Abstract PD18-09: ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1
Authors: Hurvitz Sara , Kalinsky Kevin , Ganju Vinod , Ali Kashif , Agrawal Laila , Gradishar William , Sledge George , Thummala Anu , Chan Arlene , Frentzas Sophia , Sohn Joo Hyuk , Park Kyong-Hwa , Park Keon Uk , Shannon Catherine , Drago Joshua , Tolaney Sara , Rugo Hope , Press Michael F. , Alika Alex , Xu Dong , Lu Janice , Tripathy Debu 
Published: March 2023

Abstract
Background: Amplification of the human epidermal growth factor receptor 2 (HER2) gene with consequent HER2 protein overexpression occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. The HER2-targeted ADC trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive metastatic BC (mBC) after prior trastuzumab and taxane therapy. However, disease progression occurs in all patients requiring additional therapeutic options. The use of second-generation anti-HER2 ADCs using alternative molecules is being investigated to overcome drug resistance. ARX788 is a next-generation ADC using a technology platform whereby a HER2-specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 lead to its slow release and prolongation of the peak serum pAF-AS269 concentration, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Here, early evidence of activity of ARX788 in patients previously treated with T-DM1 is shown.
Methods: ACE-Breast-03 (NCT04829604) is an ongoing global, phase 2, single-arm study evaluating ARX788 in patients with HER2+ mBC whose disease has progressed following T-DM1, T-DXd, and/or tucatinib-containing regimens. The ARX788 is administered with an initial dose of 1.5 mg/kg Q4W and subsequent doses of 1.3 mg/kg Q4W. Eligibility criteria included central laboratory confirmed HER2+ mBC per ASCO/CAP guidelines, measurable disease, and adequate organ function. Stable treated brain metastases are allowed. Patients with interstitial lung disease (ILD) or pneumonitis in prior 12 months; active ocular infections or any chronic corneal disorder; are excluded. The primary endpoint is overall response rate (ORR).
Results: At the data cutoff of 11-Jul-2022, 7 patients were enrolled in ACE-Breast-03 (v1.0) who previously experienced disease progression on T-DM1 and had response-evaluable disease. Pts had a median age of 59 years and had received a median of 5 lines of prior anti-HER2 cancer therapy (range: 2-8). None of the pts in this subset had received T-DXd or tucatinib. 5 pts were previously treated with HER2-targeted TKIs (neratinib and lapatinib), as well as an investigational HER2 ADC and responded to ARX788 (3 PR; 2 SD). Two patients had hormone receptor (HR)-positive disease and 5 had HR-negative mBC. Treatment with ARX788 remains ongoing with the median time of ARX788 therapy of 4.5 months. The confirmed ORR was 57.1% (4/7 pts) and an unconfirmed ORR of 71.4% (5/7 pts) as one pt experienced an unconfirmed response with PR after 2 cycles. The disease control rate (DCR) was 100% (7/7 pts). No drug-related grade ≥3 AEs were reported; 57.1% (4/7 pts) reported ocular AEs including grade 1 events in 3 pts (i.e., dry eye, blurred vision) and a grade 2 event in one pt (lagophthalmos). No pneumonitis or ILD was observed. ARX788 was well-tolerated, and AEs were manageable.
Conclusion: In this small cohort of patients previously treated with T-DM1, ARX788 had a manageable AE profile and demonstrated promising clinical activity (confirmed ORR 57%; DCR 100%).
Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1
ARX788 demonstrated promising clinical activity in patients previously treated with T-DM1.
Citation Format: Sara Hurvitz, Kevin Kalinsky, Vinod Ganju, Kashif Ali, Laila Agrawal, William Gradishar, George Sledge, Anu Thummala, Arlene Chan, Sophia Frentzas, Joo Hyuk Sohn, Kyong-Hwa Park, Keon Uk Park, Catherine Shannon, Joshua Drago, Sara Tolaney, Hope Rugo, Michael F. Press, Alex Alika, Dong Xu, Janice Lu, Debu Tripathy. ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-09.