Trastuzumab deruxtecan (T-DXd) combinations in patients with HER2-positive advanced or metastatic breast cancer: A phase 1b/2, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast07).
Authors: Andre Fabrice , Hamilton Erika P. , Loi Sherene , Schmid Peter , Anders Carey K. , Yu Tinghui , Boston Sarice , D'Cruz Celina M. , Herbolsheimer Pia , Jhaveri Komal L. 
Published: June 2021

TPS1096

Background: HER2-targeted therapies have improved survival in patients (pts) with HER2+ advanced/metastatic breast cancer (mBC) but challenges remain, including resistance to current HER2-targeted therapies. Also, additional treatment options are needed in pts with brain metastases (BM). In the phase 2 DESTINY-Breast01 trial, T-DXd demonstrated efficacy, with an objective response rate (ORR) of 61.4% and median progression-free survival (mPFS) of 19.4 mo in pts with previously treated HER2+ advanced/mBC (Modi SABCS 2020); data from an earlier cutoff of this trial supported approval of T-DXd in the US, Europe, and Japan. In a subgroup analysis of 24 pts with stable BM, T-DXd showed preliminary efficacy, with mPFS of 18.1 mo (Jerusalem ESMO Breast Cancer 2020). Here, we describe a phase 1b/2 trial evaluating the safety and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC, including pts with stable and active BM. Methods: DESTINY-Breast07 (NCT04538742) is a global, multicenter, open-label, phase 1b/2 trial designed to evaluate the safety, tolerability, and preliminary antitumor activity of T-DXd monotherapy and combinations in pts with HER2+ advanced/mBC. This study consists of a T-DXd monotherapy module (module 0) and 5 combination modules of T-DXd plus (1) durvalumab, (2) pertuzumab, (3) paclitaxel, (4) durvalumab + paclitaxel, or (5) tucatinib, all in pts with no or stable BM. Two additional modules consisting of (6) T-DXd + tucatinib and (7) T-DXd monotherapy will include pts with untreated BM not requiring local therapy or previously treated BM that have progressed since local therapy (active BM). The need for chronic steroids or local therapy to manage BM symptoms is exclusionary. Modules 2 to 5 will each consist of 2 parts: dose finding (part 1) and dose expansion (part 2). Modules 0, 1, 6, and 7 will include part 2 only. Part 1 of individual modules will enroll pts who have had disease progression while receiving ≥1 prior line of therapy in the metastatic setting. In part 2, pts who have received no prior therapy (modules 0 to 5) or ≤1 prior therapy (modules 6 to 7) for metastatic disease will be randomized to receive a T-DXd combination regimen or monotherapy. The primary endpoints are determination of the recommended phase 2 doses (part 1 only) and safety and tolerability of T-DXd and combinations (parts 1 and 2). Secondary endpoints include ORR, PFS, PFS2, duration of response (DoR), and overall survival (all assessed in part 2 only) and pharmacokinetics and immunogenicity (parts 1 and 2). To assess central nervous system (CNS) activity, exploratory endpoints were added, including CNS-ORR, CNS-DoR, and CNS-PFS (by RECIST version 1.1 and RANO-BM criteria) as well as cognitive and symptom assessment using CANTAB, MDASI-BT, and NANO. Clinical trial information: NCT04538742 .