Trastuzumab deruxtecan (T-DXd) in patients with HER2+ metastatic breast cancer with brain metastases: A subgroup analysis of the DESTINY-Breast01 trial.
Authors: Jerusalem Guy Heinrich Maria , Park Yeon Hee , Yamashita Toshinari , Hurvitz Sara A. , Modi Shanu , Andre Fabrice , Krop Ian E. , Gonzalez Xavier , Hall Peter S. , You Benoit , Saura Cristina , Kim Sung-Bae , Osborne Cynthia R. C. , Sagara Yasuaki , Tokunaga Eriko , Liu Yali , Cathcart Jillian , Lee Caleb C. , Perrin Christophe 
Published: June 2021

526 Background: Patients (pts) with HER2+ metastatic breast cancer (mBC) are at high risk of developing brain metastases (BMs), and treatment options are limited once BMs occur. T-DXd is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. On the basis of findings of the phase 2 DESTINY-Breast01 trial (NCT03248492), T-DXd was approved for the treatment of adult pts with HER2+ unresectable or mBC who have received ≥2 prior anti-HER2–based regimens (US and Europe) or had prior chemotherapy and are refractory to or intolerant of standard treatments (Japan). Here we describe a subgroup analysis from DESTINY-Breast01 in pts with a history of BMs. Methods: DESTINY-Breast01 is an ongoing, 2-part, multicenter, open-label, phase 2 trial of T-DXd in adult pts with HER2+ unresectable or mBC previously treated with trastuzumab emtansine. Pts with baseline BMs that were treated, asymptomatic, and did not require therapy to control symptoms were eligible for enrollment. All treatment to control symptoms had to be completed ≥60 days before randomization. An MRI of the brain every 6 wks was only required for pts with BMs at baseline. Brain lesions were considered non-target lesions, and thus collection of diameter measurements was not required. This analysis includes pts with a history of BMs at baseline who received T-DXd at the approved dose of 5.4 mg/kg every 3 wks. Results: Twenty-four pts with a history of BMs were included (data cutoff, August 1, 2019). In these pts, the objective response rate (ORR), median progression-free survival (mPFS), and median duration of response (mDoR) per independent central review with T-DXd 5.4 mg/kg were 58.3% (95% CI, 36.6%-77.9%), 18.1 mo (95% CI, 6.7-18.1 mo), and 16.9 mo (95% CI, 5.7-16.9 mo), respectively, and were comparable to those in the total pt population (N = 184) treated at 5.4 mg/kg in the DESTINY-Breast01 study (ORR, 60.9%; mPFS, 16.4 mo; mDoR, 14.8 mo; median follow-up, 11.1 mo). The pattern of disease progression was similar in pts with and without BMs with 8 of 24 pts having progressed (33%; 2 in the brain) in the BMs subgroup and 40 of 160 pts (25%; 2 in the brain) in the non-BMs subgroup, suggesting durable systemic disease control. Baseline diameters of BMs were available for 14 of 24 pts (radiotherapy prior to study enrollment was reported in 12 of 14). Among the pts with information available on baseline BM diameter, the central nervous system response rate per investigators was 50% (7 of 14 pts). Conclusions: T-DXd showed strong clinical activity in both the overall population of pts with HER2+ mBC and the subgroup of pts with BMs. The demonstrable response of BMs to treatment and durable clinical activity of T-DXd in pts with a history of BMs at baseline are promising and warrant further investigation. Clinical trial information: NCT03248492.