ARX788 on FDA Fast Track for Advanced HER2-positive Breast Cancers

ARX788 on FDA Fast Track for Advanced HER2-positive Breast Cancers

ARX788 has been given a fast track designation by the U.S. Food and Drug Administration as a monotherapy for patients with HER2-positive metastatic breast cancer previously treated with at least one anti-HER2-based regimen.

The designation helps to accelerate the clinical development and expedite the approval of promising therapies for serious diseases, by providing more frequent meetings with the FDA and discussions about therapy development.

“This is an important milestone for ARX788 that underscores the strong unmet medical need to develop new and effective treatment options for breast cancer patients whose tumors progressed on currently approved HER2 directed regimens,” Joy Yan, MD, PhD, chief medical officer of Ambrx, said in a press release.

In some breast cancers, abnormal activity of the protein HER2 helps to drive cancer growth, and these cancers are referred to as HER2-positive. These tumors often develop resistance to standard therapies and, as such, need better treatment strategies.

Because HER2 drives cancer growth in these tumors, blocking the activity of this protein can limit cancer growth and even kill cancer cells.

ARX788, developed by Ambrx, is an investigational antibody-drug conjugate (ADC) that combines the HER2-targeting antibody trastuzumab (marketed as Herceptin, among others) with two toxic payloads of amberstatin269, also known as AS269, a potent cytotoxic tubulin inhibitor. Tubulin is a major component of microtubules, which are necessary for the division of cells. Targeting tubulin disrupts the assembly of the microtubules in fast-dividing tumor cells, making them more prone to cell death.

The FDA’s decision was based on data from Phase 1 studies which evaluated the safety, tolerability, pharmacokinetic, and efficacy of ARX788 in heavily pre-treated cancer patients with HER2-positive tumors, including breast cancer. (Of note, pharmacokinetics refers to the movement of a medicine into, through, and out of the body).

The open-label, two-stage Phase 1 trial (NCT03255070), ongoing in the U.S. and Australia, has enrolled patients with HER2-positive tumors who failed to respond to treatment with Kadcyla (trastuzumab emtansine) or Enhertu (fam‐trastuzumab deruxtecan), both HER2-directed ADCs.

The trial continues to enrol participants. More information on enrolment is available here.

In the first part of the trial, participants were given six escalating doses of ARX788, delivered every three or four weeks intravenously (into the vein), to determine the recommended dose for further Phase 2 testing.

Part two will then evaluate the efficacy and safety of the determined dose.

Data presented at the 2020 San Antonio Breast Cancer Symposium revealed that ARX788 had promising antitumor activity at the recommended Phase 2 dose (1.5 mg/kg), with treated patients achieving an objective response rate (when the cancer disappears or shrinks considerably) of 67% and a disease control rate of 100% (the percentage of patients whose disease was kept under control).

The median duration of response (the time patients kept responding to treatment) and the median progression-free survival (the time patients lived without their disease worsening) have not been reached.

Importantly, ARX788 was well-tolerated, with mild or moderate adverse events observed, all of which were manageable.

“It’s our mission to drive science forward to help bring innovative therapeutic options to cancer patients and we look forward to working closely with the FDA to optimize and expedite the development of ARX788,” Yan said.