At a late-breaking oral presentation (LBA15) at the virtual 2021 ESMO Congress today, Byondis B.V., an independent, clinical-stage biopharmaceutical company creating precision medicines, reported positive results from its pivotal Phase III TULIP® study. The multi-center, open-label, randomized clinical trial compared the efficacy and safety of the company's antibody-drug conjugate (ADC) [vic-]trastuzumab duocarmazine (SYD985) to physician's choice (PC) treatment in patients with pretreated HER2-positive unresectable locally advanced or metastatic breast cancer (MBC).
"SYD985 vs. Physician's Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer" met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement over PC – 7 months for SYD985 versus 4.9 months for PC. The study also demonstrated a trend towards better overall survival (OS) for patients treated with SYD985. TULIP results were presented by Cristina Saura, M.D., head, Vall d'Hebron University Hospital Breast Cancer Unit, Medical Oncology Department, and principal investigator, Vall d'Hebron Institute of Oncology Breast Cancer Research Group in Barcelona, Spain.
"We are satisfied with the results of the TULIP study, as it bodes well for the potential of SYD985 as a new treatment option for patients with HER2-positive metastatic breast cancer, a disease typically associated with a poor prognosis," said Dr. Saura.
"The TULIP results represent a significant milestone in our R&D efforts, and we hope to make this next-generation ADC available as soon as possible to the patients whose lives we are dedicated to improve," said Byondis CEO Marco Timmers, Ph.D. "We want to thank our clinical trial sites and study participants and their families for their contributions to this important research."
Byondis is working to complete the SYD985 biological license application (BLA) and intends to submit it to the U.S. Food & Drug Administration (FDA) before the end of 2021. The company is exploring partnerships with pharma and biopharma companies to further develop and commercialize SYD985.
The therapy was granted fast track designation by the FDA in January 2018. The designation was based on promising data from heavily pre-treated last-line HER2-positive MBC patients participating in a two-part Phase I clinical trial (SYD985.001).[i]
More TULIP (SYD985.002) Results
Starting in November 2017, TULIP enrolled 437 female patients with a median age of 56 and a median of 4 before MBC treatments. The study was conducted at 83 sites in 11 countries across the United States, Canada, Europe, and Singapore. To qualify, patients had either: (1) progression during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease; or (2) progression during or after ado-trastuzumab emtansine treatment. Patients were randomly assigned (2:1) to receive SYD985 (n=291, 1.2 mg/kg q three weeks) or PC chemotherapy (n=146) until disease progression or unacceptable toxicity. The trial was powered to detect a Hazard Ratio (HR) of 0.65 at the P < 0.05 significance level.
The study's primary endpoint, blinded centrally reviewed median PFS, was 7.0 months (5.4-7.2, 95% CI) for SYD985 and 4.9 months (4.0-5.5) for PC (HR 0.64 [0.49-0.84], p = 0.002). Secondary endpoint results are as follows: investigator-assessed PFS significantly improved, 6.9 months (6.0-7.2) versus 4.6 months (4.0-5.6) for PC (HR 0.60 [0.47-0.77], p < 0.001); OS first analysis indicated HR was 0.83 (0.62-1.09, p = 0.153); and no significant differences were observed in objective response rate (ORR) or health-related quality of life (HRQoL).
The most frequently reported adverse events (AEs) for SYD985 were conjunctivitis (38.2%), keratitis (38.2%), and fatigue (33.3%). For PC, the most frequently reported AEs were diarrhea (35.8%), nausea (31.4%), and fatigue (29.9%). Interstitial lung disease/pneumonitis was reported for 7.6% of patients treated with SYD985. AEs leading to discontinuation of treatment were 35.4% and 10.2% in the SYD985 and PC groups, respectively. In the SYD985 group, these were mainly related to eye disorders (20.8%) or respiratory disorders (6.3%).
[Vic-]Trastuzumab Duocarmazine (SYD985), a Next-Generation Antibody-Drug Conjugate
[Vic-]trastuzumab duocarmazine (SYD985) incorporates Byondis' distinctive, proprietary duocarmazine linker-drug (LD) technology ByonZine®. Although in general, marketed ADCs have improved therapeutic indices compared to classical non-targeted chemotherapeutic agents, there is still a need for improvement.
The ADC [vic-]trastuzumab duocarmazine is comprised of the monoclonal antibody trastuzumab and a cleavable linker-drug 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. SYD985 is considered a form of targeted chemotherapy.
[Vic-]trastuzumab duocarmazine is currently being investigated in three other studies. Byondis initiated a Phase II clinical trial in HER2-expressing recurrent, advanced or metastatic endometrial cancer, and a Phase I study exploring the synergistic effects of [vic-]trastuzumab duocarmazine and niraparib in patients with HER2-expressing locally advanced or metastatic solid tumors. [Vic-]trastuzumab duocarmazine is also part of a new arm of the Quantum Leap Health Collaborative™ I-SPY 2 TRIAL™ investigating the neoadjuvant use of [vic-]trastuzumab duocarmazine in HER2-low early-stage breast cancer.
ByonZine®, Byondis' Distinctive, Proprietary Linker-Drug Technology
While earlier generation ADCs improved targeting and cell killing, they were unstable in the bloodstream, leading to premature release of the cytotoxic payload, impacting healthy tissue and narrowing the therapeutic window. Byondis' next-generation ADCs are highly stable in circulation and carry an intricate, inactivated, and potent cytotoxic drug that rapidly self-destructs if prematurely released, limiting damage to healthy tissue and improving the therapeutic window.
Byondis' differentiated linker-drug, vc-seco-DUBA, owes its potent antitumor activity to a synthetic duocarmycin-based cytotoxin. Duocarmycins, first isolated from Streptomyces bacteria in the 1970s, bind to the minor groove of DNA and disrupt the nucleic acid architecture, which eventually leads to tumor cell death.
The distinctive design of the selectively cleavable linker connecting the antibody to the duocarmycin drug leads to high stability in circulation and induces the efficient release of the cytotoxin in the tumor. Uptake of the activated payload by neighboring tumor cells with lower HER2 expression may improve the efficacy potential, the so-called bystander effect.
HER2-Positive MBC: A Cancer With a Poor Prognosis
Breast cancer was the world's most common cancer in 2020,[ii] with an estimated 2.3 million new cases.[iii] Its incidence is rising, particularly in developing countries, where the majority of cases are diagnosed in late stages.[iv] Breast cancer is the leading cause of cancer death for women in more than 100 countries.[v]
In metastatic or Stage 4 breast cancer, cancer spreads to other parts of the body, such as the lungs, liver, bones, or brain. Approximately 0.5 million people worldwide die from MBC every year.[vi]
In HER2-positive breast cancer, and overexpression of the human epidermal growth factor receptor 2 (HER2) protein causes out-of-control reproduction of breast cells. Research has shown that women with HER2-positive breast cancer have more aggressive disease, greater likelihood of recurrence, and poorer prognosis, compared to women with HER2-negative breast cancer. About 20 percent of all breast cancers are HER2-positive, with younger women being the most affected. Treatment of HER2-positive breast cancer can consist of the following: surgery, radiation, chemotherapy, and targeted treatments.[vii]
Driven to improve patients' lives, Byondis is an independent, privately held, clinical-stage biopharmaceutical company creating innovative precision medicines targeting intractable cancers and autoimmune diseases. The company is developing new biological entities (NBEs) and new chemical entities (NCEs) using proprietary molecular concepts, such as ByonZine®, its duocarmazine linker-drug (LD) technology, and ByonShieLD®, its site-specific conjugation technology, to create next-generation antibody-drug conjugates (ADCs).
Byondis' broad development portfolio comprises preclinical as well as early- and late-stage clinical programs, including the anti-HER2 ADC [vic-]trastuzumab duocarmazine (SYD985). The company has a dedicated team of about 400 employees, including highly educated scientists and skilled technicians working in state-of-the-art R&D and Good Manufacturing Practice manufacturing facilities on its Nijmegen campus in the Netherlands. Byondis regularly collaborates with leading, global biotechnology and pharmaceutical companies, as well as many academic research institutions. For more information, visit www.byondis.com.