A Phase 1 Study of ARX788, an HER2-Targeting Antibody-Drug Conjugate, in Patients with HER2+ Metastatic Breast Cancer

ARX788 is a novel, site-specific antibody-drug conjugate (ADC) that consists of a human HER2-targeting monoclonal antibody linked to the cytotoxic payload AS269, a highly potent tubulin inhibitor.¹ In the first-in-human study in Australia/New Zealand, delayed drug-induced pneumonitis, which occurred after 4 to 5 cycles of administration, was observed in participants at dose levels ≥1.3 mg/kg every 3 weeks.² At SABCS 2019, results were presented from a phase 1 study to evaluate safety, pharmacokinetics, and preliminary antitumor effect of ARX788 in Chinese patients with HER2+ metastatic breast cancer (MBC), with a special focus on the delayed pneumonitis.³

Patients with HER2+ MBC received intravenous ARX788 at doses of 0.33, 0.66, 0.88, 1.1, 1.3, and 1.5 mg/kg every 3 weeks or 0.88, 1.1, and 1.3 mg/kg every 4 weeks. The dose-limiting pulmonary toxicity assessment period was set to be 21 days in the 0.33-, 0.66-mg/kg every-3-weeks cohorts, and an additional 63 days (a total of 84 days) in other dose cohorts. Safety and tolerability were assessed by monitoring adverse events (AEs) and antitumor effects were evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 criteria. Pulmonary toxicity of special interest was assessed every 2 cycles of therapy by computed tomography imaging. Serum concentrations of ARX788, total antibody, and metabolite pAF-AS269 were measured and pharmacokinetic parameters were calculated. A total of 45 patients (age range, 30-67 years) received ARX788, with 31 patients treated for at least 84 days. No dose-limiting toxicities or treatment-related serious AEs were observed. Serious blood and liver toxicity that are commonly associated with ADCs was rarely observed (1 participant experienced a grade 4 decrease in neutrophil count on cycle 18 and no grade ≥3 liver toxicity was observed). Ocular events were mostly mild to moderate in severity and were reversible. Three participants experienced grade 2 drug-related pneumonitis on days 130, 172, and 224, all of which resolved after steroid treatment and ARX788 dose reduction. ARX788 ADC serum exposure increased with dose increases, with a mean terminal-phase half-life between 2.3 and 4.9 days. Among 42 evaluated participants, the overall response rate was 31% in the 1.3-mg/kg every-3-weeks cohort.

The authors concluded that ARX788 was well tolerated in heavily pretreated patients with HER2+ MBC, without evidence of grade ≥3 pneumonitis. An encouraging overall response rate was observed in the 1.3-mg/kg every-3-weeks cohort. Considering the predicted benefit–risk profile, 1.3 mg/kg every 3 weeks is the recommended dose for further development of ARX788 in patients with heavily pretreated HER2+ MBC.

References

1. Humphreys RC, et al. AACR 2015. Abstract 639.
2. Rinnerthaler G, et al. Int J Mol Sci. 2019;20:1115.
3. Hu X, et al. SABCS 2019. Abstract P1-18-16.