Earlier this week, the U.S. Food and Drug Administration (FDA) issued a complete response letter (CRL) for Byondis’ Biological License Application (BLA) for the company’s anti-HER2 antibody-drug conjugates [vic-] trastuzumab duocarmazine, also known as SYD985.
With this BLA, Byondis sought approval for the use of investigational agent in the treatment of patients diagnosed with human epidermal growth factor receptor 2 (HER2-) positive unresectable locally advanced or metastatic breast cancer (MBC), a disease with a high unmet medical need.
Advanced or metastatic breast cancer with over-expression and/or amplification of HER2 is a clinically aggressive subtype with generally poor survival outcomes. However, following the introduction of trastuzumab (Herceptin®; Genentech/Roche)*, which binds to the extracellular domain IV of HER2, preventing its activation, the survival rates of patients have greatly improved.
Beyond treatment with trastuzumab, the inclusion of other anti-HER2 drugs in daily clinical practice, has drastically improved the median overall survival (mOS) of patients diagnosed with HER2+ unresectable locally advanced or metastatic breast cancer. However, despite these major improvements, major remains, causing an considerable unmet medical need, leading to the development of a number of antibody-targeted agents, including [vic-] trastuzumab duocarmazine.
[Vic-]trastuzumab duocarmazine includes the trastuzumab antibody and a cleavable linker-payload called valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole (vc-seco-DUBA). The antibody part of [vic-]trastuzumab duocarmazine binds to HER2 on the surface of the cancer cell and the ADC is internalized by the cell. After proteolytic cleavage of the linker, the inactive cytotoxin is activated and DNA damage is induced, resulting in tumor cell death.
The BLA submitted to the FDA, and the Market Authorization Application (MAA) submitted to the European Medicines Agency (EMA), are supported by data from the pivotal Phase 3 TULIP® multi-center, open-label, randomized clinical trial comparing [Vic-]Trastuzumab Duocarmazine to physician’s choice (PC) treatment in patients with pre-treated HER2-positive unresectable locally advanced or metastatic breast cancer. 
The TULIP® clinical study, which started in November 2017, enrolled a total of 436 female patients aged 18 and over, at 83 sites across the United States, Canada, Europe, and Singapore, compared the efficacy and safety of the company’s antibody-drug conjugate (ADC) [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pretreated HER2-positive unresectable locally advanced or metastatic breast cancer (MBC).
The study results, presented at the 2021 ESMO Congress, demonstrated that the study met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement of 2.1 months over physician’s choice.** The TULIP-study also demonstrated supportive overall survival (OS) results.
According to the complete response letter, the FDA suspends the decision on the product’s approvability. In the letter, the agency requested additional information that requires time and resources that extend beyond the current evaluation period. While Byondis team is disappointed with this outcome, the company remains optimistic about [vic-]trastuzumab duocarmazine’s potential.
“We continue to believe that [vic-]trastuzumab duocarmazine can present a meaningful treatment option for patients living with HER2-positive metastatic breast cancer. We appreciate the FDA’s guidance and support and will carefully evaluate the complete response letter and consider potential next steps,” noted Marco Timmers, Ph.D., the Chief Executive Officer of Byondis.
“We will continue with the [vic-]trastuzumab duocarmazine applications in EU and UK and await the outcome of the review process,” Timmers conclude.
Note: *Trastuzumab-anns (Kanjinti®, a biosimilar* to Herceptin®) was developed by Byondis, and is the company’s first product out-licensed in an exclusive global license agreement with Amgen/Allergan.
** The TULIP study (NCT03262935) assessed the efficacy of [vic-]trastuzumab duocarmazine in patients diagnosed with advanced HER2-positive breast cancer. The study results, presented at the 2021 ESMO Congress, showed that centrally reviewed median progression-free survival (PFS) was 7.0 months [95% CI 5.4-7.2] for [vic-]trastuzumab duocarmazine and 4.9 mo [4.0-5.5] for PC (HR 0.64 [0.49-0.84]; p = 0.002). In addition, investigator-assessed PFS also demonstrated significantly improvement (6.9 mo [6.0-7.2] vs 4.6 mo [4.0-5.6]; HR 0.60 [0.47-0.77]; p < 0.001. Based on the study outcomes, the investigators concluded that treatment with [vic-]trastuzumab duocarmazine significantly improved progression-free survival (PFS) in comparison with standard physician’s choice and may provide a new treatment option for patients with pre-treated locally advanced or metastatic HER2-positive MBC. 
ISPY-P1.01:Evaluating the Safety of Weekly Paclitaxel With Trastuzumab Duocarmazine (SYD985) in Patients With Metastatic Cancer – NCT04602117
SYD985 vs. Physician’s Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (TULIP) – NCT03262935
First-in-human Study With the Antibody-drug Conjugate SYD985 to Evaluate Safety and Efficacy in Cancer Patients – NCT02277717
 [vic-] trastuzumab duocarmazine (SYD985). Drug Map. ADC Review. Online. last accesses on May 16, 2023.
 Saura Manich C. Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. ESMO Congress 2021, abstract LBA15
 TULIP® Study in Patients With HER2+ Unresectable Locally Advanced or Metastatic Breast Cancer Meets Primary Endpoint. ADC Review | Journal of Antibody-drug Conjugates. June 8, 2021. Online. Last accesses on May 16, 2023.