D. Hyman, M. Bonafede, R. O’Cearbhaill
Jul 1, 2018
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Background: Activating PI3K pathway mutations are common in endometrial and a subset of non-serous ovarian cancers and are frequently found in tumors that co-express the estrogen receptor (ER). We evaluated the safety and preliminary efficacy of miransertib, a potent pan-AKT inhibitor, in combination with the aromatase inhibitor (AI) anastrozole in pts with PIK3CA and AKT1 -mutant ER+ endometrial and ovarian cancer. Methods: Eligible patients included endometrial and ovarian cancer patients (pts) with ER+ by immunohistochemistry and a PIK3CA or AKT1 mutation documented by local sequencing assays. There was no limit to prior lines of therapy including prior AIs. Miransertib dose was escalated according to a 3+3 design. TEAEs were assessed per CTCAE v. 4.03. Tumor responses were evaluated per RECIST 1.1. Results : A total of 11 pts (8 endometrial, 3 ovarian) were enrolled (median age 60 years). Pts were treated at one of 2 miransertib doses: 200 mg QD, 5 days on/9 days off (n=6) or 150 mg QD, 5 days on/9 days off (n=5). All pts received anastrozole 1 mg QD administered continuously. 2 DLTs observed (both at the miransertib 200mg): grade 3 ALT increase and grade 3 rash. Across all cycles, a total of 4 pts experienced a Grade 3 miransertib-related AE including rash (n=2), ALT increase (n=1), and hyperglycemia (n=1). There were no grade 4/5 miransertib-related AEs. Miransertib 150mg was selected as the recommended dose. 4 pts achieved a response (1 confirmed CR, 3 unconfirmed PRs - 1 pending confirmation, see Table). All responses (confirmed and unconfirmed) were in endometrial cancer (4/8 pts). In responding pts, mutations involved PIK3CA (n=3) and AKT1 (n=1). 50% (2/4) responding pts had received ≥1 prior line of endocrine therapy. Responses were ongoing in 2 of 4 patients, with the longest continuing at 60 weeks. Conclusions : The combination of miransertib and anastrozole demonstrated a manageable safety profile and preliminary efficacy. Responses were observed in endometrial pts with PIK3CA or AKT1 mutation and those who had received prior endocrine therapy. Enrollment at the recommended combination dose is ongoing and updated response data will be presented. Citation Format: David Hyman, Michael Bonafede, Roisin O9Cearbhaill, Rachel Grisham, Dmitriy Zamarin, William Tew, Carol Aghajanian, Karen Cadoo, Claire Friedman, Ron E. Savage, Feng Chai, Brian Schwartz, Vicky Makker. A phase Ib study of miransertib (ARQ 092) in combination with anastrozole in patients with PIK3CA or AKT1 -mutant ER+ endometrial or ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT035.