Abstract PD3-07: Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: A 2-part, phase 1b, multicenter, open-label study
Authors: Hamilton Erika , Shapiro Charles L , Petrylak Daniel , Boni Valentina , Martin Miguel , Conte Gianluca Del , Cortes Javier , Agarwal Laila , Arkenau Hendrik-Tobias , Tan Antoinette R. , Debruyne Philip , Minchom Anna , Rutten Annemie , Valdes-Albini Frances , Yu Evan Y , Augustine Bincy , D'Amelio Anthony , Barrios Daniel , Hurvitz Sara A. 
Published: February 2021

Abstract
Background
T-DXd is a novel antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and membrane-permeable topoisomerase I inhibitor payload. In a phase 2 study in patients (pts) with HER2+ (IHC 3+ or IHC 2+/ISH+), unresectable or metastatic breast cancer (MBC) previously treated with trastuzumab emtansine (T-DM1), the confirmed ORR (cORR) with T-DXd was 60.9% and median PFS (mPFS) was 16.4 mo (Modi NEJM 2020). In pts with HER2-low (IHC 2+/ISH−, IHC 1+) advanced BC, cORR was 37.0% and mPFS 11.1 mo in a phase 1 study (Modi J Clin Oncol 2020). Recently, 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) or had prior chemotherapy and are refractory to or intolerant of standard treatments (Japan). In preclinical models, T-DXd combined with an anti-PD-1 antibody had greater efficacy than either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, open-label, multicenter, 2-part study of T-DXd in combination with nivolumab (Nivo) in pts with HER2-expressing (by centrally testing) MBC or advanced urothelial cancer (DS8201-A-U105; NCT03523572); interim results for the BC cohorts are presented.
Methods
Pts were aged ≥18 y and immune checkpoint inhibitor naive. Pts were enrolled in the United States and Europe. In part 1 (dose escalation), pts received T-DXd 3.2 or 5.4 mg/kg intravenously (IV) every 3 weeks (q3w) and Nivo 360 mg IV q3w to determine the recommended dose for expansion (RDE). In part 2, the RDE was given to 2 MBC cohorts: HER2+ (IHC 3+ or IHC 2+/ISH+) disease that progressed on prior T-DM1 or HER2 low (IHC 1+ or IHC 2+/ISH−) disease that progressed on prior standard treatments. The primary efficacy endpoint is cORR by independent central review (ICR) per RECIST version 1.1 in part 2. Additional endpoints include duration of response (DOR), disease control rate (DCR), PFS, OS, safety, and pharmacokinetics.
Results
52 pts with MBC were enrolled. In part 1, 4 pts received T-DXd 3.2 mg/kg (HER2+, n=3; HER2 low, n=1), 3 pts received 5.4 mg/kg (all HER2+). In part 2, 45 pts received the RDE of T-DXd 5.4 mg/kg and Nivo 360 mg (HER2+, n=29; HER2 low, n=16 [13 HR+]); median follow-up time was 7.0 and 6.9 mo, respectively.
All pts (n=48) who received RDE were female; median duration of follow-up was 6.9 mo. HER2+ pts had a median age of 55 y and median of 5 prior lines of metastatic/locally advanced therapy. At data cutoff (June 8, 2020), 56.3% of pts remained on treatment (median treatment duration: T-DXd, 6.5 mo; Nivo, 5.2 mo). HER2 low pts had a median age of 47 y, median of 4 prior lines, and 50.0% remained on treatment (median: T-DXd, 6.3 mo; Nivo, 4.9 mo).
In pts treated at RDE, the cORR by ICR in the HER2+ cohort was 59.4% (19/32, 18 PR) and for the HER2 low cohort was 37.5% (6/16, all PR). The DCR was 90.6% and 75.0% in the HER2+ and HER2-low cohorts, respectively. Median DOR was not reached in either cohort; median PFS was 8.6 mo (95% CI, 5.4-NE) for the HER2+ cohort and 6.3 mo (95% CI, 2.3-NE) for the HER2 low cohort.
Adverse events (AEs) grade ≥3 occurred in 43.8% (18.8% related to T-DXd, 18.8% to Nivo) of pts treated at RDE (n=48); anemia (16.7%) and transaminase increase (6.3%) were most common. Nausea (54.2%), fatigue (45.8%), and alopecia (41.7%) were the most common any-grade AEs. 5 pts (10.4%, all HER2+) had treatment-related interstitial lung disease (ILD) as adjudicated by an independent committee (grade 5, n=1; grade 2, n=4). No other deaths associated with a drug-related AE occurred.
Conclusions
In pts with HER2-expressing MBC, T-DXd plus Nivo demonstrated antitumor activity consistent with prior studies of T-DXd and had an acceptable safety profile in this interim analysis; whether adding IO therapy to T-DXd benefits pts requires longer follow-up and additional studies.
Citation Format: Erika Hamilton, Charles L Shapiro, Daniel Petrylak, Valentina Boni, Miguel Martin, Gianluca Del Conte, Javier Cortes, Laila Agarwal, Hendrik-Tobias Arkenau, Antoinette R. Tan, Philip Debruyne, Anna Minchom, Annemie Rutten, Frances Valdes-Albini, Evan Y Yu, Bincy Augustine, Anthony D'Amelio, Jr., Daniel Barrios, Sara A. Hurvitz. Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: A 2-part, phase 1b, multicenter, open-label study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-07.