Session: OR42-Cushing's Disease & Non-Functioning Hypothalamic-Pituitary Tumours
Room 102 (Moscone Center)
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.
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