Cargando…
A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma
BACKGROUND: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, w...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830369/ https://www.ncbi.nlm.nih.gov/pubmed/36636049 http://dx.doi.org/10.21037/jgo-22-86 |
_version_ | 1784867658564370432 |
---|---|
author | Aung, Kyaw L. McWhirter, Elaine Welch, Stephen Wang, Lisa Lovell, Sophia Stayner, Lee-Anne Ali, Saara Malpage, Anne Makepeace, Barbara Ramachandran, Makilpriya Jang, Gun Ho Gallinger, Steven Zhang, Tong Stockley, Tracy L. Fischer, Sandra E. Dhani, Neesha Hedley, David Knox, Jennifer J. Siu, Lillian L. Goodwin, Rachel Bedard, Philippe L. |
author_facet | Aung, Kyaw L. McWhirter, Elaine Welch, Stephen Wang, Lisa Lovell, Sophia Stayner, Lee-Anne Ali, Saara Malpage, Anne Makepeace, Barbara Ramachandran, Makilpriya Jang, Gun Ho Gallinger, Steven Zhang, Tong Stockley, Tracy L. Fischer, Sandra E. Dhani, Neesha Hedley, David Knox, Jennifer J. Siu, Lillian L. Goodwin, Rachel Bedard, Philippe L. |
author_sort | Aung, Kyaw L. |
collection | PubMed |
description | BACKGROUND: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor. METHODS: Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P(0)=0.15, P(1)=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling. RESULTS: Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5–1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7–not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression. CONCLUSIONS: The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC. |
format | Online Article Text |
id | pubmed-9830369 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-98303692023-01-11 A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma Aung, Kyaw L. McWhirter, Elaine Welch, Stephen Wang, Lisa Lovell, Sophia Stayner, Lee-Anne Ali, Saara Malpage, Anne Makepeace, Barbara Ramachandran, Makilpriya Jang, Gun Ho Gallinger, Steven Zhang, Tong Stockley, Tracy L. Fischer, Sandra E. Dhani, Neesha Hedley, David Knox, Jennifer J. Siu, Lillian L. Goodwin, Rachel Bedard, Philippe L. J Gastrointest Oncol Original Article BACKGROUND: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor. METHODS: Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P(0)=0.15, P(1)=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling. RESULTS: Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5–1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7–not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression. CONCLUSIONS: The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC. AME Publishing Company 2022-12 /pmc/articles/PMC9830369/ /pubmed/36636049 http://dx.doi.org/10.21037/jgo-22-86 Text en 2022 Journal of Gastrointestinal Oncology. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Original Article Aung, Kyaw L. McWhirter, Elaine Welch, Stephen Wang, Lisa Lovell, Sophia Stayner, Lee-Anne Ali, Saara Malpage, Anne Makepeace, Barbara Ramachandran, Makilpriya Jang, Gun Ho Gallinger, Steven Zhang, Tong Stockley, Tracy L. Fischer, Sandra E. Dhani, Neesha Hedley, David Knox, Jennifer J. Siu, Lillian L. Goodwin, Rachel Bedard, Philippe L. A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma |
title | A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma |
title_full | A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma |
title_fullStr | A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma |
title_full_unstemmed | A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma |
title_short | A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma |
title_sort | phase ii trial of gsk2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9830369/ https://www.ncbi.nlm.nih.gov/pubmed/36636049 http://dx.doi.org/10.21037/jgo-22-86 |
work_keys_str_mv | AT aungkyawl aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT mcwhirterelaine aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT welchstephen aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT wanglisa aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT lovellsophia aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT staynerleeanne aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT alisaara aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT malpageanne aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT makepeacebarbara aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT ramachandranmakilpriya aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT janggunho aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT gallingersteven aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT zhangtong aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT stockleytracyl aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT fischersandrae aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT dhanineesha aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT hedleydavid aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT knoxjenniferj aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT siulillianl aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT goodwinrachel aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT bedardphilippel aphaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT aungkyawl phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT mcwhirterelaine phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT welchstephen phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT wanglisa phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT lovellsophia phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT staynerleeanne phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT alisaara phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT malpageanne phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT makepeacebarbara phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT ramachandranmakilpriya phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT janggunho phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT gallingersteven phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT zhangtong phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT stockleytracyl phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT fischersandrae phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT dhanineesha phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT hedleydavid phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT knoxjenniferj phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT siulillianl phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT goodwinrachel phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma AT bedardphilippel phaseiitrialofgsk2256098andtrametinibinpatientswithadvancedpancreaticductaladenocarcinoma |