Abstract P1-18-12: A phase 1, multicenter, open-label study to assess the effect of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) on QTc and pharmacokinetics in subjects with HER2-expressing metastatic and/or unresectable breast cancer
Authors: Yamashita Toshinari , Shimomura Akihiko , Takano Toshimi , Sagara Yasuaki , Watanabe Junichiro , Tokunaga Eriko , Kikumori Kunika , Kamiyama Emi , Kamio Takahiro , Nakamura Ryo , Shinkai Tetsu , Takahashi Shunji 
Published: March 2020

Abstract
Background [Fam-] trastuzumab deruxtecan (T-DXd; formerly DS-8201a) is a novel antibody-drug conjugate with a humanized anti-HER2 antibody, peptide-based cleavable linker, and topoisomerase I inhibitor payload (MAAA-1181a). T-DXd has a drug-to-antibody ratio of ≈ 8, and the membrane permeability of the cleaved payload induces a cytotoxic bystander effect. In the phase 1 study (NCT02564900), T-DXd 5.4 and 6.4 mg/kg had a manageable safety profile and confirmed objective response rates (ORRs) of 59.5% in subjects with advanced HER2-positive breast cancer (BC) and 44% in subjects with BC with low HER2 expression.
Methods This phase 1 study of T-DXd assessing the QTc interval (by 12-lead ECG) and pharmacokinetics (PK) in subjects with HER2-expressing metastatic BC (NCT03366428) was conducted at 7 study sites in Japan. Subjects received T-DXd 6.4 mg/kg IV infusion once every 3 weeks. Data cutoff (Dec 5, 2018) occurred after all subjects completed ≥ 3 cycles (C) or discontinued.
Results 51 subjects enrolled and received T-DXd; all were female and Asian. Median age was 56 y (range, 31-79; ≥ 65 y, 25%); 8% were HER2-positive (IHC3+ or IHC2+/ISH+) and 92% were HER2-low (IHC1+, 73%; IHC 2+/ISH−, 12%); 75% were estrogen-receptor positive. Prior therapies included trastuzumab (24%), CDK4/6i (22%), T-DM1 (16%), and pertuzumab (16%); 67% had received &gt; 5 lines of therapy. At data cutoff, 63% of subjects remained on treatment; primary reasons for discontinuation were disease progression (29%) and adverse events (AEs, 4%; grade [Gr] 2 pneumonitis and Gr 2 LVEF decrease). Median duration of survival follow-up was 4.8 months (range, 1.4-8.9).
T-DXd 6.4 mg/kg was not associated with a clinically meaningful QTcF prolongation (change of &gt; 10 ms); the upper bound of the 90% CI was &lt; 10 ms at all assessments.
The PK profile of total anti-HER2 antibody was similar to that of T-DXd; MAAA-1181a exposure was low. Some accumulation (35%) of T-DXd was observed from C 1-3 (Table); mean accumulation ratio for AUCtau at C 3 was consistent with the observed t1/2 of T-DXd.
All subjects had treatment-emergent AEs (TEAEs; 67% Gr ≥ 3), most of which were gastrointestinal or hematologic disorders and primarily Gr 1 or 2. Most common Gr ≥ 3 TEAEs were neutrophil count decreased (45%), white blood cell count decreased (24%), anemia (10%), platelet count decreased (8%), lymphocyte count decreased (8%), and fatigue (6%). 2 subjects had serious TEAEs (Gr 2 nausea [drug related] and Gr 3 femur fracture [not drug related]). 1 subject had ILD (Gr 2 pneumonitis) and 4 had Gr 1 electrocardiogram QT prolonged. No grade 5 events occurred.
The unconfirmed ORR (CR + PR) was 39% (95% CI, 26%-54%), with responses seen in HR+ (37%), HR− (46%), and HER2-low (IHC 1+, 43%; IHC 2+/ISH−, 20%) BC. Median time to response was 2.9 months (range, 1.2-4.4), and the duration of response was not yet reached. The disease control rate (CR + PR + SD ≥ 5 weeks from first dosing date) was 84% (95% CI, 82%-99%).
Conclusion T-DXd 6.4 mg/kg was not associated with clinically relevant QTcF prolongation; the accumulation of T-DXd from C 1-3 was consistent with the elimination t1/2. T-DXd had a manageable safety profile, consistent with other studies. T-DXd showed preliminary antitumor activity with clinically meaningful responses in heavily pretreated subjects with metastatic HER2-expressing BC (mostly HER2-low), including HR+ and HR− disease.
Pharmacokinetic Parameters for 3 Analytes by CycleMean (SD)Median (range)Cmax, μg/mLAUCtau, μg·d/mLt1/2, dTmax, hT-DXdCycle 1 (n = 51)179 (112)677 (141)5.82 (1.11)2.08 (1.55-7.02)Cycle 3 (n = 37)154 (23.3)905 (189)7.40 (1.48)2.12 (0.70-7.15)AR Cycle 3/ Cycle 1-1.35 (0.150)--Total Anti-HER2 AntibodyCycle 1 (n = 51)165 (110)752 (185)6.35 (2.01)2.07 (1.48-7.02)Cycle 3 (n = 37)142 (27.0)1030 (256)8.27 (1.97)2.07 (0.60-7.15)AR Cycle 3/ Cycle 1-1.36 (0.219)--MAAA-1181aCmax, ng/mLAUCtau, ng·d/mLt1/2, dTmax, hCycle 1 (n = 51)12.6 (4.49)39.0 (11.2)5.74 (1.29)6.93 (3.88-191.47)Cycle 3 (n = 37)9.60 (3.89)41.5 (13.8)6.57 (1.81)6.92 (1.95-70.65)AR Cycle 3/ Cycle 1-1.09 (0.194)--AR, accumulation ratio; AUCtau, area under plasma concentration-time curve over dosing interval; Cmax, maximum concentration; HER2, human epidermal growth factor receptor 2; t1/2, half-life; Tmax, time to maximum concentration.
Citation Format: Toshinari Yamashita, Akihiko Shimomura, Toshimi Takano, Yasuaki Sagara, Junichiro Watanabe, Eriko Tokunaga, Kunika Kikumori, Emi Kamiyama, Takahiro Kamio, Ryo Nakamura, Tetsu Shinkai, Shunji Takahashi. A phase 1, multicenter, open-label study to assess the effect of [fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) on QTc and pharmacokinetics in subjects with HER2-expressing metastatic and/or unresectable breast cancer [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 P1-18-12.