Research Appraisals

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

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

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.