The HER2-targeted antibody-drug conjugate (ADC) trastuzumab rezetecan more than doubled progression-free survival compared with standard chemotherapy in patients with HER2-low advanced breast cancer in the phase 3 HORIZON-Breast06 trial.

Median progression-free survival was 16.4 months with the ADC vs 6.8 months with chemotherapy, representing a 73% reduction in the risk for disease progression or death.

Hematologic toxicity was more common with trastuzumab rezetecan, however, and patients frequently required dose modifications. The incidence of interstitial lung disease (ILD), an important safety concern with HER2-directed ADCs, was low.

Ying Fan, MD, of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, China, presented the results at the European Society for Medical Oncology (ESMO) 2026 annual meeting, being held in Madrid. 

The findings position trastuzumab rezetecan as an “effective new treatment option” for this patient population, the researchers concluded in a paper simultaneously published in JAMA.

However, questions remain about how the ADC would fit into a crowded treatment landscape, particularly alongside the widely approved trastuzumab deruxtecan (T-DXd, Enhertu).

“There is currently no evidence to guide how to integrate these two ADCs,” Maria Fernanda Mosele, MD, and Fabrice André, MD, PhD, of Gustave Roussy in Villejuif, France, wrote in an accompanying editorial.

HORIZON-Breast06 Results

Compared with T-DXd, trastuzumab rezetecan has a topoisomerase I inhibitor payload that has shown greater potency and membrane permeability in preclinical studies. It’s approved in China for several HER2-driven cancers, including HER2-positive advanced breast cancer, but remains investigational for HER2-low breast cancer and is not approved in the United States or European Union.

HORIZON-Breast06 was an open-label, randomized phase 3 trial involving 551 women with HER2-low unresectable or metastatic breast cancer at 73 centers in China. Patients had received no more than one prior line of chemotherapy for metastatic disease, and those with hormone receptor (HR)-positive disease had previously received endocrine therapy.

Patients received trastuzumab rezetecan, 6.4 mg/kg IV every 3 weeks, or physician’s choice of chemotherapy (taxanes, eribulin, capecitabine, or gemcitabine). About 73% had HR-positive disease, and 82% had not previously received chemotherapy for metastatic disease. Median follow-up was 16.5 months with trastuzumab rezetecan and 14.9 months with chemotherapy. 

The trial met both primary endpoints. Among chemotherapy-naive patients, median progression-free survival was 16.6 months with trastuzumab rezetecan vs 6.8 months with chemotherapy (hazard ratio [HR], 0.25; 95% CI, 0.19-0.33; P < .001). In the overall population, median progression-free survival was nearly identical, at 16.4 vs 6.8 months (HR, 0.27; 95% CI, 0.21-0.34; P < .001).

The benefit was also consistent across subgroups, including patients with HR-positive disease and HR-negative disease, in exploratory analyses.

Objective response rates favored the ADC (75.5% vs 41.2% with chemo), with median response durations of 15 vs 6.8 months. 

Overall survival data remain immature, Fan said. At data cutoff, 23.8% of patients receiving trastuzumab rezetecan had died vs 28.1% receiving chemotherapy. Estimated 12-month overall survival rates were 90.6% and 81.4%, respectively (HR, 0.67; 95% CI, 0.48-0.94), in a descriptive analysis.

Safety and Clinical Positioning

The progression-free survival advantage with the ADC came at the cost of greater hematologic toxicity. Grade 3 or higher treatment-related adverse events occurred in 84.1% of patients receiving trastuzumab rezetecan vs 67.9% receiving chemotherapy.

The most common severe events included neutropenia (65.2% vs 54.2%), decreased white blood cell count (56.5% vs 35.4%), and anemia (42.8% vs 4.8%). 

Those events led to dose reductions in 50.4% vs 29.2% of patients, respectively, and discontinuation in 8.7% vs 6.3%. ILD occurred in 2.5% of trastuzumab rezetecan recipients, including three cases of grade 3 or 4 disease, with no ILD-related deaths.

Mosele and André noted in their editorial that the observed ILD incidence was lower than the 12%-15% reported with T-DXd in comparable settings — although hematologic and hepatic toxicities appear to be more common with trastuzumab rezetecan in indirect comparisons.

The clinical benefit with trastuzumab rezetecan, meanwhile, falls within the same range as that reported with T-DXd, the editorialists pointed out. T-DXd is, therefore, likely to remain the preferred option where it’s approved – although trastuzumab rezetecan could provide an alternative where T-DXd is unavailable, they wrote. 

Mosele and André also cautioned that because both ADCs target HER2 and carry topoisomerase I inhibitor payloads, overlapping resistance mechanisms are possible, potentially limiting the benefit of using them sequentially. 

Other limitations include the trial’s relatively short follow-up, immature survival data, and the trial’s exclusive enrollment of patients in China.

Another ADC Shows Promise

During the same ESMO session, Shusen Wang, MD, from Sun Yat-sen University Cancer Center in Guangzhou, China, presented primary results from the phase 3 APEX-Breast01 trial.

That trial investigated rolditamig deuderuxtecan (TQB2102), a potentially first-in-class biparatopic HER2-targeted ADC designed to enhance drug internalization and delivery. It enrolled 543 patients with HER2-low recurrent or metastatic breast cancer and no prior chemotherapy in the recurrent or metastatic setting. Patients were randomly assigned to TQB2102 or physician’s choice of chemotherapy.

Among patients with HR-positive disease, the primary endpoint population, median progression-free survival was 16.4 months with the ADC vs 5.5 months with chemotherapy (HR, 0.29; P < .0001). That benefit was consistent in the overall HER2-low population, at 16.4 vs 5.5 months (HR, 0.29; P < .0001).

Overall survival data were immature, though there was a “clear trend” toward improved survival with the ADC, Wang reported. 

Grade 3 or higher treatment-related adverse events occurred in 69.1% of patients receiving TQB2102 vs 42.4% receiving chemotherapy, primarily reflecting hematologic toxicity. ILD occurred in 2.2% of ADC recipients, including three grade 3 cases, with no related deaths.

A Crowded Field 

Discussing both trials, Barbara Pistilli, MD, of Gustave Roussy, echoed some of the JAMA editorialists’ points — including the lack of any direct comparisons against another ADC.

Pistilli noted that the two trial drugs differ from T-DXd in their pharmacologic properties: Trastuzumab rezetecan features a modified topoisomerase I inhibitor payload, while TQB2102 uses a biparatopic antibody designed to enhance HER2 binding, internalization, and drug delivery. But the clinical significance remains to be seen.

“Do these pharmacological differences translate into clinically meaningful advantages as compared to approved ADCs?” Pistilli asked. “The answer is, we don’t know because we don’t have studies with head-to-head ADC comparison in this setting.”

Such comparisons, along with biomarker-driven studies, are needed to identify which patients benefit most from individual ADCs and how best to sequence the growing number of agents, Pistilli said.

HORIZON-Breast06 was sponsored by Jiangsu Hengrui Pharmaceuticals Co, Ltd, and APEX-Breast01 was sponsored by Chia Tai Tianqing Pharmaceutical Group Co, Ltd. 

Fan reported no conflicts of interest. Wang reported financial relationships with AstraZeneca, Daiichi Sankyo, Eli Lilly, and others. Pistilli reported financial relationships with AstraZeneca, Daiichi Sankyo, Lilly, and others. Mosele reported receiving personal fees from Novartis. André reported financial relationships with AstraZeneca, Daiichi Sankyo, Lilly, and others.