Cross Currents: New Frontiers in ADC Therapy for Breast Cancer

"I do hope that we reach a point where these trials can lead to an approval not just in China but also elsewhere; that we can harmonize the way trials are conducted [and] supervised so that, for instance, the FDA and EMA can be informed by Chinese trials."

In a 3-part joint interview recorded at the 2026 ESMO Congress, Paolo Tarantino, MD, PhD, of the Breast Oncology Program at Dana-Farber Cancer Institute and Harvard Medical School, and Ying Fan, MD, of the Cancer Hospital, Chinese Academy of Medical Sciences, discussed emerging antibody-drug conjugates (ADCs) for patients with HER2-low and hormone receptor (HR)–positive, HER2-negative advanced breast cancer.

The discussion is part of Cross Currents: Where East Meets West in Cancer Care, a video series produced through a collaboration between OncLive and China-based digital health platform DXY. In Cross Currents, oncologists from the United States and China compare clinical practice in their regions and discuss key data from major meetings.

At the 2026 ESMO Congress, Fan presented results from the phase 3 HORIZON-Breast06 trial, which compared trastuzumab rezetecan (SHR-A1811), a HER2-directed ADC with a topoisomerase I inhibitor payload, with physician’s choice of chemotherapy in 551 patients with HER2-low advanced breast cancer at 73 centers in China, most of whom had not received chemotherapy for metastatic disease.

The median progression-free survival (PFS) by blinded independent central review was 16.4 versus 6.8 months (HR, 0.27; 95% CI, 0.21-0.34; P < .0001), and the benefit was consistent in patients with HR-negative disease (16.5 vs 6.8 months; HR, 0.34; 95% CI, 0.22-0.54). Grade 3 or higher treatment-related adverse effects (TRAEs) occurred in 84.1% versus 67.9% of patients.

Also at the meeting, the phase 3 PANKU-Breast01 trial (NCT06343948) showed that izalontamab brengitecan (iza-bren), a bispecific EGFR × HER3 ADC, improved median PFS versus physician’s choice of chemotherapy in 383 patients in China with HR-positive, HER2-negative advanced breast cancer previously treated with endocrine therapy and 1 or 2 lines of chemotherapy (8.2 vs 4.0 months; HR, 0.41; 95% CI, 0.33-0.53; P< .0001). The objective response rate (ORR) was 40.5% versus 20.2%, and grade ≥3 TRAEs occurred in 85.3% versus 65.8% of patients.

In part 1, Tarantino noted that HER2-low disease accounts for most cases of HR-positive metastatic breast cancer and a substantial share of triple-negative disease. In the United States, patients with HR-positive disease receive endocrine therapy plus a CDK4/6 inhibitor first; HER2-low expression becomes a relevant target once disease is endocrine refractory. At that point, fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) has improved PFS versus chemotherapy in both the chemotherapy-naive setting, in the phase 3 DESTINY-Breast06 trial (NCT04494425), and the pretreated setting, in the phase 3 DESTINY-Breast04 trial (NCT03734029), which also showed an OS benefit.

Tarantino said T-DXd is given either immediately after endocrine therapy for patients with more aggressive disease or after chemotherapy, and he highlighted the emergence of additional topoisomerase I inhibitor–based ADCs, many developed in China.

Fan described a similar approach in China, where patients who progress on a CDK4/6 inhibitor may receive fulvestrant plus capivasertib (Truqap) if they have a relevant genomic alteration; otherwise, most receive chemotherapy followed by T-DXd, because the indication supported by DESTINY-Breast06 was only recently approved in China. For triple-negative disease, she noted that pembrolizumab (Keytruda) is not approved in this setting in China; patients with PD-L1–positive disease receive a taxane plus the domestic PD-1 inhibitor toripalimab, those with PD-L1–negative disease receive chemotherapy alone, and sacituzumab tirumotecan (sac-TMT) is approved for later lines.

In part 2, Fan explained that her team focused HORIZON-Breast06 on patients who had not received chemotherapy because DESTINY-Breast06 data were expected first. She said she is confident trastuzumab rezetecan will be approved in China for HR-positive disease after endocrine resistance but is less certain about HR-negative disease, because that subgroup was small and the trial was not powered for it, even though she described the PFS as unlike any she had seen in triple-negative breast cancer.

Tarantino argued for approval in both groups, noting that the DESTINY-Breast04 approval rested in part on a small exploratory cohort of patients with triple-negative disease, and that trastuzumab rezetecan and sac-TMT have different adverse effect profiles and are not interchangeable.

The pair then turned to previously treated HR-positive disease, where Tarantino identified ADC sequencing as the biggest challenge: after progression on one topoisomerase I inhibitor–based ADC, a second ADC with the same payload class is usually less effective. Fan agreed, noting that she has seen limited efficacy when switching to an ADC with a different target but the same payload, and that many ADCs in development in China, including bispecific agents, also carry topoisomerase I inhibitor payloads. Her group is evaluating dual-payload anti-HER2 ADCs after progression on T-DXd or trastuzumab rezetecan.

Tarantino added that disitamab vedotin, an ADC with a monomethyl auristatin E payload, offers a different payload option in China, where it is approved, although Fan noted its efficacy is more modest.

In part 3, Tarantino reviewed the rationale for iza-bren: a topoisomerase I inhibitor payload, a short half-life, and dual targeting of EGFR and HER3, which are overexpressed in tumors relative to healthy tissue, with preclinical data suggesting the bispecific design enhances internalization. He said the PANKU-Breast01 efficacy data are promising but that the hematologic toxicity profile will need to be managed with prophylaxis, growth factor support, or dose optimization.

The conversation closed on collaboration. Tarantino described Chinese and Western drug development as complementary and pointed to a growing number of licensing deals. Fan noted that only some Chinese agents have been licensed abroad, that Chinese companies often lack the scale to fund trials outside China, and that exporting biospecimens can be difficult. Tarantino called for harmonizing how trials are conducted and supervised so that regulators such as the FDA and the European Medicines Agency can draw on Chinese data, and Fan suggested bridging trials as an alternative to repeating full global studies for agents already approved in China.