Abstract P6-17-10: Dose justification for DS-8201a, a HER2-targeted antibody-drug conjugate, for HER2-positive breast cancer: Observed clinical data and exposure-response analyses
Authors: Tamura K , Modi S , Tsurutani J , Takahashi S , Krop IE , Iwata H , Wada R , Yin O , Garimella T , Sugihara M , Zhang L , Lee C , Yver A , Baselga J 
Published: May 2019

Abstract
Background
DS-8201a is a HER2-targeting antibody-drug conjugate with a high drug-to-antibody ratio of 7 to 8. A novel cleavable peptide-based linker joins the humanized HER2 antibody to a topoisomerase I inhibitor payload. In an ongoing phase 1 study (J101), DS-8201a was tested at doses of 0.8 to 8.0 mg/kg and tolerated with no predefined dose-limiting toxicities; 5.4 and 6.4 mg/kg doses were recommended for expansion. Subjects with HER2-positive breast cancer (BC) treated at these 2 doses had an overall response rate (ORR) of 54.5% (54/99). The phase 2 DESTINY-BREAST01 trial began enrollment in August 2017 with a dose-finding stage, including 5.4, 6.4, and 7.4 mg/kg. To determine the recommended dose for continued development in HER2-positive BC, a comprehensive analysis of observed data and exposure-response (ER) from both trials was performed.
Methods
A population-PK (PPK) model was developed using data from all subjects with available concentration data. Individual exposure parameters (Cmin, Cmax, AUC) were estimated from the PPK model and used in the ER analyses. ER analyses were conducted using logistic regression or Cox proportional hazard modeling for efficacy (ORR, duration of response, and PFS) and safety (nausea, diarrhea, left ventricular ejection fraction, neutropenia, anemia, thrombocytopenia, dose reductions due to TEAE, discontinuations due to TEAE, and interstitial lung disease [ILD]).
Results
As of 18 Apr 2018, in J101, there are 111 HER2-positive BC subjects treated at 5.4- or 6.4-mg/kg doses. As of 25 Apr 2018, DESTINY-BREAST01 enrolled 65 HER2-positive BC subjects across 3 doses (5.4, 6.4, and 7.4 mg/kg). Confirmed ORRs in J101 for HER2-positive BC subjects at 5.4 and 6.4 mg/kg were 52.6% (20/38) and 55.7% (34/61), respectively. In J101, AEs Grade ≥3 were reported in 35.6% (16/45) at 5.4 mg/kg and 50% (33/66) at 6.4 mg/kg. The relationship between DS-8201a intact Cmin and ORR was statistically significant (P=0.035). There was a trend of improved PFS with higher intact exposures (P=0.238). Statistically significant relationships were observed between exposures and the following safety endpoints based on logistic regression: neutropenia (any grade, P=0.003; Grade ≥3, P=0.037), anemia (any grade, P=0.002; Grade ≥3, P&lt;0.001), thrombocytopenia (any grade, P=0.021), dose reduction due to AE (P=0.003), discontinuations due to AE (P=0.035), and ILD/pneumonitis (any grade, P=0.017). Additionally, Cox proportional hazards modeling suggested higher risk of ILD with higher intact exposures (any grade, P&lt;0.001; Grade ≥2, P=0.007).
Conclusions
In J101, DS-8201a demonstrated an acceptable safety profile and high response rates in HER2-positive BC at both doses. The ER analyses showed a statistically significant relationship between exposures and ORR (with a trend for higher PFS at higher doses), as well as exposures and risk of key adverse events. Considering the predicted benefit/risk profile, 5.4 mg/kg is the recommended dose for continued development of DS-8201a in the DESTINY-BREAST01 trial and in phase 3 clinical trials in HER2-positive BC.
Citation Format: Tamura K, Modi S, Tsurutani J, Takahashi S, Krop IE, Iwata H, Wada R, Yin O, Garimella T, Sugihara M, Zhang L, Lee C, Yver A, Baselga J. Dose justification for DS-8201a, a HER2-targeted antibody-drug conjugate, for HER2-positive breast cancer: Observed clinical data and exposure-response analyses [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 P6-17-10.