ACE-Breast-02: A pivotal phase II/III trial of ARX788, a novel anti-HER2 antibody-drug conjugate (ADC), versus lapatinib plus capecitabine for HER2+ advanced breast cancer (ABC).

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1020 Background: ARX788 is a next-generation ADC of HER2 monoclonal antibody site-specifically conjugated with Amberstatin 269, a potent cytotoxic tubulin inhibitor. Here we report the interim result from this seamless phase II/III trial in patients who progressed on trastuzumab based therapy. Methods: This randomized study was conducted in HER2+ (FISH+ or IHC3+) ABC in 85 centers in China. Patients with unresectable or metastatic breast cancer pretreated with trastuzumab and taxane were randomized 1:1 to receive ARX788 (1.5mg/kg, IV, Q3W) or lapatinib plus capecitabine (LC, lapatinib 1250mg, QD; capecitabine 1000mg/m2 BID, d1-14, Q3W), stratified by previous chemotherapy lines (0-1 vs. >1) and visceral metastasis (yes vs. no). ARX788 was not pre-medicated with any prophylactic measures. Primary endpoint was progress-free survival (PFS) determined by Independent Review Committee (IRC). Results: As of Dec. 21, 2022, 221 patients were randomly assigned to ARX788 and 220 to LC, and 240 PFS events occurred. Efficacy results are listed in table 1. The median PFS was 11.33 months with ARX788 versus 8.25 months with LC as per IRC (HR 0.64, p=0.0006). Treatment-related adverse events (TRAEs) of any grade occurred in 98.6% (217/220) and 99.1% (213/215) of patients, respectively. TRAEs of grade 3-5 was similar in two groups (41.4% and 40.0%, respectively), commonest being blurred vision (12.3%), dry eye (9.1%), keratopathy (5.9%) and interstitial lung disease (5.9%) with ARX788 and hand-foot syndrome (18.1%), hypokalemia (5.1%), diarrhea (4.2%) with LC. 71 patients (32.3%) had interstitial lung disease with ARX788, primarily grade 1 or 2 (26.8%) with 3 (1.4%) possibly having drug-related deaths. 164 patients (74.5%) had ocular events related to ARX788, primarily grade 1 or 2 (55.5%) with no grade 4 or 5. Conclusions: ARX788 significantly prolonged PFS comparing to LC in patients with HER2+ ABC previously treated with trastuzumab and taxane. While ocular toxicity and interstitial lung disease were common and manageable, its hematological and GI toxicities under no prophylactic premedication compared favorably with already available ADCs. Clinical trial information: CTR20201708. [Table: see text]