TY - JOUR
T1 - Intermittent MEK inhibition for the treatment of metastatic uveal melanoma
AU - Khan, Shaheer
AU - Patel, Sapna P.
AU - Shoushtari, Alexander N.
AU - Ambrosini, Grazia
AU - Cremers, Serge
AU - Lee, Shing
AU - Franks, Lauren
AU - Singh-Kandah, Shahnaz
AU - Hernandez, Susana
AU - Sender, Naomi
AU - Vuolo, Kristina
AU - Nesson, Alexandra
AU - Mundi, Prabhjot
AU - Izar, Benjamin
AU - Schwartz, Gary K.
AU - Carvajal, Richard D.
N1 - Funding Information:
SK reports honoraria from Castle Biosciences. SP reports institutional clinical trial support from Bristol Myers Squibb, Foghorn Therapeutics, Ideaya Biosciences, InxMed, Lvgen, Novartis, Provectus Biopharmaceuticals, Seagen, Syntrix Bio, TriSalus Life Sciences and consulting fees from BMS, Delcath Systens, Advance Knowledge in Healthcare, Cardinal Health, Immunocore, Novartis, and TriSalus Life Sciences. AS reports advisory/personal fees from Bristol-Myers Squibb (BMS), Immunocore, Novartis, and research funding from Pfizer, BMS, Immunocore, Novartis, Targovax, Polaris, Checkmate Pharmaceuticals, Foghorn Therapeutics, Linneaus Therapeutics, and Prelude Therapeutics. GS reports stock or other ownership interests in GenCirq, Bionaut Labs, and January Therapeutics, advisory/consulting/personal fees from Bionaut Labs, Ellipses Pharma, GenCirq, Epizyme, Array BioPharma, Apexigen, Oncogenuity, OnCusp Therapeutics, Concarlo, Shanghai Pharma, Astex Pharmaceuticals, January Therapeutics, Sellas Life Sciences, PureTech Health, and Killys Therapeutics, research funding from Astex Pharmaceuticals, Incyte, Calithera Biosciences, Lilly, Daiichi Sankyo, Fortress Biotech, Karyopharm Therapeutics, Oxford Biotherapeutics, TopAlliance Biosciences, Adaptimmune, Springworks Therapeutics, and TRACON Pharma. RC reports consulting fees from Alkermes, Bristol Myers Squibb, Castle Biosciences, Delcath Systems, Eisai, Jiangsu Hengrui Pharmaceuticals, Ideaya Biosciences, Immunocore, InxMed, Iovance Biotherapeutics, Merck, Novartis, OncoSec Medical, Pierre Fabre, PureTech Health, Regeneron, Sanofi Genzyme, Sorrento Therapeutics, Trisalus and advisory board fees from Aura Biosciences, Chimeron, and Rgenix.
Funding Information:
Drug and funding for this investigator sponsored research study was provided by AstraZeneca Inc (Wilmington, DE, USA) to support the study. AstraZeneca had no role in data collection, analysis, or interpretation, or in writing this report.
Publisher Copyright:
Copyright © 2022 Khan, Patel, Shoushtari, Ambrosini, Cremers, Lee, Franks, Singh-Kandah, Hernandez, Sender, Vuolo, Nesson, Mundi, Izar, Schwartz and Carvajal.
PY - 2022/9/29
Y1 - 2022/9/29
N2 - 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.
AB - 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.
KW - intermittent dosing
KW - MEK inhibition
KW - metastatic
KW - selumetinib
KW - uveal melanoma
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U2 - 10.3389/fonc.2022.975643
DO - 10.3389/fonc.2022.975643
M3 - Article
C2 - 36249046
AN - SCOPUS:85140000192
SN - 2234-943X
VL - 12
JO - Frontiers in Oncology
JF - Frontiers in Oncology
M1 - 975643
ER -