Abstract OT-03-05: Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with other anticancer agents in patients with HER2-low metastatic breast cancer: A phase 1b, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast08)

Background In patients (pts) with HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) metastatic breast cancer (mBC), HER2-targeted therapies have greatly improved survival. However, for pts with HER2-low mBC (IHC 1+ or IHC 2+/ISH−), there are no approved HER2-directed therapies. In pts with hormone receptor (HR)+, HER2-low mBC whose disease progresses on standard first-line treatment (endocrine therapy [ET] and CDK4/6 inhibitors), median progression-free survival (PFS) with continued ET alone is ≈ 2 months, and with mTOR or PI3K inhibitors (in PIK3CA-mutant tumors) in the second-line setting, PFS ranges from 3.5 to 7.3 months, respectively (André F, et al. ESMO 2018; Dhakal A, at al. ASCO 2018; Rugo R, et al. ASCO 2020). For ET-refractory pts, chemotherapy (CTX) is the standard of care and has a poor benefit-risk ratio. The treatment landscape for pts with HR−, HER2-low mBC is even more limited, consisting largely of CTX (with or without PD-1/PD-L1 inhibitors in the first-line setting). T-DXd is an antibody-drug conjugate composed of a humanized HER2 antibody attached to a membrane-permeable topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker at a drug to antibody ratio of ≈ 8. In a recent phase 1b study, pts with heavily pretreated (median, 7.5 prior therapies) HER2-low advanced or metastatic breast cancer treated with T-DXd 5.4 or 6.4 mg/kg had a confirmed objective response rate (ORR) of 37.0% (20/54) by independent central review and a median PFS of 11.1 months, and the safety profile was generally manageable (Modi S, et al. J Clin Oncol. 2020;38:1887-1896). Here, we describe a phase 1b trial evaluating the safety, tolerability, and pharmacokinetics (PK) of T-DXd in combination with other anticancer agents in pts with HER2-low, HR+ or HR− mBC. Study Description DESTINY-Breast08 is a multicenter, open-label, 2-part study evaluating T-DXd combinations in pts with HER2-low mBC. The 5 treatment modules comprise T-DXd in combination with (1) capecitabine, (2) durvalumab + paclitaxel, (3) capivasertib, (4) anastrozole, and (5) fulvestrant. Part 1 (dose finding): Each treatment module will enroll 3 to 12 pts per dose level to determine the recommended phase 2 dose (RP2D) in combination; modules 1 through 3 will enroll irrespective of HR status, whereas modules 4 and 5 will be restricted to only HR+ pts. HR+ pts should have received ≥ 1 prior line of ET and ≥ 1 prior line of CTX; HR− pts should have received ≥ 1 prior line of CTX. Part 2 (dose expansion): Modules 1, 4, and 5 will enroll 20 pts, and modules 2 and 3 will enroll 40 pts using the RP2D determined in part 1 of each module. Patient eligibility per module in part 2 is as follows: Module 1 (HR+ or HR−): HR−, only 1 prior line of CTX for mBC; HR+, only 1 prior line of ET but no prior CTX for mBCModule 2 (HR−): no prior CTX for mBCModule 3 (HR−): only 1 prior line of CTX for mBCModules 4 and 5 (HR+): only 1 prior line of ET but no prior CTX for mBC The primary endpoint in part 1 is safety and tolerability and determination of RP2Ds. In part 2, the primary endpoint is safety and tolerability, and secondary endpoints include ORR, duration of response, and PFS (all by investigator assessment according to RECIST 1.1) as well as overall survival, PK, and immunogenicity. Citation Format: Komal Jhaveri, Erika Hamilton, Sherene Loi, Peter Schmid, Annie Darilay, Chen Gao, Gargi Patel, Magdalena Wrona, Fabrice Andre. Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with other anticancer agents in patients with HER2-low metastatic breast cancer: A phase 1b, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast08) [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 OT-03-05.