HER2CLIMB-02: Primary Analysis of a Randomized, Double-blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-positive Metastatic Breast Cancer

Background

• Tucatinib is a highly selective HER2-directed TKI1 indicated for patients with previously treated HER2+ LA/MBC, including patients with brain metastases2-6
• In HER2CLIMB, adding tucatinib to trastuzumab and capecitabine demonstrated HRs for PFS, OS, and PFS in patients with brain metastases of 0.54, 0.66, and 0.48 (P≤0.005 for all), respectively3
• The incidence of brain metastases in patients with HER2+ LA/MBC remains high7-9; combining HER2-directed therapies can improve patient outcomes in HER2+ LA/MBC10,11
• T-DM1 is a HER2-directed ADC approved for patients with HER2+ LA/MBC previously treated with trastuzumab and a taxane12
• Preclinical data have shown that the combination of tucatinib and T-DM1 results in enhanced antitumor activity compared with either agent alone13
• In a phase 1b/2 study, the combination of tucatinib and T-DM1 demonstrated encouraging antitumor activity, including intracranial responses, with a manageable safety profile14

Methods

• HER2CLIMB-02 is a randomized, double-blind, placebo-controlled phase III study to evaluate efficacy and safety of TUC + T-DM1 in pts with unresectable locally advanced or metastatic HER2+ breast cancer; ∼460 pts randomized 1:1 to receive 21-day cycles of TUC (300 mg PO BID) or placebo with T-DM1 (3.6 mg/kg IV).
• Pts must have had prior tx with Tras and a taxane in any setting, be ≥18 yrs, with an ECOG ≤1 and histologically confirmed HER2+ MBC. Prior tx with any investigational anti-HER2 or anti-EGFR agent or HER2 TKI is not permitted.

Conclusions

• Adding tucatinib to T-DM1 significantly improved PFS in patients with previously treated HER2+ LA/MBC
  • Median PFS was 9.5 vs 7.4 months (HR, 0.76; P=0.0163)
  • PFS HRs for prespecified subgroups were consistent with that of the overall population
  • Median PFS for patients with brain metastases was 7.8 vs 5.7 months (HR, 0.64)
  • OS data are immature
• Types of adverse events were consistent with those previously reported for tucatinib and T-DM1
  • Higher rate of hepatic events in the T-DM1 + Tucatinib arm; the events were generally transient, manageable, and reversible
• This is the second randomized study which included patients with brain metastases to demonstrate that a tucatinib-containing regimen delays disease progression in HER2+ LA/MBC

Hurvitz S, Loi S, O’Shaughnessy J et al. HER2CLIMB-02: Primary Analysis of a Randomized, Double-blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-positive Metastatic Breast Cancer. Presented at: 2023 San Antonio Breast Cancer Symposium, December 5-9, 2023. San Antonio, Texas.