ABSTRACT
LESSONS LEARNED: The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. BACKGROUND: Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. METHODS: Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 or Lansky 70-100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study. RESULTS: Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study-two due to disease progression and one due to pulmonary embolism not related to ENMD-2076. CONCLUSION: The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.
