Oncology · Medical Literature
[Articles] Trastuzumab rezetecan versus pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer (HORIZON-Breast01): interim analysis of a multicentre, open-label, randomised, controlled, phase 3 trial
Abstract
Trastuzumab rezetecan improved progression-free survival versus pyrotinib plus capecitabine and showed a distinct safety profile in patients with HER2-positive breast cancer, presenting as a potential new treatment option.
Clinical relevance
In patients with HER2-positive unresectable or metastatic breast cancer who have previously received trastuzumab and a taxane, does the HER2-directed antibody-drug conjugate trastuzumab rezetecan improve progression-free survival compared with the current standard-of-care regimen of pyrotinib plus capecitabine? __SNAPSHOT__ {"studyDesign":"Randomized controlled trial — multicentre, open-label, phase 3 trial (prespecified interim analysis)","setting":"50 hospitals in China","sampleSize":"n=287 (trastuzumab rezetecan: n=142; pyrotinib plus capecitabine: n=145); 414 screened, 127 ineligible","population":"Adult women (all 287 patients female) aged 18–75 years with histologically confirmed HER2-positive unresectable or metastatic breast cancer; prior taxane and trastuzumab at the advanced stage OR disease progression within 12 months of (neo)adjuvant anti-HER2 monoclonal antibody plus taxane-based therapy; measurable disease; ECOG performance status 0 or 1. Median age 55.0 years (IQR 49.0–60.0); 93% Han Chinese. Approximately 75% had IHC 3+ HER2 status; ~47% had hormone receptor-positive disease; ~75% had visceral metastases; ~47% had more than 3 organs involved. Median prior lines of therapy: 1 (range 1–4); ~80% had received 1 prior line. Approximately 75% had received prior pertuzumab; ~5% had prior T-DM1. Approximately 40–45% had primary trastuzumab resistance.","intervention":"Trastuzumab rezetecan (SHR-A1811) 4.8 mg/kg IV on day 1 of each 21-day cycle. Note: a protocol amendment transiently permitted a 6.4 mg/kg dose (November 29, 2022 – July 12, 2023); the primary analysis focuses on the 4.8 mg/kg cohort.","comparator":"Pyrotinib 400 mg orally once daily continuously plus capecitabine 1000 mg/m² orally twice daily on days 1–14 of each 21-day cycle","primaryOutcome":"Progression-free survival (PFS) per blinded independent central review (BICR) in the modified intention-to-treat population 1","followUp":"Median follow-up 15.0 months (IQR 12.9–18.5) for trastuzumab rezetecan arm; 13.9 months (IQR 11.4–17.8) for control arm; data cutoff June 30, 2025","fundingSource":"Industry (Jiangsu Hengrui Pharmaceuticals; employees listed as co-authors on the trial publication)"}
Key findings
At the prespecified interim analysis (data cutoff June 30, 2025), 124 PFS events had occurred (37 [26%] in the trastuzumab rezetecan arm vs. 87 [60%] in the control arm). The median PFS by BICR was 30.6 months (95% CI 16.8–not reached) with trastuzumab rezetecan versus 8.3 months (95% CI 6.9–11.0) with pyrotinib plus capecitabine (HR 0.22, 95% CI 0.15–0.34; p<0.0001), representing a 78% relative risk reduction in disease progression or death. The 12-month PFS rate was 84.7% (95% CI 77.0–90.0) versus 35.5% (95% CI 26.8–44.2). Investigator-assessed PFS was concordant: 33.3 months versus 8.1 months (HR 0.16, 95% CI 0.10–0.25). The absolute PFS difference at the median was approximately 22.3 months (calculated). The objective response rate (ORR) was 81.7% versus 55.9%; complete response 4.2% versus 2.8%; partial response 77.5% versus 53.1%. Median duration of response was 27.8 versus 10.9 months. Disease control rate was 95.0% versus 86.9%. Overall survival data were immature at the time of this interim analysis; investigators reported a 'strong trend' favoring trastuzumab rezetecan, with 50.3% of control-arm patients receiving a post-study anti-HER2 ADC, which may confound any OS signal. Regarding safety, grade ≥3 treatment-related adverse events were predominantly hematologic with trastuzumab rezetecan: decreased neutrophil count (54% vs. 9%), decreased white blood cell count (20% vs. 3%), and decreased platelet count (11% vs. 1%). Treatment-related serious adverse events were similar between arms (13% vs. 12%). Interstitial lung disease (ILD) occurred in 4 (3%) patients receiving trastuzumab rezetecan. Two fatal adverse events were reported: one septic shock deemed unrelated to trastuzumab rezetecan and one death of unknown cause attributed to the pyrotinib-capecitabine regimen. Median treatment duration was 19.5 months for trastuzumab rezetecan versus 7.1 months for pyrotinib and 7.5 months for capecitabine. NNT for prevention of one PFS event at 12 months (calculated): 1 / (0.847 – 0.355) ≈ 2.0 (calculated).
Practice implications
HORIZON-Breast01 demonstrates a statistically significant and numerically large PFS benefit for trastuzumab rezetecan over pyrotinib plus capecitabine in patients with previously treated HER2-positive metastatic breast cancer. The magnitude of benefit—a greater than 3.5-fold difference in median PFS and an HR of 0.22—is clinically striking and consistent across BICR and investigator assessment. However, several important limitations bear on interpretation. First, this is a prespecified interim analysis, not final trial data, and the upper confidence bound of the median PFS in the experimental arm has not yet been reached (median PFS 30.6 months, upper CI not reached). Second, overall survival data are immature and cannot be interpreted at this time, particularly given that more than half of control-arm patients received a post-study anti-HER2 ADC, which could dilute any OS advantage. Third, the comparator (pyrotinib plus capecitabine) is a China-specific standard of care; in many Western countries, trastuzumab emtansine (T-DM1) or trastuzumab deruxtecan (T-DXd) would represent the relevant second-line comparators—a critical generalizability gap. Fourth, the trial was conducted exclusively in Chinese patients (all women; 100% Chinese ethnicity), limiting extrapolation to other populations and precluding conclusions about sex differences or racial/ethnic heterogeneity. Fifth, only ~5% of patients had prior T-DM1 exposure, so the positioning of trastuzumab rezetecan relative to T-DXd and T-DM1 in international practice remains undefined. The safety profile of trastuzumab rezetecan features significant hematologic toxicity requiring careful monitoring, and ILD—though present in only 3%—requires vigilance given its serious potential with HER2-targeted ADCs. Trastuzumab rezetecan is not currently approved outside China (where it has Breakthrough Therapy Designation in HER2-positive breast cancer), and this trial's applicability to clinical practice in regions where pyrotinib is not an approved standard is limited. Importantly, only the abstract was available for this summary, and full-text review of the complete dataset (subgroup analyses, patient-reported outcomes, pharmacokinetics, and mature OS data) is required before definitive conclusions can be drawn. __LIMITATIONS__ Interim analysis only — PFS upper confidence interval not yet reached; final data pending.,Overall survival immature and uninterpretable at this data cutoff; high crossover rate (50.3% of control patients received post-study anti-HER2 ADC) will likely confound OS analysis.,Open-label design — cannot exclude assessment bias in investigator-reported outcomes, though BICR mitigates this for the primary endpoint.,Exclusively Chinese patient population (100% Chinese ethnicity, all female) — limits generalizability to other racial/ethnic groups and geographic populations.,Comparator (pyrotinib plus capecitabine) is not standard of care in most Western countries; this was not a head-to-head comparison versus T-DXd or T-DM1.,Low prior T-DM1 exposure (~5%) and no T-DXd exposure, meaning this trial does not inform sequencing in post-T-DXd settings.,Protocol amendment introduced a temporary dose modification (6.4 mg/kg); primary analysis focuses on 4.8 mg/kg group, but this adds complexity to the overall safety and efficacy dataset.,Industry-sponsored trial with Jiangsu Hengrui Pharmaceuticals employees as co-authors — potential for reporting bias.,Relatively short median follow-up (~15 months) relative to a 30.6-month median PFS estimate in the experimental arm — the PFS estimate is therefore based on a minority of events in the experimental arm and remains immature.,PFS is a surrogate endpoint; no quality-of-life or patient-reported outcome data are reported in the abstract.,Only the published abstract was available for this review; detailed subgroup, multivariate, and toxicity analyses from the full text could not be assessed. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ In previously treated HER2-positive metastatic breast cancer in a Chinese patient population, trastuzumab rezetecan demonstrated a large and statistically significant PFS benefit over pyrotinib plus capecitabine (median 30.6 vs. 8.3 months; HR 0.22), with hematologic toxicity as the dominant safety signal and a 3% rate of ILD. These results are clinically compelling in the context where pyrotinib is standard of care, but generalizability is substantially constrained by the China-exclusive population, an active comparator not used globally, immature OS data, and the absence of comparison with T-DXd or T-DM1; international practice change awaits confirmation in broader populations and clarification of optimal sequencing.