Intermittent MEK inhibition for the treatment of metastatic uveal melanoma
IntroductionUveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continu...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.975643/full |
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| author | Shaheer Khan Sapna P. Patel Alexander N. Shoushtari Grazia Ambrosini Serge Cremers Shing Lee Lauren Franks Shahnaz Singh-Kandah Susana Hernandez Naomi Sender Kristina Vuolo Alexandra Nesson Prabhjot Mundi Benjamin Izar Gary K. Schwartz Richard D. Carvajal |
| author_facet | Shaheer Khan Sapna P. Patel Alexander N. Shoushtari Grazia Ambrosini Serge Cremers Shing Lee Lauren Franks Shahnaz Singh-Kandah Susana Hernandez Naomi Sender Kristina Vuolo Alexandra Nesson Prabhjot Mundi Benjamin Izar Gary K. Schwartz Richard D. Carvajal |
| author_sort | Shaheer Khan |
| collection | DOAJ |
| description | IntroductionUveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continual dosing schedule of 75 mg BID. Preclinical studies demonstrate that intermittent MEK inhibition reduces compensatory pathway activation and promotes T cell activation. We hypothesized that intermittent dosing of selumetinib would reduce toxicity, allow for the administration of increased doses, and achieve more complete pathway inhibition, thus resulting in improved antitumor activity.MethodsWe conducted a phase Ib trial of selumetinib using an intermittent dosing schedule in patients with metastatic UM. The primary objective was to estimate the maximum tolerated dose (MTD) and assess safety and tolerability. Secondary objectives included assessment of the overall response rate (RR), progression-free survival (PFS) and overall survival (OS). Tumor biopsies were collected at baseline, on day 3 (on treatment), and between days 11-14 (off treatment) from 9 patients for pharmacodynamic (PD) assessments.Results29 patients were enrolled and received at least one dose of selumetinib across 4 dose levels (DL; DL1: 100 mg BID; DL2: 125 mg BID; DL3: 150 mg BID; DL4: 175 mg BID). All patients experienced a treatment-related adverse event (TRAE), with 5/29 (17%) developing a grade 3 or higher TRAE. Five dose limiting toxicities (DLT) were observed: 2/20 in DL2, 2/5 in DL3, 1/1 in DL4. The estimated MTD was 150 mg BID (DL3), with an estimated probability of toxicity of 29% (90% probability interval 16%-44%). No responses were observed; 11/29 patients achieved a best response of stable disease (SD). The median PFS and OS were 1.8 months (95% CI 1.7, 4.5) and 7.1 months (95% CI 5.3, 11.5). PD analysis demonstrated at least partial pathway inhibition in all samples at day 3, with reactivation between days 11-14 in 7 of those cases.ConclusionsWe identified 150 mg BID as the MTD of intermittent selumetinib, representing a 100% increase over the continuous dose MTD (75 mg BID). However, no significant clinical efficacy was observed using this dosing schedule. |
| first_indexed | 2024-04-12T18:07:47Z |
| format | Article |
| id | doaj.art-06c02e4696264c518437de0b937c94fa |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T18:07:47Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-06c02e4696264c518437de0b937c94fa2022-12-22T03:21:56ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-09-011210.3389/fonc.2022.975643975643Intermittent MEK inhibition for the treatment of metastatic uveal melanomaShaheer Khan0Sapna P. Patel1Alexander N. Shoushtari2Grazia Ambrosini3Serge Cremers4Shing Lee5Lauren Franks6Shahnaz Singh-Kandah7Susana Hernandez8Naomi Sender9Kristina Vuolo10Alexandra Nesson11Prabhjot Mundi12Benjamin Izar13Gary K. Schwartz14Richard D. Carvajal15Department of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Melanoma Medical Oncology University of Texas MD Anderson Cancer Center, Houston, TX, United StatesDepartment of Medicine Memorial Sloan Kettering Cancer Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesMailman School of Public Health, Columbia University, New York, NY, United StatesMailman School of Public Health, Columbia University, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesDepartment of Medicine Columbia University Irving Medical Center, New York, NY, United StatesIntroductionUveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continual dosing schedule of 75 mg BID. Preclinical studies demonstrate that intermittent MEK inhibition reduces compensatory pathway activation and promotes T cell activation. We hypothesized that intermittent dosing of selumetinib would reduce toxicity, allow for the administration of increased doses, and achieve more complete pathway inhibition, thus resulting in improved antitumor activity.MethodsWe conducted a phase Ib trial of selumetinib using an intermittent dosing schedule in patients with metastatic UM. The primary objective was to estimate the maximum tolerated dose (MTD) and assess safety and tolerability. Secondary objectives included assessment of the overall response rate (RR), progression-free survival (PFS) and overall survival (OS). Tumor biopsies were collected at baseline, on day 3 (on treatment), and between days 11-14 (off treatment) from 9 patients for pharmacodynamic (PD) assessments.Results29 patients were enrolled and received at least one dose of selumetinib across 4 dose levels (DL; DL1: 100 mg BID; DL2: 125 mg BID; DL3: 150 mg BID; DL4: 175 mg BID). All patients experienced a treatment-related adverse event (TRAE), with 5/29 (17%) developing a grade 3 or higher TRAE. Five dose limiting toxicities (DLT) were observed: 2/20 in DL2, 2/5 in DL3, 1/1 in DL4. The estimated MTD was 150 mg BID (DL3), with an estimated probability of toxicity of 29% (90% probability interval 16%-44%). No responses were observed; 11/29 patients achieved a best response of stable disease (SD). The median PFS and OS were 1.8 months (95% CI 1.7, 4.5) and 7.1 months (95% CI 5.3, 11.5). PD analysis demonstrated at least partial pathway inhibition in all samples at day 3, with reactivation between days 11-14 in 7 of those cases.ConclusionsWe identified 150 mg BID as the MTD of intermittent selumetinib, representing a 100% increase over the continuous dose MTD (75 mg BID). However, no significant clinical efficacy was observed using this dosing schedule.https://www.frontiersin.org/articles/10.3389/fonc.2022.975643/fulluveal melanomametastaticMEK inhibitionintermittent dosingselumetinib |
| spellingShingle | Shaheer Khan Sapna P. Patel Alexander N. Shoushtari Grazia Ambrosini Serge Cremers Shing Lee Lauren Franks Shahnaz Singh-Kandah Susana Hernandez Naomi Sender Kristina Vuolo Alexandra Nesson Prabhjot Mundi Benjamin Izar Gary K. Schwartz Richard D. Carvajal Intermittent MEK inhibition for the treatment of metastatic uveal melanoma Frontiers in Oncology uveal melanoma metastatic MEK inhibition intermittent dosing selumetinib |
| title | Intermittent MEK inhibition for the treatment of metastatic uveal melanoma |
| title_full | Intermittent MEK inhibition for the treatment of metastatic uveal melanoma |
| title_fullStr | Intermittent MEK inhibition for the treatment of metastatic uveal melanoma |
| title_full_unstemmed | Intermittent MEK inhibition for the treatment of metastatic uveal melanoma |
| title_short | Intermittent MEK inhibition for the treatment of metastatic uveal melanoma |
| title_sort | intermittent mek inhibition for the treatment of metastatic uveal melanoma |
| topic | uveal melanoma metastatic MEK inhibition intermittent dosing selumetinib |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.975643/full |
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