Background: HER2-targeted therapies have improved survival for advanced HER2-positive breast cancers (BC), but none have been approved for tumors with low levels of HER2 expression (ie, HER2 IHC 1+ or 2+/ISH-negative). Trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody attached to a potent topoisomerase I inhibitor payload by a cleavable peptide-based linker, which is designed to have broad antitumor activity in HER2-expressing tumors. It has a drug-to-antibody ratio of 7 to 8, a novel linker that is stable in plasma and that is selectively cleaved by lysosomal cathepsins which are upregulated in cancer cells, and its payload has a short systemic half-life. In 2015, a phase 1 study (NCT02564900) was initiated to evaluate the safety and efficacy of DS-8201a in subjects with advanced HER2-expressing or HER2-mutated solid tumors, including HER2-low expressing BC. In this study, the overall confirmed response rate (ORR) in the evaluable subjects was 49.3% (103/209) (April 2018 data cutoff; Iwata H, et al. ASCO 2018). Expanded results from the HER2-low expressing BC subjects are presented here.

Methods: This ongoing phase 1 trial included 2 parts. The dose escalation part served to determine the dose-limiting toxicities, the maximum tolerated dose, and to select the recommended dose for expansion (RDE). The dose expansion part further evaluated the safety, tolerability, and efficacy of the DS-8201a at the RDE (5.4 and 6.4 mg/kg; q3wks) in various advanced HER2-expressing or HER2-mutated solid tumors, including heavily pretreated HER2-low BC (IHC 1+ or 2+, ISH-negative). Enrollment of HER2-low subjects is ongoing.

Results: At the cutoff date of 18 April 2018, data from 34 HER2-low BC subjects were collected. The median age was 55.8 (range; 33, 75) years, the median number of prior endocrine therapies was 2, and the median number of prior chemotherapies was 3. In this HER2-low BC population, most patients had hormone receptor (HR)-positive disease (85.3%; 29/34); of which 17.2% (5/29) received prior treatment with a CDK4/6 inhibitor. The confirmed ORR was 50.0% (17/34), the disease control rate was 85.3% (29/34), the median time to response was 2.8 (range; 1.2, 13.8) months, the median duration of response (DOR) was 11.0 months, and the median progression-free survival (PFS) was 12.9 months. In the subgroup with HR-positive disease, the ORR was 55.2% (16/29), the median DOR was 11.0 months, and the median PFS was 13.6 months. After exclusion of 8 HER2-low subjects who received prior HER2-targeted therapy, the ORR was 46.2% (12/26). In the overall study, among the 145 BC subjects who received ≥1 dose of DS-8201a (5.4 or 6.4 mg/kg), the most frequent grade ≥3 adverse events included anemia (14.5%), and decreased counts of neutrophils (13.8%) and white blood cells (10.3%). There were 4 fatal cases of interstitial lung disease/pneumonitis in BC subjects, including 2 fatal cases in HER2-low BC subjects.

Conclusions: In this study, DS-8201a showed substantial antitumor activity and acceptable safety in heavily pretreated HER2-low BC.

Citation Format: Modi S, Tsurutani J, Tamura K, Park H, Sagara Y, Murthy R, Iwata H, Krop IE, Doi T, Redfern C, Moreno-Aspitia A, Redman R, Lee C, Sugihara M, Fujisaki Y, Takahashi S. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: Updated results of a large phase 1 study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-02.