Trastuzumab Rezetecan in ERBB2-Low Advanced Breast Cancer: The HORIZON-Breast06 Randomized Clinical Trial

Trastuzumab rezetecan (SHR-A1811) has demonstrated encouraging antitumor activity in a global phase 1 trial involving heavily pretreated patients with erythroblastic oncogene B (ERBB2)-low metastatic breast…

By Fan, Liu, Wang +27JAMAOct 23, 2026

Score██████░░░░5.5

Key numbers

95% CI
84.1% of patients

VerdictA leading story on any desk.

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Abstract

Importance Trastuzumab rezetecan (SHR-A1811) has demonstrated encouraging antitumor activity in a global phase 1 trial involving heavily pretreated patients with erythroblastic oncogene B (ERBB2)-low metastatic breast cancer. Objective To compare trastuzumab rezetecan vs physician's choice of chemotherapy in patients with ERBB2-low metastatic breast cancer. Design, setting, and participants This open-label, randomized, multicenter phase 3 trial was conducted at 73 hospitals across China. Eligible patients were females aged 18 to 75 years with centrally confirmed ERBB2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridization [ISH]-negative) unresectable locally recurrent or metastatic breast cancer who had received 1 or fewer prior lines of chemotherapy for metastatic disease, with prior endocrine therapy required for hormone receptor-positive disease. Enrollment began on June 30, 2023, and ended on August 20, 2025. The last day of follow-up for the final analysis for progression-free survival in the current study was March 20, 2026. Interventions Patients were randomly assigned (1:1) to receive trastuzumab rezetecan (6.4 mg/kg intravenously every 3 weeks; n = 277) or physician's choice of chemotherapy (n = 274). Main outcomes and measures The primary end point was progression-free survival assessed by blinded independent central review in chemotherapy-naive patients and the overall population. Results Between June 30, 2023, and August 20, 2025, a total of 551 patients were randomized, with a mean (SD) age of 54.9 (9.9) years. At the data cutoff (March 20, 2026), trastuzumab rezetecan significantly prolonged progression-free survival compared with chemotherapy in the chemotherapy-naive patients (median, 16.6 [95% CI, 14.0-19.4] months vs 6.8 [95% CI, 5.7-7.0] months; hazard ratio, 0.25 [95% CI, 0.19-0.33]; P < .001) and the overall population (median, 16.4 [95% CI, 14.0-16.8] months vs 6.8 [95% CI, 5.7-6.9] months; hazard ratio, 0.27 [95% CI, 0.21-0.34]; P < .001). The benefit was consistent in hormone receptor-negative disease (median progression-free survival: 16.5 vs 6.8 months; hazard ratio, 0.34, [95% CI, 0.22-0.54]) and hormone receptor-positive disease (median progression-free survival: 16.4 vs 6.7 months; hazard ratio, 0.24 [95% CI, 0.18-0.33]). Grade 3 or greater treatment-related adverse events occurred in 84.1% of patients (232/276) with trastuzumab rezetecan and 67.9% (184/271) with chemotherapy, most commonly decreased neutrophil count (180 [65.2%] vs 147 [54.2%]). Conclusions and relevance Trastuzumab rezetecan provided significant progression-free survival benefit over physician's choice of chemotherapy in patients with ERBB2-low advanced breast cancer, with benefit observed across all key subgroups. It exhibited the potential as a new treatment option with a distinct safety profile in this setting. Trial registration ClinicalTrials.gov Identifier: NCT05814354.

Ying Fan, Yunjiang Liu, Yongsheng Wang, Quchang Ouyang, Qingyuan Zhang, Jiuwei Cui, Jingruo Li, Qiang Ding, Xinhong Wu, Xiaojia Wang, Zhongsheng Tong, Yinduo Zeng, Wenhui Wang, Min Yan, Yili Wang, Xiaoyu Liu, Kai Li, Zhengkui Sun, Chunxiu Yuan, Ting Wang, Weimin Xie, Jing Yao, Shoubing Zhou, Jialin Hou, Zhong Ouyang, Yijing Li, Sisi Cui, Xia Zhang, Xiaoyu Zhu, Binghe Xu

The editor's rubric

Heuristic review

Leverage2 / 5: Reusable within one subfield (a technique, dataset, or protocol a few groups will adopt).; 10% of this desk’s rubric
Magnitude4 / 5: A qualitative jump: a capability or regime that did not exist before.; 20% of this desk’s rubric
Evidence5 / 5: Definitive: phase 3 randomized evidence on hard endpoints, multi-lab replication, or community verification at scale.; 32% of this desk’s rubric
Novelty3 / 5: A genuinely new approach to an open problem.; 8% of this desk’s rubric
Trajectory2 / 5: Some room to improve with obvious engineering.; 5% of this desk’s rubric
Stakes4 / 5: Large-scale human impact: millions of people, or a major industry.; 25% of this desk’s rubric

Dimension	Level	Weight	What that level means
Leverage	██░░░2/5	10%	Reusable within one subfield (a technique, dataset, or protocol a few groups will adopt).
Magnitude	████░4/5	20%	A qualitative jump: a capability or regime that did not exist before.
Evidence	█████5/5	32%	Definitive: phase 3 randomized evidence on hard endpoints, multi-lab replication, or community verification at scale.
Novelty	███░░3/5	8%	A genuinely new approach to an open problem.
Trajectory	██░░░2/5	5%	Some room to improve with obvious engineering.
Stakes	████░4/5	25%	Large-scale human impact: millions of people, or a major industry.

Editor’s rationale

Heuristic triage from title and abstract text only, not a reading of the paper. Cues found: gains (versus baseline, efficacy); novelty (open problem); design (randomized, blinded, phase 3); verification (confidence interval, p-value, independent replication); stakes (global scale, mortality, major disease).

How the score was computed

rank-2026-10-18

Score██████░░░░5.5

Score = 10 × (80% × adjusted merit / 10 + 10% × attention + 10% × freshness)

Desks place stronger verdicts first, then use this score to order work within the same verdict.

Merit: 7.9 / 10; Weighted rubric, evidence-gated.
Adjusted merit: 5.9 / 10; Shrunk toward the desk prior by editor confidence (50%).
Attention: 0%; Citations, upvotes, points, mentions.
Freshness: 80%; Half-life decay since publication.

Citations0 (reference 20, via openalex, Oct 26, 2026, 06:17 UTC)

The record

Reviewed by heuristic-v10 on Oct 26, 2026, 06:17 UTC. Paper type: clinical.
Categories: Journal Article
LEAD, No.1 in the Front page edition of October 26, 2026.
LEAD, No.1 in the Medicine edition of October 26, 2026.