Background [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate with a HER2 antibody, peptide-based cleavable linker, and a novel topoisomerase I inhibitor payload. In a phase 1 trial, the objective response rate (ORR) was 59.5% (66/111) and median progression-free survival (PFS) was 22.1 mo in subjects with HER2-positive metastatic breast cancer (BC) previously treated with T-DM1 (Tamura, Lancet Oncol, 2019). DESTINY-Breast01 (NCT03248492) is an open-label, international, multicenter, phase 2 registration study of T-DXd in subjects with centrally confirmed HER2-positive metastatic BC.

Methods Part 1 of this 2-part study was performed in 2 stages (pharmacokinetics and dose finding; T-DXd 5.4, 6.4, 7.4 mg/kg) and served to identify the recommended Part 2 dose (RP2D). In Part 2, subjects were treated at the RP2D. Subjects in Parts 1 and 2a were required to have metastatic BC that progressed on or after T-DM1. Subjects in a small additional cohort (Part 2b) had discontinued T-DM1 for reasons other than progression. The primary endpoint was ORR (complete response [CR] + partial response [PR]) per independent central review (ICR). Additional endpoints included disease control rate (DCR; CR + PR + stable disease [SD]), duration of response (DOR), and PFS. Abstract results represent 6 mo of follow-up from the date the last subject enrolled in the study.

Results As of data cutoff (March 21, 2019), 253 subjects were enrolled and 184 received the RP2D (5.4 mg/kg), 4 of which were enrolled in Part 2b. All subjects were female, 55% were white, and 38% were Asian. Median age was 55 y (range, 28-96 y; ≥ 65 y, 24%); 53% were hormone receptor (HR) positive and 45% were HR negative. Median number of prior treatment regimens was 6 (range, 2-27), including trastuzumab (100%), T-DM1 (100%), pertuzumab (66%), and other HER2-targeted regimens (54%). The reported best response to T-DM1 before enrollment was 22% CR or PR, 21% SD, and 36% progressive disease (PD); 21% were not evaluable. At data cutoff, 60% of subjects remained on T-DXd treatment; primary reasons for discontinuation were PD (21%) and treatment-related adverse events (TEAEs, 8%).

The confirmed ORR by ICR in subjects treated at the RP2D in Parts 1, 2a, and 2b was 60% (111/184 [95% CI, 53%-68%]). ORRs were consistent across subgroups, including those with prior pertuzumab (64%) and those with ≥ 3 prior regimens (59%). The DCR was 97% (95% CI, 94%-99%); only 5 of 184 subjects did not have SD or better at the time of first post-baseline scan. As of the data cutoff, median DOR and PFS had not been reached; median duration of follow up was 7.2 mo (range, 0.7-17.2 mo).

In the 184 subjects, the median treatment duration was 6.9 mo (range, 0.7-16 mo); 70% had > 6 mo of treatment. TEAEs occurred in 99% of subjects (grade ≥ 3, 51%); the most common any-grade TEAEs were gastrointestinal (nausea [77%], vomiting [45%], constipation [34%], decreased appetite [29%], and diarrhea [27%]), alopecia (48%), fatigue (48%), and hematologic (decreased neutrophil count [31%] and anemia [26%]). Most common grade ≥ 3 AEs were decreased neutrophil count (17%), nausea (7.6%), anemia (6.5%), decreased lymphocyte count (5.4%), and fatigue (5.4%). 15 subjects (8.2%) had interstitial lung disease (ILD) adjudicated as ILD related to T-DXd by an independent adjudication committee; ILD was primarily grade 1 or 2 (6.0%; no grade 3 or 4; 2.2% grade 5).

[Additional follow up and first DOR/PFS data will be presented at the meeting.]

Conclusion Overall, T-DXd treatment demonstrated clinically meaningful and durable activity in a heavily pretreated patient population with HER2-positive metastatic BC. T-DXd had a generally manageable safety profile, with ILD identified as a risk warranting proactive awareness and management.

Citation Format: Ian E Krop, Cristina Saura, Toshinari Yamashita, Yeon Hee Park, Sung-Bae Kim, Kenji Tamura, Fabrice André, Hiroji Iwata, Yoshinori Ito, Junji Tsurutani, Joohyuk Sohn, Neelima Denduluri, Christophe Perrin, Kenjiro Aogi, Eriko Tokunaga, Seock-Ah Im, Keun Seok Lee, Sara Hurvitz, Javier Cortes, Caleb Lee, Shuquan Chen, Lin Zhang, Javad Shahidi, Antoine Yver, Shanu Modi. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-03.