Genomic Profiling of Metastatic Uveal Melanoma and Clinical Results of a Phase I Study of the Protein Kinase C Inhibitor AEB071.

Abstract

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.

• Authors: Sophie Piperno-Neumann, James Larkin, Richard D Carvajal, Jason J Luke, Gary K Schwartz, F Stephen Hodi, Marie-Paule Sablin, Alexander N Shoushtari, Sebastian Szpakowski, Niladri Roy Chowdhury, A Rose Brannon, Thiruvamoor Ramkumar, Leanne de Koning, Adnan Derti, Caroline Emery, Padmaja Yerramilli-Rao, Ellen Kapiteijn
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 19 Issue 4 Pg. 1031-1039 (04 2020) ISSN: 1538-8514 [Electronic] United States
• PMID: 32029634 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Pyrroles
• Quinazolines
• sotrastaurin
• Protein Kinase C

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics)
• Female
• Follow-Up Studies
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Maximum Tolerated Dose
• Melanoma (drug therapy, genetics, pathology)
• Middle Aged
• Neoplasm Metastasis
• Prognosis
• Protein Kinase C (antagonists & inhibitors)
• Pyrroles (pharmacokinetics, pharmacology)
• Quinazolines (pharmacokinetics, pharmacology)
• Tissue Distribution
• Uveal Neoplasms (drug therapy, genetics, pathology)
• Young Adult