | oxford-uuid:4c26091e-a5f8-40c2-a1b1-b69bc5f7c99c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T21:53:36Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:4c26091e-a5f8-40c2-a1b1-b69bc5f7c99c2022-03-26T15:47:47ZDifferences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:4c26091e-a5f8-40c2-a1b1-b69bc5f7c99cEnglishSymplectic Elements at Oxford2012Kraeber-Bodéré, FCarlier, TNaegelen, VShochat, ELumbroso, JTrampal, CNagarajah, JChua, SHugonnet, FStokkel, MGleeson, FTessier, J UNLABELLED: Two mitogen-activated protein kinase kinase (MAPK2, also known as MEK) inhibitors were assessed with (18)F-FDG PET in separate phase I clinical studies, clearly illustrating the potential of metabolic imaging for dose, dosing regimen, and compound selection in early-phase trials and utility for predicting nonresponding patients. METHODS: (18)F-FDG PET data were collected during 2 independent, phase I, dose-escalation trials of 2 novel MEK inhibitors (RO5126766 and RO4987655). PET acquisition procedures were standardized between the 2 trials, and PET images were analyzed centrally. Imaging was performed at baseline; at cycle 1, day 15; and at cycle 3, day 1. A 10-mm-diameter region of interest was defined for up to 5 lesions, and peak standardized uptake values were determined for each lesion. The relationship between PET response and pharmacokinetic factors (dose and exposure), inhibition of extracellular-signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells, and anatomic tumor response as measured by Response Evaluation Criteria in Solid Tumors was investigated for both compounds. RESULTS: Seventy-six patients underwent PET, and 205 individual PET scans were analyzed. Strong evidence of biologic activity was seen as early as cycle 1, day 15, for both compounds. (18)F-FDG PET revealed striking differences between the 2 MEK inhibitors at their recommended dose for phase II investigation. The mean amplitude of the decrease in (18)F-FDG from baseline to cycle 1, day 15, was greater for patients receiving RO4987655 than for those receiving RO5126766 (47% vs. 16%, respectively; P = 0.052). Furthermore, a more pronounced relationship was seen between the change in (18)F-FDG uptake and dose or exposure and phosphorylated ERK inhibition in peripheral blood mononuclear cells in patients receiving RO4987655. For both investigational drugs, PET responses tended to be greatest in patients with melanoma tumors. (18)F-FDG was able to identify early nonresponding patients with a 97% negative predictive value. CONCLUSION: These data exemplify the role of (18)F-FDG PET for guiding the selection of novel investigational drugs, choosing dose in early-phase clinical development, and predicting nonresponding patients early in treatment. |
| spellingShingle | Kraeber-Bodéré, F Carlier, T Naegelen, V Shochat, E Lumbroso, J Trampal, C Nagarajah, J Chua, S Hugonnet, F Stokkel, M Gleeson, F Tessier, J Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. |
| title | Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. |
| title_full | Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. |
| title_fullStr | Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. |
| title_full_unstemmed | Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. |
| title_short | Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. |
| title_sort | differences in the biologic activity of 2 novel mek inhibitors revealed by 18f fdg pet analysis of imaging data from 2 phase i trials |
| work_keys_str_mv | AT kraeberboderef differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT carliert differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT naegelenv differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT shochate differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT lumbrosoj differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT trampalc differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT nagarajahj differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT chuas differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT hugonnetf differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT stokkelm differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT gleesonf differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials AT tessierj differencesinthebiologicactivityof2novelmekinhibitorsrevealedby18ffdgpetanalysisofimagingdatafrom2phaseitrials |