Abstract P2-13-25: A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer
Authors: Krop Ian , Hamilton Erika , Jung Kyung Hae , Modi Shanu , Kalinsky Kevin M , Phillips Gail , Shi Rong , Monemi Sharareh , Mamounas Michael , Saad Ola , Choeurng Voleak , Commerford Renee , Cho Eunpi , Ungewickell Alexander , LoRusso Patricia 
Published: March 2022

Abstract
Background: Despite the success of multiple HER2-targeted agents in HER2+ breast cancer (BC), resistance remains a challenge and novel therapies are needed. DHES0815A is a THIOMABTM antibody-drug conjugate consisting of a humanized IgG1 anti-HER2 monoclonal antibody (mAb) conjugated to the DNA alkylating agent PBD-MA. The reduced potency of PBD-MA compared to PBD dimers and the stability of the conjugation site and linker were designed to improve tolerability, whereas the binding of the mAb to a HER2 epitope distinct from trastuzumab and pertuzumab was designed to enable combination therapy with existing HER2 therapies. Methods: This first-in-human, Phase I, open-label, multicenter, dose escalation study used a 3+3 dose escalation design to assess the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of DHES0815A in patients with metastatic HER2-positive BC refractory to established therapies (NCT03451162). DHES0815A (0.6-6.0 mg/kg) was administered intravenously every 3 weeks (Q3W) until intolerable toxicity or disease progression. Results: A total of 14 patients were treated with DHES0815A; all had ≥3 prior lines of therapy. Thirteen patients discontinued treatment due to progressive disease (43%), adverse events (AE; [29%]) symptomatic deterioration (14%) or other (7%); 1 patient remains on treatment. DHES0815A was initially well-tolerated for doses up to 2.4 mg/kg. At 4.0 mg/kg and 6.0 mg/kg, the first dose was also well-tolerated with no dose limiting toxicities, however, following 3 or more cycles at 4.0 mg/kg or 2 or more cycles at 6.0 mg/kg, safety events involving skin, eyes, and lung emerged. Skin events were reported in 50% of patients (all doses) and related events occurring in n≥2 patients included pruritus (36%), rash (36%), and skin hyperpigmentation (21%). Ocular toxicities were reported in 57% and related events occurring in n≥2 patients included photophobia (21%), conjunctivitis, eye pain, and dry eye (each 14%). Lung toxicities were reported in 36% of patients; events occurring in n≥2 included pneumonitis (14%). Other related skin, ocular, and pulmonary events occurring in 1 patient (7%) included palmar-plantar erythrodysaesthesia, macular rash, blurred vision, eyelid edema, periorbital edema, blepharitis, punctate keratitis, wheezing, allergic rhinitis, and pneumothorax. Most events were grade 1 or 2 although 3 patients experienced grade 3 ocular events (blepharitis, eye pain, photophobia). Due to these AEs, DHES0815A dose was decreased to 2.4 mg/kg Q3W for all enrolled patients and accrual was stopped. All 5 patients receiving doses of 4.0 mg/kg and 6.0 mg/kg discontinued due to AEs. At lower doses, 1 patient receiving 2.4 mg/kg developed grade 2 rash at Cycle 21 and 1 patient receiving 1.2 mg/kg developed grade 1 rash, pruritis, and skin hyperpigmentation between Cycles 28-30. Nonlinear PK of antibody-conjugated PBD-MA (acPBD-MA) was observed due to target mediated drug disposition at 0.6, 1.2, and 2.4 mg/kg; PK approached linear at 4.0 mg/kg. Minimal systemic exposure of unconjugated PBD-MA was observed. Overall, 1 patient (7%) in the 1.2 mg/kg cohort achieved a confirmed complete response. As of 10Jun21, this patient remains on study after more than 32 months on treatment. Ten patients (86%) showed a confirmed best overall response of stable disease (86%). Conclusion: Despite some anti-tumor activity observed with DHES0815A, development in HER2-positive BC has been discontinued due to safety concerns and the narrow therapeutic window. Toxicities observed in skin, lung, and eyes are clinically apparent only after repeated dose administration. If future exploration of PBD-MA-based constructs is performed in the clinic, close monitoring for delayed toxicities is warranted.
Citation Format: Ian Krop, Erika Hamilton, Kyung Hae Jung, Shanu Modi, Kevin M Kalinsky, Gail Phillips, Rong Shi, Sharareh Monemi, Michael Mamounas, Ola Saad, Voleak Choeurng, Renee Commerford, Eunpi Cho, Alexander Ungewickell, Patricia LoRusso. A phase I dose-escalation study of DHES0815A, a HER2-targeting antibody-drug conjugate with a DNA monoalkylator payload, in patients with HER2-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-25.