Abstract C041: Safety and pharmacokinetic results from a phase 1, multicenter, open-label study of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with advanced HER2-positive breast cancer

Background: Anti-HER2 therapies are beneficial for patients with HER2+ gastric or breast cancer (BC). [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is an antibody-drug conjugate (ADC) composed of an anti-HER2 antibody (Ab) conjugated by a peptide-based cleavable linker to a novel exatecan-derived topoisomerase I inhibitor (MAAA-1181a). The phase 1 study (NCT02564900) of T-DXd conducted at study sites in the US and Japan showed a manageable safety profile at the recommended doses for expansion (5.4 and 6.4 mg/kg) and a confirmed objective response rate (ORR) of 59.5% in subjects with HER2+ BC; however, safety and pharmacokinetic (PK) analyses from other Asian populations are lacking. Methods: This is a phase 1, open-label study (NCT03368196) conducted at 2 sites in Taiwan. Eligible HER2+ BC subjects were ≥ 20 years of age and received T-DXd 6.4 mg/kg intravenously once every 3 weeks until unacceptable toxicity, progressive disease (PD), or withdrawal from the study. The primary objective was to assess the safety and tolerability of T-DXd. Secondary objectives included assessment of PK and efficacy and incidence of anti-drug Abs (ADA) against T-DXd. Results: All subjects (N = 12) were Asian and female with HER2+ BC (11 IHC3+; 1 IHC2+); median age was 55 y (range, 36-69 y). Prior HER2-directed treatments included trastuzumab (100%), pertuzumab (50%), T-DM1 (33%), and lapatinib (8.3%). At data cutoff (Sept 14, 2018), the median treatment duration was 20 wk (range, 12-24 wk), and treatment was ongoing in all 12 subjects. The ORR (complete response [CR] + partial response [PR]) among 11 evaluable subjects was 36.4% (95% CI, 10.9%-69.2%; all PR); the disease control rate (CR + PR + SD) was 100% (95% CI, 71.5%-100.0%). By data cutoff, all subjects experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3, 58.3%), none of which led to discontinuation. The most common TEAEs were nausea (58%), decreased platelet count (58%), increased aspartate aminotransferase (50%), decreased white blood cell count (42%), decreased appetite (33%), anemia (33%), and fatigue (25%). One drug-related serious AE (febrile neutropenia) occurred, and 2 TEAEs led to dose reductions (grade 3 febrile neutropenia and grade 4 decreased platelet count). One AE of special interest occurred (grade 1 LVEF decrease). No events of pulmonary toxicity occurred and no deaths were reported. At cycle 1, the mean maximum concentration (Cmax) and area under the curve (AUCtau) of T-DXd were 157 µg/mL (SD, 19.1) and 631 day•µg/mL (SD, 173), respectively; for MAAA-1181a, the Cmax was 11.9 ng/mL (3.79) and the AUC was 36.1 day•µg/mL (9.71). PK parameters of total anti-HER2 Ab were similar to those of T-DXd. Some accumulation of T-DXd (57%) was seen at cycle 3 (Cmax, 163 µg/mL [SD, 19.5]; AUCtau, 991 day•µg/mL [SD, 109]). These PK results were similar to those of T-DXd, total HER2 Ab, and MAAA-1181a reported in other studies in HER2+ BC. All subjects were negative for ADA at all assessments. Conclusions: This is the first report of the efficacy, safety, and PK of T-DXd in Taiwan; T-DXd showed a manageable safety profile with no new safety signals. Despite the small number of subjects, results were similar to those previously reported and provide additional evidence of the clinical benefit of T-DXd in subjects with HER2+ tumors. Citation Format: Dwan-Ying Chang, Chia-Chi Lin, Tom Wei-Wu Chen, Ching-Hung Lin, Jih-Hsiang Lee, Ta-Chung Chao, Chun-Yu Liu, Issei Achiwa, Emi Kamiyama, Yasuyuki Okuda, Caleb Lee, Yee Chao. Safety and pharmacokinetic results from a phase 1, multicenter, open-label study of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with advanced HER2-positive breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C041. doi:10.1158/1535-7163.TARG-19-C041