FDA Action Moves ARX788 Forward in the Treatment of HER2-Positive Breast Cancer

ARX788 received a nod from the FDA early in 2021 based on promising preclinical and phase 1 trial data demonstrating its efficacy in patients with HER2-positive breast cancer following progression on other agents.

Fast track designation was granted to the anti-HER2 antibody-drug conjugate ARX788 as monotherapy for the treatment of patients with advanced or metastatic HER2-positive breast cancer following at least 1 prior HER2-targeting regimen in the metastatic setting, announced the agent’s developer Ambryx Inc.1

A site-specific antibody-drug conjugate, ARX788 consists of an anti-HER2 monoclonal antibody linked to the highly potent tubulin inhibitor AS269.

Preclinical studies of HER2-positive breast cancer demonstrated that ARX788 induced greater tumor suppression as compared with ado-trastuzumab emtansine (T-DM1; Kadcyla) in both HER2-high and HER2-low models and prompted responses for in vitro and in vivo cancer models that were resistant to T-DM1.2,3

Phase 1 clinical trials have also demonstrated feasibility of its use in heavily pretreated patients with HER2-positive breast cancer and serve as the basis of the designation, which will help expedite the drug’s development and review with the aim of getting it to patients with unmet medical need.

“This is an important milestone for ARX788 that underscores the strong unmet medical need to develop new and effective treatment options for [patients with] breast cancer whose tumors progressed on currently approved HER2-directed regimens,” Joy Yan, MD, PhD, Ambrx Chief Medical Officer, said in a press release. “It’s our mission to drive science forward to help bring innovative therapeutic options to [patients with] cancer and we look forward to working closely with the FDA to optimize and expedite the development of ARX788.”

A phase 1 study (CTR20171162) of ARX788 was presented at the 2019 San Antonio Breast Cancer Conference which showed that the drug was well tolerated in a cohort of Chinese patients who had failed prior therapy with trastuzumab (Herceptin).4

In 48 evaluable participants, 19 had a partial response and 25 experienced stable disease with various dose levels of ARX788, for a disease control rate of 91.7%. Responses and progression-free survival increased in step with the dose level used. 

Only 2 treatment-related adverse events of grade 3 or greater were reported in 51 enrolled patients and no dose-limiting toxicities or maximum-tolerated dose was observed at the data cut-off date in November 2019. The investigators noted that serious blood and liver toxicities typically associated with antibody-drug conjugates were rarely observed, with only one case of grade 4 neutrophil count decrease noted.

Treated patients had a median age of 52 years and a majority (62.7%) had HER2 expression confirmed via immunohistochemistry (IHC3+). About half (47%) were also refractory therapy with lapatinib (Tykerb).

A 2-part phase 1 dose-escalation trial is currently ongoing in the United States and Australia in patients with HER2-expressing cancers, including breast tumors (NCT03255070). The phase 1a portion is designed to determine the recommended phase 2 dose (RP2d); phase 1b will look at the RP2D to assess end points of safety and objective response rate.


1. FDA grants ARX788 fast track designation for HER2-positive metastatic breast cancer. News release. January 4, 2021. Accessed January 5, 2021. https://prnmedia.prnewswire.com/news-releases/fda-grants-arx788-fast-track-designation-for-her2-positive-metastatic-breast-cancer-301199951.html

2. Skidmore L, Sakamuri S, Knudsen NA, et al. ARX788, a site-specific anti-HER2 antibody-drug conjugate, demonstrates potent and selective activity in HER2-low and T-DM1-resistant breast and gastric cancers. Mol Cancer Ther. 2020;19(9):1833-1843. doi: 10.1158/1535-7163.MCT-19-1004

3. Barok M, Le Joncour V, Martins A, et al. ARX788, a novel anti-HER2 antibody-drug conjugate, shows anti-tumor effects in preclinical models of trastuzumab emtansine-resistant HER2-positive breast cancer and gastric cancer. Cancer Lett. 2020;473:156-163. doi:10.1016/j.canlet.2019.12.037

4. Hu X, Zhang J, Ji D, et al. A phase 1 study of ARX788, a HER2-targeting antibody-drug conjugate, in patients with metastatic HER2-positive breast cancer. Cancer Res. 2020;80(suppl 4):P1-18-16. doi:10.1158/1538-7445.SABCS19-P1-18-16

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