FDA Grants Fast Track Status to ADC ARX788 for HER2+ Metastatic Breast Cancer

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January 5th, 2021 -The FDA has granted a fast track designation to the investigational antibody-drug conjugate ARX788 for use as a monotherapy in the treatment of patients with advanced or metastatic HER2-positive breast cancer who have previously received 1 or more HER2-targeted regimens in the metastatic setting.

The FDA has granted a fast track designation to the investigational antibody-drug conjugate (ADC) ARX788 for use as a monotherapy in the treatment of patients with advanced or metastatic HER2-positive breast cancer who have previously received 1 or more HER2-targeted regimens in the metastatic setting.¹

The decision was based on data from phase 1 trials that evaluated the safety and tolerability of the agent, along with its preliminary efficacy and pharmacokinetic profile.

“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, chief medical officer of Ambrx, stated 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.”

The novel, site-specific ADC is comprised of a HER2-targeted monoclonal antibody that is linked to the cytotoxic payload AS269, which is a strong tubulin inhibitor. Proprietary technology allows for the incorporation of a non-natural amino acid into a predetermined site on the heavy chain of the monoclonal antibody; AS269 is conjugated specifically to the non-natural amino acid.

Preclinical trials of the ADC showed that that agent had high serum stability in mice and a relatively long half-life of 12.5 days. Moreover, when the agent was compared with the use of ado-trastuzumab emtansine (T-DM1; Kadcyla) in HER2-low cell lines, ARX788 demonstrated superior activity with no activity in normal cardiomyocyte cells.² The ADC also hindered tumor growth in HER2-low xenograft models.

ARX788 was also found to showcase efficacy in in vitro and in vivo models of HER2-positive breast cancer and gastric cancer that were resistant to T-DM1.³ Specifically, the agent substantially inhibited growth on all 5 HER2-positive cell line that were evaluated, including 2 gastric cancer cell lines that had acquired resistance to T-DM1.

Most recently, data from a phase 1 trial (CTR20171162) evaluating the agent in Chinese patients with metastatic HER2-positive breast cancer were presented during the 2020 San Antonio Breast Cancer Symposium. The ADC was found to elicit encouraging responses with favorable tolerability in heavily pretreated patients without grade 3 or greater pneumonitis.⁴

A total of 45 Chinese patients had been enrolled to the trial. Patients received the ADC intravenously at 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, or 0.88 mg/kg, 1.1 mg/kg, or 1.3 mg/kg every 4 weeks. Investigators evaluated dose-limiting toxicities (DLTs) for 21 days in the subgroups of patients who received the agent at a dose of either 0.33 mg/kg or 0.66 mg/kg every 3 weeks. The other dose cohorts were evaluated for an additional 63 days.

Results showed that among 42 evaluable patients, the ADC elicited an overall response rate (ORR) of 31%; in the cohort of patients who received the agent at a dose of 1.3 mg/kg every 3 weeks, the ORR was even higher, at 42%.

Regarding safety, no DLTs or serious treatment-related toxicities were observed. Moreover, serious blood or liver toxicities were rarely noted, with only 1 patient reporting decreased neutrophil count on cycle 18 that was grade 4 in severity. Notably, ocular and pulmonary toxicities required special intervention. However, the majority of the ocular effects reported ranged from mild to moderate in severity and were determined to be reversible.

Drug-associated pneumonitis was observed in 3 patients; these effects were grade 2 and were observed on days 130, 172, and 224. With the administration of steroids, all of these cases resolved, and patients were able to continue treatment with the ADC at a reduced dose.

References

FDA grants ARX788 fast track designation for HER2-positive metastatic breast cancer. News release. Ambrx. January 4, 2021. Accessed January 5, 2021. http://prn.to/38hoiA3.
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
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
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