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Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar
Ghassan K Abou-Alfa1,2, Robert Mayer3, Alan P Venook4
1Weill Medical College at Cornell University, New York, New York, USA.
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.
Insights
This study evaluated ENMD-2076 for fibrolamellar carcinoma (FLC), finding limited efficacy. Further research should explore combination therapies targeting DNAJB1-PRKACA.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Fibrolamellar carcinoma (FLC) is a rare liver cancer subtype (0.85% of cases).
- FLC is characterized by the DNAJB1-PRKACA gene fusion, leading to Aurora kinase A (AURKA) overexpression.
- ENMD-2076 is a targeted therapy designed as a selective inhibitor of AURKA.
Purpose of the Study:
- To assess the efficacy and safety of ENMD-2076 as a single agent in patients with incurable FLC.
- To determine the overall objective response rate (ORR) as the primary endpoint.
Main Methods:
- A single-arm clinical trial enrolled 35 patients with pathologically confirmed FLC.
- Patients received ENMD-2076 based on body surface area.
- Efficacy was assessed by RECIST v1.1 criteria; secondary endpoints included progression-free survival (PFS) and overall survival (OS).
Main Results:
- One patient (3%) achieved a partial response (PR), and 20 patients (57%) had stable disease (SD).
- Median time to progression (TTP), PFS, and OS were 5, 3.9, and 19 months, respectively.
- Hypertension was the most common serious adverse event; no deaths were attributed to the drug.
Conclusions:
- ENMD-2076 demonstrated limited single-agent activity in FLC, not supporting further evaluation in this context.
- Future therapeutic strategies may require targeting both the DNAJB1-PRKACA fusion and its downstream effectors simultaneously.
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