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Randomized, Double-Blind Phase 3 Study of Tucatinib or Placebo in Combination with T-DM1 for Subjects with Unresectable Locally Advanced or Metastatic HER2+ Breast Cancer

Conference Correspondent

Tucatinib is an orally available HER2 small-molecule tyrosine kinase inhibitor being developed as a novel treatment for patients with HER2+ metastatic breast cancer (MBC), including those with brain metastases. Although treatment with ado-trastuzumab emtansine (T-DM1) has led to significant improvements in progression-free survival (PFS) and overall survival (OS), further improvements in therapy are needed, especially for patients with MBC and brain metastases. Based on evidence that dual targeting of HER2 may lead to further improvements in efficacy in MBC, a phase 1b trial showed that the combination of tucatinib with T-DM1 demonstrated a median PFS of 8.2 months (95% confidence interval, 4.8-10.3) and an objective response rate of 47% in subjects with measurable disease.1 Sixty percent of subjects treated with this combination had baseline brain metastases and showed a brain-specific response rate of 36% in subjects with measurable central nervous system disease.1 Tucatinib with T-DM1 was found to have a tolerable safety profile. This encouraging clinical activity, including in subjects with brain metastases, provided the rationale for a randomized trial to further evaluate this combination.

At SABCS 2019, the study design was presented for a randomized, double-blind, placebo-controlled, international, multicenter phase 3 study to evaluate the efficacy and safety of tucatinib in combination with T-DM1 in subjects with unresectable locally advanced or metastatic HER2+ breast cancer.2 Subjects will have had prior treatment with a taxane and trastuzumab in any setting (adjuvant, neoadjuvant, or metastatic). The primary objective of the study will be to compare PFS between the treatment arms per investigator assessment, with OS as a key secondary end point. Prior pertuzumab therapy will be allowed, but not required. Subjects with stable, progressing, or untreated brain metastases not requiring immediate local therapy will be eligible for inclusion in the trial. Approximately 460 subjects will be randomized 1:1 to receive 21-day cycles of either tucatinib (300 mg orally twice daily) or placebo in combination with T-DM1 (3.6 mg/kg intravenously). Disease response and progression will be assessed, and radiographic disease evaluations will be performed every 6 weeks for the first 24 weeks, and every 9 weeks thereafter. A subset of subjects will participate in a pharmacokinetic substudy.


References

  1. Borges VF, et al. JAMA Oncol. 2018;4:1214-1220.
  2. Hurvitz S, et al. SABCS 2019. Abstract OT2-01-01.

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