FDA Grants Orphan Drug Designation to ARX788 for HER2+ Gastric Cancer

The FDA has granted an orphan drug designation to ARX788 for the treatment of patients with HER2-positive gastric cancer, according to a press release from developer Ambrx.¹

ARX788 is a homogenous antibody-drug conjugate (ADC) targeting the HER2 receptor that is being investigated in a phase 1 study of patients with previously treated advanced gastric cancer. Thesite-specific ADC is made of a noncleavable AS269 drug linker and amino acid–enabled conjugation technology.^1,2

“The ongoing phase 1 ACE-Gastric-01 trial has shown promising anti-tumor activity in HER2-positive advanced gastric patients who have been previously treated with trastuzumab and chemotherapy in the metastatic setting,” said Feng Tian, PhD, president and CEO of Ambrx, in a statement. “Receiving orphan drug designation from the FDA is an important milestone in our ongoing efforts to develop ARX788 for a wide range of HER2-positive cancers. We are proud to be targeting a rare disease that is currently severely underserved by advancing ARX788 into additional clinical trials.”

Findings from the phase 1 ACE-Gastric-01 trial are expected to be released by the end of the year and the global phase 3 ACE-Gastric-02 trial is expected to begin in the second half of the year. The phase 3 trial is planned to enroll patients with HER2-positive gastric or gastroesophageal junction cancer and randomize them to receive either ARX788 or physician’s choice of therapy in the second-line setting.

ARX788 has demonstrated preclinical activity for HER2-positive breast and gastric cancers, including those who have developed resistance to T-DM1 (trastuzumab emtansine; Kadcyla). In comparison with T-DM1 across a panel o cancer cell lines, ARX788 demonstrated superior activity in lower HER2-expressing cell lines in vitro. The agent also outperformed T-DM1 in xenograft models with both high and low HER2 expression.²

The ADC is being investigated in an ongoing dose-escalation phase 1 study (NCT03255070) in patients with advanced cancers with HER2 expression. In the study, HER2 expression is being determined by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) testing.

Phase 1a of the study is focused on determining the recommended phase 2 dose of the ADC and phase 1b is exploring safety and efficacy of the agent at the recommended phase 2 dose in 3 expansion cohorts: advanced breast cancer tumors with HER2 expression IHC3+ or IHC2+/ISH+, advanced breast cancer tumors with HER2 IHC2+/ISH– or IHC1+/ISH–, and advanced gastric cancer tumors with HER2 expression IHC3+ or IHC2+/ISH+.

ARX788 will be administered intravenously every 3 or 4 weeks at 6 sequential doses until the recommended phase 2 dose is determined.

The primary end point of the study is safety in terms of adverse events and the outcome measure for the second portion of the trial is objective response rate (ORR). Secondary end points include tumor response and pharmacokinetics.

ARX788 has already demonstrated promise in the breast cancer setting and was granted an FDA fast track designation earlier in the year for the treatment of patients with advanced or metastatic HER2-positive breast cancer who have received at least 1 prior anti-HER2 regimen in the metastatic setting.

_References

_{Ambrx Granted Orphan Drug Designation for ARX788 for the Treatment of Gastric Cancer. News release. Ambrx. March 17, 2021. Accessed March 17, 2021.}

_{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}