OR42-3 Changes in corticotroph tumor size and plasma ACTH levels in Cushing's disease (CD) patients during long-term treatment with the glucocorticoid antagonist mifepristone (MIFE)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR42-Cushing's Disease & Non-Functioning Hypothalamic-Pituitary Tumours
Clinical
Tuesday, June 18, 2013: 9:15 AM-10:45 AM
Presentation Start Time: 9:45 AM
Room 102 (Moscone Center)
Maria Fleseriu*1, James W Findling2, Christian A Koch3, Sven-Martin Schlaffer4, Michael Buchfelder5 and Coleman Gross6
1Northwest Pituitary Center, Oregon Health & Science University, Portland, OR, 2Medical College of Wisconsin, Menomonee Falls, WI, 3University of Mississippi Medical Center, Jackson, MS, 4University of Erlangen, 91054 Erlangen, Germany, 5Univ of Erlangen-Nuremberg, Erlangen, Germany, 6Corcept Therapeutics, Berkeley, CA
Rationale: Pituitary effects of long-term glucocorticoid antagonist therapy in CD patients (pts) are not well understood. We present ACTH and corticotroph tumor size data from the SEISMIC study and its long-term extension (ext).

Methods: SEISMIC, a 24 week (wk) multicenter open label study of MIFE (300–1200 mg qday), included 43 pts with CD s/p failed surgery; 27 continued in the ext. ACTH was measured at baseline and during MIFE (wk 2, 6, 10, 16, 24 in SEISMIC; then every 3 months [mo] in ext). MRIs (baseline, wk 10 and 24 and then every 6 mo) were retrospectively centrally analyzed in blinded fashion.

Results: Thirty-one (72%) women and 12 (28%) men, age 45±12 y received MIFE for a median of 23.1 mo (range:0.8-44.6). Mean (±SD) ACTH levels (normal 5-50 ng/L) rose from baseline (62.7±51.4 ng/L) by wk 2 (97.2±71.3 ng/L, p<0.0001), plateaued by wk 10 (135.1±116.6 ng/L, p<0.0001), and declined but were mildly higher than baseline 6 wk after discontinuation (73.7±56.8 ng/L, p=0.03).  In the ext, peak ACTH levels were similar (130.2 ± 80.5, p=0.14) to those during the first 24 wk. During SEISMIC and its ext, the maximum fold increase was 8.8 and 7.9, respectively. Increases in ACTH >1.5, >2, >3 >4, >5 fold during MIFE were seen in 88%, 72%, 47% 30% and 16% of pts, respectively. Baseline ACTH was lower in pts with prior pituitary radiation (N=18) compared to those without it (45.8±25.8 vs 86.1±67.7 ng/L, p=0.01) and increases were less in radiated pts until wk 6 (1.7±0.8 vs 2.3±1.0 fold, p=0.03) but not later.  ACTH was linearly related to MIFE dose (p=0.0002); dose changes of ≥600 mg resulted in statistically significant changes in ACTH (p=0.0013).  Of 36 pts with ≥1 post baseline MRI for analysis, 24 and 20 received MIFE for ≥12 mo and ≥24 mo, respectively. Seventeen had visible tumors, including 10 macroadenomas (macro).  Tumor progression occurred in 4 pts: 1 pt had early progression (wk 10) of a large macro and 3 pts (2 macro, 1 micro) had gradual tumor enlargement in long-term follow up (20-36 mo).  There was no progression in 19 pts without tumor on baseline MRI. ACTH increase in pts with progression (2.6-5.2 fold maximum) was similar to those without.

Conclusion: Significant dose-dependent increases in plasma ACTH are expected in CD pts treated with MIFE.  Corticotroph tumor progression may occur, but pts may have significant increases in ACTH levels without evidence of tumor growth. Follow-up MRI is recommended, particularly in pts with macro.

Disclosure: MF: Principal Investigator, Corcept, Principal Investigator, honorarium, consultant, Principal Investigator, honorarium, consultant. JWF: Ad Hoc Consultant, Corcept. CAK: Principal Investigator, Corcept, Consultant, Novo Nordisk, Speaker, Ipsen. SMS: Researcher, Corcept. MB: Researcher, Corcept. CG: Employee, Corcept.

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by Corcept Therapeutics