HER2CLIMB-05: A Phase III Study of Tucatinib Versus Placebo in Combination With Trastuzumab and Pertuzumab as First-Line Maintenance Therapy for HER2+ Metastatic Breast Cancer

Clinical Snapshot

Key Findings

• P Value: P < 0.0001

• Effect Size: Hazard ratio 0.641 favouring tucatinib arm

• Primary Outcome: Investigator-assessed progression-free survival significantly improved with tucatinib

• Nnt Or Sensitivity: Median PFS: 24.9 months (tucatinib) vs 16.3 months (placebo) - 8.6 month improvement

• Confidence Interval: 95% CI: 0.514 to 0.799

Clinical Application

Requires access to tucatinib and established HER2-targeted therapy infrastructure. Monitoring for hepatotoxicity and diarrhoea management essential Tucatinib currently PBS-listed for later-line HER2+ MBC. This study may support PBS expansion to first-line maintenance. Aligns with NCCN and ESMO guidelines for HER2+ MBC management Australian patients with HER2+ metastatic breast cancer suitable for first-line maintenance therapy after induction treatment

Abstract

PURPOSE: The HER2CLIMB-05 study (ClinicalTrials.gov identifier: NCT05132582) is investigating the efficacy and safety of adding tucatinib to trastuzumab and pertuzumab as first-line (1L) maintenance therapy in patients with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC). METHODS: Patients with centrally confirmed HER2+ MBC without evidence of progression post induction therapy and no or asymptomatic brain metastases (BM) were enrolled. Patients were randomly assigned 1:1 to tucatinib (300 mg) or placebo twice a day combined with trastuzumab/pertuzumab. The primary end point is investigator-assessed progression-free survival (PFS); secondary end points include overall survival (OS), PFS per blinded independent central review, CNS-PFS, and safety. RESULTS: Between March 2022 and July 2024, 654 patients were randomly assigned to tucatinib (n = 326) and placebo (n = 328) arms. All patients were female (median age, 54 years), 69.3% had de novo MBC, 52.6% were hormone receptor-positive, and 12.4% had presence/history of baseline BM. In this primary analysis, PFS was statistically significantly improved with addition of tucatinib versus placebo (hazard ratio, 0.641 [95% CI, 0.514 to 0.799]; P < .0001; median PFS: 24.9 v 16.3 months); a PFS benefit was seen regardless of the presence/absence of BM or hormone receptor status. OS data remain immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (ALT: 28.2%; AST: 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥3. In the tucatinib arm, 13.5% discontinued tucatinib because of TEAEs. CONCLUSION: Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC.

References

1. 1.Dieras, V., Curigliano, G., Martin, M., Lerebours, F., Tsurutani, J., Savard, M. F., Jerzak, K. J., Hu, X., Martins de Aquino Pimentel, L. C., O'Sullivan, C. C., Tokunaga, E., Okines, A., Huang, C. S., Jacot, W., Sohn, J., Cronemberger Silva, E., Mueller, V., Yang, S., Granata, G., Shen, Q., Santarpia, L., & Hamilton, E. (2026). HER2CLIMB-05: A Phase III Study of Tucatinib Versus Placebo in Combination With Trastuzumab and Pertuzumab as First-Line Maintenance Therapy for HER2+ Metastatic Breast Cancer. Journal of Clinical Oncology, 44(17). https://doi.org/10.1200/JCO-25-02600