Cell-free DNA in uveal melanoma: Results from the first-in-human trial of mivebresib (ABBV-075).

Abstract

e14526 Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Cell free DNA (cfDNA) is a non-invasive mechanism for monitoring malignancy in UM patients. BET proteins activate transcription of oncogenic genes, and mivebresib (ABBV-075) is a potent pan-BET inhibitor. In the first-in-human phase 1 study, safety and pharmacokinetics of mivebresib were assessed in patients with advanced cancer (NCT02391480). We compared cfDNA mutational dynamics with the survival of UM patients treated with mivebresib. Methods: Adult patients with metastatic solid tumors and ≥1 line of prior treatment were treated with mivebresib on a schedule of daily; 3 days/week; or 4 days on, 3 days off. Two mL of plasma cfDNA (≥10ng) in 5 patients (3 progressive disease [PD], 2 stable disease [SD]) were sequenced with a targeted 63-gene panel (68 Kb) to ≥800X unique depth after barcode-based error-suppression and genomic alterations discovered in all patients. Results: As of May 2018, 10 UM patients received ≥1 dose of mivebresib with median 8.1 weeks (range, 3.6–39.6) of treatment. The median age was 55 years (range, 37–73). 9 patients experienced a treatment-emergent adverse event (TEAE), most commonly (≥40% patient incidence), dysgeusia (60%), thrombocytopenia and nausea (40%, each). 9 patients were evaluable, 4 achieved a best response of SD and 5 PD (RECIST v1.1). The mean pretreatment cfDNA concentration was 21.0 ng/mL (N = 5 with plasma available). cfDNA levels increased in two patients by 0.6% (SD) and 64.4% (PD). In PD patients, elevated cfDNA concentration (32.7 ng/mL [PD] vs 3.5 ng/mL [SD]) was associated with shorter progression-free survival and overall survival. At baseline, the cfDNA mutational load (median mutant molecules/mL plasma) of pathogenic (COSMIC) mutations with AF ≥1% was highest in PD (893.9; range, 78-4951.5) vs SD patients (53.1; range, 9.3-606.2) and negatively correlated with the patient’s survival (R2= 0.531). In 1 PD patient, multiple TP53 (C23G, V203M) and CDKN2A (A148T, L63P) mutations were acquired by the time of progression. Conclusions: These data suggest cfDNA as a potential marker for survival of UM patients. Further investigation of BET inhibition in this population is warranted. Clinical trial information: NCT02391480.