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(7_Suppl):Abstract nr CT260.