New ADCs Aim to Strengthen the HER2+ Breast Cancer Paradigm and Join T-DXd and T-DM1

Joyce O’Shaughnessy, MD

The next-generation antibody-drug conjugate (ADC) ARX788 generated excitement when it received fast track designation from the FDA for patients with HER2-positive metastatic breast cancer and again when it yielded a significant improvement in progression-free survival (PFS) vs lapatinib (Tykerb) plus capecitabine and showed a trend toward overall survival (OS) improvement.1,2

Differing from the topoisomerase I inhibitor payload of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), ARX788 has an AS269 payload site specifically conjugated to the antibody.1,3 The drug is under investigation in the phase 2 ACE-Breast-03 trial (NCT04829604) in patients who previously received T-DXd.4

“ARX788 is in active development, and phase 2 data [from the phase 2/3 ACE-Breast-02 study (CTR20201708) showed] it’s a highly active anti-HER2–directed therapy. It has a microtubule inhibitor payload and has [not only shown] activity against HER2-amplified disease but also HER2-low disease,” Joyce O’Shaughnessy, MD, said in an interview with OncologyLive.

In ACE-Breast-02, patients with metastatic or locally advanced HER2-positive disease who received prior therapy with trastuzumab (Herceptin) and a taxane achieved a median PFS of 11.33 months (95% CI, 8.44- 13.83) by blinded independent central review when treated with ARX788 (n = 221) vs 8.25 months (95% CI, 6.93-8.71) among those given lapatinib plus capecitabine (n = 220; HR, 0.64; 95% CI, 0.49-0.82; stratified log-rank P = .0006).1 At 18.6% maturity, with a median follow-up of 14.23 months, the preliminary OS analysis revealed that the median OS was not reached (NR; 95% CI, NR-NR) in the ARX788 arm vs NR (95% CI, 23.59-NR) in the chemotherapy arm (HR, 0.71; 95% CI, 0.46-1.10).

Keeping a Close Eye on Ocular Toxicities and ILD

“[ARX788] has good tolerability, [although] it can cause interstitial lung disease [ILD], so we have to be aware of that as we are for T-DXd. It’s been able to help patients [in a] late-line [setting]. It’s a very exciting, active, and safe [agent],” O’Shaughnessy said.

In ACE-Breast-02, 6 patients (2.7%) experienced fatal treatment-related adverse effects (TRAEs), which included ILD (n=3), pneumonitis (n=1), and respiratory failure (n = 2); 1 patient with ILD and 1 patient with respiratory failure also had a lung infection.

Additionally, treatment-emergent AEs (TEAEs) in the investigative vs control arm led to dose reduction (23.6% vs 37.7%), dose interruption (67.3% vs 50.7%), treatment discontinuation (6.8% vs 1.9%), and death (5.0% vs 3.7%). The most common grade 3 or higher TRAEs were blurred vision (12.3% vs 0.0%), dry eye (9.1% vs 0.0%), keratopathy (5.9% vs 0.0%), and ILD (5.9% vs 0.0%), respectively.

“For dry eye, the over-the-counter refresh moisturizing eye drops [are] recommended. One drop [can be given] 3 to 4 times a day [to] preventively avoid the eyes getting dried out,” O’Shaughnessy said. “Sometimes patients must have a dose reduction, and that tends to help. It’s rare for patients to have inflammation of the cornea or anything like that from dry eyes getting bad. We will send the patient to an ophthalmologist if they need to go, but most do fine with the eye drops and then a dose reduction if they need one.”

Certain newer ADCs are no exception to having ocular AEs, as the toxicities remain prevalent with the drug class. Data from the phase 3 TULIP trial (NCT03262935) showed that despite a statistically significant improvement in PFS observed with the ADC vic-trastuzumab duocarmazine (SYD985; n = 291) vs physician’s choice of therapy (n = 146), 78.1% of patients treated with the ADC experienced ocular AEs.5

Treatment discontinuation rates in the study were 35.4% vs 5.8%, respectively, and 20.8% of patients discontinued trastuzumab duocarmazine due to ocular toxicities. The recovery rates of grade 3 or higher keratitis, conjunctivitis, and dry eye were 80.5%, 94%, and 58% in the investigative arm, respectively.

“[The drug] unfortunately did not lead to FDA approval, because although it had some improvement over standard chemotherapy plus trastuzumab regarding PFS, it had eye toxicity and ILD and some deaths from [pneumonitis]. [Therefore], it did not receive regulatory approval because of the toxicity, so that’s not going to [move] further in development,” O’Shaughnessy noted.

Battle of the ADCs: T-DXd vs T-DM1

The role of ADCs continues to evolve in the HER2-positive space, and data are expected soon from the phase 3 DESTINY-Breast05 trial (NCT04622319) examining T-DXd vs ado-trastuzumab emtansine (T-DM1; Kadcyla), which O’Shaughnessy noted could change standard of care.6 To dive deeper into the evolving paradigm, join O’Shaughnessy as she chairs the 24th Annual International Congress on the Future of Breast Cancer® (IBC) occurring on the east coast in New York, New York, from July 11 to 12, 2025.7

For additional crucial conversations on the study and new data surrounding this drug class, the conference will also be occurring on the west coast in San Diego, California, from July 18 to 19, 2025, where Sara Hurvitz, MD, FACP, will join O’Shaughnessy as cochair.8

“By the time we get to IBC East/West...[for] HER2-positive breast cancer in the curative setting, we may have the DESTINY-Breast05 data. It may be that T-DXd is going to be better than T-DM1 in patients who have residual disease after preoperative chemotherapy and trastuzumab/ pertuzumab [Perjeta]. That would be a major change. Then we’ll hopefully see first-line T-DXd [data] in the phase 3 DESTINY-Breast09 trial [NCT04784715]—that could be absolutely practice changing as well [if results are positive]. There may be a lot to talk about at the IBC conferences with HER2-positive breast cancer.”