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).Patients and 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 BID combined with trastuzumab/pertuzumab. Primary endpoint is investigator-assessed progression-free survival (PFS); secondary endpoints 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, 0.799]; P < 0.0001; median PFS: 24.9 vs 16.3 months); a PFS benefit was seen regardless of presence/absence of BM or hormone receptor status. OS data remains immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (alanine aminotransferase: 28.2%; aspartate aminotransferase: 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 due to TEAEs.Conclusions – 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.