SYD985

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- Nguyen

2016 San Antonio Breast Cancer SymposiumPublication

Number: P6-12-02

Title: SYD985, a novel anti-HER2 ADC, shows promising activity in patients with HER2-positive and HER2-negative metastaticbreast cancer

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 minorgroove of DNA, and subsequently causes irreversible DNA-alkylation. SYD985 has demonstrated unprecedented anti-tumoractivity 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-humanphase 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 to2.4 mg/kg SYD985. Patients enrolling in the first expanded cohort will be treated with 1.2 mg/kg SYD985. In this cohort a total of48 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-positivebreast 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 overallresponse HER2 status N 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 todoses 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.