Abstract P6-12-02: SYD985, a novel anti-HER2 ADC, shows promising activity in patients with HER2-positive and HER2-negative metastatic breast cancer
Authors: Aftimos PG , van Herpen CM , Mommers EC , Koper NP , Goedings P , Oesterholt M , Awada A , Desar IM , Lim J , Dean E , Rolfo C , Macpherson I , Banerji U 
Published: March 2017

Abstract
Background:
SYD985 is a HER2-targeting antibody-drug conjugate (ADC) based on trastuzumab and a cleavable linker-duocarmycin (vc-seco-DUBA) payload. Following proteolytic cleavage the synthetic duocarmycin prodrug is activated, binds to the minor groove of DNA, and subsequently causes irreversible DNA-alkylation. SYD985 has demonstrated unprecedented anti-tumor activity in preclinical breast cancer models with high (HER2 3+) or moderate/low expression of HER2 (HER2 2+ and HER2 1+). Clinical data of patients with HER2-positive and HER2-negative breast cancer treated with SYD985 in an ongoing first-in-human phase I trial (NCT02277717) in patients with locally advanced or metastatic solid tumors are presented.
Trial design:
Main inclusion criteria are ECOG performance status 0-1, left ventricular ejection fraction ≥ 55%, and adequate organ function. Patients are treated with SYD985 every three weeks until tumor progression or unacceptable toxicity. Thirty nine patients, including 26 breast cancer patients, were enrolled in the dose-escalation part and treated with doses varying from 0.3 mg/kg to 2.4 mg/kg SYD985. Patients enrolling in the first expanded cohort will be treated with 1.2 mg/kg SYD985. In this cohort a total of 48 patients with HER2-positive breast cancer (IHC 3+ or ISH positive) will be enrolled from May 2016 onwards. HER2 status was determined locally in the dose-escalation part but will be done centrally in the expanded cohort part of the trial. Tumor evaluation (RECIST 1.1) is performed every 6 weeks.
Results:
Enrolled breast cancer patients were heavily pretreated with a median of 7 systemic therapies. All patients with HER2-positive breast cancer were previously treated with trastuzumab and ado-trastuzumab emtansine (T-DM1). As of 16 May 2016, tumor evaluation data were available for 19 of the 26 enrolled breast cancer patients. In total, 8 partial responses were observed of which 6 were confirmed by a second CT-scan. The number of cycles administered ranged from 1 to 11. Ten of the 26 patients are still on treatment.
Best overall response HER2 statusN EvaluablePRSDPDORR All dosesORR Doses ≥1.2 mg/kgHER2-positive (all T-DM1 pretreated)1458136%42%HER2-negative (IHC 1+/2+ and ISH neg)531160%75%Overall1989242%50%
One dose-limiting toxicity occurred at 2.4 mg/kg SYD985, i.e. pneumonitis (grade 5). Overall, SYD985 is well tolerated up to doses of 1.8 mg/kg every 3 weeks. The most frequently reported drug-related AEs were conjunctivitis, stomatitis, fatigue, and decreased appetite. The majority of drug-related AEs were of mild or moderate intensity.
Conclusion:
SYD985 shows promising efficacy in both HER2-positive and HER2-negative metastatic breast cancer patients with an acceptable safety profile. SYD985 may offer a new targeted treatment option for patients who have become refractory to the available HER2-targeting therapies, and potentially for breast cancer patients who are not indicated for HER2-targeting therapies. Updated data, including additional results of up to 48 HER2-positive breast cancer patients, will be presented during the meeting.
Citation Format: Aftimos PG, van Herpen CM, Mommers EC, Koper NP, Goedings P, Oesterholt M, Awada A, Desar IM, Lim J, Dean E, Rolfo C, Macpherson I, Banerji U. SYD985, a novel anti-HER2 ADC, shows promising activity in patients with HER2-positive and HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-12-02.