Editor's Note: The 2024 American Society of Clinical Oncology (ASCO) Annual Meeting concluded successfully. At this conference, two studies from Professor Xichun Hu’s team at Fudan University Shanghai Cancer Hospital were featured as a rapid oral report and a poster display. The studies are titled "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)" (Abstract 1020) and "LEONARDA-2: Lerociclib plus letrozole versus placebo plus letrozole in HR+/HER2- advanced or metastatic breast cancer" (Abstract 1052). "Oncology Frontier" invited Professor Xichun Hu to introduce the background and latest data of these studies at the conference.Study : ACE-Breast-02 (Abstract 1020)
ARX788 is a novel anti-HER2 ADC that conjugates to the potent cytotoxic microtubule inhibitor Amberstatin 269 at specific sites. At the 2024 ASCO conference, we reported interim results of the seamless phase II/III trial (ACE-Breast-02) in patients progressing on trastuzumab-based treatment.
ACE-Breast-02 was conducted at 85 centers in China, targeting HER2+ (FISH+ or IHC3+) advanced breast cancer (ABC) patients. Unresectable or metastatic breast cancer patients previously treated with trastuzumab and taxanes were randomized 1:1 to receive ARX788 (1.5 mg/kg IV every three weeks) or lapatinib plus capecitabine (LC, lapatinib 1250 mg daily; capecitabine 1000 mg/m² twice daily on days 1-14 every three weeks), stratified by prior lines of chemotherapy (0-1 vs. >1) and visceral metastases (yes vs. no). No prophylactic measures were taken before ARX788 administration. The primary endpoint was PFS assessed by BIRC.
As of December 21, 2022, 221 patients were randomized to ARX788, and 220 to LC, with 240 PFS events reported. With a median follow-up of 11.14 months, ARX788 showed a median PFS of 11.33 months versus 8.25 months for LC (HR 0.64, P=0.0006).
TRAEs of any grade occurred in 98.6% (217/220) and 99.1% (213/215) of patients, respectively. Grade 3-5 TRAEs were similar (41.4% vs. 40.0%), with the most common ARX788-related TRAEs being blurred vision (12.3%), dry eye (9.1%), keratopathy (5.9%), and interstitial lung disease (5.9%). LC-related TRAEs included hand-foot syndrome (18.1%), hypokalemia (5.1%), and diarrhea (4.2%).
Interstitial lung disease occurred in 71 patients (32.3%) treated with ARX788, mainly grade 1 or 2 (26.8%), with three (1.4%) possible drug-related deaths. ARX788-related ocular events were reported in 164 patients (74.5%), mainly grade 1 or 2 (55.5%), with no grade 4 or 5 events.
Researcher Commentary: Professor Xichun Hu:
At this year’s ASCO conference, our team’s study was selected for a rapid oral report (Abstract 1020: ACE-Breast-02: A pivotal phase II/III trial of ARX788, a novel anti-HER2 antibody-drug conjugate, versus lapatinib plus capecitabine for HER2+ advanced breast cancer). ARX788 is a novel anti-HER2 ADC that conjugates Amberstatin 269, a potent cytotoxic microtubule inhibitor, at specific sites, maintaining a stable drug-to-antibody ratio (DAR) of around 2.
Phase I clinical trial results of ARX788 in advanced breast cancer showed good therapeutic efficacy for HER2-positive breast cancer patients, with an ORR of 65.5% and a median PFS of 17.02 months at the recommended dose of 1.5 mg/kg every three weeks. At this conference, we reported the interim results of the seamless phase II/III trial in patients progressing on trastuzumab-based treatment.
In this study, we initially enrolled 160 patients and evaluated the feasibility of continuing recruitment after patient visits at the fourth cycle, ultimately enrolling 441 patients. The results showed a median PFS of 11.33 months for the ARX788 group compared to 8.25 months for the LC group (HR 0.64, P=0.0006). This indicates that ARX788 can reduce the risk of disease progression by 36% in HER2-positive advanced breast cancer patients. When designing this clinical trial, the standard second-line treatment for HER2-positive advanced breast cancer patients in China was capecitabine plus lapatinib. However, with changing treatment protocols, this is no longer the standard treatment, which partly explains why our trial received a rapid oral report rather than a full oral presentation.
ARX788 employs new technology, resulting in very low free drug concentration in the blood, leading to lower gastrointestinal and hematologic toxicity compared to other ADCs. Moreover, no prophylactic measures (e.g., antiemetic drugs) are required before its use. The most common toxicity is liver toxicity, but the severity is generally low. Special attention should be given to interstitial lung disease, primarily occurring after four months of treatment, but it is generally preventable and controllable. Ocular toxicity appears earlier (within three months), so early patient education on ocular toxicity is essential.
