Abstract PO036: Patients with recurrent epithelial endometrial cancers (EEC) and <i>Wnt</i> signaling alterations demonstrated greater clinical benefit when treated with DKN-01 monotherapy
Authors: Rebecca Arend, Cesar Castro, Erica Hamilton, Kristopher LyBarger, Linda Duska, Michael Kagey, William Bradley, Jasgit Sachdev, Cynthia A. Sirard, David M. O'Malley
Journal: Clinical Cancer Research (2021)

Abstract Background: Dickkopf-1 (DKK1) modulates Wnt signaling, promotes tumor growth through a CKAP4-AKT signaling pathway and contributes to an immune suppressive tumor microenvironment. DKN-01, a neutralizing DKK1 antibody has demonstrated safety and clinical activity in advanced gynecologic malignancies. We report response and survival outcomes in EEC patients (pts) treated with DKN-01 monotherapy by tumor genetics (Wnt signaling alterations and PI3K/AKT mutations). Methods: Pts with recurrent EEC were treated with DKN-01 as monotherapy (mono) or in combination with paclitaxel in a phase 2 basket trial (NCT03395080) whereby ≥50% must have had a Wnt signaling alteration. Here we report on EEC mono group only. Clopper-Pearson confidence intervals and logistic regression were used to study the association of Wnt signaling alterations with clinical benefit (CR, PR or SD) following DKN-01 monotherapy; Kaplan-Meier estimates/Cox-PH models were used for analyses of progression free survival (PFS) and overall survival (OS). Results: As of 30 December 2019, 29 EEC pts enrolled; 21 pts (72%) had Wnt signaling alterations [ARID1A most common (11 pts, 38%)] and 25 (86%) had PI3K/AKT mutations [PIK3CA in 13 pts (45%)]. Median number of prior therapies was 4 (range 1, 9); 20 pts (69%) had endometrioid histology and 19 pts (66%) had G2/G3 tumor grade at diagnosis. 26 pts were evaluable, 20 pts Wnt altered and 6 pts non-Wnt altered; 24 pts with and 2 pts without PI3K/AKT mutations. In the Wnt altered group, there was 1 cCR, 1 cPR, 8 SD (6 durable SD &amp;gt;120 days) and 10 PD compared with 0 responders, 1 SD and 5 PD in the non-Wnt altered group. In the 24 pts with PI3K/AKT mutations there was 1 cCR, 1 cPR, 8 SD (6 durable SD &amp;gt;120 days) and 14 PD compared with 1 SD and 1 PD in the 2 pts without PI3K/AKT mutations. The 2 responding pts had PI3KCA mutations in common. Probability of 6 month PFS/OS was 30% (95% CI:12.3, 50.1) and 70% (95% CI: 45.1, 85.3) for Wnt altered pts vs 18% (95% CI: 0.8, 53.8) and 50% (95% CI: 11.1, 80.4) for non-Wnt altered, respectively. Conclusions: DKN-01 has single agent activity in heavily pretreated EEC pts. EEC pts frequently had Wnt signaling alterations and PIK3/AKT mutations; greater clinical benefit was demonstrated in pts whose tumors had Wnt signaling alterations. This study is ongoing and updated results will be presented. Citation Format: Rebecca Arend, Cesar Castro, Erica Hamilton, Kristopher LyBarger, Linda Duska, Michael Kagey, William Bradley, Jasgit Sachdev, Cynthia A. Sirard, David M. O'Malley. Patients with recurrent epithelial endometrial cancers (EEC) and Wnt signaling alterations demonstrated greater clinical benefit when treated with DKN-01 monotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO036.