In a late-breaking oral presentation (LBA15) at the virtual 2021 ESMO Congress, positive results were presented from the pivotal Phase III TULIP® study (SYD985.002; NCT03262935), a multi-center, open-label, randomized clinical trial comparing the efficacy and safety of the company’s antibody-drug conjugate [vic-]trastuzumab duocarmazine (SYD985; Byondis) to physician’s choice (PC) treatment in patients with pretreated HER2-positive unresectable locally advanced or metastatic breast cancer (MBC).

Breast cancer was the world’s most common cancer in 2020 [1], with an estimated 2.3 million new cases [2]. Its incidence is rising, particularly in developing countries, where the majority of cases are diagnosed in late stages [3]. Breast cancer is the leading cause of cancer death for women in more than 100 countries [4].

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 [5].

In HER2-positive breast cancer, 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 [6].

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A novel ADC
[Vic-]trastuzumab duocarmazine is an antibody-drug conjugate that incorporates a distinctive, proprietary duocarmazine linker-drug (LD) technology called ByonZine®  being developed by Byondis.

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The invetigational ADC is comprised of 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.

[Vic-]trastuzumab duocarmazine is currently being investigated in three other studies, including 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. The drug 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.

Tulip Trial
In the presentation during the 2021 annual ESMO meeting, Cristina Saura, M.D., head, Vall d’Hebron University Hospital Breast Cancer Unit, Medical Oncology Department, and principal investigator in the Tulip study at the Vall d’Hebron Institute of Oncology Breast Cancer Research Group in Barcelona, Spain, showed that the trial met its primary endpoint of progression-free survival (PFS), demonstrating a statistically significant improvement over physician’s choice – 7 months for SYD985 versus 4.9 months for physician’s choice.

The study also demonstrated a trend towards better overall survival (OS) for patients treated with SYD985.

“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,” Saura explained.

“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 improving,” noted Marco Timmers, Ph.D., Chief Executive Officer of Byondis.

“We want to thank our clinical trial sites and study participants and their families for their contributions to this important research,” Timmers added.

Study
Starting in November 2017, TULIP trial enrolled 437 patients with a median age of 56 and a median of 4 prior 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%).

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 in order 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) [7].

A novel linker 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.

Clinical trials
SYD985 vs. Physician’s Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (TULIP)- NCT03262935

Reference
[1] Cancer. World Health Organization, World Health Organization, Mar 3 2021, Online. Last accessed on September 30, 2021.
[2] Sung H; Ferlay J; Siegel RL; Laversanne M; Soerjomataram I; Jemal A; Bray F; “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.” CA: a Cancer Journal for Clinicians, U.S. National Library of Medicine, May 2021.[Pubmed]
[3] Breast Cancer: Prevention and Control. World Health Organization, Jan 21.2016, Online. Last accessed on September 30, 2021.
[4] Metastatic Breast Cancer: a Major and Growing Burden. UICC, 2 July 2019. Online. Last accessed on September 30, 2021.
[5] Cardoso F; Spence D; Mertz S; Corneliussen-James D; Sabelko K; Gralow J; Cardoso MJ; Peccatori F; Paonessa D; Benares A; Sakurai N; Beishon M; Barker SJ; Mayer M; “Global Analysis of Advanced/Metastatic Breast Cancer: Decade Report (2005-2015).” Breast (Edinburgh, Scotland), U.S. National Library of Medicine, Apr 19 2018. [Pubmed]
[6] Madell, R. “HER2 Breast Cancer: What Is It, Treatment, and More.” Healthline.com. Dec. 14, 2020, Online. Last accessed on September 30, 2021.
[7] Banerji, U, et al. Trastuzumab Duocarmazine in Locally Advanced and Metastatic Solid Tumours and HER2-Expressing Breast Cancer: a Phase 1 Dose-Escalation and Dose-Expansion Study. The Lancet Oncology, Elsevier, June 27, 2019. Online. Last accessed on September 30, 2021.

Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy © 2019 – 2021 European Society for Medical Oncology (ESMO). Used with Permission.

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