A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer.

Abstract

1014 Background: SYD985, (vic-)trastuzumab duocarmazine, is a HER2-targeting antibody-drug conjugate with a cleavable linker-duocarmycin payload that causes irreversible alkylation of the DNA in tumor cells. The dose-escalation part of a Phase I study was completed previously; we herein present preliminary efficacy data of the breast cancer expansion cohorts and safety data of all expansion cohorts (breast, gastric, urothelial and endometrial cancer). Methods: HER2 tumor expression was determined by a central lab and had to be immunohistochemistry (IHC) 1+ or higher; HER2-positive was defined as IHC 2+/3+/ISH+ and HER2-low as IHC 1+/2+/ISH-. Patients were treated with 1.2 mg/kg SYD985 IV every 3 weeks until disease progression or unacceptable toxicity. Tumor evaluation scans were done every 6 weeks. Results: Ninety-nine (99) breast cancer patients were enrolled. Of the 50 patients with HER2-positive breast cancer, the majority received 3 or more prior HER2-targeting regimens in the locally advanced or metastatic setting, including (ado-)trastuzumab emtansine in 80% of the patients. Preliminary results showed that SYD985 demonstrated an overall response rate (ORR) of 33% and a median PFS of 9.4 months. At the time of data cut-off, 8 patients (16%) received SYD985 for over one year and 5 patients (10%) continued to receive treatment. Efficacy has also been demonstrated in heavily pretreated patients with HER2-low metastatic breast cancer, including hormone-receptor positive (N = 32) and triple-negative breast cancer (N = 17). The ORRs were 27% and 40%, respectively, with several patients ongoing on SYD985. The safety profile was manageable and mainly characterized by grade 1 and 2 events. The most common adverse drug reactions were fatigue, dry eyes, conjunctivitis and increased lacrimation. Grade 3/4 adverse drug reactions most commonly reported included neutropenia (6%) and conjunctivitis (4%). Conclusions: SYD985 shows promising efficacy in heavily pretreated patients with breast cancer, in both HER2-positive and HER2-low tumors with or without hormone receptor expression. A Phase III study (TULIP) is currently ongoing in HER2-positive breast cancer patients. Clinical trial information: NCT02277717.