Abstract CT035: A phase Ib study of miransertib (ARQ 092) in combination with anastrozole in patients with PIK3CA or AKT1-mutant ER+ endometrial or ovarian cancer
Authors: Hyman David , Bonafede Michael , O'Cearbhaill Roisin , Grisham Rachel , Zamarin Dmitriy , Tew William , Aghajanian Carol , Cadoo Karen , Friedman Claire , Savage Ron E. , Chai Feng , Schwartz Brian , Makker Vicky 
Published: August 2018

Abstract
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.
*pt had PD at 24 weeks but continues for ongoing benefit at 56 weeks.Pt IDPrimary SiteHistologyGradeMutationLines of prior therapyBest RECIST response (confirmed)Duration on treatment (weeks)1EndometrialMixed endometriod/serous1PIK3CA H1047R3CR60+2EndometrialEndometriod2PIK3CA H1047R4uPR24*3EndometrialEndometriod1PIK3CA H1047R4SD124EndometrialSerous3PIK3CA R115L1PD85EndometrialEndometriod1PIK3CA E545K and H1047L2NE46OvarySerous3PIK3CA H1047R5PD77OvaryEndometriod1PIK3CA T1025S2PD88EndometrialSerous3PIK3CA N345K2uPR169OvarySerous3PIK3CA E542K5PD510EndometrialSerous3AKT1 E17K1uPR**12+11EndometrialSerous3PIK3CA C901F3PD9*pt had PD at 24 weeks but continues for ongoing benefit at 56 weeks**pending confirmation
Citation Format: David Hyman, Michael Bonafede, Roisin O'Cearbhaill, 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.