Abstract 327: Antitumor efficacy of trastuzumab deruxtecan in combination with adavosertib in HER2-expressing Cyclin E amplified gastroesophageal cancers
Authors: DiPeri Timothy P. , Evans Kurt W. , Raso Gabriela , Rizvi Yasmeen Q. , Zheng Xiaofeng , Kirby Bryce , Kong Kathleen , Keyomarsi Khandan , Ajani Jaffer A. , Yap Timothy A. , Meric-Bernstam Funda 
Published: June 2022

Abstract
Purpose: Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate approved for patients with HER2-positive gastric/gastroesophageal junction (GEJ) cancers. Amplification of CCNE1, which encodes cyclin E, has been proposed as a mechanism of resistance to HER2-targeted therapies. The Wee1 kinase inhibitor adavosertib (AZD1775) has demonstrated enhanced antitumor activity in the setting of cyclin E overexpression. We investigated the efficacy of T-DXd in combination with adavosertib in HER2-expressing cancers with and without co-amplification of CCNE1.
Methods: Frequency of CCNE1 amplification was determined among patients with ERBB2 amplification in a clinical genomic database at the MD Anderson Cancer Center (MDACC) and within The Cancer Genome Atlas (TCGA). Sulforhodamine B assay, western blotting, and Annexin V staining were used to determine the effects of T-DXd and DXd in combination with adavosertib in vitro. Four HER2-expressing gastric/GEJ patient-derived xenograft (PDX) models with or without co-amplification of CCNE1 were tested with T-DXd in combination with adavosertib in vivo. Tumor volume and body weights were measured twice weekly and treatment responses were assessed by the relative treatment-to-control ratio, waterfall plots, and event-free survival (event defined as the day which tumors doubled in size from baseline).
Results: Of 515 patients identified at MDACC with ERBB2 amplification, 60 (11.6%) had co-amplification of CCNE1. Of the 405 patients identified within the TCGA with ERBB2 amplification, 43 (10.6%) had co-amplification of CCNE1. Tumor types with the highest frequency of ERBB2/CCNE1 co-amplification were gastric/GEJ (38.1% MDACC, 31.0% TCGA), endometrial (25.0% MDACC, 29.6% TCGA), and ovarian (15.4% MDACC, 15.4% TCGA). Adavosertib was synergistic in combination with DXd in four cell lines with ERBB2 amplification, CCNE1 amplification, or ERBB2/CCNE1 co-amplification. Both DXd and T-DXd upregulated cyclin E and γH2AX protein expression at 24 and 96 hours, and the combination of DXd or T-DXd with adavosertib enhanced apoptosis. T-DXd induced durable tumor regression in two HER2 amplified and HER2 overexpressing gastroesophageal PDX cancer models with HER2 amplification/3+ overexpression and concomitant cyclin E amplification/expression. Adavosertib enhanced the antitumor activity of T-DXd in two HER2 low, cyclin E amplified gastroesophageal cancer PDX models (one with an ERBB2 G778A mutation).
Conclusions: ERBB2 and CCNE1 are frequently co-amplified. Our findings provide supporting rationale for combining T-DXd with adavosertib in HER2-expressing cancers with CCNE1 co-amplification. Further study is needed to determine if therapeutic induction of cyclin E with DXd may sensitize to Wee1 kinase inhibition in patients without cyclin E amplification as well.
Citation Format: Timothy P. DiPeri, Kurt W. Evans, Gabriela Raso, Yasmeen Q. Rizvi, Xiaofeng Zheng, Bryce Kirby, Kathleen Kong, Khandan Keyomarsi, Jaffer A. Ajani, Timothy A. Yap, Funda Meric-Bernstam. Antitumor efficacy of trastuzumab deruxtecan in combination with adavosertib in HER2-expressing Cyclin E amplified gastroesophageal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 327.