ARX788 Meets PFS End Point in HER2+ Metastatic Breast Cancer

The antibody-drug conjugate ARX788 was found to significantly improve progression-free survival compared with an active control in patients with HER2-positive locally advanced or metastatic breast cancer.

Daniel O’Connor

Daniel O’Connor

The antibody-drug conjugate (ADC) ARX788 was found to significantly improve progression-free survival (PFS) compared with an active control in patients with HER2-positive locally advanced or metastatic breast cancer, meeting the prespecified interim primary efficacy end point of the phase 3 ACE-Breast-02 trial being conducted in China.1

The trial enrolled a total of 441 patients who previously received treatment with trastuzumab (Herceptin) and a taxane. Study participants were randomly assigned in a 1:1 fashion to receive the humanized anti-HER2 monoclonal antibody or the control regimen of lapatinib (Tykerb) plus capecitabine. Blinded independent review committee–assessed PFS served as the primary end point.

An Independent Data Monitoring Committee conducted an interim analysis when two-thirds of the PFS occurred. NovoCodex plans to connect with the National Medical Products Administration to discuss the submission of an application seeking the marketing approval of the ADC for use in China.

“We congratulate our partner, NovoCodex on this positive phase 3 study,” Daniel O’Connor, chief executive officer of Ambrx, stated in a press release. “The positive results from this large phase 3 study provide further support for our rationale to develop ARX788 globally in HER2-positive breast cancer patients.”

ARX788 is composed of a HER2-targeted monoclonal antibody that is linked to the cytotoxic payload AS269. With the use of proprietary technology, a non-natural amino acid can be incorporated into a predetermined site on the heavy chain of the monoclonal antibody. AS269 is conjugated to the non-natural amino acid.

Preclinical data have indicated that ARX788 had high serum stability and a relatively long half-life of 12.5 days when administered to mice. In HER2-low cell lines, ARX788 was found to have superior activity vs ado-trastuzumab emtansine (T-DM1; Kadcyla); the former did not have activity in normal cardiomyocyte cells.2 Moreover, in HER2-low xenograft models, the ADC inhibited cancer growth.

ARX788 has also demonstrated activity in vitro and in vivo models of HER2-positive breast and gastric cancers.3 Specifically, ARX788 hindered growth on all 5 HER2-positive cell lines examined, including 2 gastric cancer cell lines that had acquired resistance to T-DM1.

Data from a phase 1 trial (CTR20171162) showed that the ADC elicited responses with acceptable tolerability in heavily pretreated Chinese patients with metastatic HER2-positive breast cancer without grade 3 or higher pneumonitis.4

The agent was evaluated at the following doses given every 3 weeks: 0.33 mg/kg, 0.66 mg/kg, 0.88 mg/kg, 1.1 mg/kg, 1.3 mg/kg, or 1.5 mg/kg every 3 weeks. It was also examined at 0.88 mg/kg, 1.1 mg/kg, or 1.3 mg/kg every 4 weeks.

In 42 evaluable patients, ARX788 induced an overall response rate (ORR) of 31%. In those who received the ADC at a dose of 1.3 mg/kg given every 3 weeks, the ORR was 42%.

No dose-limiting toxicities or serious adverse effects (AEs) related to treatment were reported. Serious blood or liver toxicities were noted to be rare. Only 1 patient had grade 4 decreased neutrophil count on cycle 18. Notably, ocular and pulmonary AEs required special intervention although these effects ranged from mild to moderate severity and proved reversible.

Three patients had treatment-related pneumonitis; these cases were grade 2 in severity and were noted on days 130, 172, and 224. All cases resolved after treatment with steroids. These patients went on to receive ARX788 at a reduced dose.

In January 2021, the FDA granted a fast track designation to ARX788 for use as a potential therapeutic option in patients with advanced or metastatic HER2-positive breast cancer who received 1 or more prior HER2-targeted regimens in the metastatic setting.5


  1. ACE-Breast-02 pivotal phase 3 study of Ambrx’s ARX788 for the treatment of HER2 positive metastatic breast cancer achieves positive results. News release. Ambrx Bipharma Inc. March 1, 2023. Accessed March 1, 2023.
  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 cancer. Mol Cancer Ther. 2020;19(9):1833-1843. doi:10.1158/1535-7163.MCT-19-1004
  3. Barok M, Joncour VL, 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. Abstract P1-18-16: a phase 1 study of ARX788, a HER2-targeting antibody-drug conjugate, in patients with metastatic HER2-positive breast cancer. Cancer Res. 2020;80(4). doi:10.1158/1538-7445.SABCS19-P1-18-16
  5. FDA grants ARX788 fast track designation for HER2-positive metastatic breast cancer. News release. Ambrx. January 4, 2021. Accessed March 1, 2023.
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