Results for the ACE-Breast-02 study were presented at the American Society of Clinical Oncology 2024 on 3 June. This randomised trial, conducted across 85 centres in China, compared Ambrx Biopharma’s antibody-drug conjugate (ADC) ARX788 (anvatabart opadotin), a HER2-targeting antibody conjugated to Amberstatin 269 with a non-cleavable linker, to a combination of lapatinib + capecitabine (LC) in patients with metastatic breast cancer (mBC) previously treated with Herceptin (trastuzumab) and chemotherapy.

ARX788 is attempting to enter a crowded field, Enhertu (trastuzumab deruxtecan) is the standard of care in this setting in the US. But in markets such as China, where access is more limited even though it gained an approval in this setting in February 2023, other options such as Kadcyla (trastuzumab emtansine), or HER family-targeting TKIs such as Jiangsu Hengrui Medicine's Irene (pyrotinib), and GSK's Tykerb (lapatinib), are commonly used.

In ACE-Breast-02, ARX788 managed to prolong progression-free survival (PFS) compared to LC, with ARX788 having a PFS of 11.33 months (95% confidence interval [CI]: 8.44, 13.83) and LC having a PFS of 8.25 months (95% CI: 6.93, 8.71) with a hazard ratio (HR) of 0.64 (95% CI: 0.49, 0.82). Grade 3 or higher adverse events (AE) occurred in 41.4% of experimental arm patients and 40% of control arm patients. Comparing these results to those of the EMILIA trial, published in 2012, which resulted in the approval of Kadcyla in mBC, where Kadcyla increased PFS to 9.6 months from 6.4 months with LC (HR: 0.65, 95% CI: 0.55, 0.85), we see a similar HR between these two trials with similar conditions. However, Kadcyla reduced the rate of AEs, Grade 3 or above, from 57% with LC to 41% with Kadcyla. The point of comparing these trials is to show that Ambrx has managed to produce an ADC that is about as effective at treating mBC as Kadcyla.

While the headline results for this trial are positive, the choice of control demonstrates a lack of confidence on behalf of Ambrx that its drug could beat Kadcyla in a head-to-head trial. The choice of control means that a US or European approval will not be possible. At the time ACE-Breast-02 started, a head-to-head trial between Enhertu and Kadcyla was already underway. ARX788 is in a rough spot, while some other HER2-targeting ADCs, such as Pfizer and Remegen’s Aidixi (disitamab vedotin), are in Phase III trials in the same setting with the same control arm (LC), others are in head-to-head trials against Kadcyla, such as Duality Biologics’ DB-1303. When looking at clinical data to decide on treatment algorithms, clinicians will prioritise drugs that have been trialed against more robust control arms, even in more price-sensitive markets such as China.