The Quantum Leap Healthcare Collaborative™, a 501c(3) charitable organization established as a collaboration between medical researchers at University of California, San Francisco, and Silicon Valley entrepreneurs, has selected [vic-]trastuzumab duocarmazine, also known as SYD985, for a new investigational treatment arm in its ongoing I-SPY 2 TRIAL™ for neoadjuvant treatment of locally advanced breast cancer.
[Vic-]trastuzumab duocarmazine is an investigational antibody-drug conjugate or ADC being developed by Netherlands-based Byondis. The new I-SPY 2 TRIAL* treatment arm will focus on treatment for Human Epidermal Growth Factor Resceptor 2 (HER2-) low early-stage breast cancer.
The I-SPY 2 TRIAL is a standing phase II randomized, controlled, multicenter study aimed at rapidly screening promising treatments in specific subgroups of women with newly-diagnosed, high-risk, locally advanced breast cancer (Stage II/III).
In simple terms, the I-SPY-2 Trial’s innovative and adaptive design demonstrates a high or low Bayesian predictive probability of success, allowing an investigational drug to either ‘graduate’ or to be ‘dropped’ from the trial arms, after which a new drug may enter. The primary endpoint is pathologic complete response (pCR), which is considered a valid surrogate endpoint because it appears to be associated with improved event-free survival (EFS) and Overall Survival (OS). Secondary outcomes include molecular characteristics or biomarker signatures, safety data, and long-term relapse-free survival (RFS), and OS.
One of the unique features of the trial is that it is a pre-competitive collaborative effort by a consortium that includes the U.S. Food and Drug Administration (FDA), industry, patient advocates, philanthropic sponsors, and clinicians from 16 major U.S. cancer research centers.
Over the last decades, HER2-targeted therapies have been recognized as a major step forward in delivering individualized targeted therapy for patients with breast cancer. These therapies, with trastuzumab being the first anti-HER2 strategy to be approved by the FDA for the treatment of HER-2 positive breast cancer, have greatly improved survival for patients in both the adjuvant and neoadjuvant settings and in patients with metastatic disease.
Today, dual blockade with trastuzumab (Herceptin®; Genentech/Roche) and pertuzumab (Perjera®; Genentech/Roche), in combination with chemotherapy, including, but not limited to, paclitaxel (Taxol®) or docetaxel (Taxotere®), is generally recommended as the first-line therapy for patients with HER2-positive metastatic breast cancer. 
But despite therapeutic advances, progression-free survival (PFS), and overall survival (OS) of patients treated with trastuzumab and chemotherapy-based regimens remains relatively low.
In the second line, patients often receive ado-trastuzumab emtansine (Kadcyla®; T-DM1; Genentech/Roche), but there remains a major unmet medical need in the treatment of HER2-positive breast cancer patients, especially for women with third-line and beyond metastatic breast cancer and women who develop metastatic disease to the brain.** For these women, lapatinib (Tykerb®; Novartis), a tyrosine kinase inhibitor (TKI), and capecitabine (Xeloda®; Genentech/Roche) are often considered as an option.
Ado-trastuzumab emtansine, an antibody-drug conjugate (ADC), is a form of targeted therapy in which monoclonal antibodies targeting specific receptors expressed on tumor cell membranes. Although the drug, which comprises the trastuzumab antibody, a linker, and the tubulin inhibitor DM1, has shown to be effective in the treatment of advanced breast cancer, the majority of patients will eventually develop resistance to this drug.
Based on this observation, various groups of researchers have been working on the development of alternative ADCs. Among the results is [fam] trastuzumab deruxtecan-nxki (Enhertu®; DS-8201a; Daiichi Sankyo and AstraZeneca), a novel ADC incorporating an anti-HER2 antibody, a newly developed, enzymatically cleavable peptide linker, and a novel, potent, exatecan-derivative topoisomerase I inhibitor (DXd). Trastuzumab deruxtecan is designed to deliver a potent cytotoxic payload to HER2-expressing tumor cells while limiting off-target toxicity in normal, healthy cells. The novel peptide-based linker is stable in plasma and is thought to be selectively cleaved by lysosomal enzymes such as cathepsins that are upregulated in the tumor microenvironment.
Trastuzumab deruxtecan has a drug-to-antibody-ratio (DAR) of 8, which is higher than that of trastuzumab emtansine (3.5), making the drug more effective against cancers with low-HER2 expression.
Byondis’ [vic-] trastuzumab duocarmazine which includes the same antibody as trastuzumab emtansine and trastuzumab deruxtecan, has excellent targeting and specific anti-tumor activity against HER2. But in contrast to trastuzumab emtansine, which has a non-reducible thioether linker, N-succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC, designated MCC after conjugation) and releases the Lys-linker-payload to kill the cells, trastuzumab duocarmazine has a cleavable linker and a duocarmycin prodrug payload known as seco-DUBA, which is effective in the picomolar range. As a result, [vic-] trastuzumab duocarmazine has a similar targetability in comparison to trastuzumab emtansine, but, at the same time, also reduces trastuzumab emtansine resistance and demonstrates improved efficacy in heterogeneous tumors.
Although currently marketed and commercially available ADCs have improved therapeutic indices and targeted cell killing compared to classical non-targeted chemotherapeutic agents, earlier generations of ADCs did not necessarily result in a more significant improvement in response and overall survival (OS), as compared to standard therapies among patients with HER2+ disease. Scientists believe that this is caused by the fact that these ADCs are often unstable in the bloodstream, leading to an early release of the cytotoxic payload and directly impacting normal, healthy tissue, narrowing the therapeutic window.
To solve this problem, [vic-]trastuzumab duocarmazine carries an intricate, inactivated cytotoxic (pro) drug that rapidly self-destructs in case it is prematurely released. This approach will, according to Marco Timmers, Ph.D., Chief Executive Officer of Byondis, “…Limit the damage to healthy tissue and improves the therapeutic window.”
Against the standard of care
The new I-SPY 2 treatment arm will evaluate [vic-]trastuzumab duocarmazine against standard of care therapy in Stage II/III early-stage, high-risk breast cancer patients, with a focus on tumors with heterogeneous and low HER2 expression. As part of the agreement, Byondis supplies the investigational drug and provides financial and regulatory support, while Quantum Leap, as a sponsor, provides the clinical sites and clinical expertise.
“We are pleased to collaborate with Quantum Leap, the FDA, and other key stakeholders to study the potential [[vic-]trastuzumab duocarmazine] as neoadjuvant therapy in a wider spectrum of breast cancer tumors,” Timmers said.
“Our hope is that we can improve on current disease outcomes for cancer patients in an early stage of the disease,” he added.
[Vic-] Trastuzumab duocarmazine, is currently one of four ADC’s being developed by Byondis. The investigational drug is the company’s most advanced ADC development program, targeting a range of HER2-positive cancers such as metastatic breast cancer (MBC) and endometrial (uterine) cancer. The company is currently conducting a Phase III study of [vic-]trastuzumab duocarmazine to compare its efficacy and safety to physician’s choice treatment in patients with HER2-positive unresectable locally advanced or metastatic breast cancer.
Previously, the FDA granted fast track designation for SYD985 based on promising data from heavily pre-treated last-line HER2-positive MBC patients participating in a two-part Phase I clinical trial.
Low expression of HER2
This new investigational study arm is designed to evaluate if [vic-]trastuzumab duocarmazine will limit tumor growth in a population of patients whose tumors are not normally treated with HER2-targeted therapies. Specifically, these tumors have low expression of HER2 and require better HER2-targeted drugs in order to be as effectively treated as HER2+ patients.
Byondis’ [vic-]trastuzumab duocarmazine is being developed for the treatment of HER2 expressing or HER2 mutant tumors. In nonclinical and clinical studies, the investigational drug demonstrated potent antitumor activity.
Based on the preliminary clinical observations in a Phase I study, [vic-]trastuzumab duocarmazine demonstrated antitumor activity in HER2-expressing cancers including breast cancer.
An earlier phase I study in patients with histologically confirmed, locally advanced, or metastatic tumors, concluded that [vic-]trastuzumab duocarmazine is effective in patients with high HER2 levels in their tumor, as well as in a subset of patients with lower levels of expression of the HER2 protein (HER2-low).
In comparison, currently approved ADC indicated for the treatment of HER2-positive disease suggest than patients with lower levels of HER2 have shorter progression-free survival compared to patients with higher HER2 levels.
The [vic-]trastuzumab duocarmazine arm of the I-SPY 2 clinical trial will be open for randomization to the HER2-low subset of the HER2- I-SPY 2 population, further defined as HER2-low by HER2 Immuno-histochemical staining (i.e. IHC 1+ and 2+) and in-situ hybridization. Tumors will be further characterized by genetic testing using MammaPrint® (MP1 or MP2; Agendia) and by hormone receptor status (HR+ or HR-). Within the HER2 negative patient population, patients will be excluded for HER2 IHC 0 and ISH negative.
“This I-SPY 2 TRIAL arm is designed to test a less toxic and a potentially highly effective approach where we need better options for patients,” explained Laura J. Esserman, MD, MBA, Professor, Departments of Surgery and Radiology, and Affiliate Faculty, Institute for Health Policy Studies, UCSF, Director of the Carol Franc Buck Breast Care Center and Co-Leader, Breast Oncology Program, UCSF Helen Diller Family Comprehensive Cancer Center, and Lead Principal Investigator for the I SPY 2 TRIALs.
“Low levels of HER2 protein expression are not sufficient to generate a response to traditional HER 2 treatment currently on the market. [vic-]trastuzumab duocarmazine works differently and is a promising way to deliver a targeted toxin. We need to continue to push to find better therapies. The I-SPY investigators are excited to partner with Byondis to test this agent in I-SPY 2,” Esserman concluded.
* I-SPY-2 Trial is the Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular analysis.
** Approximately 50% to 60% of women with HER2-positive breast cancer will, at some point in their disease course, will develop brain metastases.
SYD985 in Patients With HER2-expressing Recurrent, Advanced or Metastatic Endometrial Carcinoma – NCT04205630
Phase I Study of SYD985 With Niraparib in Patients With Solid Tumors – NCT04235101
First-in-human Study With the Antibody-drug Conjugate SYD985 to Evaluate Safety and Efficacy in Cancer Patients – NCT02277717
SYD985 vs. Physician’s Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (TULIP) – NCT03262935
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