FDA Issues CRL for Trastuzumab Duocarmazine in Advanced HER2+ Breast Cancer


The FDA requests additional information requiring time and resources extending beyond the current evaluation period for vic-trastuzumab duocarmazine in advanced HER2-positive breast cancer.

The FDA has issued a complete response letter for a biologics license application (BLA) for vic-trastuzumab duocarmazine (SYD985) as a treatment for patients with HER2-positive, unresectable, locally advanced or metastatic breast cancer, according to a press release from Byondis B.V.1

Supporting data for the BLA for trastuzumab duocarmazine in HER2-positive unresectable locally advanced or metastatic breast cancer came from the phase 3 TULIP trial.

Supporting data for the BLA for trastuzumab duocarmazine in HER2-positive unresectable locally advanced or metastatic breast cancer came from the phase 3 TULIP trial.

The FDA has suspended its decision on approving trastuzumab duocarmazine following the complete response letter, and requested additional information requiring time and resources beyond the current review period for the agent.

“We continue to believe that [trastuzumab duocarmazine] can present a meaningful treatment option for patients living with HER2-positive metastatic breast cancer,” Marco Timmers, PhD, chief executive officer at Byondis, said in the press release. “We appreciate the FDA’s guidance and support and will carefully evaluate the complete response letter and consider potential next steps.”

The BLA for trastuzumab duocarmazine in the aforementioned indication was supported by findings from the phase 3 TULIP trial (NCT03262935). According to data presented at the 2021 European Society for Medical Oncology Congress, the median progression-free survival (PFS) was 7.0 months (95% CI, 5.4-7.2) following treatment with trastuzumab duocarmazine vs 4.9 months (95% CI, 4.0-5.5) with investigator choice chemotherapy (Hazard ratio [HR], 0.64; 95% CI, 0.49-0.84; P = .002).2 Additionally, the investigator-assessed median PFS was 6.9 months (95% CI, 6.0-7.2) vs 4.6 months (95% CI, 4.0-5.6) in each respective treatment arm (HR, 0.60; 95% CI, 0.47-0.77; P < .001).

In the multi-center, open-label, phase 3 TULIP trial, patients were randomly assigned 2:1 to receive 1.2 mg/kg of trastuzumab duocarmazine every 3 weeks or physician’s choice therapy until disease progression or unacceptable toxicity.

The primary end point was PFS. Secondary end points included overall survival (OS), objective response rate, investigator-assessed PFS, and health-related quality of life (HRQOL).

Patients 18 years and older with histologically confirmed unresectable locally advanced or metastatic breast cancer and disease progression during or after at least 2 HER2-targeting treatment regimens were eligible for enrollment on the trial. Additional eligibility criteria included having HER2-positive tumors, measurable or non-measurable disease per RECIST v1.1 criteria, an ECOG performance status of 0 to 2, an estimated life expectancy of more than 12 weeks at the time of randomization, and adequate organ function and blood cell counts.

Patients who had a history of infusion-related reactions and/or hypersensitivity to trastuzumab or severe, uncontrolled systematic disease at screening were not eligible to enroll on the trial.

The median OS was 20.4 months in the trastuzumab duocarmazine arm vs 16.3 months in the chemotherapy arm, although these data were not statistically significant (HR, 0.83; 95% CI, 0.62-1.09; P = .153). Investigators reported no statistically significant differences in HRQOL between the treatment arms.

The most common adverse effects (AEs) in the TULIP trial included conjunctivitis (38.2%), keratitis (38.2%), and fatigue (33.3%) among those receiving trastuzumab duocarmazine. Additionally, 7.6% of patients developed interstitial lung disease/pneumonitis. Grade 5 AEs were reported in 2 patients. Treatment discontinuation occurred in 35.4% of patients primarily due to AEs, the most common of which included eyes disorders (20.8%) and respiratory disorders (6.3%).


  1. U.S. Food and Drug Administration issues complete response letter for Byondis’ [vic-]trastuzumab duocarmazine. News release. Byondis B.V. May 15, 2023. Accessed May 16, 2023. bit.ly/3o77iXU
  2. Manich CS, O’Shaughnessy J, Aftimos PG, et al. LBA15 – Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER-positive locally advanced or metastatic breast cancer. Ann Oncol. 2021;23(suppl 15):S1283-S1346. doi:10.1016/annonc/annonc741

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