The Food and Drug Administration (FDA) has accepted the Biologics License Application (BLA) for [vic-]trastuzumab duocarmazine (SYD985) for the treatment of patients with HER2-positive unresectable locally advanced or metastatic breast cancer (MBC).

The investigational product is an antibody-drug conjugate (ADC) comprised of the anti-HER2 monoclonal antibody trastuzumab and a cleavable linker-drug called valine-citrulline-seco-duocarmycin-hydroxybenzamide-azaindole. Upon binding to HER2 through its antibody component, the ADC is internalized. Following proteolytic cleavage of the linker, the inactive cytotoxin is activated and DNA damage is induced, resulting in tumor cell death.

The BLA is supported by data from the open-label, randomized phase 3 TULIP trial ( Identifier: NCT03262935), which evaluated the efficacy and safety of [vic-]trastuzumab duocarmazine in 437 patients with HER2-positive locally advanced MBC, who had received 2 or more previous MBC regimens or previous MBC treatment with trastuzumab emtansine. Patients were randomly assigned 2:1 to receive [vic-]trastuzumab duocarmazine intravenously every 3 weeks or physician’s choice of chemotherapy. The median number of prior MBC treatments was 4 (range, 1 to 16).

The primary endpoint was progression-free survival (PFS). Secondary endpoints were investigator-assessed PFS, overall survival (OS), objective response rate (ORR) and health-related quality of life (HRQoL).

Results showed that centrally reviewed median PFS was 7 months for [vic-]trastuzumab duocarmazine and 4.9 months for chemotherapy (hazard ratio [HR], 0.64; 95% CI, 0.49-0.84; P =.002); investigator-assessed PFS was 6.9 months for [vic-]trastuzumab duocarmazine vs 4.6 months for chemotherapy arm (HR, 0.60; 95% CI, 0.47-0.77; P <.001). Findings also demonstrated supportive OS results (HR, 0.83 (95% CI, 0.62-1.09; P =.153). There were no significant differences observed in ORR or HRQoL.

As for safety, interstitial lung disease/pneumonitis was reported in 7.6% of patients treated with [vic-]trastuzumab duocarmazine, including two grade 5 events. Treatment discontinuation due to adverse events occurred in 35.4% of patients in the [vic-]trastuzumab duocarmazine arm and 10.2% of those in the chemotherapy arm; these were mainly related to eye or respiratory disorders.

The most frequently reported adverse events for [vic-]trastuzumab duocarmazine were conjunctivitis (38.2%), keratitis (38.2%), and fatigue (33.3%). In the chemotherapy arm, the most frequently reported adverse events were diarrhea (35.8%), nausea (31.4%) and fatigue (29.9%). 

“Women with HER2-positive breast cancer generally have a more aggressive disease, greater likelihood of recurrence and poorer prognosis,” said Byondis Chief Medical Officer Jan Schellens, MD, PhD. “Today’s SYD985 BLA acceptance by the FDA is an important step forward toward our goal of providing a much-needed alternative for these patients.”

A Prescription Drug User Fee Act (PDUFA) action date of May 12, 2023 has been set for the application.


  1. FDA accepts Byondis’ Biologics License Application for [Vic-] trastuzumab duocarmazine (SYD985) in HER2-positive metastatic breast cancer. News release. Byondis B.V. Accessed July 12, 2022.–trastuzumab-duocarmazine-syd985-in-her2-positive-metastatic-breast-cancer-301584658.html
  2. Manich CS, O’Shaughnessy J, Aftimos PG, et al. Primary outcome of the phase III SYD995.002/TULIP trial comparing [vic] trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Presented at: European Society for Medical Oncology (ESMO) Congress 2021; September 16 to 21, 2021. Abstract LBA15.