Abstract CT260: A phase II trial of defactinib combined with avutometinib in patients with metastatic uveal melanoma

Abstract Background: Outcomes remain poor for patients with metastatic uveal melanoma (MUM). Therapies targeting commonly mutated G-protein pathway-associated GNAQ and GNA11 have not been met with clinical success. Recent kinome-wide CRISPR-Cas9 screens revealed that FAK and RAF/MEK co-targeting may provide a new network-based precision therapeutic strategy for MUM treatment. Methods: This is an investigator-initiated, prospective, single-arm, single-institution, phase II study evaluating the combination of a FAK inhibitor (defactinib, VS-6063) with a RAF/MEK inhibitor (avutometinib, VS-6766) for the treatment of MUM NCT04720417. Defactinib was given 200mg twice daily and avutometinib was given 3. 2mg twice a week. Both drugs were given for 3 weeks on and 1 week off (28-day cycle). The primary endpoint of the study is disease control rate (DCR) including complete response (CR), partial response (PR), and stable disease (SD) as determined by RECIST version 1. 1 after two cycles. Secondary endpoints include progression free survival (PFS), overall survival (OS), and safety. The trial was designed using a Simon’s two stage design where in stage I, a total of 8 patients would be accrued and if there are ≤2 overall responses, further enrollment would be stopped with the conclusion that DCR cannot be ≥50%. An additional 10 patients would be accrued in stage II, resulting in a total sample size of 18 patients. Results: Twelve patients with MUM were treated with the combination. Median lines of prior therapy was 2 (range 0-7), with 3 patients (25%) being treatment naïve. After 2 cycles, 6 patients achieved SD (50%) while the other 6 patients developed PD. No patients achieved CR or PR. Median duration of treatment was 2. 6 months for all patients, and 5. 6 months for patients with SD. With a median follow up of 16. 5 months, the median PFS was 2. 6 months and median OS was 18. 4 months. All adverse events (AE) were Grade 1-2 except one Grade 3 AE of asymptomatic elevated CPK that resolved with holding treatment and did not recur upon restarting. Most common AEs were rash (100%), diarrhea (66. 7%), peripheral edema (50%), nausea (50%), fatigue (50%), and blurred vision (41. 7%). No dose reductions were required for any patients. Reduction of active ERK (pERK) was observed in 2 patients that achieved SD, but not in 2 patients that had PD. Trial enrollment was stopped early by study sponsors before the anticipated accrual of 18 patients due to no patients having significant reduction in disease. Conclusions: In this phase II study of the combination regimen of FAK and RAF/MEK inhibitors, stable disease was achieved in half of patients with MUM. Treatment was well tolerated with only one transient asymptomatic grade 3 CPK elevation. Further research should seek to elucidate an optimal combination treatment strategy such as FAK and PKC inhibitors for improved blocking of the downstream pathways of GNAQ/GNA11 driver mutations. Citation Format: Rino S. Seedor, Mizue Terai, Amry Majeed, Ryota Tanaka, Andrew E. Aplin, Marlana Orloff, Alfredo A. Molinolo, J Silvio Gutkind, Takami Sato. A phase II trial of defactinib combined with avutometinib in patients with metastatic uveal melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr CT260.