Dose justification for [fam-] trastuzumab deruxtecan (DS-8201a) in HER2-positive breast cancer

Abstract

Abstract Background In an ongoing phase 1 study (J101) of [fam-] trastuzumab deruxtecan (DS-8201a), a novel HER2-targeted antibody drug conjugate, 5.4 and 6.4 mg/kg doses were recommended for expansion. The phase 2 DESTINY-Breast01 trial began with a dose-finding stage. To determine the recommended dose for continued development in HER2+ BC, a comprehensive analysis of observed data and exposure-response (ER) from both trials was performed. Methods A population-PK (PPK) model was developed including all subjects with available PK data. Individual PK parameters were estimated from the PPK model and used in the ER analyses, using logistic regression or Cox proportional hazard modeling for efficacy and safety. Results As of Apr 2018, 111 HER2+ BC subjects were treated at 5.4 or 6.4 mg/kg in J101 and 65 subjects were enrolled across 3 doses (5.4, 6.4, and 7.4 mg/kg) in DESTINY-Breast01. Confirmed objective response rates (ORRs) at 5.4 and 6.4 mg/kg in J101 were 52.6% (20/38) and 55.7% (34/61), respectively. In J101, grade ≥3 AEs occurred in 35.6% (16/45) at 5.4 mg/kg and 50% (33/66) at 6.4 mg/kg. The relationship between intact Cmin and ORR was statistically significant (P = 0.035). There was a trend for improved progression-free survival with higher intact exposures (P = 0.238). There were statistically significant relationships 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 Conclusions Considering the predicted benefit/risk profile, 5.4 mg/kg is the recommended dose for continued development in HER2+ BC.