A Phase II Trial of Defactinib Combined with Avutometinib in Patients with Metastatic Uveal Melanoma
Document Type
Article
Publication Date
7-11-2026
Abstract
Background: Treatment options are limited, and outcomes remain poor for patients with metastatic uveal melanoma (MUM). We conducted an investigator-initiated, prospective, single-arm, single-institution, phase II study evaluating the combination of an FAK inhibitor (defactinib) with a RAF/MEK inhibitor (avutometinib) for the treatment of MUM. Methods: From February 2021 through January 2023, 12 patients with MUM were treated with the combination of defactinib and avutometinib. Defactinib was given 200 mg twice daily, and avutometinib was given 3.2 mg twice a week. Both drugs were given for 3 weeks on and 1 week off (28-day cycle). Disease control rate was the primary endpoint of this study. Results: Median lines of prior therapies for the patients were two. After two cycles, six patients achieved stable disease while six patients developed progressive disease (disease control rate of 50%). With a median follow-up of 20.0 months, the median progression-free survival was 3.0 months and the median overall survival was 20.0 months. The combination was quite tolerable for patients, with no patients requiring dose reduction or discontinuation. Trial enrollment was stopped early by study sponsors before the anticipated accrual of 18 patients due to no patients having a significant reduction in disease. Conclusions: This is the first study reporting on the use of an FAK inhibitor combination in MUM. Further research should seek to elucidate an optimal combination treatment strategy for MUM, such as FAK and PKC inhibitors, for improved blockade of the signaling pathways downstream of GNAQ/GNA11 driver mutations.
Recommended Citation
Seedor, Rino S.; Terai, Mizue; Koshkin, Sergei A.; Aplin, Andrew E.; Orloff, Marlana; Sharpe-Mills, Erin; Naccarato, Madeleine; Mills, Aurora; Molinolo, Alfredo A.; Gutkind, J. Silvio; and Sato, Takami, "A Phase II Trial of Defactinib Combined with Avutometinib in Patients with Metastatic Uveal Melanoma" (2026). Kimmel Cancer Center Faculty Papers. Paper 187.
https://jdc.jefferson.edu/kimmelccfp/187
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
42512298
Language
English
Comments
This article is the author’s final published version in Cancers, Volume 18, Issue 14, 2026, Article number 2232.
The published version is available at https://doi.org/10.3390/cancers18142232. Copyright © 2026 by the authors.