Intermittent MEK inhibition for the treatment of metastatic uveal melanoma Journal Article

Authors: Khan, S.; Patel, S. P.; Shoushtari, A. N.; Ambrosini, G.; Cremers, S.; Lee, S.; Franks, L.; Singh-Kandah, S.; Hernandez, S.; Sender, N.; Vuolo, K.; Nesson, A.; Mundi, P.; Izar, B.; Schwartz, G. K.; Carvajal, R. D.
Article Title: Intermittent MEK inhibition for the treatment of metastatic uveal melanoma
Abstract: Introduction: Uveal 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. Methods: We 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. Results: 29 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. Conclusions: We 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. Copyright © 2022 Khan, Patel, Shoushtari, Ambrosini, Cremers, Lee, Franks, Singh-Kandah, Hernandez, Sender, Vuolo, Nesson, Mundi, Izar, Schwartz and Carvajal.
Keywords: metastatic; uveal melanoma; selumetinib; mek inhibition; intermittent dosing
Journal Title: Frontiers in Oncology
Volume: 12
ISSN: 2234-943X
Publisher: Frontiers Media S.A.  
Date Published: 2022-09-29
Start Page: 975643
Language: English
DOI: 10.3389/fonc.2022.975643
PROVIDER: scopus
PMCID: PMC9557946
PUBMED: 36249046
Notes: Article -- Export Date: 1 November 2022 -- Source: Scopus
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