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A three-arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel in metastatic uveal melanoma

Lookup NU author(s): Professor Ruth Plummer

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2024 The AuthorsAims: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel. Patients and methods: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level. Results: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved. Conclusions: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing.


Publication metadata

Author(s): Sacco JJ, Jackson R, Corrie P, Danson S, Evans TRJ, Ochsenreither S, Kumar S, Goodman A, Larkin J, Karydis I, Steven N, Lorigan P, Plummer R, Patel P, Psarelli E, Olsson-Brown A, Shaw H, Leyvraz S, Handley L, Rawcliffe C, Nathan P

Publication type: Article

Publication status: Published

Journal: European Journal of Cancer

Year: 2024

Volume: 202

Online publication date: 09/03/2024

Acceptance date: 04/03/2024

Date deposited: 09/04/2024

ISSN (print): 0959-8049

ISSN (electronic): 1879-0852

Publisher: Elsevier Ltd

URL: https://doi.org/10.1016/j.ejca.2024.114009

DOI: 10.1016/j.ejca.2024.114009

Data Access Statement: Data are available upon reasonable request.


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Funding

Funder referenceFunder name
AstraZeneca
Cancer Research UK

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