Editor’s Note At the 2025 San Antonio Breast Cancer Symposium (SABCS 2025), results were presented from a study titled “HER2CLIMB-05: A Randomized, Double-Blind Phase III Study of Tucatinib versus Placebo in Combination with Trastuzumab and Pertuzumab as Maintenance Therapy for HER2-Positive Metastatic Breast Cancer” (Abstract No. GS1-01). This study explored an intensified strategy for first-line maintenance therapy in patients with HER2-positive metastatic breast cancer (HER2+ MBC). Oncology Frontier invited Professor Xiaoyun Mao from The First Hospital of China Medical University to provide a detailed overview and expert commentary on the study, with the aim of optimizing clinical decision-making.Study Overview
Study Title
Chinese Title: 图卡替尼对比安慰剂联合曲妥珠单抗和帕妥珠单抗用于HER2+转移性乳腺癌维持治疗的Ⅲ期随机双盲研究
English Title: A Randomized, Double-Blind, Phase 3 Study of Tucatinib versus Placebo in Combination with Trastuzumab and Pertuzumab as Maintenance Therapy for HER2-Positive Metastatic Breast Cancer
Study Background
For patients with HER2-positive metastatic breast cancer, delaying disease progression and prolonging chemotherapy-free survival remain key clinical goals and ongoing challenges. The current standard of care consists of induction therapy with a taxane plus trastuzumab and pertuzumab (THP), followed by maintenance therapy with trastuzumab and pertuzumab (HP). However, most patients experience disease progression within 1–2 years, and some are unable to tolerate second-line therapy, leading to limited survival outcomes.
Previously, the HER2CLIMB study demonstrated that the highly selective HER2 tyrosine kinase inhibitor (TKI) tucatinib (TUC), in combination with capecitabine and trastuzumab, significantly improved progression-free survival (PFS) and overall survival (OS) in heavily pretreated patients with HER2+ MBC. Building on this evidence, investigators initiated the phase III randomized controlled HER2CLIMB-05 trial to evaluate the efficacy and safety of tucatinib combined with HP as first-line maintenance therapy, aiming to provide a more effective intensification strategy for this patient population.
Study Methods
A total of 654 patients with HER2+ MBC who had completed 4–8 cycles of THP induction therapy without disease progression were enrolled and randomized 1:1 to receive either TUC + HP (n = 326) or placebo + HP (n = 328), to assess the efficacy and safety of intensified dual-target maintenance therapy.
- Eligibility Criteria: Patients had centrally confirmed HER2+ MBC, ECOG performance status 0–1, no disease progression after 4–8 cycles of THP induction therapy, and no brain metastases or asymptomatic brain metastases.
- Randomization and Treatment: Patients were randomized 1:1. The experimental arm received tucatinib (300 mg orally twice daily) plus HP ± endocrine therapy (ET), while the control arm received placebo plus HP ± ET. Each treatment cycle lasted 21 days.
- Stratification Factors: Randomization was stratified by disease presentation (de novo vs recurrent), hormone receptor (HR) status (positive vs negative), and history of brain metastases, ensuring balanced baseline characteristics.
- Endpoints: The primary endpoint was investigator-assessed PFS per RECIST v1.1. Secondary endpoints included OS and central nervous system PFS (CNS-PFS), among others.
Study Results
Significant Benefit in the Primary Endpoint: Median PFS reached 24.9 months in the TUC + HP group, compared with 16.3 months in the placebo + HP group, representing an 8.6-month improvement and a 36% reduction in the risk of disease progression or death.
Consistent Benefit Across All Prespecified Subgroups: All predefined subgroups derived PFS benefit from the TUC + HP regimen, demonstrating strong consistency. Subgroup analysis by HR status revealed differential benefit, with PFS prolonged by 12.3 months in the HR-negative subgroup and by 6.9 months in the HR-positive subgroup.
Positive Trend in Overall Survival: Although median OS was not yet mature, the risk of death was reduced by 46.1% in the TUC + HP group (HR = 0.539; 95% CI: 0.303–0.957), suggesting early survival benefit.
Clinical Benefit in Patients with Baseline Brain Metastases: In patients with baseline brain metastases, median CNS-PFS was 8.5 months in the TUC + HP group versus 4.3 months in the placebo + HP group, an improvement of 4.2 months. While this difference did not reach statistical significance (HR = 0.719; 95% CI: 0.406–1.273), it suggests a promising therapeutic direction for this high-risk population.
Manageable Safety Profile: The most common treatment-emergent adverse events (TEAEs) in the TUC + HP group were diarrhea and elevated liver enzymes, predominantly grade 1–2. Grade ≥3 TEAEs occurred in 42.3% of patients, and treatment discontinuation due to TEAEs occurred in 13.8%. No new fatal safety signals were identified.
Study Conclusions
In first-line maintenance therapy for HER2+ MBC, the TUC + HP regimen significantly prolonged PFS compared with standard HP therapy, reducing the risk of progression or death by 36% and extending median PFS beyond two years. All patient subgroups benefited, with particularly pronounced advantages in high-risk populations such as HR-negative patients and those with brain metastases. The safety profile was manageable, with diarrhea, nausea, and elevated liver enzymes as the most common adverse events, most of which were low grade. Longer follow-up is needed to confirm long-term OS benefit, optimize toxicity management, and validate the applicability of this regimen in broader clinical settings.
Expert Commentary
The HER2CLIMB-05 study introduces an innovative dual-targeting strategy with TUC + HP, extending first-line maintenance PFS in HER2+ MBC beyond two years for the first time and reducing the risk of progression or death by 36%, representing a major breakthrough in this field. The strength of this design lies in advancing tucatinib earlier in the treatment course, into the maintenance phase after induction chemotherapy and dual antibody therapy. Through extracellular dual blockade with HP combined with precise intracellular inhibition of the HER2 tyrosine kinase domain by tucatinib, this regimen achieves comprehensive and sustained suppression of HER2 signaling, leading to more durable disease control.
Tucatinib is an orally administered, highly selective small-molecule TKI. Unlike monoclonal antibodies that target the extracellular domain of HER2, tucatinib penetrates cells and directly inhibits HER2 tyrosine kinase activity. Its high selectivity allows for more specific blockade of HER2 signaling compared with pan-HER TKIs, reducing off-target inhibition of other HER family receptors and thereby lowering the risk of adverse effects. In this study, common TEAEs with TUC + HP included diarrhea, nausea, and elevated liver enzymes, most of which were grade 1–2. The incidence of grade ≥3 diarrhea was only 6.1%, meeting the core requirement for long-term tolerability in a maintenance setting.
Another key advantage of tucatinib is its strong ability to penetrate the blood–brain barrier. Brain metastases occur in 30%–50% of patients with HER2-positive breast cancer and are associated with poor prognosis. The blood–brain barrier limits the efficacy of many large-molecule therapies, making brain metastases particularly difficult to treat. As a small-molecule agent, tucatinib achieves cerebrospinal fluid concentrations approximately 36% of plasma levels, making it one of the HER TKIs with the highest central nervous system penetration. In this study, tucatinib extended CNS-PFS by 4.2 months in patients with brain metastases, offering an important optimization strategy for both treatment and maintenance in this high-risk population.
Notably, all prespecified subgroups benefited from the TUC + HP regimen. The benefit was especially pronounced in the HR-negative subgroup, historically more difficult to treat, where PFS was extended by 12.3 months—substantially greater than in the HR-positive subgroup—providing valuable evidence to support individualized treatment selection.
However, several limitations should be acknowledged. The study enrolled patients with no disease progression after induction therapy and good performance status, which may introduce selection bias. Data on efficacy and safety in patients with poorer performance status or suboptimal induction response remain limited. OS data are not yet mature; although a positive trend is observed with a 46.1% reduction in mortality risk, only 51 death events had occurred at the time of analysis, and median OS has not been reached. Whether the substantial PFS benefit will translate into durable OS improvement requires longer follow-up.
In addition, differences in brain imaging frequency and discontinuation of routine brain imaging after systemic progression may affect the accuracy of CNS-PFS assessment. From a safety perspective, the incidence of grade ≥3 TEAEs and treatment discontinuation was higher in the TUC + HP group than in the placebo + HP group. Hepatotoxicity and diarrhea were the primary reasons for dose modification or discontinuation, warranting careful patient selection and monitoring, particularly in patients with baseline liver dysfunction or gastrointestinal comorbidities.
Future Perspectives
With longer follow-up, we anticipate clearer OS benefit, further solidifying the role of TUC + HP as first-line maintenance therapy in HER2+ MBC. Building on the dual-targeting concept established by this study, future research may explore additional combinations of dual antibodies with TKIs, enabling stratified precision treatment based on molecular characteristics.
The PATINA study previously demonstrated that adding the CDK4/6 inhibitor palbociclib to treatment regimens for HR-positive, HER2+ MBC prolonged PFS by 15 months. Whether combining tucatinib with palbociclib in HR-positive, HER2-positive patients could achieve synergistic benefit is an intriguing and promising research direction.
Further investigation is also warranted into mechanisms underlying differential subgroup benefit, biomarker-driven patient selection, individualized toxicity management strategies, and the potential expansion of intensified maintenance strategies into the adjuvant setting for early-stage HER2-positive breast cancer. These efforts may ultimately deliver longer survival and improved quality of life for patients with HER2-positive breast cancer.
Professor Xiaoyun Mao Chief Physician, Doctoral Supervisor Administrative Deputy Director, Department of Breast Surgery The First Hospital of China Medical University
Shijin Wang MD–PhD Program Student (Class of 2022), Oncology China Medical University (Supervisor: Professor Xiaoyun Mao)
