Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Patients with metastatic UM (n = 153) were treated with AEB071 in a phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1,400 mg. First-cycle dose-limiting toxicities were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses ≥700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks). High-depth, targeted next-generation DNA sequencing was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM. In conclusion, the protein kinase C inhibitor AEB071 was well tolerated, and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of protein kinase C inhibitors with other compounds in metastatic UM.

中文翻译：

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转移性葡萄膜黑色素瘤的基因组分析和蛋白激酶 C 抑制剂 AEB071 的 I 期研究的临床结果

多达 50% 的葡萄膜黑色素瘤 (UM) 患者会发展为转移性疾病，对此没有有效的全身治疗。本研究旨在评估口服蛋白激酶 C 抑制剂 AEB071 在转移性 UM 患者中的安全性和有效性，并对转移性肿瘤样本进行基因组分析，旨在提出联合治疗方案。在 I 期单臂研究中，转移性 UM 患者（n = 153）接受了 AEB071 治疗。患者每天接受的 AEB071 总剂量为 450 至 1,400 毫克。在 13 名患者 (13%) 中观察到第一周期剂量限制性毒性。这些是最常见的胃肠系统毒性，并且与剂量相关，发生在剂量≥700 毫克/天时。观察到初步临床活性，3% 的患者达到部分缓解，50% 的患者病情稳定（中位持续时间为 15 周）。对 89 个转移性肿瘤活检样本进行了高深度、靶向的下一代 DNA 测序。观察到先前在 UM 中发现的突变，包括 GNAQ、GNA11、BAP1、SF3B1、PLCB4 的突变和染色体臂 8q 的扩增。观察到 GNAQ/GNA11 突变的频率与之前报道的相似（93%），证实了在转移性 UM 中抑制下游效应子 PKC 的治疗窗口。总之，蛋白激酶 C 抑制剂 AEB071 耐受性良好，在转移性 UM 中观察到适度的临床活性。基因组发现与先前在初级 UM 中的报告一致。一起，