Background PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. Methods We conducted a single‐arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1‐4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss‐of‐function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. Results Twenty‐eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1‐3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy‐evaluable patients, the ORR was 16% (90% CI, 7%‐100%), and the clinical benefit rate was 28% (90% CI, 16%‐100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression‐free survival and overall survival were 2.5 months (95% CI, 1.2‐3.0) and 9.2 months (95% CI, 5.0‐15.9), respectively. The most common all‐grade treatment‐related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. Conclusion In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single‐agent activity and a manageable safety profile.

5582 Background: Monoclonal antibodies Durvalumab (D) and Tremelimumab (T) inhibit binding of programmed cell death ligand 1 (PDL1) to PD1 and inhibit activation of cytotoxic T-lymphocyte-associated protein 4 (CTLA4), respectively, resulting in improved tumor immunosurveillance. There is rationale to study D and DT based on recent genomic and tumor microenvironment evaluation of endometrial cancer (EC). Methods: Eligible patients (pts) were randomized to D or DT. Pts received D 1500 mg intravenously (IV) every 4 weeks (wks). DT therapy pts received D 1500 mg IV every 4 wks and T 75 mg IV every 4 wks for 4 cycles, followed by D 1500 mg IV every 4 wks until progression or unacceptable toxicities. Pts were stratified by histology with 10 carcinosarcoma or MSI-H EC pts per arm. Efficacy assessments were every 8 wks and treatment related adverse events (TRAEs) were assessed per CTCAE v.4.03. The primary endpoint was overall response rate (ORR) by RECIST v1.1. Descriptive statistics and 90% one sided CI are reported. Progression free survival (PFS) rate at 24 wks (PFS24wks) was estimated by Kaplan Meier method. Results: At planned interim analysis, 56 pts were enrolled (28 per arm). 15 pts: carcinosarcoma, 15 pts: endometrioid (3: Gr1), 14 pts: serous, and 12 pts: other histology. 5(9%) pts: MSI-H, 48(86%) pts: microsatellite stable (MSS), 3(5%): unknown. 2 pts were excluded due to early death. 27 pts per arm were evaluable for efficacy. In the D arm: 1 pt had complete response (CR)(MSS) and 3 pts had a partial response (PR) (2:MSS, 1:MSI-H) with an ORR of 14.8% (CI: 6.6-100%). The median PFS was 7.6 wks and PFS24wks was 13.3% (CI 6.1-100%). Median duration of response (DOR) was 16 wks in the D arm. In the DT arm, 2 pts achieved CR (1:MSI-H, 1:MSS) and 1 had PR (MSS). The ORR was 11.1% (CI: 4.2-100%). Median PFS was 8.1 wks, PFS24wks was 18.5% (CI 10.1-100%) and DOR was 8 wks. Grade 3 TRAEs occurred in 2 (7%) pts in D and 9 (32%) pts in DT. Grade 4 TRAEs occurred 1 (4%) pt in D and 3 (11%) pts in DT. 2 pts discontinued due to a TRAE. Most common TRAEs in total were fatigue (23%), diarrhea (20%), nausea (14%), vomiting (13%) and pruritis (11%). Conclusions: D and DT show modest activity in EC. No new safety signals were identified. Second stage accrual is ongoing. Clinical trial information: NCT03015129.

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Background: Activating mutations of the PI3K/mTOR pathway are highly prevalent in endometrial cancers (EC), but monotherapy targets of this pathway have shown modest activity and are associated with poor tolerance. LY3023414 is a selective inhibitor of class I PI3K isoforms, mTOR, and DNA-PK. Building on phase I experience of LY3023414, we sought to evaluate the efficacy and safety of LY3023414 in PI3K pathway activated advanced EC. Methods: Eligible patients (pts) had PI3K pathway activation defined as (1) loss of PTEN function including whole or partial gene deletion, frame shift mutations, or non-sense mutations (PTEN missense mutations excluded) or (2) activating mutation in PIK3CA, AKT1, PIK3R1, PIK3R2, or mTOR. Up to 4 prior lines of therapy were allowed. Each cycle was 21 days. Efficacy assessments were performed every 2 cycles and treatment-related adverse events (AEs) were assessed per CTCAE v. 4.03. The primary objective was best overall response rate by RECIST 1.1. Results: Of the 28 pts enrolled, 25 (89%) had 1-2 lines of therapy and 3 pts (11%) had 3-4 prior lines of therapy. LY3023414 was dosed at the RP2D of 200 mg orally twice daily. Three pts were excluded from efficacy assessment due to toxicity, noncompliance or early patient withdrawal. The clinical benefit rate (CBR), defined as the percentage of pts with complete response (CR) + partial response (PR) + stable disease (SD) ≥12 weeks, was 56% (14/25). Five patients achieved PR; 9 pts achieved SD at best response. Three of the 5 PRs were sustained from 44-52 weeks; 1 pt with PR is still on therapy > 84 weeks. The median PFS and median OS were 2.53 (CI 1.18-2.99) months and 9.24 (CI 5-NR) months, respectively. Twenty-one pts underwent further genomic sequencing; 16 pts (76%) had a PIK3CA mutation, 6 pts (29%) had a PIK3R1 and 10 pts (48%) had a PTEN mutation. There were no significant co-mutations identified and a correlation of molecular alterations with response was not identified. Across all cycles, the most common grade 3 LY3023414-related adverse events (AEs) were lymphopenia (n=10), hypokalemia (n=5), hypophosphatemia (n=4), hyponatremia (n=3), and anemia (n=3). There were 3 LY3023414-related grade 4 AEs: allergic reaction (n=1), CPK rise (n=1) and hyponatremia (n=1). There were no LY3023414-related G5 AEs. Conclusions: In PI3K pathway-altered, heavily pretreated advanced EC, LY3023414 demonstrated a manageable safety profile and promising single-agent efficacy. Enrollment is now complete and updated response data will be presented. Citation Format: Maria M. Rubinstein, David Hyman, Imogen Caird, Roisin O'Cearbhaill, Rachel Grisham, William Tew, Martee Hensley, Paul Sabbatini, Carol Aghajanian, Alexia Iasonos, Helen Won, Duygu Selcuklu, Catherine Zimel, Vicky Makker. Single-arm, open-label, phase II study of LY3023414 for the treatment of recurrent or persistent endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr B18.