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Phase I Study of Single Agent ZW25 Continues to Show Clinical Benefit in Heavily Pretreated HER2-High Patients

Published on 05th December

Data covering the completed dose escalation portion of its Phase I study of ZW25 (Zymeworks) , a novel Azymetric™ bispecific antibody targeting two distinct domains of the HER2 receptor, will be presented on Friday December 8th from 5:00-7:00pm CT at the San Antonio Breast Cancer Symposium (SABCS), being held in San Antonio, Texas.

ZW25 is Zymeworks’ lead product candidate currently being evaluated in a Phase 1 clinical trial in the United States. It is a bispecific antibody, based on Zymeworks’ Azymetric™ platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding.

This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding and removal of HER2 protein from the cell surface, and potent effector function and has led to significant anti-tumor activity in preclinical models of HER2-expressing cancer.

The HER2–mediated signaling pathway is believed to contribute to tumor growth in a number of cancers.

Dose escalation
A total of 22 patients have been enrolled in the Phase I study of ZW25. These patients had HER2-expressing cancers (either HER2 IHC 1+, 2+ or 3+, or FISH-positive) whose cancer had progressed after treatment with all therapies known to confer clinical benefit andn including 11 patients with breast cancer, eight with gastric, gastroesophageal junction, or esophageal (GE) cancer, and three with other HER2-expressing cancers.

HER2 status was assessed in archived or fresh biopsies locally and at a central laboratory. Patients with HER2-high breast cancer (HER2 IHC 3+ or IHC2+ and FISH-positive) had to have received previous treatment with trastuzumab, pertuzumab, and T-DM1.


For an overview of oral and poster presentations about antibody-drug conjugates (ADCs) to be presented during the annual San Antonio Breast Cancer Symposium, December 5-9, 2017, Click here.


Part one of the multi-part study was a standard dose escalation where patients received ZW25 either weekly at 5 mg/kg (n=3), 10 mg/kg (n=6), or 15 mg/kg (n=7) or bi-weekly (once every two weeks) at 20 mg/kg (n=6) in cycles of four weeks each.*

The study results showed six Partial Responses (PR) across all dosing groups including two new PRs from the 20 mg/kg bi-weekly cohort as well as clinical benefit (Confirmed PR or Stable Disease/SD ≥ 6 moths) of single agent ZW25 observed in heavily pretreated HER2-high breast and GE cancer patients.

In addition, the study-results’ highlights include:

  • Breast cancer patients received a median of six prior HER2-targeted regimens for metastatic disease; partial response in 56% (5/9) of breast cancer patients with measurable disease, with 89% (8/9) experiencing a decrease in target lesions.
  • Three HER2-high GE cancer patients with measurable disease showed tumor shrinkage, including one Confirmed PR (71% decrease in target lesions) and one SD for > 6 months.
  • ZW25 was well-tolerated at all doses and schedules, with the most common adverse events being diarrhea, infusion reactions, or nausea, all Grade 1 or 2 in severity.
  • The dose escalation portion of the Phase I trial is complete and enrollment in the expansion cohorts is underway.

Durable disease control
Seventy-nine percent of breast and GE cancer patients with measurable disease (11/14) had a decrease in target lesions per RECIST criteria. The best overall response (BOR) in 17 response-evaluable (defined as undergoing at least one tumor restaging) breast and GE cancer patients was six PR (35%), three SD (18%) and eight progressive disease (PD; 47%).

“The expanding dataset continue to show responses and durable disease control with both weekly and every other week dosing and demonstrate the potential of ZW25 to address unmet medical need across multiple indications,” noted Diana Hausman, MD, Chief Medical Officer of Zymeworks.

“We are seeing meaningful clinical benefit with single agent treatment in breast and gastric cancer patients who have progressive disease after numerous standard of care regimens. These early results, while impressive in their own right, are also distinct from other investigational agents being evaluated in refractory HER2-expressing cancer patients and support the continued evaluation of ZW25 both as a single agent and in combination with other cancer therapeutics,” Hausman added.

Prior treatment
Of the eleven breast cancer patients, all were HER2-high and had received a median of six prior HER2-targeted regimens for metastatic disease including trastuzumab (n=11), T-DM1 (n=11), pertuzumab (n=9), and lapatinib (n=7) as well as other investigational agents. The BOR in these heavily pretreated patients was five PR (45%), two SD (18%), and three PD (27%), for an overall disease control rate (Complete Response, PR, or SD) of 64%. At least one PR was observed in every dosing group. Of the eight GE patients, six were evaluable for response, and had received a median of four prior systemic regimens, including trastuzumab in all patients.

Three of five patients with measurable disease had a decrease in tumor size, including one patient continuing on treatment with a Confirmed PR and 71% decrease in target lesions, as well as a second patient with SD for over 6 months.

“There is an ongoing need for novel treatments for patients who have exhausted available options for their HER2-expressing cancers,”  explained  Erika P. Hamilton, MD, Director of the Breast Cancer and Gynecologic Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tennessee.

“The preliminary anti-tumor activity and tolerability we have seen with single agent ZW25 has been encouraging. We are excited to be enrolling patients in the expansion cohort portion of this study,” she added.

Further enrollment
Enrollment is underway for the second part of the study utilizing ZW25 every other week at 20 mg/kg in four expansion cohorts spanning HER2-high breast, HER2-high gastric, HER2-intermediate breast and other HER2-gene amplified cancers.

“The dose escalation portion of the Phase I trial has been a success, demonstrating the tolerability and single agent anti-tumor activity of ZW25,” said Ali Tehrani, Ph,D, one of Zymeworks‘ co-founders and currently serves as President and CEO of the company.

“These data bring us one step closer to initiating a single agent registrational trial with the goal of submitting an initial Biologics License Application (BLA) for ZW25 in 2021. We plan to provide an update on the expansion cohort portion of the trial at the American Society of Clinical Oncology Annual Meeting in 2018,” Tehrani added.


* Additional trial data
Patients with HER2-high gastric or gastroesophageal cancers had to have been previously treated with trastuzumab. Patients could have measurable or non-measurable tumor lesions per RECIST 1.1. Patients with known active brain metastases were excluded from the study. Patients were assessed during treatment for safety, including changes in cardiac function, tumor response per RECIST 1.1 every 8 weeks, ZW25 drug levels, and potential development of anti-drug antibodies. No dose-limiting toxicities were seen at any dose level or schedule. The most common adverse events were diarrhea, infusion reactions, or nausea, all Grade 1 or 2 in severity. There were no treatment-related serious adverse events, cardiac events or decreases in left ventricular ejection fraction.

Last Editorial Review: November 5, 2017

Featured Image: Nurse Assisting Patient Undergoing Mammogram Courtesy: © 2017. Fotolia | Used with permission.

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