Zymeworks announced the start of a Phase 2 trial examining its experimental cancer treatment ZW25, in combination with Pfizer’s CDK4/6 inhibitor Ibrance (palbociclib) and the hormone therapy Faslodex (fulvestrant), in people with advanced breast cancer.
An agreement with Pfizer to make Ibrance available to the Zymeworks-sponsored study helped to move it forward.
The trial (NCT04224272) is recruiting up to 76 patients with locally advanced breast cancer who received prior treatment or with metastatic breast cancer. The cancer must also be positive for a hormone receptor (HR) and for the HER2 protein.
The open-label, two-part trial is now enrolling at South Texas Accelerated Research Therapeutics in San Antonio, with plans to expand to additional sites in the U.S., Canada, and Spain. Information is available here.
Investigators in the study’s first part will evaluate the tolerability and safety of ZW25, in combination with Ibrance and Faslodex, and confirm the recommended dosages of ZW25 and Ibrance. That will be achieved by measuring the number of adverse events, dose-limiting toxicities, and lab abnormalities reported in treated patients.
Evidence of early efficacy is the goal of the second part. Here, investigators will determine the anti-tumor activity of the combination therapy at the established doses by measuring the proportion of patients alive and without disease progression at six months.
Secondary efficacy measures include the proportion of patients who respond to treatment, duration of responses, and progression-free survival, or the length of time that patients go without disease worsening, both during and after the treatment.
Patients in the trial will receive ZW25 intravenously (into the bloodstream) every two weeks, oral Ibrance once daily, and Faslodex as an intramuscular injection every two weeks initially, and then every four weeks. The trial is expected to conclude in June 2023.
“The initiation of this Phase 2 trial and collaboration with Pfizer mark significant milestones in our progress towards establishing ZW25 as the foundational HER2 therapy in multiple regimens across breast and other cancers,” Diana Hausman, MD, chief medical officer at Zymeworks, said in a press release.
“Together, ZW25 and palbociclib have the potential to improve anti-tumor activity and minimize side effects for people living with advanced HER2‑positive, HR-positive breast cancer,” Hausman added.
Many breast cancers overproduce a protein called HER2, making it an ideal target for therapies. ZW25 is an antibody designed to attach itself to two specific regions of HER2, a property called biparatropic binding.
This increases its binding compared to antibodies attaching a single region, potentially improving the removal of the HER2 protein from the cell surface and blocking HER2 signaling overall, ultimately leading to anti-tumor activity.
ZW25 is also being evaluated for its ability to combat HER2-positive tumors in additional Phase 1 (NCT02892123) and Phase 2 (NCT03929666) trials. These studies include cancers of the breast, gastroesophageal, colorectal, biliary, and salivary gland, and are assessing ZW25 as a single agent and in combination with standard chemotherapy.
The FDA has granted ZW25 fast track designation as a first-line treatment of gastroesophageal adenocarcinoma in combination with standard of care chemotherapy, and an orphan drug designation for the treatment of both gastric and ovarian cancers.
The novelty of Zymeworks’ new Phase 2 trial comes from the combination of ZW25 with Ibrance and Faslodex, instead of chemotherapeutic agents.
Ibrance is an oral medication that works to limit cell growth. It accomplishes this by blocking the activity of cyclin-dependent kinase (CDK) 4/6, two proteins required for cell division. CDK 4/6 inhibitors can trap cancer cells in a state, called G1 arrest, that does not allow them to divide.
Faslodex, marketed by AstraZeneca, also functions by limiting cell growth, but it does so through hormone therapy. This is because some breast cancers require estrogen for cell growth. Faslodex is designed to competitively bind to estrogen receptors on the cancer cells, thereby reducing the amount of estrogen that can reach these cells, ultimately limiting cell growth.
A previous Phase 3 trial, called PALOMA-3 (NCT01942135), found a significantly better survival rate in breast cancer patients given Ibrance and Faslodex in combination, compared to those treated with Faslodex alone.
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